VictorJuiz/thesis huggingface dataset:
Identification and characterisation of new models for age-related hearing loss

Age-related hearing loss (ARHL), or Presbycusis, is the most prevalent sensory impairment observed in the elderly. It is a progressive, symmetrical, age-related sensorineural hearing loss, most pronounced at higher frequencies. ARHL is a multifactorial disease, with contribution from both environmental and genetic factors. To date, little progress has been made in determining the genetic loci involved. The aim of my doctorate studies is to elaborate upon the genetics underlying ARHL through the identification and characterization of ENU-induced mouse models of ARHL.
This approach has identified trombone, a recessive model of ARHL arising from the Harwell Ageing Screen. Recurrent auditory phenotyping at 2, 6, 9 and 12 months of age shows that affected animals display elevated ABR thresholds from 9 months of age, when compared to littermates, and these are further increased at 12 months of age. Genome mapping studies identified a 12.5Mb critical region on chromosome 2 and next generation sequencing identified a T&GT;C mutation in the novel deafness gene Slc4a10, causing a leucine to proline substitution in the encoded protein. Immunohistochemical staining of cochlear sections demonstrates that Slc4a10 is expressed in the type II and V fibrocytes of the spiral ligament of wildtype mice, whereas no labelling is observed in Slc4a10trmb/trmb mice. In addition, ultrastructural studies show progressive sensory hair cell loss (inner and outer) in the Slc4a10trmb/trmb mice from &GT;6 months of age. Furthermore, histological assessment of the lateral wall identified strial thinning in the Slc4a10trmb/trmb mice. Given the expression pattern and morphological changes observed, endocochlear potentials were measured in these mice. This identified that Slc4a10trmb/trmb mice have a chronically low endocochlear potential compared to their wildtype and heterozygous littermates.
My findings establish the presence of Slc4a10 in the inner ear and suggest an important role for this sodium-coupled bicarbonate transporter in normal auditory function. I hypothesize that trombone is a novel model of strial presbycusis and further functional characterization of this model promises to increase our understanding of the pathobiology associated with age-related hearing loss.

Advisor: Bowl, M
Brown, S
King, A
The genetics of autoimmune and proteinuric disease

The genetics of complex common diseases are not fully understood, but rare variants with large phenotypic effects contribute to heritability. The objective of this thesis is to identify rare variants of relevance to autoimmune and renal disease, by developing ways of analysing whole genome sequencing (WGS) data and exploring the variants identified. Forward genetic experimental approaches are used, both in mutagenised mice, and in humans with extreme trait forms of the steroid resistant nephrotic syndrome (SRNS) and systemic lupus erythematosus (SLE). This work demonstrates that N–ethyl–N–nitrosourea (ENU) mutations can be distinguished within WGS data, including a hypomorphic mutation in Lamb2 in a strain with the nephrotic syndrome, a murine model for the milder spectrum of human Pierson syndrome. In a B–cell deficient ENU strain the causative mutation in Lyn was isolated by sequencing multiple affected mice and applying an implementation of the Lander–Green algorithm to search for identity by descent. This method for the first time overcomes a rate-limiting step in ENU programmes and offers the potential to accelerate gene discovery, eliminating the need for out–crossing and conventional linkage analysis. Knowledge of the ENU genomic intervals allowed calculation of a mutation frequency, 1.5 mutations per mega base, and modelling of an efficient ENU strategy. Short–lists of candidate variants from 14 unrelated patients with steroid resistant nephrotic syndrome or systemic lupus erythematosus provide a substrate for future experiments, for example a candidate in the Wiskott–Aldrich syndrome gene was excluded using DNA from family members. In conclusion, WGS coupled with identity by descent analysis offers a powerful tool to improve the efficiency of ENU programmes. Rare variant discovery in humans without obvious Mendelian inheritance is more challenging and will require strategies to prioritise variants that combine bioinformatic filters and experimental verification in a high throughput way.

Advisor: Cornall, R
Mid-infrared laser spectroscopy for trace gas detection

Laser spectroscopy offers a powerful and adaptable toolkit of techniques for sensitive and selective gas detection. New semiconductor laser sources that can emit high power midinfrared radiation at room temperature have reawakened interest in exploiting the spectrally separated, strongly absorbing ro-vibrational transitions in this region. The aim of this thesis is the demonstration of absorption spectroscopy methods with interband cascade lasers (ICLs) and quantum cascade lasers (QCLs) to detect gases relevant to physiology and atmospheric science.
Modulation of laser frequency via the injection current can increase instrument performance and prevent long-term drifts in laser output. An 8.2 μm QCL was locked to a CH4 rovibrational line using a 3f signal, limiting the laser frequency deviation to 3 MHz over 120 s. Frequency modulation spectroscopy (FMS) at 20 MHz demonstrated a twofold improvement for NO measured with a 5.3 μm QCL despite residual amplitude modulation. Broadband RF current perturbation of a 5.3 μm QCL was shown to broaden the laser linewidth and enhance the sensitivity of off-axis cavity-enhanced absorption spectroscopy (CEAS) tenfold.
Optical-feedback CEAS (OF-CEAS), which achieves high intracavity power and elongated periods of resonant cavity excitation, was performed using V-shaped and linear optical cavities. ICL and EC-QCL sources were utilized for the first time for sensitive OF-CEAS detection of VOCs and N2O. OF-CEAS using a V-shaped cavity and 3.2 μm ICL achieved an αmin of 2:5x10-8 cm-1 for N2O measurements. While the 5 μm EC-QCL achieved similar single-scan precision, mode-hopping prevented consistent measurements. The novel use of a linear optical cavity for OF-CEAS was demonstrated theoretically and experimentally with a 5.3 μm QCL to achieve excellent sensitivities (4 x 10-9 cm-1 Hz-1/2). The successful demonstration of these techniques paves the way for new QCL and ICL technology to be incorporated in future laser absorption spectrometers for the laboratory, field, and clinic.

Keywords: trace gas detection
modulation spectroscopy
infrared spectroscopy
Advisor: Ritchie, G
Examining the contribution of dentate gyrus granule cells and ambiguity toward the stress response and behaviour of the rodent

The hippocampus and adult-born neurons have been implicated in regulating the stress response and disambiguating conflicting goal-related information. How these functions interact to promote adaptive behaviour has not been investigated. In this thesis, hippocampal lesions or pharmaco-genetic ablation of adult neurogenesis in mice ('TK mice') was used to dissect this relationship. Hippocampal lesions or selectively ablating adult neurogenesis decreased defensive behaviours toward a partially reinforced fear conditioned cue ('ambiguous fear conditioning'). Conversely, these animals did not show these impairments when a cue reliably predicted a footshock ('reliable fear conditioning'). In TK mice, this same pattern of results was also seen in Fos expression levels in the dentate gyrus and CA3. In additional experiments, baseline novelty-suppressed feeding behaviour (latency to eat a familiar food) did not differ between genotypes. After reliable fear conditioning, TK mice took longer to eat the food, suggesting increased anxiodepressive-like behaviour. After ambiguous fear conditioning, however, TK showed quicker latencies to eat, suggesting decreased anxiodepressive-like behaviour, as compared to wildtype mice. Clamping corticosterone levels was used to determine its role in adaptive responding to prior stress. Preventing experience-induced increases in corticosterone did decrease the latency for wildtype mice to eat after ambiguous fear conditioning, whereas TK mice were unaffected. Finally, another set of experiments were designed to see if ambiguity would affect appetitive behaviour in a non-spatial T-maze task with conflicting goal responses. It was found that mice with hippocampal lesions, but not TK mice, tended to choose an arm associated with a large reward less often if the other arm contained a small reward, as compared to their respective control groups. Similarly, hippocampal-lesioned mice, but not TK mice, chose an arm that was always associated with the presence of a reward less often if the other arm ambiguously predicted a reward. All of the above results suggest that the hippocampus, especially adult-born neurons, is necessary to disambiguate salient conflicting memories that underlie goal responses and that this disambiguation biases goal-related behaviour in an adaptive manner.

Keywords: stress
neuroscience
psychology
dentate gyrus
Advisor: Bannerman, D
Models of men: The construction and problematization of masculinities in the Islendingasogur

This thesis examines masculinities in the Íslendingasögur. It attempts to uncover the dominant model of masculinity that operates in the sagas, outlines how masculinities and masculine characters function within these texts, and investigates the means by which the sagas, and saga characters, may subvert masculine dominance. The thesis applies to men and masculinities in saga literature the same scrutiny traditionally used to study women and femininities.
The first – introductory – chapter reviews the limited scholarship that presently exists on masculinities in Old Norse literature. It then proposes a new model for the critical study of saga masculinities, drawing on sociological theories of hegemonic and subordinated masculinities. The second chapter ranges across the entire Íslendingasaga corpus in order to demonstrate how masculinity inflects homosocial relationships (and thus virtually all aspects of saga texts). It also suggests that almost all masculine characters have a problematic relationship with masculinity as a result of the intersectional nature of subject formation. The third chapter, focusing on Njáls saga, argues that the male body is used to undermine the prevailing model of masculinity. It is argued that the Njála author purposefully deploys somatic indices that have gendered significance to show embodied resistance to the demands of masculinity. The fourth chapter examines the representation and treatment of a character (Grettir Ásmundarson) that embodies masculinity to an exceptional degree, but who nevertheless – or perhaps for that reason – experiences a problematic relationship with masculinity. Finally, an epilogue briefly investigates some of the ways in which female characters may undermine and problematize the masculinity of men and the category of masculinity itself. Ultimately, this thesis shows that masculinity is not simply glorified in the sagas, but is represented as being both inherently fragile and a burden to all characters, masculine and non-masculine alike.

Keywords: Sagas of Icelanders
Íslendingasögur
Old Norse
Advisor: O'Donoghue, H
The Romance of the Rose in fourteenth-century England

This thesis traces the afterlife of the Romance of the Rose in fourteenth-century England. Whether it was closely imitated or only faintly recalled, I argue that the Rose exercised its influence on fourteenth-century English literature in two principal ways. Firstly, in the development of a self-reflexive focus on how meaning is produced and transmitted. Secondly, in a concern with how far the author’s intentions can be recovered from a work, and to what extent the author must claim some responsibility for the meaning of a text after its release into the world of readers. In the Rose, many of these issues are presented through the lens of a disordered erotic desire, and questions of licit and illicit textual and sexual pleasures loom large in the later responses. My investigation focuses on four English writers: William Langland, John Gower, the Gawain-Poet, and Geoffrey Chaucer. In my final chapter I suggest that the Rose ceased to be a generative force in English literature in the fifteenth century, and I try to offer some explanations as to why.
In examining the influence of the Rose in England I am not trying to suggest a linear transmission of cultural dominance, but rather a complex and plural process of interaction that expands to include texts that both antedate and post-date the Rose — especially Neoplatonic allegories and Ovid, on the one hand, and, on the other, Deguileville and Machaut. The individual English writers I look at are not seen as having a single and stable attitude towards the Rose; instead, I argue, the Rose emerges as a way of thinking about the interaction between texts, how meaning is produced, and how authorial ownership is claimed or refused.
Using not only literary evidence but also detailed archival research into the manuscript circulation of the Rose, I question the usefulness of 'English' and 'French' as critical categories for the study of late-medieval literature, and attempt to show that, for a certain kind of literary activity, the Rose occupied a central position in England: not a stable foundation of cultural authority, but a realm of self-questioning subversion and instability.

Advisor: Perkins, N
Swift, H
The dynamics of a changing arctic ocean

The Arctic Ocean is undergoing a period of rapid transition, and many different aspects of its environment (ocean, sea ice, and atmosphere) are changing faster than has ever previously been observed. Motivated by the role that the Arctic plays in the global climate and ocean circulation, the aim of this thesis is to investigate how the changing environment is affecting the dynamics and circulation of the Arctic Ocean.
Observations show that freshwater accumulation in the Beaufort Gyre of the western Arctic Ocean has accelerated over the past decade. First, a simple process model and idealised perturbations to the annual cycle in ocean surface stress are used to show that the decline in Arctic sea ice cover and an increase in the annual mean momentum flux can explain this accelerated accumulation. The adjustment timescale and quantity of freshwater accumulated are determined by a balance between Ekman pumping and an eddy-induced volume flux, highlighting the importance of eddies in the changing Arctic.
Sea ice decline may also drive periodic increases in vertical mixing. Using a 1D model of the Arctic Ocean water column, the competing effects of elevated vertical mixing and enhanced freshwater input on the stratification, the stability of the cold halocline, and the sea ice cover at the surface are explored. An elevated diffusive heat flux driven by stronger vertical mixing has little effect on the sea ice. Instead, the erosion of the cold halocline, which isolates the sea ice from the warm Atlantic water, represents the most important feedback for ongoing sea ice melt.
The changing Arctic Ocean will further affect the freshwater export to either side of Greenland; however, local dynamics will also be important. In this chapter, the vertical structure of the tides in Nares Strait in the Canadian Arctic Archipelago are explored, as tidal turbulence may represent an important frictional constraint for the freshwater flow in this region. The tides propagate as either standing or progressive waves, and the vertical structure is set by the proximity of the semi-diurnal critical latitude, the requirement of no normal flow through the coast, and the strong stratification at the surface. There is little temporal variability in the vertical structure, and tidal dissipation is comparable in magnitude to that over the highly dissipative region of the northwest European Shelf.

Keywords: Arctic dynamics
Advisor: Johnson, H
Lique, C
Negotiating violence: the construction of identity amongst adivasi Christians in Udaipur district, Rajasthan

This thesis elucidates processes of identity construction that have taken place amongst Bhil Christians in Udaipur district, Rajasthan, in the context of the endemic anti- Christian violence that has been carried out by Hindu nationalist organisations and adherents in this area since the late 1990s. My work explores how Bhil Christians engage with this, and seeks to make both an empirical and analytical contribution to existing analyses of anti- Christian violence by shifting the focus away from the construction of majoritarian Hindu identities in India’s tribal belt, and placing it instead on the minority Christian community. Utilising a tripartite typology of violence (direct, structural and cultural) as its starting point, this thesis addresses questions of how Bhil Christians construct and perform their identity in this context, and how they understand and negotiate their relationships with both non-Christian communities and the state in their localities. This aims to situate Christians as agents in the construction of their own identities, rather than simply having 'otherness' imposed on them as a result of Hindu nationalist mobilization and rhetoric. This study shows that Bhil Christians are involved in a dualistic process of strategically emphasizing both difference and similarity between Christians and Hindus, while making recourse to an overarching adivasi identity that, in various ways, serves to challenge and often undermine the damaging constructions of Christianity that are propagated by the Sangh Parivar. At the same time, they foreground a Christian identity that is decisively shaped by notions of agency, moral uplift, and assertion; these are ideas that are informed by longer histories of adivasi self- and community making, but have acquired important new meaning and relevance in the context of anti-Christian violence.

Advisor: Gooptu, N
Protein engineering to capture and kill cancer cells

The formation of protein assemblies to carry out sophisticated functions is constantly gaining attention in nano-biotechnology. However protein assemblies are often linked through non-covalent interactions, limiting the stability of the complexes and the resilience to forces. Force resistance is crucial for magnetic isolation of circulating tumour cells (CTCs), when a specific protein interaction must withstand the forces pulling a captured cell in the magnetic field. CTCs are present in the blood of cancer patients at very low frequency, making their isolation extremely challenging. However, CTC isolation provides an important approach to enable cancer prognosis and personalised therapy. By optimizing the nanotechnology of the antibody-magnetic bead linkage, the membrane fluidity of the cancer cells, and the affinity of the antibody binding we developed a new approach to minimize the level of tumour markers required to immunomagnetically capture cancer cells. To improve the sensitivity of cancer cell detection even further, a peptide-peptide covalent ligation system was used to generate self-assembled polymers of affibodies (an antibody-like scaffold). Affibody polymers allowed the establishment of multivalent interactions with cell-surface tumour markers, greatly improving the recovery of tumour cells expressing low levels of cancer biomarkers.
However, those polymers had a mixture of lengths and there was no control over polymer sequence. Using orthogonal sequential isopeptide bond formation, we synthesized sequence-controlled proteins chains and used these immuno-assemblies as potent inducers of apoptosis of cancer cells. The approaches presented in this thesis show the importance of generating covalent protein polymers for cell isolation and killing, potentially opening up new directions for cancer biotechnology.

Advisor: Howarth, M
Relating the midbrain dopaminergic system to hippocampal cell assembly dynamics associated with spatial memory function

Central to the understanding of memory is a detailed understanding of the processes contributing to how some information is retained as memories, yet other information is not. Relevant to this is the question, does value and saliency information coded by dopaminergic neurons of the ventral tegmental area (VTA) affect hippocampal memory function and how might this arise? In order to address this question, I performed large scale extracellular recordings combined with optogenetic activation of dopaminergic neurons in mice. Tetrodes were located in the VTA and pyramidal cell layer of the CA1 subfield of the dorsal hippocampus. Midbrain dopaminergic neurons were made to express a chimeric protein formed of the light activated ion channel channelrhodopsin-2 and enhanced yellow florescent protein (ChR2-eYFP) through injection of a Cre activated viral construct in the VTA of DAT-IRES-Cre+/- mice. Mice explored familiar and novel open fields in the presence or absence of photostimulation. Periods of sleep and rest were recorded before and after each exploration in order to calculate the reactivation strength of hippocampal waking firing activity during subsequent sleep; a process thought to aid the stabilisation of representations enhancing their retention as memories. ChR2-eYFP expressing axons were present in the dorsal hippocampus demonstrating a direct dopaminergic projection from the midbrain to the hippocampus. Units isolated from midbrain tetrodes showed a sustained increase in mean firing rate during exploration of a novel over a familiar environment, indicating they have the potential to drive sustained dopamine release in target structures in response to such a sustained novelty cue. Hippocampal reactivation strength after exploration of a novel environment was higher than that seen after exploration of a familiar environment and this was further enhanced by burst mode photoactivation of dopaminergic neurons at their cell bodies in the VTA or at the afferent dopaminergic fibres in the dorsal CA1. A second group of mice performed a spatial learning task on a maze dubbed the 'crossword maze'. Photostimulation during learning trials did not increase the rate of learning but it did increase performance in a probe test held one hour after the end of the learning trials. Additionally, there was enhanced reinstatement of the hippocampal spatial representation during the probe test and it was preceded by enhanced reactivation of the newly formed representation in the intervening rest period. These findings reveal that midbrain dopaminergic neurons, encoding salient information about an environment, promote hippocampal network dynamics associated with memory persistence, thus modulating hippocampal memory function according to the value of the information to be remembered.

Advisor: Dupret, D
Magill, P