VictorJuiz/thesis huggingface dataset:
Investigating TDP43 biological dysfunction through the characterisation of Tardbp ENU mouse mutants: implications for neurodegeneration
Keywords: mouse models of neurodegeneration
amyotrophic lateral sclerosis
TDP43 proteinopathies
TDP43
frontotemporal demential
neurodegeneration

TDP43 is a highly conserved ubiquitously expressed protein which performs multiple roles in RNA metabolism, including regulation of gene expression, pre-mRNA splicing and the regulation of micro-RNA biogenesis. It belongs to the hnRNP family and interacts extensively with other proteins and RNA to perform its known biological functions and, analogously to other proteins from the same family, is proposed to autoregulate its own protein levels.
TDP43 biological dysfunction plays a pivotal role in the aetiology and pathophysiology of ALS and FTLD-TDP given that abnormally cleaved mislocalised fragments of TDP43, which are polyubiquitinated and hyperphosphorylated, constitute histopathological hallmarks of these diseases. Moreover, mutations in TARDBP (the gene encoding TDP43), most of which located in exon 6 that encodes the Glycine-rich C-terminal of the protein, are causative of ALS and FTLD-TDP. Additionally, widespread dysfunction in RNA metabolism involving TDP43 target genes is found in tissue samples from patients who suffered from these two neurodegenerative diseases.
Mechanistic dissection between TDP43 dysfunction and downstream neurodegeneration has remained elusive given that both over-expressor cellular and mouse models and conditional deletion or knockdown models have been shown to develop behavioural dysfunction and, in some cases, neurodegeneration with associated dysfunction in RNA metabolism.
In this thesis a reverse genetics approach was taken and two Tardbp ENU mutant mouse models were characterised, TardbpF210I (mutation in the RRM2 of TDP43) and TardbpM323K (mutation in the C-terminal domain of TDP43). Strikingly, both mutants showed significant phenotypes in TDP43-dependent splicing, with the F210I mutation leading to a "loss of normal splicing function" and the M323K mutation an "augmented alternative exon selection" leading to a splicing phenotype opposite to the observed as a consequence of the "loss of normal splicing function" caused by the F210I protein at the genome-wide level.
Full behavioural characterisation of heterozygous mice for these two ENU mutations did not identify any phenotypes associated with neurodegeneration, but preliminary data suggests that homozygous mice for the M323K mutation may suffer from synaptic dysfunction. Therefore, despite developing genome-wide splicing changes as a consequence of TDP43 biological dysfunction, neither of the mutant mouse lines developed neurodegeneration.
In conclusion, the characterisation of Tardbp ENU mouse mutants has revealed that TDP43 dysfunction leading to "loss of normal splicing function" or "augmented alternative exon selection" is not sufficient to cause, on its own, neurodegeneration in the laboratory mouse within its normal lifespan.
The importance of gender ideology and identity: the shift to factory production and its effect on work and wages in the English textile industries, 1760-1850
Keywords: domestic production
life-cycle
wages
trade unions
labour history
Industrial Revolution
factory production
eighteenth century
gender
nineteenth century
textiles
work
regional variation
England

Textile manufacture in England had always employed a high proportion of women and this continued to be the case during the period 1760-1850. However, these industries underwent dramatic changes in both the nature and location of production, and women’s employment opportunities altered. Whilst in some cases technological advances reduced the strength required to perform a given process, making women more attractive to employers, this was not always the case. Urbanisation and factory production increased trade union influence, which often acted to the detriment of women’s access to well-paid occupations. The long standardised hours worked away from the home typically required of factory workers made it harder for women to combine textile work with the mothering and domestic responsibilities expected of them. As well as making it harder for women to work throughout their life, this discouraged investment in human capital of females by both themselves and their parents. Ideological resistance to women’s work outside of the home increased as the Industrial Revolution progressed. The more formalised work hierarchy created by factory production meant that resistance to female authority became increasingly important for denying women access to the best paid occupations. Ideology was not merely a response to material factors, but helped determine decisions made by economic actors. This thesis draws on a number of parliamentary reports over the period 1802-67. Not only do these reports provide a wealth of qualitative information, they also contain quantitative information which enables me to track male and female factory earnings over the life-cycle, by region and industry. The information in the parliamentary reports is used in conjunction with business records of various firms, covering both domestic and factory workers, as well as the writings of numerous contemporary observers.
Phosphoramidite ligand design for the enantioselective conjugate addition of alkylzirconium reagents to enones
Keywords: Ligands
Organic synthesis
Copper
Zirconium
Conjugate addition
Quantitative structure selectivity relationship

The development of new methods to make carbon-carbon bonds asymmetrically remains a challenge in organic chemistry. Indeed, the development of highly selective methods often proceeds on a trial and error basis. The way chiral information is transferred to the substrate is unclear in many reactions, limiting further development. We focus here on developing an asymmetric conjugate addition of alkylzirconium nucleophiles to Michael acceptors. The development of new phosphoramidite ligands, supported by a computer based model, allowed further development of the reaction.
First, existing methods to introduce enantioselectively chirality are described. Then we discuss ligands, and modern ways to parameterise experimental data using computational methods. In chapter two, after discussing the use of alkenes as reagents, especially processes initiated by hydrometallation, we describe a new conjugate addition reaction using cyclic enones that achieves both high yields and levels of enantioselectivity.
In chapter three, various applications of phosphoramidite ligands are discussed and we describe the synthesis of a variety of different phosphoramidites and identification of important structural features of these ligands. New, efficient ligands are obtained and a computer model is developed to account for the selectivity of the reaction discussed in chapter two. Chapter four describes the development of an enantioselective synthesis of quaternary centres with novel ligands used to optimise the new system. Lastly, chapter five describes the extension of the method to some linear enones, using different ligands.
Overall, we have developed a variety of ligands which were used to expand the enone scope of a conjugate addition and an understanding of what factors make these ligands effective.
Regulating stem cell fate within microenvironmental niches
Keywords: transplantation
gene knockdown
haemopoietic stem cells
hematopoietic stem cells
microenvironmental niches
gene silencing
hypoxia
stem cell niche
lentiviral transduction
bone marrow
adhesion and migration of cells
blood

Improving the repopulation potential of human umbilical cord blood (UCB) haemopoietic stem cells (HSCs) remains a paramount goal in HSC transplantation (HSCT) therapy. This implies enhancing the homing and engraftment potential of UCB-CD34+CD133+ cells to the bone marrow (BM). Although an array of molecules continues to be identified as ‘key’ homing molecules, the molecular mechanisms controlling HSC homing are still not fully understood. The regulatory implications of hypoxia in the BM, with the concomitant stabilisation of hypoxia inducible transcription factor-1α (HIF-1α), are becoming more apparent, yet at the commencement of this thesis no study had explored whether hypoxia induced signalling can be adopted to regulate the homing and engraftment of transplanted HSCs.
The aim of this DPhil project was thus to investigate whether hypoxic conditions as detected in the BM influence the adhesion of UBC-CD133+ cells to osteoblasts, BM stromal cells and BM endothelial cells-60 (BMEC-60), as well as their transmigration towards chemokine SDF-1α across BMEC-60. Increasing the exposure of UCB-CD133+ cells to 1.5% O2 doubled the percentage of transmigrating cells (p<0.05), and while hypoxia stimulated UCB-CD133+ cells preferentially adhered to IL-1β stimulated BMEC-60, their adhesion to non-stimulated (BMEC-60) was significantly improved (p<0.001). To help unravel the underlying molecular mechanisms, we attempted to examine the potential involvement of hypoxia regulated scaffolding protein HEF-1/NEDD9/Cas-L (HEF-1) in the increased percentage of migrating UCB-CD133+ cells after hypoxia pre-conditioning. The role of HEF-1 in HSCs is unexplored, and its multifunctional contribution in a variety of processes including cell migration, attachment and invasion make HEF-1 a prime candidate as a contributing homing molecule. After identifying a suitable short-hairpin RNA (shRNA) sequence to knockdown HEF-1, generating lentiviral (LV)-particles in house and optimising transduction protocols, HEF-1 knockdown was achieved in haemopoietic model cell lines KG-1 and KG-1A (KG-1/KG-1A–HEF1). Significantly decreased KG-1A–HEF1 cell adhesion to non-stimulated BMEC-60 was detected. Together, these studies provide a promising platform to further explore the role of HEF-1 in hypoxia induced UCB-CD133+ cell transmigration towards the key homing molecule SDF-1α.
Cardiovascular disease risk factors, weight, and the strategies to tackle future risk in school aged children
Keywords: education
cardiovascular disease
obesity
children
health behaviour

Background: Cardiovascular disease (CVD) can have its beginnings in childhood, especially if the child is overweight. Without intervention, increased risk factors in childhood track in adulthood, putting the individual at increased risk for early cardiovascular morbidity and mortality. As a result, childhood health outcomes are an increasingly popular area for health research. However, little progress has been made on the most effective way to enable children to lead healthy lives.
Methods: This thesis incorporated five studies. Firstly, a systematic review and meta-analysis of 63 papers involving nearly 50,000 school children examined the relationship between body mass index (BMI) categories and CVD risk factors. Secondly, a focus group study with 46 students to discuss their knowledge and attitudes towards health, health behaviours and health education. Thirdly, a focus group study with six mothers to discuss screening weight in childhood, and their perceptions of childhood health and health education. Fourthly, a component analysis to establish the characteristics of nine successful educational interventions on children’s health. Finally, a pilot intervention and feasibility study involving 314 students.
Results: Overweight and obese BMI categories were associated with substantial increases in CVD risk factors measured and that the association with obesity was greater than that with being overweight. The focus group studies found that the depth of knowledge and the perceived depth of knowledge that participants had about CVD risk factors affected their attitudes and behaviours, although not in the same way. The pilot intervention was deemed feasible. A significant change was brought about in the students’ knowledge of cardiovascular disease and raised their self-efficacy towards ensuring the health of their hearts.
Conclusion: The effect of obesity on cardiovascular risk factors is greater than that of being overweight. Additionally, studies in this area are hindered by inconsistent measurements and definitions of the BMI categories. Secondly, both parents and children need to be equipped with deep knowledge and understanding to facilitate attitude and behaviour change towards healthy living. Finally, the pilot intervention should be trialled in a randomised, controlled trial.
Constructing the self in language and narrative in the work of Grazia Deledda
Keywords: identity
narrative
Grazia Deledda
autobiography

This thesis examines the presence of modernist ideas regarding identity, language and narrative in the work of the neglected Sardinian author, Grazia Deledda (1871-1936). It has the overall aim of redefining Deledda’s later work as modernist for she has been disregarded by most critics and is generally classed as a minor, veristic writer. Drawing Deledda out of these restricted interpretations, this thesis demonstrates that Deledda straddles two literary modes, for she matures beyond veristic influences and looks forward to modernist ideas, particularly regarding the complex nature of the self.
The thesis approaches Deledda from an entirely new perspective in that it focuses upon the crisis of identity in Deledda’s work, and its construction in the narrative of her novels, and its integral relationship with the theme of language. The theoretical framework of Julia Kristeva, Paul Ricoeur and Adriana Cavarero enables an innovative study of identity as a linguistic and narrative construct in Deledda’s work. I maintain that Deledda’s characters construct, control and understand their identities through their application of language or their command of narrative perspective, voicing their inner selves through linguistic self-expression.
This study engages in a close textual analysis of three of Deledda’s key texts. La madre (1920) and Il segreto dell'uomo solitario (1921) illustrate Deledda’s movement away from verismo. Their protagonists suffer a crisis of identity which is bound up in linguistic expression and/or narrative control. Cosima (1937), which is Deledda’s most autobiographical text, displays the author’s close affinity with her writing. Creating a fiction of her own life, Deledda becomes both narrator and protagonist, self and other in the exploration of her own identity, which is integrally connected to the act of writing. The very composition of this text demonstrates the construction of identity in language and narrative which is illustrated within Deledda’s other works.
Group size dependent benefits in microbe cooperation
Keywords: cooperative infection
Group size
synergy
risk assessment

Microbes produce many molecules that are important for their growth and development, and the production and exploitation of these public goods has become an important paradigm in the field of microbial social evolution. Here I explore this type of microbial sociality in two primary chapters.
In the first chapter I focus on the relationship between the shape of the benefit curve and cellular density with a model assuming three types of benefit functions: diminishing, accelerating, and sigmoidal (accelerating then diminishing). I classify the latter two as being synergistic and argue that sigmoidal curves are common in microbial systems. Synergistic benefit curves interact with group sizes to give very different expected evolutionary dynamics. In particular, whether or not and to what extent microbes evolve to produce public goods depends strongly on group size. This synergy can create an evolutionary trap'' which can stymie the establishment and maintenance of cooperation. By allowing density dependent regulation of production (quorum sensing), this trap may be avoided.
In the second chapter I focus again on group size benefits, but with a particular focus on pathogen risk assessment. Many pathogens are thought to behave collectively, and yet the models used in assessing microbial risk assume otherwise. In particular the dominant paradigm, articulated in the Independent Action Hypothesis, is that infecting microorganisms do not interact with each other and that each cell has an independent likelihood of causing infection. Initial data from a bacteria-insect system suggest that indeed the Independent Action Hypothesis may be incorrect and leads to poor risk assessment at low doses. I argue that more attention to mechanisms of infection is essential for accurate risk assessment.
Talking politics and watching the border in Northern Burundi, c. 1960-1972
Keywords: politics
borderlands
Burundi
genocide
Rwanda

This is the history of a turbulent borderland in a time of transition. Colonialism redefined the meaning of borders in Burundi, and in the traumatic shift from colonial rule to Independence it became dangerous to live on the frontier. Responding to Newbury’s plea to ‘bring the peasant back in’ to the written history of the Great Lakes region, the thesis takes a micro-history approach, viewing the tumultuous events of the 1960s and 1970s from the perspective of the hills and the homestead. The border with Rwanda, as experienced in the two communes of Kabarore and Busiga, is tested as the point of encounter between society and state in this crucial time. It reveals the function and dysfunction of political linkage, and the tensions of being a citizen and a subject in the margins of a political community ruled by suspicion and paranoia. The themes - dissent, collaboration, elimination, repression - link this local history to the flow of national politics and the making of a new African state.
Taking as its scope the pivotal period from decolonisation to the military state’s ‘selective genocide’, enacted against its Hutu population, the thesis identifies ‘vigilance’ as the most productive concept by which to study concepts of governance, political community and political linkage in the Great Lakes at the vital point of transformation. A communicative act that blends the stance of the citizen and the subject to shape a means of cautious cooperation and mutual recognition between people and state, vigilance also proved the destructive weapon that violently distilled the population into a subjugated peasantry beneath a bloodied state. The interaction on the border reveals these vital issues in acute contrast, opening the door to their examination elsewhere. This thesis studies the border; its conclusions may be chased far beyond it.
Kinematics and shapes of galaxies in rich clusters
Keywords: astrophysics
galaxies
kinematics
spectroscopy
cluster of galaxies
ellipticity
astronomy

In this work we have studied the relationship between the kinematics and shapes of Early Type Galaxies (ETGs) in rich clusters. In particular we were interested to extend the kinematic morphology density relation to the richest clusters. We obtained data from FLAMES/GIRAFFE to probe the stellar kinematics of a sample of 30 ETGs in the massive cluster Abell 1689 at z = 0.183, to classify them as Slow Rotators (SRs) or Fast Rotators (Frs). To date, this is the highest redshift cluster studied in this way. We simulated FLAMES/GIRAFFE observations of the local SAURON galaxies to account for the bias introduced compared to the ATLAS3D sample, which we used as a local comparison. We find that the luminosity function of SRs in Abell 1689 is the same as that in ATLAS3D, down to the faintest objects probed (MK ≈ -23). The number fraction of SRs over the ETG population in Abell 1689 is fSR = 0.15 +/- 0.03, consistent with the value found in the Virgo Cluster. However, within the cluster, fSR rises sharply with the projected number density of galaxies, rising from fSR = 0.01 in the least dense bin to fSR = 0.58 in the densest bin. We conclude that the fraction of SRs is not determined by the local number density of galaxies, but rather by the physical location within the cluster. This might be due to dynamical processes which cause SRs (on average more massive) to sink in the gravitational potential of the cluster.
Next we explore the distribution of projected ellipticity ε in galaxies belonging to a sample of clusters from SDSS (z ε
= 0.4 (a proxy for FRs) varies from cluster to cluster. We find some significant variations. We go on to probe the projected shape as a function of projected cluster-centric radius. In both samples we find that on average galaxies have progressively rounder projected shapes at lower cluster-centric projected distance. In the SDSS sample we show that this trend exists above and beyond the trend for brighter galaxies to be more common near the centre of clusters (bright galaxies are on average rounder). In order to disentangle the trend for SRs (which are rounder) to be more common near the centre of clusters, we isolate a subsample of FRs only, by considering only galaxies with ε > 0.4. We find that even the intrinsically flat FRs are on average rounder at lower projected cluster-centric distance. We conclude that the observed trend is due either to the dynamic heating of the stellar discs being strongest near the centre of clusters, or due to an anti-correlation of the bulge fractions with the cluster-centric distance.
Authority, philosophical anarchism, and legitimacy
Keywords: legitimacy
philosophical anarchism
authority

One way to prompt people to act is to claim that one’s commands impose duties upon some persons to act and subsequently to command those persons. This is the approach of practical authority. The claim of practical authority is ingredient to a predominant conception of the state. This thesis argues that the state’s claim to practical authority is both unjustified and morally wrong; it defends philosophical anarchism. The philosophical anarchist argument advanced here begins with a defence of a presumption against practical authority. It then argues that no argument for the practical authority of the state overcomes that presumption. Thus the state’s claim to practical authority is unjustified. The philosophical anarchist’s position suggests that we rethink both the normative claim ingredient to the concept of the state and the relationship between states and persons. This thesis suggests that states claim legitimacy – that is, states claim that the potentially coercive legal directives that they enact are all-things-considered morally permissible. The thesis outlines the ideal of legitimacy in political philosophy, an ideal distinct from authority. An analysis of legitimacy requires an analysis of coercion. The thesis develops a specific account of the pro tanto wrongfulness of coercion that locates the wrongfulness of coercion not with the badness of the outcomes that the coercee faces but rather with the beliefs and intentions of the coercer. Two upshots emerge from that account. The first is that legal directives are not necessarily coercive. The second is that the conditions which render coercion pro tanto wrongful also render the state’s claim to practical authority wrongful. However, whereas coercion is justifiable by an appeal to reasons that defeat its pro tanto wrongfulness, the philosophical anarchist shows that the state’s claim to practical authority is not so justifiable. Therefore, the state’s claim to practical authority is decisively wrongful.