VictorJuiz/thesis huggingface dataset:
Natural history and pathogenesis of IgG4-related disease
Keywords: IgG4
IgG4-related disease
Plasma cells
B cells

IgG4-related disease (IgG4-RD) is a systemic fibro-inflammatory condition characterised by elevated serum IgG4 and an abundance of IgG4 plasma cells in involved organs. The natural history of disease and pathogenic mechanisms are poorly understood, and are explored in this thesis.
The diagnosis of IgG4-RD is a challenge. Evidence to support a serum IgG4 level of 2.8g/l in differentiating IgG4-RD from non-IgG4-RD conditions, a serum IgG1:IgG4 ratio of 0.24 in differentiating IgG4-sclerosing cholangitis from primary sclerosing cholangitis with elevated serum IgG4, and the role of serum IgE in those with a history of allergy and atopy is provided. Furthermore, observational data highlighting new environmental risk factors and disease associations are revealed. Despite being considered a benign corticosteroid-responsive condition, evidence for disease relapse, organ dysfunction and failure, malignancy and mortality in a prospective cohort is shown. Patterns of disease presentation and levels of serum IgG4 and IgE at diagnosis are used to identify those who relapse and develop multi-organ disease.
A single antigen initiating disease has yet to be found. Polyclonal IgG4 responses to multiple environmental antigens in IgG4-RD are reported, and evidence against Helicobacter pylori plasminogen binding peptide as a microbial antigen is shown. Novel HLA class II associations, linked to disease susceptibility in a UK cohort provide support for immune-mediated pathogenesis. Gene expression analysis implicates cytokines in driving IgG4 switch and proliferation, chemokines in trafficking and homing of lymphocytes to end organs, complement proteins in the classical and lectin pathways, and members of the TGF-beta pathway as putative immune drivers of disease. Differences in the phenotype of IgG1 and IgG4 B cells in health and IgG4-RD are reported, including responses to complement activation and immune complexes. Finally, elevated IgE levels, the presence of IgE-positive mast cells in involved tissues, and up-regulation of the Fc-Epsilon receptor on the surface of IgG4 cells, support the role of an IgE-mediated response.
The genetic control of agricultural pests (Plutella xylostella, L. and Tribolium castaneum, Herbst)
Keywords: Paternal effect
RNAi
Female lethal
Sperm lethal
Spermiogenesis
Tribolium castaneum
Markov Chain Monte Carlo Method
Food production
transformation
dsRNA
Plutella xylostella
Diamondback moth
Red flour beetle
Sterile insect technique
Spermatogenesis
piggyBac

The interaction between an increasing global human population and a number of important long-term trends and issues are putting strain on food production. Insects represent a significant food security concern causing up to 15% of global crop losses. Conventional chemical methods are ineffective; inducing resistance and degrading the environment. Sustainable alternatives are sought.
The sterile insect technique provides a sustainable solution. Genetic engineering can augment this historic technique by replacing radiation-induced sterilization with sperm-specific nuclease expression to introduce double-stranded DNA breaks in the gametes of mass-reared and released males. This paternal-effect system is dependent on elucidation of appropriate sperm-specific promoters and suitable chaperone-nuclease combinations. This thesis develops this technology in the SIT neglected insect orders, the Lepidoptera and Coleoptera. Specifically the Plutella xylostella (Plutella xylostella, L.) and the red flour beetle (Tribolium castaneum, Herbst).
I provide the foundations for a paternal-effect genetic-control-system in both species by developing a conditional sperm-specific expression system in Plutella xylostella and a female-specific expression system in Tribolium.
Mass-rearing insects for the genetic control of a species can be augmented by recent developments in RNAi. I show that the sex ratio of Tribolium can be adjusted by treatment with dsRNA transformer, producing pseudomales as an additional bonus.
In addition, an exploratory data analysis of producing transgenic lines in insects using piggyBac was undertaken. As well as providing a comprehensive compendium and assessment of the transgenic literature, something not yet published elsewhere, a predictive model was produced that could be very useful to a wide diversity of researchers in insect molecular biology, developmental biology, disease biology and genetics.
It is hoped that this work will contribute towards the effective control of the Plutella xylostella in the near term, and form a model for the sustainable control of other lepidopteran and coleopteran species through genetic pest management.
Characterisation of cello: an ENU-induced mouse model of early-onset hearing loss
Keywords: deafness
sensorineural
ear
mouse
Helios
auditory
genetics
biology
Ikaros
transcription factor
hearing

cello is a recessive mouse model of early-onset, sensorineural hearing loss that was identified from a large-scale N-ethyl-N-nitrosourea (ENU) mutagenesis screen undertaken at MRC Harwell. Linkage analysis and whole-genome sequencing identified that cello mice have a non-synonymous point mutation in Ikaros family zinc finger 2 (Ikzf2), which encodes a zinc finger transcription factor called helios.
To investigate the role of helios in the auditory system, cello mice underwent comprehensive molecular, phenotypic and functional characterisation. The cello mutation was found to disrupt a highly conserved, zinc-coordinating residue in the final C-terminal zinc finger domain of helios. In vitro analyses demonstrated that mutant helios can still localise to the nucleus, but has an impaired ability to homodimerise – a prerequisite for DNA binding. In both Ikzf2+/+ and Ikzf2cello/cello cochleae, helios is expressed in the nuclei of the outer hair cells (OHCs) from the first postnatal week, coinciding with a critical period of OHC functional maturation. Although Ikzf2cello/cello exhibit severely impaired hearing at postnatal day (P) 16, cochlear morphology appears grossly normal up to one month of age, after which the OHCs and inner hair cells begin to progressively degenerate. Transcriptome profiling was subsequently undertaken to identify potential target genes of helios in the auditory system. Results suggested that loss of helios function leads to dysregulation of over 450 genes in Ikzf2cello/cello cochleae at P8. This included the OHC-specific genes Slc26a5 (which encodes the OHC motor protein, prestin) and Ocm (oncomodulin), both of which were significantly decreased in Ikzf2cello/cello mutants compared to Ikzf2+/+ controls. Electrophysiological studies demonstrated that Ikzf2cello/cello OHCs fail to acquire full electromotility, a property that is fundamental to their function, but otherwise mature normally. Using luciferase reporter assays, wild-type helios was found to induce transactivation of the Slc26a5 promoter, whilst this ability was lost in the mutant protein. Additional in silico network analyses identified helios as a putative direct regulator of 40 genes that are enriched in the OHCs and upregulated during development, which suggests that helios has a key role in regulating the maturing OHC transcriptome.
Overall, the work presented in this thesis identifies Ikzf2 as a novel hearing loss-causing gene and establishes that the helios transcription factor is essential for OHC functional maturation in the mammalian auditory system.
The 3rd century A.D. In south-western Asia Minor: epigraphic studies into civic life and diplomatic relations with Rome
Keywords: Roman History
Epigraphy
Asia Minor
3rd century AD
Ancient Anatolia

This thesis studies the inscriptions produced by the southern and western settlements on the Anatolian peninsula – modern Turkey – from the death of the emperor Commodus (AD 192) to Diocletian's accession (284). The 3rd century AD, a period of fundamental transition between the high and late Roman imperial ages, has traditionally been considered an age of crisis and decline. This crisis supposedly affected civic life as members of the local communities were not willing or financially able to take part in politics. Against this prevalent opinion in scholarship, the purpose of this study is to analyse the abundant epigraphic evidence surviving from this region in order to reassess the local activity of such political communities.
The first chapter intends to determine whether the effects of the Constitutio Antoniniana on the nomenclature of the peregrine (i.e. non-Roman) population can be used as a reliable dating criterion. It also explains the methodology on which my collection of epigraphic evidence has been based. The second chapter examines the families, individuals, institutions and celebrations comprising the civic life of Ephesus, Lydia, Aphrodisias and Southern Anatolia (esp. Termessos, Perge and Side) in the first half of the 3rd century. These four case studies demonstrate a high level of local activity, which was recorded with inscriptions resembling those produced in the 2nd century AD. The third chapter analyses the communication between these local communities and the ruling power of Rome. On the one hand, this analysis describes the prevalent diplomatic procedures followed and their motivations. On the other, it evaluates the testimonies attesting direct contact between the population of south-western Asia Minor and imperial representatives such as governors, administrators and soldiers. The final chapter deals with the particular circumstances affecting the production of inscriptions in the region from 250 to 284.
These four chapters demonstrate that the civic life of south-western Asia Minor can be studied from a local perspective and beyond the narrow methodological framework imposed by adherence to the model of the '3rd century crisis'. The contextualised analysis of epigraphic evidence provided shows strong elements of continuity in the civic life of the region and its relation with Rome. The same analysis also concludes that the stark decline and changes of the inscriptions produced in the second half of the 3rd century were not only caused by internal factors. According to these results, this thesis hopes to contribute to the reconsideration of the Anatolian peninsula in such a crucial period of the history of the Roman Empire.
'A force for peace': Expanding the role of the UN Secretary-General under Trygve Lie, 1946-1953
Keywords: United Nations
UN secretary-general
Trygve Lie

The UN secretary-general plays an important political role in world politics, yet the UN Charter describes him merely as “the chief administrative officer of the Organization.” How did such a development come about? The existing narrative tends to emphasise the contribution made by Dag Hammarskjöld, the United Nation’s second secretary-general from 1953 to 1961. This thesis argues that there are two problems with this narrative. First, it overlooks the precedents set under the first UN secretary-general, Trygve Lie, who was in office from 1946 to 1953. Second, it places too much emphasis on the personal role played by Hammarskjöld, and fails to adequately consider the importance of institutional factors.
The main empirical contribution of this thesis is to highlight the importance of precedents set during the first years of the UN’s existence while Lie was secretary-general. Through his active stance on political issues in relation to Iran, Palestine, Berlin, Chinese representation, and Korea, as well as his consistently strong defence of the UN’s unity and principles, Trygve Lie succeeded in carving out space for the secretary-general to act autonomously on political issues, which later secretaries-general could build on.
The thesis’ main theoretical contribution is to emphasise the importance of institutional factors in the development of the UN secretary-general’s political role. In a conceptual framework based on institutionalism, the thesis explains how the UN secretary-general should be understood to play a ‘role’ within the ‘institution’ of the United Nations, and how this makes change of the role and the institution possible. Furthermore, through an examination of the founding of the United Nations and early expectations for the role of the secretary-general, the thesis shows that the institution of the United Nations had been set up from the start in such a way that it not only allowed for an expansion of the office of UN secretary-general, but also made such an expansion likely. The body of the thesis demonstrates how this process played out over time, by examining Lie’s activities as secretary-general, and offering a historical narrative of several episodes where the institution ‘pulled’ to expand the office, just as much as, or even more than, Lie ‘pushed’ for the same outcome.
Acceptability judgement tasks and grammatical theory
Keywords: experimental syntax
grammatical theory
introspection
research methodology
acceptability judgement tasks
computational linguistics

This thesis considers various questions about acceptability judgement tasks (AJTs).
In Chapter 1, we compare the prevalent informal method of syntactic enquiry, researcher introspection, to formal judgement tasks. We randomly sample 200 sentences from Linguistic Inquiry and then compare the original author judgements to online AJT ratings. Sprouse et al., 2013, provided a similar comparison, but they limited their analysis to the comparison of sentence pairs and to extreme cases. We think a comparison at large, i.e. involving all items, is more sensible. We find only a moderate match between informal author judgements and formal online ratings and argue that the formal judgements are more reliable than the informal judgements. Further, the fact that many syntactic theories rely on questionable informal data calls the adequacy of those theories into question.
In Chapter 2, we test whether ratings for constructions from spoken language and constructions from written language differ if presented as speech vs as text and if presented informally vs formally. We analyse the results with an LME model and find that neither mode of presentation nor formality are significant factors. Our results suggest that a speaker’s grammatical intuition is fairly robust.
In Chapter 3, we quantitatively compare regular AJT data to their Z-scores and ranked data. For our analysis, we test resampled data for significant differences in statistical power. We find that Z-scores and ranked data are more powerful than raw data across most common measurement methods.
Chapter 4 examines issues surrounding a common similarity test, the TOST. It has long been unclear how to set its controlling parameter δ. Based on data simulations, we outline a way to objectively set δ. Further results suggest that our guidelines hold for any kind of data.
The thesis concludes with an appendix on non-cooperative participants in AJTs.
Let’s talk! An intervention supporting children’s vocabulary and narrative development through sustained planned pretend play and group shared storybook reading in the early years
Keywords: intervention
group shared storybook reading
oral language
narrative
planned pretend play
Early years
vocabulary

An intervention, which targeted three- and four-year-old children’s oral language, was developed for this study. The intervention was run over twice-weekly sessions, for ten weeks. Incorporating good Early Years practice, the first session in the week was a group shared storybook reading session with a puppet, where dialogic discussion took place and the children practised sequencing the story using visual prompts. The second weekly session consisted of planning, acting out and reviewing a planned pretend play episode based on the storybook which was read in that week’s first session.
Ninety-four children were randomly assigned to a control or treatment group and were tested at pre- and post-test on a battery of vocabulary and narrative assessments. The results of a Randomised Control Trial were positive in favour of the intervention. The most important of these results was a statistically significant effect on the receptive vocabulary of the children in the treatment group, with a large effect size, as measured by the standardised British Picture Vocabulary Scales (Dunn et al., 1997). There was also a significant effect on productive vocabulary, as measured by a Researcher-Designed Vocabulary Test (RDVT). This test was devised for the purpose of this study, testing one-word vocabulary, taken directly from the storybooks in the intervention. As this is not a norm-referenced, standardised test, caution is advisable in the interpretation of this result.
A further positive effect concerned the narrative skills of the children in the treatment group, when compared to the children in a control group – the Mean Length of Utterance (MLU) score was higher in the treatment group, with a medium effect size.
By examining the intervention by Randomised Control Trial, this study responds to the call from Lillard et al (2013) for more experimental research on pretend play and narrative. The acknowledgement of the role of the adult in the intervention coupled with the positive effect on the children’s MLU and receptive vocabulary mean that the intervention, with further development, has the potential to be used as a Professional Development tool for supporting language development in the Early Years in the UK, in the future.
The context of organic residues in archaeological vessels of ceramic and bronze
Keywords: Britain
Greece
Israel
Ceramic Analysis
Bronze Corrosion
Vessel Use
Archaeology
Organic Residues

Since the 1970s, the study of molecular organics preserved in archaeological ceramics, commonly referred to as organic residue analysis, has been used to infer vessel use and study dietary, economic, and ritual activities in the past. The purpose of this project is to analyse organic residues from a variety of ancient vessels and attempt to understand further the relationship between molecular organic preservation and vessel characteristics. It has been previously assumed that the absorption of these organics in the ceramic matrix is predominantly responsible for their preservation. The clarification of this or other preservative mechanisms and the further understanding of the relationships of vessels with their contents has a direct impact on the interpretation of organic residues and vessel use. The first section addresses the preservation of molecular organics in pottery vessels from Tel Kabri, Israel; Tel Megiddo, Israel; and Lefkandi, Greece. The one hundred and thirty-three samples from these three sites represent vessels used in domestic, burial, ritual, and elite contexts from the Early Bronze Age through the Iron Age Eastern Mediterranean.
The focus of the study is the quantification of residue yields and identification of potential links with vessel properties and characteristics of the ceramic samples. Sequential extractions using two methods, conventional chloroform/methanol solvent extraction and direct FAME extraction/derivatisation, were applied to the sherds to test the absorption and adsorption of organics into ceramic materials. The majority of samples were tested non-destructively, enabling the comparison of residue yields to certain vessel properties and characteristics displayed in the same sherds. Where available, data concerning vessel form, sampling location on the vessel profile, thickness measurements were recorded, and XRF measurements were taken, with this in mind.
The second section investigates the question of whether bronze and copper alloy vessels have the capability to preserve molecular organics within their corrosion products. Twenty-two samples of corrosion and associated material from five Early Roman bronze vessels found in cremation burials during the A2 Pepperhill to Cobham project in County Kent, United Kingdom were studied for organic material. These samples provide some of the first evidence that the residues of original content are preserved in copper alloy vessels either through entrapment in or reactions with copper corrosion.
Right ventricular outflow limitation and capacity for exertion associated with age and iron status
Keywords: Hyperoxia
Hypoxia
Hypoxia-inducible factor
Exercise
Hypoxic pulmonary vasoconstriction
Aging
Iron homeostasis

This thesis is concerned with the role of iron in modulating right ventricular (RV) afterload during exercise in healthy people aged between 50 and 80 years. This is predicated on the requirement of the hypoxia-inducible factor (HIF) pathway for ferrous iron. A secondary objective is to examine the reactive oxygen species (ROS) hypothesis in human hypoxic pulmonary vasoconstriction (HPV) using exposure to hyperoxia.
Chapters 3 and 4 describe basal relationships that may affect the HIF pathway and exercise capacity during ageing. These were explored in 113 participants using blood tests and exercise tests. Age and inflammatory factors, C-reactive protein, and ferritin were associated with impaired exercise capacity. In addition, ageing did not significantly affect haematological variables or iron status indicators.
Chapters 5 and 6 describe the effect of a single intravenous iron infusion on the haematological variables in 32 participants in a randomised, placebo-controlled and double-blinded study. The effects of iron infusion on RV afterload during light exercise, and exercise capacity during heavy exercise, were examined in these participants. With iron infusion, erythropoietin production, and the increase in RV afterload during light exercise were blunted, potentially indicating involvement of the HIF pathway. However, blunting of RV afterload neither influenced the cardiac output during light exercise nor exercise capacity.
Chapter 7 describes a study of 11 healthy volunteers, which investigated the ROS hypothesis in HPV using acute isocapnic hypoxia following an 8-hour exposure to hyperoxia. This sustained hyperoxic exposure did not influence the hypoxic behavior of the pulmonary vasculature.
This thesis demonstrates the complex relationship between iron status and exercise capacity in older adults. It shows that the decrease in RV afterload during exercise caused by intravenous iron supplementation does not lead to an augmented cardiac output or exercise capacity. Finally, it calls into question the role of ROS in HPV.