VictorJuiz/thesis huggingface dataset:
Studies in peptide chemistry

The thesis discusses the design of potential inhibitors of Angiotensin Converting Enzyme (ACE). The synthesis of pep tide inhibitors containing arginine and histidine-type residues is described. Successful incorporation of these residues during peptide synthesis requires the use of protecting groups on the side-chains* and new developments in this area are described.
Ch. 1 reviews the currently available protecting groups for histidine. A methodology for regiospecific introduction of protecting groups of type ROCH2-, via their corresponding chloromethyl ethers, is described. A convenient synthesis of these reagents (specifically t-Butoxymethylchloride, Dum-Cl and 2,4,6-TrimethyIbenzyloxymethyl- chloride, Tom-Cl) is given.
Ch. 2 demonstrates that a knowledge of the location of histidine protecting groups has become mandatory, both in peptide synthesis and elsewhere. Two methods) a), nuclear Overhauser enhancement measurements and b), a procedure involving methylation, deprotection and amino-acid analysis are presented, which have allowed the differentiation of ? and ? derivatised histidines.
Ch. 3 reviews the currently available protecting groups for arginine. Using 2-phenylethyIguanidine as a model for arginine, a number of haloacylguanidines and 5,5-disubstituted pyrimidinones wBe synthesised, and this chapter describes their structures, and the potential use of the corresponding reagents in protecting arginine during peptide synthesis.
Ch. 4 describes the synthesis of his tidyIphenylalanylarginine and several variants on this structure. Biological data showing the level of inhibition both of A.C-E- and of Renal ^ndopeptidase by these compounds is presented. The syntheses also provide a further demonstration of the efficacy of the recently introduced benzyloxymethyI, (Bom)protecting group.

Advisor: Jones, J
Characteristics and differentiation of cells involved in bone formation

Postnatal marrow stronal cells culture in vitro contain cells which are osteogenic when implanted in vivo in diffusion chambers, but these have never formed bone in vitro. The purpose of this work was to develop in vitro culture methods to enhance the number and osteoblastic characteristics of rabbit marrow stromal cells and to investigate the expression of alkaline phosphatase as a possible sign of early osteogenic differentiation.
Alkaline phosphatase (AP) is considered a phenotypic marker for the osteoblast line, and culture conditions were adjusted to maximize this enzyme's activity in stromal cells in vitro. Hydrocortisone (1018 to 10-6 M) caused dose-dependent changes in seme characteristics of the adherent cells from marrow: growth rate was higher; AP activity was increased up to 100 times the control level and an extracellular matrix was produced by the cells at confluence. However, there was no difference in the amount of bone formed in diffusion chambers frcm stromal cells grown with or without hydrocortisone.
By culturing marrow explants rather than dissociated cells, growth rate and AP activity of the confluent cells were further increased. Some calcification occurred in these explant cultures but appeared to be non-specific. When explants were cultured on collagen lattices, much larger areas of calcification occurred in association with AP-positive stromal cells. Migrating out of the lattice onto the culture flask were cells with high AP activity and low proliferative potential.
The degree of inhibition by hcmoarganine and phenylalanine, heat lability and electrqphoretic mobility of the AP activity in crude extracts of cultured marrow cells, bone, kidney, liver, intestine, spleen, thymus, lung and brain were compared. AP in bone, stromal cells, spleen and lung were indistinguishable using these criteria. AP from other tissues each had unique characteristics.
Monoclonal antibodies to AP extracted frcm bone were produced. These reacted with AP on the surface of a subpopulation of marrow stromal cells, which can be isolated using the fluorescence-activated cell sorter. The antibodies will also be useful for AP staining at the light and electron microscope levels.
In conclusion, AP present on the surface of some strcmal cells has properties of the bone isoenzyme, although this AP form may not be tissue-specific. AP activity in cultured stromal cells is increased in the presence of hydrocortisone. Monoclonal antibodies can be used to isolate AP+ stromal cells for further investigation of their osteogenicity.

Advisor: Triffitt, J
Measuring neutrino oscillation parameters using vμ disappearance in MINOS

MINOS is a long-baseline neutrino oscillation experiment. It consists of two large steel-scintillator tracking calorimeters. The near detector is situated at Fermilab, close to the production point of the NuMI muon-neutrino beam. The far detector is 735 km away, 716 m underground in the Soudan mine, Northern Minnesota.
The primary purpose of the MINOS experiment is to make precise measurements of the "atmospheric" neutrino oscillation parameters (Δm2atm and sin22θatm). The oscillation signal consists of an energy-dependent deficit of vμ interactions in the far detector. The near detector is used to characterize the properties of the beam before oscillations develop. The two-detector design allows many potential sources of systematic error in the far detector to be mitigated by the near detector observations.
This thesis describes the details of the vμ-disappearance analysis, and presents a new technique to estimate the hadronic energy of neutrino interactions. This estimator achieves a significant improvement in the energy resolution of the neutrino spectrum, and in the sensitivity of the neutrino oscillation fit. The systematic uncertainty on the hadronic energy scale was re-evaluated and found to be comparable to that of the energy estimator previously in use.
The best-fit oscillation parameters of the vμ-disappearance analysis, incorporating this new estimator were: Δm2 = 2.32+0.12-0.08 x 10-3eV2 sin22θ > 0.90 (90% C.L.). A similar analysis, using data from a period of running where the NuMI beam was operated in a configuration producing a predominantly ̅vμ beam, yielded somewhat different best-fit parameters Δ̅m2 = (3.36+0.46-0.40 (stat.}) &pm; 0.06(syst.)) x 10-3eV2, sin22̅θ =0.86+0.11-0.12(stat.)&pm; 0.01(syst.). The tension between these results is intriguing, and additional antineutrino data is currently being taken in order to further investigate this apparent discrepancy.

Keywords: neutrino
minos
Advisor: Barr, G
Chaucerian metapoetics and the philosophy of poetry

This thesis places Chaucer within the tradition of philosophical poetry that begins in Plato and extends through classical and medieval Latin culture. In this Platonic tradition, poetry is a self-reflexive epistemological practice that interrogates the conditions of art in general. As such, poetry as metapoetics takes itself as its own object of inquiry in order to reinforce and generate its own definitions without regard to extrinsic considerations. It attempts to create a poetic-knowledge proper instead of one that is dependant on other modes for meaning. The particular manner in which this is expressed is according to the idea of the loss of the Golden Age. In the Augustinian context of Chaucer’s poetry, language, in its literal and historical signifying functions is an effect of the noetic fall and a deformation of an earlier symbolism. The Chaucerian poems this thesis considers concern themselves with the solution to a historical literary lament for language’s fall, a solution that suggests that the instability in language can be overcome with reference to what has been lost in language. The chapters are organized to reflect the medieval Neoplatonic ascensus. The first chapter concerns the Pardoner’s Old Man and his relationship to the literary history of Tithonus in which the renewing of youth is ironically promoted in order to perpetually delay eternity and make the current world co-eternal to the coming world. In the Miller’s Tale, more aggressive narrative strategies deploy the machinery of atheism in order to make a god-less universe the sufficient grounds for the transformation of a fallen and contingent world into the only world whatsoever. The Manciple’s Tale’s opposite strategy leaves the world intact in its current state and instead makes divine beings human. Phoebus expatriates to earth and attempts to co-mingle it with heaven in order to unify art and history into a single monistic experience. Finally, the Nun’s Priest’s Tale acts as ars poetica for the entire Chaucerian Performance and undercuts the naturalistic strategies of the first three poems by a long experiment in the philosophical conflict between art and history. By imagining art and history as epistemologically antagonistic it attempts to subdue in a definitive manner poetic strategies that would imagine human history as the necessary knowledge-condition for poetic language.

Keywords: Miller's Tale
Nun's Priest's Tale
historicism
Plato
Canterbury Tales
Ovid
philosophy
Neoplatonism
Pardoner's Tale
Manciple's Tale
metaphor
Geoffrey Chaucer
metapoetics
Advisor: Gillespie, V
The cytoarchitecture of the human anterior cingulate cortex and its involvement in mood disorder

The biological mechanisms proposed to underlie primary mood disorder do not usually include a neuropathological component. Over recent years, a significant imaging literature attests to structural abnormalities in various brain regions in mood disorder, and has encouraged neuropathological investigations. Although the neuropathological understanding of mood disorder is still rudimentary, structural correlates have begun to emerge. The studies described in this thesis investigate the neuropathology of the anterior cingulate cortex in mood disorder.
The anterior cingulate cortex is extremely diverse and complex, particularly in respect to its cytoarchitecture and functional organisation. These details are important when considering the precise localisation and clinical correlates of the neuropathological changes of this region in disease. Accordingly, I performed a detailed analysis of the cytoarchitecture of the human anterior cingulate cortex, as a prelude to investigations of this region in mood disorder. I measured several morphometric parameters within different anatomical levels and both hemispheres of the anterior cingulate cortex. Overall I found a clear distinction in the cellular composition of the supragenual and subgenual regions of the anterior cingulate cortex. The subgenual region demonstrated a lower glial density and smaller neurons in comparison to the supragenual region. A modest difference in neuronal density was also observed, with a higher density in the deep layers of the subgenual cortex compared to the deep layers of the supragenual cortex. Total cortical depth was also thinner in the subgenual region. This work may have important implications for the interpretation of imaging and pathological data in mood disorder.
To assess the cytoarchitecture of this brain region in mood disorder, I examined several morphometric indices in addition to various parameters of gene expression in post mortem brains. I found a range of cytoarchitectural abnormalities in the supragenual anterior cingulate cortex in mood disorder. The most prominent change included a reduction in glial density, which was evident in all layers of the cortex. Glial fibrillary acidic protein was also reduced, providing some evidence for astrocyte involvement. Various neuronal changes were also observed in the mood disorder group. These included layer-specific reductions in pyramidal neuron density and a modest change in the density of cairetinin-immunoreactive neurons. I did not find any evidence supporting synaptic pathology in the anterior cingulate cortex in mood disorder.
These findings extend previous evidence of cytoarchitectural alterations in the anterior cingulate cortex in mood disorder and in particular emphasise the prominent involvement of glial cells in the neuropathology of this disease. The origins of the glial (and neuronal) deficits in mood disorder remain to be established, but they are likely to have pathophysiological consequences.

Advisor: Harrison, P
Geogrid reinforcement of granular layers on soft clay: a study at model and full scale

The mechanisms by which a geogrid acts to reinforce a granular layer over a soft clay were investigated with reference to trafficking of unpaved roads. The research involved a programme of physical testing at both model and full scale. Model tests were carried out for monotonic and cyclic loading of a dual footing on to a layer of granular material that was compacted over a consolidated kaolin sample. The tests were made in conditions of plane strain at a quarter scale, and included a scaled geogrid at the base of the granular layer. Measurements of footing load, displacements and photographic observations through a perspex front face to the test box were used to identify the reinforcing actions of the geogrid. A virtual work procedure was adopted in analysis of the results for both unreinforced and reinforced layers. The procedure accounts for lateral restraint of the subgrade and a membrane action in the reinforced tests, and allows a comparison of the cyclic test results with an equivalent monotonic bearing capacity. Load tests were also made on footing plates at full scale, involving a similar arrangement of compacted granular layers over prepared London clay and including a high strength polymer geogrid. Examination of the test results allowed a qualitative assessment of the model performance and the reinforcing mechanisms attributed to the geogrid.

Keywords: unpaved roads
soil reinforcement
Advisor: Milligan, G
Dynamics of nanostructured light emitted diodes

Experimental investigations of the optical properties of GaN nanostructured light emitting diode (LED) arrays are presented. Microphotoluminescence spectroscopy with pulsed and continuous wave lasers was used to probe the carrier dynamics and emission mechanisms of nanorod LED arrays fabricated by a top down etching method. Results show a possible reduction in internal electric field as nanorod diameter decreases. Localisation effects were also observed, affecting the spectral shape of the nanorod emission.
Under two-photon excitation, quantum dot-like sharp spectral peaks in the PL spectra are found to exist in abundance amongst all the nanorod samples. The optical properties of these localised states, which are shown to be associated with the nanorod free-surfaces, are characterised using non-linear and time resolved spectroscopy.
An investigation into spatially resolved single nanorods was also carried out. Single nanorods were isolated, and characterised using pulsed lasers. The etching is shown to increase the carrier decay life-time at extended intervals over several hundred ns. The temporal evolution and excitation power density dependence of the quantum dot-like states are also presented for the first time. The long lived localised states are thought to arise from surface effects, in particular Fermi-surface pinning, causing localisation and spatial separation of carriers.
Additional work on nano-pyramid array LEDs, with quantum wells on semi-polar surfaces is also presented. Optical properties using micro-photoluminescence are compared to cathodoluminescence studies. An uneven distribution of emission wavelengths across the pyramid facet is thought to lead to an emission mechanism involving carriers transferring between multiple spatially localised states.
Finally, experimental techniques and fabrication methods for future work are documented in detail.

Keywords: Gallium nitride
light emitting diodes
dynamics
quantum optoelectronics
photoluminescence
quantum wells
Advisor: Taylor, RA
Synthesis and reactivity of allylic fluorides under transition metal catalysis

In this thesis, C-F bond activation and C-F bond construction under platinum and iridium catalysis is described.
Chapter 1 provides a general introduction on the use of transition metal catalysis for the formation and activation of Csp³-F bonds in organofluorine compounds.
In Chapter 2, an investigation on the reactivity of allylic fluorides, under platinum and palladium catalysed alkylation conditions, is presented. The relative reactivity of fluoride versus other commonly used leaving groups was compared via internal competition experiments. Fluoride showed a different reactivity profile, when subjected to Pt and Pd catalytic systems. Based on the observed reactivity trend, a Pd-catalysed fluorination reaction of allylic alcohol derivatives was successfully developed, within the group.
In Chapter 3, a new iridium catalysed fluorination using branched, E- or Z-linear allylic carbonates is described. The catalyst [Ir(COD)Cl]₂ leads to an unexpected regio- and stereoretentive selectivity, affording fluorinated products not accessible via palladium catalysis. The effect of a fluoride additive on the selectivity of the Ir-catalysed alkylation reaction is also presented. A highly efficient 18F-fluorination variant for this new catalytic transformation is reported.
Chapter 4 gives full experimental procedures and characterisation data for all compounds.

Keywords: organometallic catalysis
fluorine chemistry
Advisor: Gouverneur, V
Tumour-stroma interaction in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is characterised by an abundant desmoplastic reaction driven by pancreatic stellate cells (PSCs). There is accumulating evidence that PSCs influence the malignant phenotype of PDAC. The aim of this study was to analyse the tumour response to radiation treatment in the presence of PSCs and to investigate the cytokine network in the coculture of PSCs and pancreatic cancer cells (PCCs). PSCs were used in coculture with different PCC lines. Clonogenic survival assays of several PCC lines cocultured with PSCs showed decreased radiosensitivity. This effect was abrogated by inhibition of the β1-integrin/FAK signalling pathway. Furthermore, tumour regrowth experiments after irradiation showed that coinjected PSCs were radioprotective for PCCs after single-dose and fractionated irradiation in xenografts. In addition, we examined the expression of 50 proteins in the supernatants of PCCs and PSCs in mono- and coculture conditions. The detected cytokine expression profile of PSCs included many proinflammatory factors. Also, we identified IP-10 as the chemokine with the highest differential upregulation in PSCs by paracrine stimuli from five different PCC lines. Human PDAC with a high stroma component had elevated IP-10 mRNA expression. IP-10 did not stimulate tumour cell growth and migration in our conditions even though several PCCs expressed its cognate receptor CXCR3. Nevertheless, we discovered that in human PDAC samples IP-10 and CXCR3 mRNA levels correlated with the presence of CD3ε, CD4, FoxP3, CTLA4 and CD39 used as surrogate markers for T regulatory cells (Tregs), known to exert an immunosuppressive effect. In conclusion, these data demonstrate that PSCs enhance survival of PCCs to radiation by activating β1-integrin/FAK signalling. Furthermore, the interaction between the tumour stroma in pancreatic cancer may support an immunosuppression by chemoattraction of Tregs following upregulation of IP-10. Further characterisation of the paracrine signalling between PCCs, PSCs and immune cells will improve the understanding of pancreatic cancer biology and could lead to the identification of new targets for multimodal therapy.

Keywords: Stroma
Pancreatic Stellate Cells
Microenvironment
Pancreatic cancer
Advisor: Brunner, T
Comparative approaches to the genetics of human neuropsychiatric disorders

In this thesis, I investigate the genetics of neuropsychiatric disorders by analysing large data sets derived from high-throughput experiments, using novel comparative genomics approaches. In the first project, I explore characteristics of rare, de novo copy number variants identified among autism patients by employing various bioinformatics resources including Mouse Genome Informatics phenotypes, Gene Ontology terms, and protein-protein interactions. I describe how I objectively identified a number of mouse model phenotypes that are significantly associated with autism, and that provide insight into the aetiologies for both copy number deletions and duplications.
In the second project, I investigate the genetics of obsessive-compulsive disorder by resequencing genomic regions of human case-control cohorts and the best spontaneous disease model organisms, namely dogs with canine compulsive disorder, and breed-matched controls. Targeted sequencing experiments yielded a large number of high-quality genetic variants in both humans and dogs. I prioritised variants and genes using case- control comparisons and functional annotations such as types of mutation, evolutionary conservation status and regulatory marks.
In turn, I generated several hypotheses that are experimentally tractable. Replication of these findings in a larger cohort is necessary, although it lies beyond the scope of this thesis. Results from both projects indicate that the analytical frameworks employed in this thesis could be profitably applied to other neuropsychiatric disorders.

Keywords: disease genomics
high-throughput sequencing
copy number variants
computational biology
comparative genomics
Advisor: Ponting, C
Webber, C
Bloodlines, borderlines, shadowlines: forms of belonging in contemporary literature from partition areas

This thesis explores cosmopolitan and humanist literary interventions by Palestinian, Israeli, Indian and Pakistani writers to the rise of ‘ethnically’ defined cultural and political narratives of community. It uses a comparative framework to look at contemporary authors such as Amitav Ghosh, Raja Shehadeh, Kamila Shamsie, Uzma Aslam Khan and David Grossman, who deconstruct the biologically defined border as a repressive literary, cultural and political metaphor in favour of more open-ended categories of identity and community.
I argue that in deconstructing the epistemology of the exclusive boundary through cosmopolitan and humanist philosophies, these international writers demonstrate the impossibility of shedding all borders in their own work. Their ‘borderless’ aesthetic that constantly conjures the border is thus indicative of the interrelated nature of cosmopolitan and sectarian identities in a globalized modernity. Moreover, it is suggestive of the ambivalent relationship between politically-conscious postcolonial texts (which draw political lines) and the emerging field of World literature that is coming to be defined by its ability to appeal to the “universal”.

Keywords: partition
nationhood
Palestine
Israel
community
world literature
Pakistan
India
postcolonial literature
Advisor: Mukherjee, A