VictorJuiz/thesis huggingface dataset:
Determining the mechanism of pathogenesis of mucolipidosis type IV and related lysosomal storage disorders for development of novel therapies
Keywords: Niemann Pick C
TRP channel
lysosomal
storage
rare disease
calcium
mucolipidosis type IV

Mucolipidosis type IV (MLIV) is a rare, autosomal recessive, neurodegenerative, lysosomal storage disorder. MLIV is caused by mutations in a gene (MCOLN1) encoding a TRP channel family member known as Mucolipin 1 or TRPML1. TRPML1 is a lysosomal transmembrane protein that appears to be required for normal lysosomal pH regulation, recycling of molecules and membrane reorganisation including lysosomal biogenesis, fusion and exocytosis. The exact function of the channel is unknown but it is permeable to multiple ions including Ca2+, Na+ and K+, possibly also Fe2+ and Zn2+. How normal TRPML1 function regulates lysosomal processes is not clearly understood. Mutations in the MCOLN1 gene can lead to complete loss of TRPML1 function, partial loss of function or mislocalisation, all of which lead to lysosomal dysfunction, lysosomal lipid storage and ultimately neurodegeneration. The disease processes that lead to neurodegeneration are poorly understood and at present no therapy exists for MLIV.
We have discovered that TRPML1 results in regulating lysosomal Ca2+ homeostasis that is the opposite of the Ca2+ dysregulation associated with Niemann-Pick type C disease (NPC). Our findings indicate that disrupted function of TRPML1 leads to enhanced Ca2+ release via the NAADP receptor, recently shown to be the lysosomal two-pore channel TPC2. This indicates that TRPML1 is not the NAADP receptor as suggested by others, indeed NAADP mediated Ca2+ release is enhanced with multiple NAADP induced lysosomal Ca2+ release events occurring in TRPML1 null cells compared to single releases in normal cells. This phenotype appears to be responsible for the cellular dysfunction associated with MLIV disease cells, enhanced lysosomal fusion, defective endocytosis and potentially even altered lysosomal pH. Several of these phenotypes are normalised by the NAADP receptor specific antagonist Ned-19. These findings illustrate that the NAADP receptor is central to MLIV disease pathology and may be a novel candidate for disease therapy.
The social worlds and identities of young British Sikhs and Hindus in London
Keywords: Intergroup Contact
Assimilation
Sociology
British-Sikh
Ethnic Identity
Dual-identities
Social Identity
Multiculturalism
Identities
Britishness
Social boundaries
British-Hindu
Ethnic minorities
Nationalism

This thesis is centred on exploring the identity options and orientations of young British Indians, from Sikh and Hindu backgrounds, who are British born and living in the London area. Recent socio-political debates have assumed a lack of Britishness amongst these young people, an assumption that is rooted in the belief that high bonding capital within ethnic minorities has led to a lack of bridging capital. This thesis argues that such statements are an essentialisation of the reality of these young people. In fact, their sources of belonging are far more complex, and far less threatening than we may be led to believe. Through the utilisation of eighty in-depth interviews, this thesis presents the intricate social worlds of these young people and the range of orientations (positive and negative) they feel towards component parts of their social worlds, as well as examining the strength and permeability of boundaries that demarcate these social worlds. The final substantive chapter deals with Britishness, and uncovers and presents the different perceptions and understandings that these young people have about British national identity and the ways in which it is accommodated (or not) alongside other important sources of belonging. It is found that a multi-dimensional approach to identity and belonging is best suited to understand the diverse and highly individualistic trajectories of these young people and that 'diverse-dual identities' are the most common pattern of belonging in this particular empirical case.
This thesis make a significant contribution to the existing theoretical frameworks on identity and assimilation as well as the current socio-political debates on Britishness and the cultural integration of ethnic minorities in Britain, by presenting data on an under-researched group, British Indians, and highlighting the range of experiences within this group and the sources of this diversity.
Risk, childhood, morality, and the internet: an anthropological study of internet sexual offending
Keywords: child abuse media
child pornography
risk
child abuse
the Internet
sexual offenders
Internet sexual offending
morality
Internet sexual offenders
sexual offending
ethnography
online crime
anthropology
childhood

This thesis is an anthropological study of Internet sexual offending, more specifically the viewing of child abuse media. It is based on 17 months of participant-observation in UK group programs for individuals who had downloaded illegal child abuse media, semi-structured interviews with participants, program staff, and police, and staff focus groups. Through engaging directly with offenders and those managing them, it provides an in-depth, qualitative understanding of how Internet use and perceptions of online spaces play a key role in Internet sexual offending, while also asking broader questions about online sociality, morality, and effects on normative behaviour. The central argument posits that in moving beyond commonplace explanations for Internet offending, more attention must be given to Internet use, perceptions and constructions of online spaces, and effects on social norms to explain this phenomenon. It then follows to suggest that for some offenders, these elements can be instrumental in their sexualization of children and choice to view abusive media.
The thesis specifically explores why and how some people in the UK engage with illegal child abuse media, with particular attention to notions of risk, childhood, morality, and the Internet. Employing Foucauldian and neo-Foucauldian theory, anthropology of the Internet, and constructionist theories of childhood, focus is placed on multiple areas: the potential social, emotional, sexual, and Internet-specific factors associated with offending; participants' relationships with the Internet and constructions of online spaces; participants' perceptions of childhood and children online and offline; and, societal and institutional efforts to respond to the above, including the larger justice system and fieldwork group program. The general research areas are social science of the Internet, childhood studies, human sexuality, group therapeutic processes, policy and law, and research methodology and ethics.
The language of legislation and the politicisation of British judges
Keywords: politics
judges
constitution
language
law

Over the course of the 20th and 21st Centuries the judiciary have increasingly made decisions that have affected the substantive content and the procedural implementation of public policy. The aim of this thesis is to provide an explanation for this political behaviour in judges by introducing the Legislative Politicisation of the Judiciary Theory to the debate. The theory proposes that the key independent causal variable is the language of Parliamentary legislation.
The argument is that as legislation has been increasingly used to delegate power from Parliament to its various agents, the language used has become more indeterminate in order to enable discretion. Such indeterminacy creates an institutional problem where the orders of the sovereign Parliament are not clear, and to resolve this uncertainty in the Rule of Law the judges must intervene. The political behaviour of judges is therefore stimulated by a change in the legislative supply-side rather than a change in the behavioural demand-side, and the judges are acting as professional technocrats charged with ensuring the efficacious implementation of Parliamentary legislation.
A new discourse analysis methodology has been created for this thesis that provides evidence of change in the language of legislation between 1920 and 2010. A total of 8,328 sections of primary and secondary legislation have been hand-coded, with results showing that 3% of sections in 1920 (21 sections in real terms) were “Henry VIIIth clauses”, where power to make new law was delegated by Parliament; by 2010 this had increased to 16% (400 sections in real terms).
The political woman in German women's writing 1845-1919
Keywords: Fanny Lewald
Louise Otto-Peters
women's literature
Louise Aston
Malwida von Meysenbug
Hedwig Dohm
Mathilde Franziska Anneke
19th century literature
feminism
political literature

This thesis analyses the depiction and its function of politically active women in novels by six female authors from the margins of the democratic revolution of 1848 and the first German women’s movement. The thesis asks (i) what their political stance was in relation to democratic developments and women’s rights, (ii) how they rendered their political convictions into literary form, (iii) which literary images they used, criticised, or invented in order to depict politically active women in their novels in a positive light, and (iv) which narrative strategies they employed to ‘smuggle’ politically and socially radical ideas into what were sometimes only ostensibly conventional plots. The thesis combines intertextual analysis with poetic analyses of individual texts in order to highlight deviant elements in narrative strategy, imagery, or text-internal appraisals by the narrator or author. In order to contextualise the chosen texts as well as my analyses, it draws on the historical environment (social and legal developments, revolutions, technological progress) for the definition of what can be considered radical and political in the period 1845-1919. Additionally, the thesis is firmly grounded in feminist theory, which provides the instruments for highlighting the concepts and circumstances in which the six authors’ works are situated. The essays and novels analysed were written before feminist theory was established; however, their proto-feminist observations, demands, and discursive tactics contributed much to the formation and institutionalisation of feminist thought and, ultimately, theory. In their efforts to construct a positive role model for the political woman, the six authors chosen are united in their notion that such a role model should evolve from bourgeois values of family and work ethics, but the examples manifested in their novels show a great variety of degrees of radicalism.
Radio astronomy instrumentation for redshifted hydrogen line science
Keywords: aperture arrays
spectrometers
radio astronomy
intensity mapping

This thesis presents instrumentation with which to measure the abundance of neutral hydrogen gas in the Universe. Measuring where the Universe’s hydrogen is, and tracing how its distribution evolves with time, holds the key to understanding how galaxies evolve, the nature of dark energy, and how the first cosmic structures formed. In particular, this thesis looks at instrumentation for 21-cm intensity mapping telescopes. In 21-cm intensity mapping, the collective emission of many galaxies is measured, without individual detections. This technique promises to allow detection of the baryonic acoustic oscillation peaks in the power spectrum of the Universe’s matter distribution. Such a detection would increase constraints on cosmological parameters.
There are two main approaches to designing a 21-cm intensity mapping instruments: using a filled aperture instrument such as a single-dish telescope, or using a sparse aperture instrument such as an interferometric array of dipoles. This thesis investigates analogue components for a sparse aperture instrument operating at 1.0-1.5 GHz. As part of this work, a 16-element sparse aperture array was designed and constructed. To test the array’s performance, field testing was conducted; the results of which are presented here.
In addition to this, I have designed a new digital spectrometer for redshifted hydrogen line science, named HISPEC. A copy of this spectrometer has been installed on the Parkes 64 m telescope, as a digital signal processor for the 21-cm multibeam receiver. HISPEC has increased instantaneous bandwidth, higher interchannel isolation, and improved quantization efficiency as compared to the existing backend, MBCORR. The HISPEC equipped multibeam receiver is an ideal instrument for 21-cm intensity mapping at redshifts z<0.2.
Dynamics of cognitive control and flexibility in the anterior cingulate and prefrontal cortices
Keywords: Human
Deep Brain Stimulation
Cognitive Flexibility
Transcranial Magnetic Stimulation
Linear Ballistic Accumulator
Cortical Network
Primate
Cognitive Control
Prefrontal cortex
Neuropsychology
Conflict-monitoring
Anterior cingulate

The body of work hereby presented aims at better defining the specific mechanisms underlying cognitive control and flexibility, and to investigate the neural substrates that might support these dynamics. More specifically, the anterior cingulate (ACC), dorsolateral prefrontal (dlPFC) and frontopolar (FPC) cortices have been proposed to play a fundamental role in monitoring and detecting the presence of environmental contingencies that require the recruitment of cognitive control (such as competition between responses in the presence of conflicting information), implementing cognitive control, and supporting higher-order cognitive processing, respectively. This thesis investigates the effects of damage to these regions, and of interference with their activity, on these processes. It also argues for the importance of dissociating possible separate cognitive control components that might differently contribute to behavioural adjustments (such as caution and attention/task-relevant processing), and provides one of the first attempts to quantify them within the parameters of a mathematical model of choice response-time, the Linear Ballistic Accumulator (LBA). The results confirm the crucial role of the dlPFC in modulating behavioural adjustments, as both damage and interference with this region’s activity significantly affect measures of conflict-induced behavioural adaptation. It is hypothesized that dlPFC might drive behavioural adjustments by encoding recent conflict history and/or supporting the automatization of a newly advantageous behavioural strategy during the early stages after a change in conflict levels. When a task does not involve competition between a habit and instructed behaviour, lesions or interference with ACC’s activity do not appear to affect behaviour in a manner that is consistent with the classic conflict-monitoring framework. It is suggested that its role might be better described as a more general monitoring and confirmatory mechanism that evaluates both actual and potential outcomes of an action, in order to proactively guide adjustments away from contextually disadvantageous responses. Finally, lesions to the FPC do not affect abstract-rule integration, but do impair the early stages of acquisition of a new abstract rule, when a previously rewarded rule stops being rewarded, and specifically when acquisition is dependent on self-initiated exploration. This suggests a role for FPC in the evaluation of multiple concurrent options in order to aid the development of new behavioural strategies.
A high resolution electron backscatter diffraction study of heterogeneous deformation in polycrystal copper
Keywords: plasticity
copper
deformation
dislocations
High Resolution Electron Backscatter Diffraction (HR-EBSD)

Understanding the plastic deformation mechanisms in polycrystals is a long-standing fundamental problem and its improvement has significant potential impact on the increase in materials resistance to typical failure modes such as fatigue cracking and stress corrosion cracking and hence the increase in the materials strength. However many deformation models are yet to be validated as quantitative experimental results at mesoscale to correlate dislocations and microstructure features are limited.
This thesis furthers the High Resolution EBSD (HR-EBSD) technique in Geometrically Necessary Dislocation (GND) density measurement from qualitative analysis with a typical map size of 100 μm x100 μm to quantitative analysis with a map of 500 μm x500 μm by determining the optimised scanning step size (0.5 μm) and detector binning level (4x4 binning). This allows a statistically large number of grains to be sampled. Combining with obtained crystallographical information from a conventional EBSD system, systematic studies on GNDs behaviours with respect to a range of microstructure features such as grain boundaries and triple junctions were conducted on monotonically deformed polycrystal copper samples under tension. Relatively high GND density points were found near triple junctions and some grain boundaries whereas the low GND density points tend to appear near the grains’ interiors. These tendencies are particularly profound in low and moderately deformed samples. Hence more detailed analyses were performed to investigate the relations of GND density and the properties of grain boundaries and triple junctions.
These quantitative analyses were complemented with direct visual assessment. The visual inspection provides interesting findings such as the strong GND structure dependence on grain orientations and GND structure development through increasing deformation; grain-grain interaction influences on GND structure development and GND structures near triple junctions. These GND density studies provide experimental results to validate some of the existing plastic deformation models for instance Ashby’s model of hardening and Hall-Petch relation. However, some of the new observations on GND structures at mesoscale cannot be fully rationalised by existing proposed mechanisms. Hence new models have been proposed that these GND structures might be generated from the intersections of different slip systems which occurred in various parts of a grain, or by the dislocation piling-up at some microstructural features e.g. triple junctions and twin boundaries.
Variations in past and present ocean circulation assessed with U-series nuclides
Keywords: uranium
thorium
ocean circulation
Antarctic Bottom Water
protactinium
Indian Ocean
proxy
sea water
sediment
paleoceanography

This thesis considers the use of two U-series nuclides – 231 Pa and 230 Th – as proxies for studying ocean circulation. A total of six water-column profiles of 231 Pa, 230 Th, and 232 Th have been measured from two regions of the southwestern Indian Ocean: the Madagascar and Mascarene Basins; and the southeastern continental margin of South Africa. Measurement by MC-ICP-MS of 10 litre water samples is possible for samples with as little as 4 and 2 fg of 231 Pa and 230 Th and yields typical uncertainties of 6% and 14% respectively. These profiles show that the scavenging and advection histories of water masses can affect their 231 Pa concentration, with distinct variations superimposed on a general increase in concentration with depth due to reversible scavenging. A 1D particle scavenging model is used to show that sedimentary (231 Paxs /230 Thxs )0 is most representative of the (231 Pa/230 Th) of the bottom most water mass at any one locality, although in turn this water mass (231 Pa/230 Th) will be dependent not only on its advection and scavenging history but also the 231 Pa and 230 Th concentrations of the overlying water masses during advection. Acknowledgment that sedimentary (231 Paxs /230 Thxs )0 is “set” by the bottommost water mass is important for interpretation of scenarios where changes in depth of circulation, as well as circulation strength, may have occurred. A record of sedimentary (231 Paxs /230 Thxs )0 has been recovered from a 6 m Kasten core from the Mascarene Basin covering the past 140 ka, in order to reconstruct flow of AABW into the basin. The (231 Paxs /230 Thxs )0 measured is below the production ration of 0.093 and shows no significant variation. This indicates that (231 Paxs /230 Thxs )0 is sensitive to changes in particle productivity and circulation at this location and that there has been little or no change in either environmental variable over the last full interglacial-glacial cycle. This finding is in contrast to other ocean basins, particularly the North Atlantic, where large changes in circulation are observed.
The selective properties of verbs in reflexive constructions
Keywords: binding theory
reflexives
lexical functional grammar
Anaphora
Russian
French
Austronesian languages
Dutch
Fijian
English

This dissertation investigates the relationship between verbs and reflexive markers within reflexive constructions, setting forth the hypothesis that the verb plays a determining role in anaphoric binding. The work builds upon Dalrymple’s (1993) argument that binding constraints are lexically specified by anaphoric elements and demonstrates that reflexive requirements can be lexically specified for distinct groups of verbs, an approach which offers another level of descriptive clarity to theories of anaphoric binding and introduces a means of predicting reflexive selection in domains where syntactic constraints do not readily apply. This is shown to be particularly pertinent in languages with more than one reflexive type that have overlapping syntactic binding domains.
The hypothesis is substantiated by data from five typologically distinct languages: English, Dutch, French, Russian, and Fijian. Contributing to this data set, new empirical evidence in favour of previously unrecognized reflexive forms in the Fijian language is introduced in this work.
Following Sells et al. (1987), it is demonstrated that reflexive constructions are definable over four different components of linguistic representation and a quadripartite linguistic analysis is, therefore, adopted that incorporates c-structure, f-structure, lexical structure, and semantic structure within a Lexical Functional Grammar theoretical framework. The level of semantic structure is found to be particularly interesting since the realization of a reflexive construction is shown to be influenced by differing semantic requirements between verbs and reflexives. On the basis of several semantic tests, verbs in reflexive constructions are shown to have two different predicate structure types, ‘transitive’ and ‘intransitive’, and reflexive markers are shown to have three different internal semantic structures, ‘strict’ (x,x), ‘close’ (x,f(x)), and ‘near’ (x,y).
The syntactic, semantic, and lexical characteristics of the reflexives and verbs analyzed over the data set presented in this work result in the identification of eight different reflexive/verb types and the establishment of two implicational relationships:
Reflexive markers in lexically intransitive reflexive constructions have no semantic content.
Verbs that take a reflexive argument with a strict (x,x) or close (x,f(x)) internal structure must be intransitive at the semantic component of linguistic structure.
These results contribute to our understanding of anaphoric binding theory, directed verb categories, the syntax-semantics interface, and the licensing of multiple reflexive types within a given language.