VictorJuiz/thesis huggingface dataset:
Modelling divisive inhibition in the primary visual cortex from optogenetic circuit mapping data
Keywords: Divisive Inhibition
Optogenetics
Vision

Recurrent networks are abundant in the neocortex and are recognised as a means of amplifying feedforward thalamic sensory inputs. However, when operating at high gain, which is necessary for this signal amplification, the standard recurrent network firing rate model suffers from increased reaction times to rapidly changing stimuli. Divisive inhibition has been proposed as a means of bypassing this coupling of system gain and time constant. In my thesis I focus on the importance of inhibition in recurrent networks in visual information processing. This was motivated by a recent study where the presence and absence of translaminar inhibition distinguished cells in the primary visual cortex. I apply several divisive inhibition schemes to an existing recurrent network model of simple and complex cells. The schemes are studied analytically and also simulated to assess how well they can be integrated into this existing model whilst simultaneously solving the coupled system gain and time constant problem. Though each scheme has its benefits, I propose that a mixture of schemes is likely in real physiology.
Nanostructured thin film pseudocapacitive electrodes for enhanced electrochemical energy storage
Keywords: Electrode fabrication
Pseudocapacitor
Supercapacity
Spray deposition

This thesis presents work relating to the fabrication of novel thin film electrodes for energy storage applications, with a focus on low cost, nanostructured transition metal oxides, and electrode manufacture by atomised spray deposition.
Iron oxide (FeOx) nanowires were synthesised hydrothermally and combined with multi-walled carbon nanotubes (MWNT) in sprayed electrodes, which provided the necessary conductivity enhancement for effective energy storage. The spray processing technique allowed for facile control over the relative fraction of MWNTs in the sprayed electrodes. Optimised electrodes were investigated in a range of aqueous electrolytes, and the best energy storage behaviour occurred in Na2SO3 with a maximum capacitance from cyclic voltammetry of 312 Fg-1 at a scan rate of 2 mVs-1. The FeOx/MWNT electrodes were investigated for their suitability as lithium-ion battery anodes and showed reasonable energy storage behaviour.
Nickel oxide (NiO) electrodes were manufactured by hydrothermal synthesis and annealing followed atomised spray deposition. The performance of the NiO electrodes was enhanced though combination with aqueous graphene suspensions, produced in-house by ultrasonic exfoliation of graphite. The processing route used to combine the nanomaterials was considered and a co-synthesis route resulted in the best performing electrodes. Different substrates were investigated, as the most commonly used Ni-foam substrate reacted with the basic electrolytes necessary for electrochemical activity of NiO.
NiO/graphene electrodes showed charge/discharge capacitances of up to 571 Fg-1 at a current density of 10 Ag-1, which was maintained at over 300 F/g at a very high current density of 100 Ag-1.
Asymmetric supercapacitor devices were constructed using various combinations of FeOx, NiO, and commercial carbon black electrodes to extend the operating potential window beyond the ~1.23 V limit of symmetric aqueous-electrolyte devices. Power densities of over 20 kWkg-1 were achieved for an FeOx/MWNT-carbon device, which was comparable with current commercial carbon-only supercapacitors.
Characterisation of T cells induced by candidate conserved region HIV-1 vaccines in healthy HIV-1/2 negative volunteers
Keywords: HIVconsv
HIV Vaccines
conserved regions

HIV-1 has claimed the lives of millions of people globally and continues to spread despite development of highly active antiretroviral therapy. In 2013, 2.1 million new infections occurred and over 35 million people were living with HIV-1 infection. A prophylactic HIV-1 vaccine that can prevent infection or reduce viremia and subsequent transmission will always be an important part of the solution to bring this epidemic under control.
In this thesis, the first HIV-1 vaccine candidate to focus on conserved regions of the virus (HIVconsv) was assessed in a phase I clinical trial conducted in healthy HIV-1/2 negative volunteers in Oxford. The HIVconsv T-cell immunogen was delivered using three leading vaccine modalities (DNA (D), modified vaccinia virus Ankara (M) and chimpanzee adenovirus serotype 63 (C)), in several novel heterologous prime-boost regimens.
The frequency of T cells elicited through HIVconsv vaccination in the CM and DDDCM regimens surpassed that of previous HIV-1 cell-mediated vaccines. A large proportion of these T cells produced multiple cytokines and proliferated in response to recall peptides. The breadth of T-cell responses were also greater than the non-efficacious STEP study vaccine, with an average of 10 T-cell epitopes per vaccine recipient recognised across CM and DDDCM regimens. In vitro HIV-1 control mediated by CD8&plus; T cells was demonstrated for all vaccinees receiving the CM regimen, mainly against clade A (U455) and clade B (IIIB) isolates. Two vaccinees, demonstrated superior control of 6/8 and 7/8 viruses from the panel. The CM regimen induced significantly higher magnitudes of viral inhibition compared to the DDDCM or DDDMC regimens, with this regimen showing potential to overcome the disadvantage for subjects of carrying non-protective HLA alleles.
Investigation of T-cell specificities revealed that the frequencies of T cells specific for conserved Gag but more so Pol regions significantly correlated with in vitro virus control. Direct examination of peptide expanded T-cell lines showed that all Pol pool- and limited Gag pool-specific cell lines reduced HIV-1 replication in vitro. In most individuals, targeting multiple HIV-1 epitopes concomitantly resulted in higher levels of virus inhibition than targeting a single viral epitope and two T-cell specificities showed enhanced control of HIV-1; the first within Pol (TAFTIPSI) and second from Gag (TERQANFL). These data support further development of the conserved region strategy for T-cell vaccines against HIV-1.
Measuring neutrino oscillation parameters using vμ disappearance in MINOS
Keywords: neutrino
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.
Chaucerian metapoetics and the philosophy of poetry
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

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.
Geogrid reinforcement of granular layers on soft clay: a study at model and full scale
Keywords: unpaved roads
soil reinforcement

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.
Dynamics of nanostructured light emitted diodes
Keywords: Gallium nitride
light emitting diodes
dynamics
quantum optoelectronics
photoluminescence
quantum wells

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.
Synthesis and reactivity of allylic fluorides under transition metal catalysis
Keywords: organometallic catalysis
fluorine chemistry

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.
Tumour-stroma interaction in pancreatic cancer
Keywords: Stroma
Pancreatic Stellate Cells
Microenvironment
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.
Comparative approaches to the genetics of human neuropsychiatric disorders
Keywords: disease genomics
high-throughput sequencing
copy number variants
computational biology
comparative genomics

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.
Bloodlines, borderlines, shadowlines: forms of belonging in contemporary literature from partition areas
Keywords: partition
nationhood
Palestine
Israel
community
world literature
Pakistan
India
postcolonial literature

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”.
Targeting protein-protein interactions for cancer therapy
Keywords: PPI
cancer
protein-protein interaction
CDK2/cyclin

Protein-protein interactions (PPIs) are key drug targets and recent breakthroughs in this area are providing insight into the types of molecules needed to selectively and potently inhibit a target traditionally seen as untractable. The rules that have been used to design classic substratecompetitive drugs (for example Lipinski's rule of five) may not apply in this new field in the same way. Here I present work performed in three systems that are well-validated drug targets for oncogenesis: the CDK2/cyclin A complex, the PLK1 Polobox domain and MDM2. In each case the site of the protein-protein interaction is defined and understood and the rationale for pharmaceutical intervention is clear. I use these as a model system to evaluate the characteristics of drugs that target protein-protein interaction sites and present work on the development of inhibitors as potential leads for subsequent drug development. In Chapter 1 I introduce the problems, challenges and rewards of PPI drug development; in Chapter 2 I present co-crystal structures of MDM2 with isoindolinone inhibitors; in Chapter 3 I detail attempts to co-crystallise the Plk1 Polobox with inhibitors and screen potential inhibitors; in Chapter 4 I present the results of screening to identify inhibitors of Cyclin A recruitment; and in Chapter 5 I discuss other strategies for inhibition of the CDK2/cyclin A complex, including results with a covalent inhibitor. Through these projects I have been able to demonstrate the wide applicability of the PPI inhibition approach, identify key features of drugs able to inhibit PPIs and contribute to drug design in each system.