VictorJuiz/thesis huggingface dataset:
Analysis of the quasicontinuum method and its application
Keywords: Quasicontinuum method; atomistic/continuum coupling; coarse-graining; a priori error analysis; a posteriori error analysis

The present thesis is on the error estimates of different energy based quasicontinuum (QC) methods, which are a class of computational methods for the coupling of atomistic and continuum models for micro- or nano-scale materials.
The thesis consists of two parts. The first part considers the a priori error estimates of three energy based QC methods. The second part deals with the a posteriori error estimates of a specific energy based QC method which was recently developed.
In the first part, we develop a unified framework for the a priori error estimates and present a new and simpler proof based on negative-norm estimates, which essentially extends previous results.
In the second part, we establish the a posteriori error estimates for the newly developed energy based QC method for an energy norm and for the total energy. The analysis is based on a posteriori residual and stability estimates. Adaptive mesh refinement algorithms based on these error estimators are formulated.
In both parts, numerical experiments are presented to illustrate the results of our analysis and indicate the optimal convergence rates.
The thesis is accompanied by a thorough introduction to the development of the QC methods and its numerical analysis, as well as an outlook of the future work in the conclusion.
The Chinese revolutionary army in the reform era, 1985-2010
Keywords: China

This thesis studies the way that the single-party state has renovated the political identity of the armed forces in the reform era of the People’s Republic of China (PRC). It argues that the Chinese Communist Party succeeded in doing so and therefore was able to use the national military as a prop of continued single-party rule.
Engaging with theories of civil-military relations, this study challenges the dominant view of military professionalism according to which an armed force must be separate from politics to become truly professional. I show that the People’s Liberation Army (PLA) professionalization process, triggered by the establishment of the National Defense University in 1985, was completed by 2010, when the National Mobilization Law was issued. It provided the PLA with clear responsibility, esprit de corps, and area of expertise, these three core components of professionalism being put under firm regulatory control. This process, however, was not isolated from the political developments under way in the PRC during the same period. Instead, the ruling party turned the military into an active agent of its ‘spiritual civilization’ policy by tying it more closely to local governments, by giving it the duty to teach civic education to university students and the wider population, and by committing an increasing number of troops and other PLA resources to the United Nations peacekeeping program.
This work is based on an extensive reading of the untranslated literature published, mainly, by the PLA itself, to account for the way that it adapted its tradition of ‘political work’ (the system of indoctrination and human resource management linking it to the ruling party) to the requirements of military professionalism. I completed this account with about 60 interviews with Chinese serving and retired military personnel, foreign military attachés, and students with experience of military training in Chinese universities.
Time trends in childhood cancer: Britain 1966-2005
Keywords: childhood cancer
under-diagnosis
Poisson regression
deprivation
UK
CNS tumours
standardised rates
leukaemia
imaging
acute lymphoblastic leukaemia
epidemiology
affluence
fatal infection hypothesis
incidence
capture-recapture
completeness
time trend
paediatric
cancer registration
socioeconomic status
hospital episode statistics
temporal trends
international classification of childhood cancers
delayed diagnosis
Britain
National Registry of Childhood Tumours
childhood
flow method
artefact
cancer diagnosis
geographical variation
birth cohort
cancer

Increasing time trends in the recorded incidence of childhood cancer have been reported in many different settings. The extent to which these trends reflect real changes in incidence, rather than improvements in methods for diagnosis and registration, is controversial. Using data from the National Registry of Childhood Tumours (NRCT), this thesis investigates time trends in cancer diagnosed under age 15 in residents of Britain during 1966-2005 (54650 cases), and considers potential sources of artefact in detail.
Several different methods are used to estimate completeness of NRCT registration. The history of methods for diagnosis and registration of childhood cancers in Britain is described, and predictions are made for effects on recorded incidence.
For each of the 12 main diagnostic groups, Poisson regression is used to fit continuous time trends and ‘step’ models to the annual age-sex-standardised rates by year of birth and year of diagnosis. Age-specific rates by period, and quinquennial standardised rates for diagnostic subgroups, are shown graphically. For three broad groups (leukaemia, CNS tumours and other cancer), geographical variation is compared by period of diagnosis. The results of these analyses are discussed in relation to the predicted artefacts.
The evidence for a positive association between affluence and recorded incidence of childhood leukaemia is briefly reviewed. A special form of diagnostic artefact, the ‘fatal infection’ hypothesis, is proposed as an explanation of both this association and the leukaemia time trend. This hypothesis is examined in a novel test based on clinical data.
The recorded incidence of childhood cancer in Britain increased in each of 12 diagnostic groups during 1966-2005 (from 0.5% per year for bone cancer to 2.5% for hepatic cancer, with 0.7% for leukaemia). Evidence presented here suggests that these increases are probably artefacts of diagnosis and registration. The potential implications for epidemiological studies of childhood cancer should be considered.
Characterisation of the human two-pore channels
Keywords: calcium
NAADP
two-pore channels

The Ca²⁺-mobilising messenger NAADP has been shown to play a key role in the regulation of mammalian physiology. Recently, the two-pore channels (TPCs) have been proposed as an NAADP-gated Ca²⁺ channel.
Chapter 1 introduces the TPCs as the major candidates in governing NAADP-mediated Ca²⁺-release from acidic stores. Chapter 2 explains the methodologies developed and used.
Chapter 3 demonstrates the successful immunopurification of HsTPC2 and its incorporation into an artificial lipid bilayer. K⁺ and Ca²⁺ currents were seen in reponse to nM - μM concentrations of NAADP; with the open probability (P₀) fitting a bell-shaped concentration-response curve. Ligand sensitivity was shown to be regulated by luminal [Ca²⁺], whereby a 20-fold increase in [Ca²⁺] lumen (10 μM to 200 μM) caused a 100-fold reduction in the EC50 from ≈ 500 nM to 5 nM. Furthermore, a reduction in luminal pH from 7.2 to 4.8 reduced the P₀ but 1 μM Ned-19 inhibiting all channel activity.
Chapter 4 investigates the in situ properties of HsTPC2 by the purification and patch clamp of intact lysosomes from cells overexpressing HsTPC2. Three methods of purification were compared: differential centrifugation, whole lysosome immunoprecipitation and magnetic chromatography. Techniques involving lysosomal swelling and whole cell homogenisation were also optimised to ensure minimal contamination by non-lysosomal proteins. Whole lysosome patch clamping revealed NAADP-induced, Ca²⁺-specific currents in response to NAADP, but not cADPR, IP₃ or Ned-19. High concentrations of NAADP (mM) and Ned-19 (μM) showed prolonged ≈ 5 minutes) inhibition of channel activity.
Chapter 5 explores the protein-protein interactions of the purified HsTPC2 and identifies a heterodimeric interaction between HsTPC1 and HsTPC2 was further dissected by coimmunoprecipitation, colocalisation and FRET studies. Despite clear evidence that both isoforms independently form homodimers, it is likely that heterodimerisation is a dynamic interaction only seen in a subset of the channel population.
Chapter 6 discusses the results obtained in the wider context of cell physiology.
Why and how is silk spun? : integrating rheology with advanced spectroscopic techniques
Keywords: small angle scattering
Spinning
Cocoon
Bombyx mori
Silk
Rheology
infrared spectroscopy

This thesis investigates the mechanisms behind natural silk spinning by integrating rheology, spectroscopy and small angle scattering to better understand this process and to guide our efforts towards mimicking Nature’s ways of producing high performance fibres.
As a result of natural selection, arthropods such as spiders and moths have evolved the ability to excrete silk proteins in a highly controlled manner. Spun from liquid feedstocks, silk fibres are used ex vivo to build structures with mechanical properties currently unmatched by industrial filaments. As yet, relatively little attention has been directed to the investigation of spinning under biologically relevant conditions. To better understand how and why silk is spun, this thesis bridges the gap between liquid silk flow properties and structure development.
To directly connect the two, I have developed and deployed novel experimental platforms that combine infrared spectroscopy and small angle scattering with rheology. This approach has clarified long-standing ambiguities on the structural root of silk’s apparently complex flow properties. Small angle scattering revealed the length scales involved in the flow induced solidification under a range of spinning conditions. Mo reover, infrared spectroscopy offered a unique perspective into silk’s formation process immediately after excretion.
In a similar manner to the post-extrusion tuning of the properties of partly solidified spider silk filaments, this thesis has revealed that silkworm silk fibres are far from completely formed once excreted. One might describe the filaments of mulberry silkworm as seeded molten polymers that form its hydrogen bonding network and crystallises slowly on site. Consequently, it enlightens that post-spinning conditions are equally paramount for silkworm silk, giving an explanation for the relatively poorer mechanical properties. The comparison of silks from a range of species, allowed this hypothesis to be extended to wild silkworm silk. My insights into spinning had the fortuitous repercussion of facilitating silk fibre solubilisation leading to the development of better artificial silk feedstocks flowing like native silks. With these findings, I believe we are now in an improved position to conceive artificial fibres with properties rivalling those of Nature.
Selective permeabilisation of the blood-brain barrier at sites of metastasis.
Keywords: metastasis
imaging
SPECT
Cancer
drug delivery
doxorubicin
MRI
chemotherapy

Over one in five cancer patients will develop brain metastases and prognosis remains poor. Effective chemotherapeutics for primary systemic tumours have limited access to brain metastases owing to the blood-brain barrier (BBB). The aim of this study was to develop a strategy for specifically permeabilising the BBB at sites of cerebral metastases.
Tumour necrosis factor was injected intravenously into mouse models of haematogenously induced brain metastasis. BBB permeability was assessed through histology and in vivo MRI and SPECT. Tumour burden and neuroinflammation were assessed after injection of TNF with Caelyx or a novel therapeutic. Mechanism of permeabilisation was investigated through histology and receptor-specific agonist antibodies.
Administration of TNF dose-dependently permeabilised the BBB to exogenous tracers selectively at sites of brain metastasis, with peak effect after six hours. Metastasis-specific uptake of radiolabelled trastuzumab was also demonstrated following systemic cytokine administration. Administration of liposomal doxorubicin formulations in conjunction with TNF reduced tumour burden and mean metastasis size. Localised expression of TNFR1 was evident on the vascular endothelium associated with brain metastases. Human brain metastases displayed a similar TNF receptor profile compared to the mouse model.
These findings describe a new approach to selectively permeabilise the BBB at sites of brain metastases, thereby enabling detection of currently invisible micrometastases and facilitating tumour-specific access of chemotherapeutic agents. We hypothesize that this permeabilisation works primarily though TNFR1 activation and, owing to the similar TNFR1 expression profiles in mouse models and human condition, the strategy has the potential for clinical translation.
The role of Topoisomerase II in replication in mammalian cells
Keywords: DNA combing
DNA replication
siRNA screening
Topoisomerase
synthetic lethality
DNA repair
Werner Syndrome

Topoisomerase 2α (Topo2α) is an essential protein with DNA decatenating enzymatic properties, indispensable for chromosome decatenation and segregation. It is a target for a plethora of antitumour drugs and Topo2α protein levels have been associated with the success of treatment, but also drug resistance and secondary malignancies. Although unique in its ability to resolve catenated chromosomes, the role of Topo2α in other steps of DNA metabolism, such as DNA replication elongation and termination have been elusive. A thorough understanding of the role of Topo2α in the cell will not only allow for increased insight into the mechanisms it is involved in, but it will also shed light on proteins and pathways that can act as back-up in its absence, and therefore hopefully expand the basis on which to improve treatment options.
Through a synthetic lethal interaction (SLI) screen with an siRNA library targeting 200 DNA repair and signalling genes, Topo2α emerged as being synthetic lethal to Werner protein (WRN), a RecQ helicase involved in maintaining genome integrity mainly in S phase, and the loss of which leads to Werner Syndrome (WS), a segmental progeroid syndrome. The screen was performed in WRN deficient cells, with the initial aim to find proteins that act to buffer against loss of viability, which is the central idea in the concept of synthetic lethality in the absence of WRN. The screen revealed an SLI between WRN and Topo2α and although we were unable to fully validate this, it spurred the question of Topo2α’s role in DNA replication.
The findings in this thesis suggest that Topo2α is not required for DNA elongation and timely completion of S phase, and that simultaneous loss of the closely related isoform Topo2β does not affect replication, suggesting that these proteins do not act in parallel back-up pathways during replication. Interestingly, cells accumulate in the polyploid fraction after both depletion and inhibition of Topo2α, albeit with different kinetics. The mechanistic basis of this phenotype remains to be understood through further research, but it is highly interesting as aneuplidity and polyploidy are implicated in the initial stages of tumour development.
Generation and application of semantic networks from plain text and Wikipedia
Keywords: natural lanuage processing
semantic networks

Natural Language Processing systems crucially depend on the availability of lexical and conceptual knowledge representations. They need to be able to disambiguate word senses and detect synonyms. In order to draw inferences, they require access to hierarchical relations between concepts (dog isAn animal) as well as non-hierarchical ones (gasoline fuels car). Knowledge resources such as lexical databases, semantic networks and ontologies explicitly encode such conceptual knowledge. However, traditionally, these have been manually created, which is expensive and time consuming for large re- sources, and cannot provide adequate coverage in specialised domains.
In order to alleviate this acquisition bottleneck, statistical methods have been created to acquire lexical and conceptual knowledge automatically from text. In particular, unsupervised techniques have the advantage that they can be easily adapted to any domain, given some corpus on the topic. However, due to sparseness issues, they often require very large corpora to achieve high quality results. The spectrum of resources and statistical methods has a crucial gap in situations when manually cre- ated resources do not provide the necessary coverage and only limited corpora are available. This is the case for real-world domain applications such as an NLP system for processing technical information based on a limited amount of company documentation.
We provide a large-scale demonstration that this gap can be filled through the use of automatically generated networks. The corpus is automatically transformed into a network representing the terms or concepts which occur in the text and their relations, based entirely on linguistic tools. The net- works structurally lie in between the unstructured corpus and the highly structured manually created resources. We show that they can be useful in situations for which neither existing approach is ap- plicable. In contrast to manually created resources, our networks can be generated quickly and on demand. Conversely, they make it possible to achieve higher quality representations from less text than corpus-based methods, relieving the requirement of very large scale corpora.
We devise scaleable frameworks for building networks from plain text and Wikipedia with varying levels of expressiveness. This work creates concrete networks from the entire British National Corpus covering 1.2m terms and 21m relations and a Wikipedia network covering 2.7m concepts. We develop a network-based semantic space model and evaluate it on the task of measuring semantic relatedness. In addition, noun compound paraphrasing is tackled to demonstrate the quality of the indirect paths in the network for concept relation description. On both evaluations we achieve results competitive to the state of the art. In particular, our network-based methods outperform corpus-based methods, demonstrating the gain created by leveraging the network structure.
Studies on Aedes polynesiensis introgression and ecology to facilitate lymphatic filariasis control
Keywords: lymphatic filariasis
sterile insect technique
Aedes polynesiensis
Wolbachia

The mosquito Aedes polynesiensis, a member of the Aedes scutellaris complex, is the main vector in the South Pacific region of the Wuchereria bancrofti parasite, the causative agent of lymphatic filariasis (LF), and is also a major nuisance biter. Decades of Mass Drug treatment (MDA) have not been successful in elimination LF. Two non-vector species in the Ae. scutellaris complex were introgressed with Ae. polynesiensis to attempt to obtain lines that would produce cytoplasmic incompatibility (CI) with wild populations and / or LF-refractoriness. Despite selection of progeny from Brugia-challenged, non-infective females at each backcross, no refractory line was acquired. However, three lines from crosses between aposymbiotic Ae. polynesiensis and Ae. riversi displayed CI and male mating competiveness suitable for the purpose of population suppression using the incompatible insect technique (IIT). A population study was conducted of potential release sites and the evaluation of monitoring tools for Ae. polynesiensis on Moorea and Tetiaroa, French Polynesia. There was no evidence of active migration between selected islets on the atoll of Tetiaroa, suggesting it is a suitable site for field releases of CI males. The BioGents Sentinel trap was shown to be an efficient and convenient trap suitable for Ae. polynesiensis monitoring. The effects of temperature and larval density on life-table parameters relevant to IIT were examined, including: larval survivorship, developmental time to pupation, male to female ratio, male pupae yield, male size and adult male survival. These findings were used to design and conduct a 14-week field experiment testing CI male strain against an isolated population, using optimized rearing conditions. Approximately 8000 males were released weekly on motu Onetahi, Tetiaroa atoll. Significant sterility was induced by Wolbachia in the targeted female population, supporting the development and scale-up of this approach toward Ae. polynesiensis nuisance and LF transmission reduction.
Discovery and measurement of the Higgs boson in the WW decay channel
Keywords: Higgs boson
ATLAS
LHC

In the Standard Model of particle physics, the non-zero masses of the W and Z bosons and the fermions are generated through interactions with the Higgs field, excitations of which correspond to Higgs bosons. Thus, the experimental discovery of the Higgs boson is of prime importance to physics, and would confirm our understanding of fundamental mass generation.
This thesis describes a search for the gg → H → WW → lνlν process of Higgs boson production and decay. It uses the LHC Run I dataset of pp collisions recorded by the ATLAS detector, which corresponds to an integrated luminosity of 4.5 fb−1 at √ s = 7 TeV and 20.3 fb−1 at √ s = 8 TeV. An excess of events is observed with a significance of 4.8 standard deviations, which is consistent with Higgs boson production. The significance is extended to 6.1 standard deviations when the vector boson fusion production process is included. The measured signal strength is 1.11+0.23-0.21 at mH = 125 GeV. A cross section measurement of WW production, a major background to this search, is also presented using the √ s = 7 TeV dataset only.