CD8+ T Cell Serotype-Cross-Reactivity is a Predominant Feature of Dengue Virus Infections in Humans: A Dissertation

The four serotypes of dengue virus (DENV 1-4) have a significant and growing impact on global health. Dengue disease encompasses a wide range of clinical symptoms, usually presenting as an uncomplicated febrile illness lasting 5-7 days; however, a small percentage of infections are associated with plasma leakage and bleeding tendency (called dengue hemorrhagic fever, DHF), which can result in shock. Epidemiological studies indicate that severe dengue disease most often occurs during secondary heterotypic DENV infection. Additionally, plasma leakage (the hallmark of DHF) coincides with defervescence and viral clearance, suggesting that severe disease arises from the immune response to infection rather than a direct effect of the virus. A number of studies have found increased levels of markers of immune cell activation in patients with DHF compared to patients with the less severe form of disease (DF). These markers include IFNγ, TNFα, soluble CD8, soluble IL-2 receptor, soluble TNF receptor, and CD69, which support a role for T cells in mediating immunopathology. Because of the high homology of DENV 1-4, some degree of serotype-cross-reactivity is seen for most T cell epitopes. A high percentage of DENV-specific T cells recognize multiple DENV serotypes, as demonstrated by peptide-MHC (pMHC) tetramer binding and in vitro functional assays performed on PBMC from subjects vaccinated with an experimental DENV vaccine or naturally-infected subjects with secondary (\u3e1) DENV infection. This thesis sought to address several gaps in the literature, specifically whether T cell responses differ in primary versus secondary (natural) infection. We studied the frequency, phenotype, and function of DENV-specific T cells. We demonstrated substantial serotype-cross-reactivity of antigen-specific T cells generated in response to naturally-acquired primary as well as secondary DENV infection. The frequency of A11-NS3133 epitope-specific T cells during acute infection did not correlate with disease severity. However, the peak frequency occurred earlier in primary infection while the frequency of CD45RA+ T cells declined quicker in secondary infection, suggesting the expansion of DENV-specific memory T cells. DENV-immune T cells exhibited different functional capabilities that were dependent on the particular serotype of infection. Specifically, DENV-1 or -3 stimulation of A11-NS3133 epitope-specific T cell lines resulted in robust function that included IFNγ production, whereas DENV-2 stimulation resulted in limited function that often included MIP-1β but not IFNγ production. These data support a role for T cells in DENV infection and offer new insights into their potential contribution to dengue pathology

The symbolic model for algebra : functions and mechanisms

The symbolic mode of reasoning in algebra, as it emerged during the sixteenth century, can be considered as a form of model-based reasoning. In this paper we will discuss the functions and mechanisms of this model and show how the model relates to its arithmetical basis. We will argue that the symbolic model was made possible by the epistemic justification of the basic operations of algebra as practiced within the abbaco tradition. We will also show that this form of model-based reasoning facilitated the expansion of the number concept from Renaissance interpretations of number to the full notion of algebraic numbers

Analysis of Cell-Mediated Immune Responses in Support of Dengue Vaccine Development Efforts

Dengue vaccine development has made significant strides, but a better understanding of how vaccine-induced immune responses correlate with vaccine efficacy can greatly accelerate development, testing, and deployment as well as ameliorate potential risks and safety concerns. Advances in basic immunology knowledge and techniques have already improved our understanding of cell-mediated immunity of natural dengue virus infection and vaccination. We conclude that the evidence base is adequate to argue for inclusion of assessments of cell-mediated immunity as part of clinical trials of dengue vaccines, although further research to identify useful correlates of protective immunity is needed

Nonlinear directional coupler for polychromatic light

We demonstrate that nonlinear directional coupler with special bending of waveguide axes can be used for all-optical switching of polychromatic light with very broad spectrum covering all visible region. The bandwidth of suggested device is enhanced five times compared to conventional couplers. Our results suggest novel opportunities for creation of all-optical logical gates and switches for polychromatic light with white-light and super-continuum spectrum.Comment: 3 pages, 3 figure

The application of graph theory and percolation analysis for assessing change in the spatial configuration of pond networks

Pond networks support high levels of biodiversity when compared to other freshwater ecosystems such as rivers, lakes and streams. The persistence of species in these small, sometimes ephemeral, aquatic habitats depends on the dispersal of individuals among ponds in the landscape. However, the number of ponds across the landscape is at a historical low as urbanisation and intensified agricultural practices have led to a substantial loss of ponds (nodes in the pond network) over more than a century. Here, we examine the extent and drivers of pond loss in a heavily urbanised landscape (Birmingham, UK) over 105 years and determine how pond loss influences key structural properties of the pond network using graph theoretic approaches. Specifically, we calculated minimum spanning trees (MST) and performed percolation analyses to determine changes in both the spatial configuration and resilience of the pond network through time. Pond numbers declined by 82% between ca1904 and 2009, such that pond density decreased from 7.1 km-2 to 1.3 km-2. The MST analyses revealed increased distance between ponds in the network (i.e. edge length increased) by up to 49% over the 105-year period, indicating that ponds in the modern landscape (2009) were considerably more isolated, with fewer neighbours. This study demonstrates that graph theory has an excellent potential to inform the management of pond networks in order to support ecological communities that are less vulnerable to environmental change