Vaccinia virus protein B14, an inhibitor of NF-κB activation, and its counterpart in MVA

Vaccinia virus (VACV) encodes multiple proteins which modulate NF-[kappa]B activation to evade the host immune response. One example is B14, a virulence factor that reduces NF-[kappa]B activation via interaction with IKK [Beta]. B14 has orthologues in many VACV strains, including modified virus Ankara (MVA), which lacks many of the immunomodulators present in other VACV strains. Here, the MVA counterpart of B14, protein 183, was characterised. 183R was both removed from MVA and inserted into the B14R locus of a VACV strain Western Reserve (WR) lacking B14R, but in each case there was no change of phenotype. Protein 183 shares 95 % amino acid identity with B14 but, unlike B14, was unstable in eukaryotic cells, unless protein degradation was inhibited. Protein 183 did not inhibit NF-[kappa] B activation in response to cytokine stimulation, as does B14, nor did it restore the virulence phenotype of WR lacking B14R back to wild type. Therefore, the mutations incurred by 183 during the derivation of MVA have rendered the protein non-functional. However, other MVA immunomodulators remain to be characterised and this thesis describes a bacterial artificial chromosome (BAC) system that may facilitate the improvement of MVA in its role as a vaccine vector. To further characterise VACV modulation of NF-[kappa] B, a VACV WR strain was constructed lacking B14 and another VACV modulator of NF-[kappa]B, WR A49. Initial characterisation showed no change with this mutant virus in replication or spread. The effect of the B14 on NF-[kappa]B was further characterised by studying the B14-IKK [Beta] interaction using IKK[Beta] and B14 mutants. Residues 300 to 480 of IKK [Beta] were shown to be required for the interaction and a mutant encompassing this region co-purified to a degree with B14 when expressed in E. coli. In addition, mutagenesis showed that B14 residue F130 is required for the interaction of the two proteins

A CBPR Partnership Increases HIV Testing Among Men Who Have Sex With Men (MSM): Outcome Findings From a Pilot Test of the CyBER/testing Internet Intervention

The Internet has emerged as an important tool for the delivery of health promotion and disease prevention interventions. Our community-based participatory research (CBPR) partnership developed and piloted CyBER/testing, a culturally congruent intervention designed to promote HIV testing among men who have sex with men (MSM) within existing Internet chat rooms. Using a quasi-experimental, single-group study design, cross-sectional data were collected from chat room participants, known as “chatters,” at pretest (n=346) and post-test (n=315). Extant profile data also were collected to describe the demographics of the online population. The intervention significantly increased self-reported HIV testing among chatters overall, increasing rates from 44.5% at pretest to nearly 60% at post-test (p<.001). Furthermore, chatters who reported having both male and female sexual partners had nearly 6 times the odds of reporting HIV testing at post-test. Findings suggest that chat room-based HIV testing intervention may increase testing among MSM who may be difficult to reach in traditional physical spaces

The Capital Structure and Governance of a Mortgage Securitization Utility

We explore the capital structure and governance of a mortgage-insuring securitization utility operating with government reinsurance for systemic or 'tail' risk. The structure we propose for the replacement of the GSEs focuses on aligning incentives for appropriate pricing and transfer of mortgage risks across the private sector and between the private sector and the government. We present the justification and mechanics of a vintage-based capital structure, and assess the components of the mortgage guarantee fee, whose size we find is most sensitive to the required capital ratio and the expected return on that capital. We discuss the implications of selling off some of the utility's mortgage credit risk to the capital markets and how the informational value of such transactions may vary with the level of risk transfer. Finally, we explore how mutualization could address incentive misalignments arising out of securitization and government insurance, as well as how the governance structure for such a financial market utility could be designed

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Vaccinia virus protein B14, an inhibitor of NF-κB activation, and its counterpart in MVA

Vaccinia virus (VACV) encodes multiple proteins which modulate NF-[kappa]B activation to evade the host immune response. One example is B14, a virulence factor that reduces NF-[kappa]B activation via interaction with IKK [Beta]. B14 has orthologues in many VACV strains, including modified virus Ankara (MVA), which lacks many of the immunomodulators present in other VACV strains. Here, the MVA counterpart of B14, protein 183, was characterised. 183R was both removed from MVA and inserted into the B14R locus of a VACV strain Western Reserve (WR) lacking B14R, but in each case there was no change of phenotype. Protein 183 shares 95 % amino acid identity with B14 but, unlike B14, was unstable in eukaryotic cells, unless protein degradation was inhibited. Protein 183 did not inhibit NF-[kappa] B activation in response to cytokine stimulation, as does B14, nor did it restore the virulence phenotype of WR lacking B14R back to wild type. Therefore, the mutations incurred by 183 during the derivation of MVA have rendered the protein non-functional. However, other MVA immunomodulators remain to be characterised and this thesis describes a bacterial artificial chromosome (BAC) system that may facilitate the improvement of MVA in its role as a vaccine vector. To further characterise VACV modulation of NF-[kappa] B, a VACV WR strain was constructed lacking B14 and another VACV modulator of NF-[kappa]B, WR A49. Initial characterisation showed no change with this mutant virus in replication or spread. The effect of the B14 on NF-[kappa]B was further characterised by studying the B14-IKK [Beta] interaction using IKK[Beta] and B14 mutants. Residues 300 to 480 of IKK [Beta] were shown to be required for the interaction and a mutant encompassing this region co-purified to a degree with B14 when expressed in E. coli. In addition, mutagenesis showed that B14 residue F130 is required for the interaction of the two proteins.EThOS - Electronic Theses Online ServiceGBUnited Kingdo