Project 1: Impaired iNKT generation on deletion of chemokine receptors homing to the thymic medulla and Project 2: The requirement for co-stimulation in generation and homeostasis of conventional and memory-phenotype regulatory T-cells

Project 1: Invariant natural killer T-­cells (iNKT) are a subset of unconventional T-­cells arising from the same pool of CD$^4$+8$^+$ double-­‐positive (DP) precursors as conventional T-­cells, but are distinct in their T-­cell receptor (TCR) specificity -­ recognizing CD1d-­bound glycolipids -­ as well as constitutive expression of memory cell markers and cytokine mRNA. Development of iNKT within the thymus is drastically different in terms of both the molecular requirements, and the transcriptional processes involved. However, like conventional thymocytes, they are known to undergo positive and negative selective processes to screen TCR functionality and auto-­reactivity, albeit on contrasting cell types – DP thymocytes and dendritic cells respectively. Progressive maturational stages are defined by expression of activation and NK-­ cell markers. Conventional thymocytes up-­regulate the chemokine receptors CCR4 and CCR7 post-­positive selection, which control re-localization to the medulla, where they are negatively selected on self-­‐antigens promiscuously expressed by medullary epithelial cells. On deletion of these chemokine receptors, development is unaffected, but auto-­reactive T-­ cells escape deletion, and cause auto-­immunity in the periphery. Our work has demonstrated that deletion of either receptor severely impedes thymic generation of iNKT, although only CCR4 is expressed on developing iNKT, suggesting localization of other CCR7$^+$ cell types with iNKT is vital to their development. Project 2: Natural regulatory T-­cell (nTreg) are a T-­cell subset developed in the thymus which possess the unique capability to actively suppress antigen-­specific CD4 responses in the periphery, which have been shown to be essential in the prevention of auto-­immunity through deletion of their lineage-­defining transcription factor Foxp3. Foxp3$^+$ nTreg possess T-­cell receptors (TCRs) with high auto-reactivity relative to conventional cells, and are believed to require strong TCR-­ligation and co-stimulation during negative selection for the production of CD25$^+$ precursors. More recently, it has been demonstrated that peripheral Treg are a heterogenous population, consisting of death-­prone, as well as highly suppressive effector-­memory subsets, which can be separated on the basis of expression of the activation markers ICOS and CD44. In this study, we have demonstrated ICOS$^+$CD44$^+$ memory Treg to have unique homeostatic requirements from conventional CD4 memory cells, which depend on provision of co-­stimulation by TNF superfamily members CD30L and OX40L for survival. We did however discover a role for OX40 signaling in development of nTreg, as well as establishing redundancy in mTEC expression of the co-stimulatory molecules CD80/86 and ICOSL, the former of which has been identified as a key molecule for generation of both nTreg precursors and ICOS$^{hi}$CD44$^{hi}$ Treg

A Caratheodory theorem for the bidisk via Hilbert space methods

If \ph is an analytic function bounded by 1 on the bidisk \D^2 and \tau\in\tb is a point at which \ph has an angular gradient \nabla\ph(\tau) then \nabla\ph(\la) \to \nabla\ph(\tau) as \la\to\tau nontangentially in \D^2. This is an analog for the bidisk of a classical theorem of Carath\'eodory for the disk. For \ph as above, if \tau\in\tb is such that the $\liminf$ of (1-|\ph(\la)|)/(1-\|\la\|) as \la\to\tau is finite then the directional derivative D_{-\de}\ph(\tau) exists for all appropriate directions \de\in\C^2. Moreover, one can associate with \ph and $\tau$ an analytic function $h$ in the Pick class such that the value of the directional derivative can be expressed in terms of $h$

Operator monotone functions and L\"owner functions of several variables

We prove generalizations of L\"owner's results on matrix monotone functions to several variables. We give a characterization of when a function of $d$ variables is locally monotone on $d$-tuples of commuting self-adjoint $n$-by-$n$ matrices. We prove a generalization to several variables of Nevanlinna's theorem describing analytic functions that map the upper half-plane to itself and satisfy a growth condition. We use this to characterize all rational functions of two variables that are operator monotone

Multivariate characterisation of dual-layered catalysts, reliability and durability of Polymer Electrolyte Membrane Fuel Cells

Hydrogen fuel cells have held out the promise of clean, sustainable power generation for decades, but have failed to deliver on that potential. Inefficiencies in research and development work can be overcome to increase the rate of new knowledge acquisition in this field. A number of medical and engineering disciplines utilise a wide variety of statistical tools in their research to achieve this same end, but there has been little adoption of such statistical approaches within the fuel cell research community. This research undertakes a design of experiments (DoE) approach to the analysis of multiply-covarying (M-ANOVAR) factors by using historic data, and direct experimental work, on a wide variety of polymer electrolyte membrane fuel cells (PEMFCs) cathode gas diffusion media (GDM) and dual layered catalyst structures. This research developed a gradient of polarisation regions' approach; a method for making robust numerical comparisons between large numbers of samples based on polarisation curves, while still measuring the more usual peak power of the PEMFC. The assessment of polarisation gradients was completed in a statistically robust fashion that enabled the creation of regression models of GDMs for multiple input and multiple output data sets. Having established the multivariate method; a set of possibly co-varying factors, a DoE approach was used to assess GDM selection, dual layered catalyst structures and degradation of membrane electrode assembly (MEA) performance over time. Degradation studies monopolise resources to be monopolised for protracted periods. M-ANOVAR allows the addition of other factors in the study, and the total efficiency of the degradation experiment is increased. A 20% reduction in the number of samples to be tested was achieved in the case study presented in this thesis (compared to the usual one factor at a time (OFAT) approach). This research highlights the flexibility and efficiency of DoE approaches to PEMFC degradation experimentation. This research is unique in that it creates catalyst ink formulations where the variation in catalyst loading in each sub-layer of the catalyst layer (CL) was achieved by having a different concentration of the catalyst material on the carbon supports. The final M-ANOVAR analysis indicates a simple average of the individual responses was appropriate for the experiments undertaken. It was shown that low concentration dual layer catalysts on paper GDMs have improved performance compared to paper GDMs with uniform, single layer catalysts: Demonstrating reduced platinum concentrations to achieve equivalent open cell performance. The time to peak power during testing (how long after starting the test it takes to achieve the maximum performance in the cell) was strongly impacted by GDM selection. Furthermore, there was a strong suggestion that previously published results crediting a change in performance due to a single layer, or multi-layered catalyst structures may, in fact, have been due to the selection of GDM used in the experiment instead

Living Things

Living Things is a multi-part, multi-media installation which explores the mutual and cyclical impacts between us, objects, and environment. The work is separated into two parts, or “ecophases,” which form a narrative for the life cycle of the things we are surrounded by. Ecophase 1, exhibited in the artist’s studio. Home. Mutual dependence: Our role breathing life into our belongings through use and care. Their role as points of reference for the way we live. Making sense of what surrounds us; perception of objects altered by association, memory, engagement. Ecophase 2, a site-specific installation taking place outside the building. Outliving human use, past functionality but still there, abandoned and overgrown. Trash gets another chance at life when we pay attention to it—admiring its random and persistent interference with the natural environment as a form of art or as an uneasy reminder of our irresponsible consumption

Comparative genomics of Shiga toxin encoding bacteriophages

Background Stx bacteriophages are responsible for driving the dissemination of Stx toxin genes (stx) across their bacterial host range. Lysogens carrying Stx phages can cause severe, lifethreatening disease and Stx toxin is an integral virulence factor. The Stx-bacteriophage vB_EcoP-24B, commonly referred to as 24B, is capable of multiply infecting a single bacterial host cell at a high frequency, with secondary infection increasing the rate at which subsequent bacteriophage infections can occur. This is biologically unusual, therefore determining the genomic content and context of 24B compared to other lambdoid Stx phages is important to understanding the factors controlling this phenomenon and determining whether they occur in other Stx phages. Results The genome of the Stx2 encoding phage, 24B was sequenced and annotated. The genomic organisation and general features are similar to other sequenced Stx bacteriophages induced from Enterohaemorrhagic Escherichia coli (EHEC), however 24B possesses significant regions of heterogeneity, with implications for phage biology and behaviour. The 24B genome was compared to other sequenced Stx phages and the archetypal lambdoid phage, lambda, using the Circos genome comparison tool and a PCR-based multi-loci comparison system. Conclusions The data support the hypothesis that Stx phages are mosaic, and recombination events between the host, phages and their remnants within the same infected bacterial cell will continue to drive the evolution of Stx phage variants and the subsequent dissemination of shigatoxigenic potentia

Product and other fine structure in polynomial resolutions of mapping spaces

Let Map_T(K,X) denote the mapping space of continuous based functions between two based spaces K and X. If K is a fixed finite complex, Greg Arone has recently given an explicit model for the Goodwillie tower of the functor sending a space X to the suspension spectrum \Sigma^\infty Map_T(K,X). Applying a generalized homology theory h_* to this tower yields a spectral sequence, and this will converge strongly to h_*(Map_T(K,X)) under suitable conditions, e.g. if h_* is connective and X is at least dim K connected. Even when the convergence is more problematic, it appears the spectral sequence can still shed considerable light on h_*(Map_T(K,X)). Similar comments hold when a cohomology theory is applied. In this paper we study how various important natural constructions on mapping spaces induce extra structure on the towers. This leads to useful interesting additional structure in the associated spectral sequences. For example, the diagonal on Map_T(K,X) induces a `diagonal' on the associated tower. After applying any cohomology theory with products h^*, the resulting spectral sequence is then a spectral sequence of differential graded algebras. The product on the E_\infty -term corresponds to the cup product in h^*(Map_T(K,X)) in the usual way, and the product on the E_1-term is described in terms of group theoretic transfers. We use explicit equivariant S-duality maps to show that, when K is the sphere S^n, our constructions at the fiber level have descriptions in terms of the Boardman-Vogt little n-cubes spaces. We are then able to identify, in a computationally useful way, the Goodwillie tower of the functor from spectra to spectra sending a spectrum X to \Sigma ^\infty \Omega ^\infty X.Comment: Published by Algebraic and Geometric Topology at http://www.maths.warwick.ac.uk/agt/AGTVol2/agt-2-28.abs.htm