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Despite the availability of live attenuated measles virus vaccines, a large number of measles-associated deaths occur among infants in developing countries during the "window of susceptibility" (age 4-9 months). During this period declining maternal antibody titers are no longer protective against wild-type measles virus (MV) and impede successful immunization with the live attenuated vaccines. Therefore, the development of a safe vaccine that would induce protective immunity in the presence of maternally derived MV-specific antibodies in young infants and would close the "window of susceptibility" is desirable. Since adenoviruses have been shown as suitable vaccine candidates capable of eliciting potent protection against mucosal infectious diseases, the ability of an adenovirus-vectored anti-measles vaccine to elicit robust immune responses against MV was assessed in this study. Mice immunized intramuscularly or intranasally with a combination of human adenovirus serotype 5 (Ad5) recombinants expressing MV hemagglutinin (H) and fusion (F) glycoproteins developed MV-specific neutralizing antibody titers similar for both routes of immunization. However, intramuscular immunization of mice with Ad5 recombinants resulted in induction of a predominant T helper type (Th1) immune response, whereas intranasal immunization induced a balanced Th1/Th2 immune response. Furthermore, intranasal immunization resulted in increased titers of MV-specific immunoglobulin A (IgA) in lungs in comparison to intramuscularly immunized animals. The ability of the Ad5 recombinants to induce protective immune responses in cotton rats by different routes of administration was also evaluated. Cotton rats that received a single dose of the Ad5 recombinants intramuscularly or intranasally experienced a rise in MV-specific neutralizing antibody titers and reduction of the viral RNA load in the lung tissue after intranasal MV challenge. In addition, the largest reduction in viral replication was observed in the group of cotton rats inoculated with the Ad5 recombinants intranasally. Based on these observations, the Ad5-based vaccine appears to be a suitable candidate against measles. Furthermore, a capability of purified globular head domain of MV H protein produced in a human cell line to induce MV-specific immune responses in mice was tested. Subcutaneous immunization of mice with the recombinant protein alone resulted in both humoral and cell-mediated immunity, characterized by the production of MV-specific serum IgG and neutralizing antibodies, as well as interferon-gamma and interleukin 5 (IL-5) production by in vitro restimulated splenocytes. The former responses were further enhanced by formulation of the protein with aluminium hydroxide. However, very low numbers of INF-gamma secreting cells and low levels of IgG2a in the serum suggested a Th2 immune response. Novel adjuvants (Th1-directing), as well as MV F protein should be considered for the inclusion into the vaccine formulations to induce more balanced Th1/Th2 immune responses against measles.

Despite the availability of live attenuated measles virus vaccines, a large number of measles-associated deaths occur among infants in developing countries during the "window of susceptibility" (age 4-9 months). During this period declining maternal antibody titers are no longer protective against wild-type measles virus (MV) and impede successful immunization with the live attenuated vaccines. Therefore, the development of a safe vaccine that would induce protective immunity in the presence of maternally derived MV-specific antibodies in young infants and would close the "window of susceptibility" is desirable. Since adenoviruses have been shown as suitable vaccine candidates capable of eliciting potent protection against mucosal infectious diseases, the ability of an adenovirus-vectored anti-measles vaccine to elicit robust immune responses against MV was assessed in this study. Mice immunized intramuscularly or intranasally with a combination of human adenovirus serotype 5 (Ad5) recombinants expressing MV hemagglutinin (H) and fusion (F) glycoproteins developed MV-specific neutralizing antibody titers similar for both routes of immunization. However, intramuscular immunization of mice with Ad5 recombinants resulted in induction of a predominant T helper type (Th1) immune response, whereas intranasal immunization induced a balanced Th1/Th2 immune response. Furthermore, intranasal immunization resulted in increased titers of MV-specific immunoglobulin A (IgA) in lungs in comparison to intramuscularly immunized animals. The ability of the Ad5 recombinants to induce protective immune responses in cotton rats by different routes of administration was also evaluated. Cotton rats that received a single dose of the Ad5 recombinants intramuscularly or intranasally experienced a rise in MV-specific neutralizing antibody titers and reduction of the viral RNA load in the lung tissue after intranasal MV challenge. In addition, the largest reduction in viral replication was observed in the group of cotton rats inoculated with the Ad5 recombinants intranasally. Based on these observations, the Ad5-based vaccine appears to be a suitable candidate against measles. Furthermore, a capability of purified globular head domain of MV H protein produced in a human cell line to induce MV-specific immune responses in mice was tested. Subcutaneous immunization of mice with the recombinant protein alone resulted in both humoral and cell-mediated immunity, characterized by the production of MV-specific serum IgG and neutralizing antibodies, as well as interferon-gamma and interleukin 5 (IL-5) production by in vitro restimulated splenocytes. The former responses were further enhanced by formulation of the protein with aluminium hydroxide. However, very low numbers of INF-gamma secreting cells and low levels of IgG2a in the serum suggested a Th2 immune response. Novel adjuvants (Th1-directing), as well as MV F protein should be considered for the inclusion into the vaccine formulations to induce more balanced Th1/Th2 immune responses against measles.

Yes / We report the encapsulation of highly hydrophobic 16-electron organometallic ruthenium and osmium carborane complexes [Ru/Os(p-cymene)(1,2-dicarba-closo-dodecarborane-1,2-dithiolate)] (1 and 2) in Pluronic® triblock copolymer P123 core–shell micelles. The spherical nanoparticles RuMs and OsMs, dispersed in water, were characterized by dynamic light scattering (DLS), cryogenic transmission electron microscopy (cryo-TEM), and synchrotron small-angle X-ray scattering (SAXS; diameter ca. 15 and 19 nm, respectively). Complexes 1 and 2 were highly active towards A2780 human ovarian cancer cells (IC50 0.17 and 2.50 μM, respectively) and the encapsulated complexes, as RuMs and OsMs nanoparticles, were less potent (IC50 6.69 μM and 117.5 μM, respectively), but more selective towards cancer cells compared to normal cells. / We thank the Leverhulme Trust (Early Career Fellowship no. ECF-2013-414 to NPEB), the University of Warwick (Grant no. RDF 2013-14 to NPEB), the Swiss National Science Foundation (Grant no. PA00P2_145308 to NPEB and PBNEP2_142949 to APB), the ERC (Grant no. 247450 to PJS), EPSRC (EP/G004897/ 1 to APB, and EP/F034210/1 to PJS), Institute of Advanced Study (IAS) – University of Warwick (Fellowship to JJSB), and Science City (AWM/ERDF) for support. We thank the Wellcome Trust (055663/Z/98/Z) for funding to the Electron Microscopy Facility, School of Life Sciences, University of Warwick.

This work develops theoretical and applied results for variational convex analysis. First we present the basic tools of analysis necessary to develop the core theory and applications. New results concerning duality principles for systems originally modeled by non-linear differential equations are shown in chapters 9 to 17. A key aspect of this work is that although the original problems are non-linear with corresponding non-convex variational formulations, the dual formulations obtained are almost always concave and amenable to numerical computations. When the primal problem has no solution in the classical sense, the solution of dual problem is a weak limit of minimizing sequences, and the evaluation of such average behavior is important in many practical applications. Among the results we highlight the dual formulations for micro-magnetism, phase transition models, composites in elasticity and conductivity and others. To summarize, in the present work we introduce convex analysis as an interesting alternative approach for the understanding and computation of some important problems in the modern calculus of variations. / Ph. D.