Approved for public release; distribution in unlimited. / U.S. naval doctrine has been dominated by the Mahanian concept of massing large capital ships for over one hundred years. Yet, it was a Cyclone-class patrol craft, a USCG cutter, and an Australian frigate that pushed up the Khor-Abd-Allah waterway and opened up the port of Umm Qasr, Iraq, during the Second Gulf War. They continue to protect it and the surrounding oil infrastructure from attack from insurgents and terrorists today. With the navy's current interest in transformation, the question arises, is the navy as presently configured well suited for today's threats? This thesis explores the question of how should the navy meet threats to national interests. This is accomplished through historical analysis of an event that is similar to the situation today: The Philippine Insurrection (1899-1902). This episode showcases the shortcomings of the navy's conventional approach to military operations other than war, and the need for change. In today's asymmetric environment, the past provides insight into effective means for handling these types of threats. This thesis concludes that the navy needs to diversify itself to incorporate different ship platforms, platforms that incorporate the utility of old with the technology of new. / Lieutenant, United States Navy

A uveíte autoimune é uma doença inflamatória crônica, caracterizada pela resposta imune a antígenos oculares. É mediada por linfócitos T CD4+ com perfil TH1, e responsável por uma parcela significativa de casos de deficiências visuais e cegueira. Embora efetivos, os tratamentos disponíveis estão associados a efeitos adversos importantes. Logo, a busca de novos alvos terapêuticos mais específicos tem sido o objetivo principal no campo da imunoterapia. Nesse trabalho foi avaliada a eficiência do antagonista seletivo de CD28, mPEG PV1-Fab´(PV1), no tratamento da uveíte autoimune experimental (EAU). Camundongos tratados com PV1 exibiram menores graus de doença quando comparados a controles não tratados. Tal achado foi acompanhado de uma diminuição da ativação de linfócitos T, tanto nos olhos quanto nos órgãos linfoides periféricos desses animais. Mais ainda, o tratamento com PV1 levou a uma diminuição da população de linfócitos T reguladores e de células do tipo TH1. Portanto, concluiu-se que PV1 é eficaz no tratamento da EAU por agir em linfócitos T efetores. / Autoimmune uveitis is a T-cell mediated disease that targets mainly the posterior eye pole. Similar to human uveitis, experimental autoimmune uveitis (EAU) is mostly dependent on T cells with a TH1 phenotype. Although many treatment strategies are available, most of them focus on general immunossuppression, resulting in undesirable side effects. Thus, the development of more specific therapies is the major aim in the field of immunotherapy. Here we evaluated the efficacy of mPEG PV-1-Fab´ (PV1), a specific CD28 antagonist, in the treatment of EAU. Our results indicate that PV1 blocks T cell activation by decreasing expression of different costimulatory molecules. Furthermore, PV1 treatment led to a decrease of Treg cell population in peripheral lymphoid organs. Also, IFN-g production by CD4+ cells and TH1 lymphocytes population were decreased. Altogether, our results raise this CD28 blockade strategy as a potential tool for the treatment of autoimmune disorders in the eye, and indicate that mPEG PV1-Fab acts mainly on IFN-g production and TH1 polarization.

Neste trabalho é apresentado o cálculo, pelo grupo de renormalização numérico, da condutância AC através de uma nanoestrutura acoplada a gases eletrônicos, a baixa temperatura e no regime de resposta linear. Este sistema apresenta a competição entre dois efeitos: blo¬queio Coulombiano e efeito Kondo. Nosso modelo considera gases eletrônicos unidimensionais que são unidos pelas extremidades para formar um anel, no qual a corrente é induzida por um fluxo magnético oscilante com freqüência . Nós partimos de um modelo tight-binding de vizinhos mais próximos para os gases eletrônicos e, deste modo, o potencial vetor é facilmente incorporado ao Hamiltoniano por condições de contorno torsionais. Uma barreira de potencial entre os gases eletrônicos e a nanoestrutura é simulada em termos de uma taxa de tunelamento entre a nanoestrutura e os sítios adjacentes menor que aquela entre entre sítios vizinhos no anel. A capacitância da nanoestrutura é pequena, o que implica que nós podemos considerar mudanças no número de elétrons dentro da mesma por apenas uma unidade. Como conseqüência, o Hamiltoniano é mapeado no Hamiltoniano de Anderson com correlação U entre os elétrons. Uma voltagem de gate controla a energia da impureza (da nanoestrutura), 0. Plotada como função de , a condutância mostra dois picos característicos do bloqueio Coulombiano, em freqüências correspondentes às energias para adicionar um elétron à nanoestrutura e para remover um elétron da nanoestrutura respectivamente. No regime Kondo, 0 > 0 > -U (ou seja, para voltagens de gate tais que a nanoestrutura isolada teria estado fundamental com degenerescência de spin), um pico (Kondo) adicional aparece próximo à = 0. Plotada como função de Vg, a condutância DC mostra um largo pico no regime Kondo, caindo rapidamente a zero para voltagens resultando em um estado fundamental não degenerado para a nanoestrutura isolada. Uma relação entre a condutância e a densidade espectral do nível da impureza é obtida e utilizada para interpretar os resultados numéricos. / In this work a renormalization-group calculation of the low-temperature AC conductance in the linear response regime through a nanostructure coupled to metallic leads is presented. This system shows a competition between two effects: the Coulomb blockade and the Kon¬do effect. Our model considers one-dimensional leads which are connected to form a ring, in which a current is induced by a magnetic flux oscillating at the frequency . We start from a nearest-neighbor tight-binding model for the leads and in this way the potential vector is easily incorporated in the model Hamiltonian by twisting boundary conditions. A potential barrier between the leads and the nanostructure is simulated in terms of a tunneling rate between the nanostructure and the adjacent sites in the leads, which is smaller than the one between neighbors sites in the leads. The capacity of the nanostructure is small, which implies that substantial energy changes are associated with each electron transfered to the nanostructure. As a consequence, the model Hamiltonian maps onto the spin-degenerate Anderson Hamiltoni¬an with correlation U between the electrons. A gate voltage Vg controls the impurity (i.e., nanostructure) energy 0. Plotted as a function of , the conductivity shows two Coulomb-blockade peaks, at the energy needed to add an electron to and to remove an electron from the nanostructure, respectively. In the Kondo regime 0 > 0 > -U (i.e., for gate voltages such that the isolated nanostructure would have a spin-degeneration ground state), an addition (Kondo) peak appears near = 0. Plotted as functions of Vg, the static conductivity shows a broad peak in the Kondo regime and drops rapidly to zero for voltages resulting in a non-degenerate nanostructure ground state. A relation between the conductance and the spectral density of the impurity is obtained and used to interpret the numerical results.

Le CTLA4 permet de maintenir la tolérance du soi et prévient le développement d’auto-immunités. Contenu au sein de vésicules intra-cytoplasmiques des lymphocytes T au repos, le CTLA4 est exprimé à la membrane plasmique suite à l’activation du TCR, on le qualifie de rétrocontrôle inhibiteur du système immunitaire (ICB). L’anticorps bloquant le CTLA4, l’ipilimumab induit un contrôle immunitaire à long terme chez une fraction de patients atteints de mélanomes métastatiques. Deux études cliniques de phase III ont conduit à son autorisation de mise sur le marché dans le traitement du mélanome métastatique par la FDA et l’EMA en 2011. Cependant le blocage du CTLA4 est souvent associé au développement d’effets indésirables liés à l’immunité, irAEs, majoritairement au niveau de la peau et de l’intestin, deux sites colonisés par la flore microbienne. Afin de continuer le développement des ICB et des combinaisons de traitements, de nombreux efforts visent à découpler l’efficacité anti-tumorale de la toxicité associée à l’anti-CTLA4. Bien que la stimulation du système immunitaire soit responsable des effets thérapeutiques de l’anti-CTLA4, aucun biomarqueur immunologique d’efficacité n’a été décrit. Dans notre première étude nous avons étudié le mécanisme d’action de l’anti-CTLA4 et nous avons décrit un rôle de l’IL-2 et de ses récepteurs dans l’activité anti-tumorale de l’anticorps. Nous avons également décrit la fraction soluble du récepteur à l’IL-2, le sCD25 comme un biomarqueur potentiel de résistance au traitement. Une concentration élevée de sCD25 dans le sérum des patients atteints de mélanome prédit la résistance à l’ipilimumab. Dans notre second projet, nous avons révélé le rôle du microbiote intestinale et particulièrement de bactéries Gram négatives, des Bacteroides, dans l’efficacité anti-tumorale de l’anti-CTLA4. L’absence d’efficacité du blocage du CTLA4 chez les animaux dépourvus de flore intestinale peut être rétablie par l’administration de Bacteroides fragilis, ou bien de DC, ou encore de lymphocytes T spécifiques de B. fragilis, sans déclencher de colites. Ces travaux suggèrent de nouvelles stratégies thérapeutiques pour espérer améliorer la balance bénéfice / toxicité / coût de l’ipilimumab. / CTLA4, cytotoxic T lymphocyte antigen-4, which is present in the intracytoplasmic vesicles of resting T cells, is upregulated at the surface of activated T cells where it maintains self-tolerance and prevents autoimmunity. The CTLA4-blocking antibody, ipilimumab, induces immune-mediated long term control of metastatic melanoma in a fraction of patients, leading to its approval by the US Food and Drug Administration (FDA) and the European Medical Agency (EMA) in 2011 for the treatment of advanced metastatic melanoma. However, blockade of CTLA4 by ipilimumab often results in immune-related adverse events (irAEs) at sites that are exposed to commensal flora, namely the gut and the skin. Uncoupling efficacy from toxicity is a challenge for the development of immune checkpoint blockers and therapeutic combinations. Although ipilimumab undoubtedly exerts its therapeutic effects via immunostimulation, relevant immune biomarkers that predict treatment efficiency remain elusive. Firstly, we unravel a role for IL-2 and IL-2 receptors in the anticancer activity of CTLA-4 blockade. Importantly, our study provides an immunologically relevant biomarker, elevated serum sCD25, which predicts resistance to CTLA-4 blockade in patients with melanoma. Secondly, we show that the antitumor effects of CTLA4 blockade depend upon intestinal Gram-negative bacteria, mostly Bacteroides species. These bacteria accumulate at the bottom of the intestinal crypts and elicit an IL-12-dependent Th1 immune response specific for distinct Bacteroides species, both in tumor bearing mice and in cancer patients. CTLA4 blockade lost its anticancer efficacy in antibiotic-treated or germ-free mice. This defect could be overcome by oral administration of Bacteroides fragilis (Bf), immunization with Bf polysaccharides, or adoptive transfer of Bf-specific T cells, all of which in the absence of colitis. Our study unravels the key role of Bacteroides in the immunostimulatory effects of CTLA4 blockade, suggesting novel strategies for safely broadening its clinical use

No description available.

No description available.

To study transport properties in single InAs nanowires (NW) with etched constrictions, a bunch of back-gated single InAs NW devices were made. The standard device contained a NW section with an etched constriction, placed between two pre-patterned side-gates. For comparison, devices either without etched constriction or without side-gates were also fabricated. Transport measurement results of three devices were presented and discussed. The device without side-gates exhibited Coulomb blockade due to electron tunneling through double quantum dots (QDs). The device without the etched constriction displayed conductance quantization. The standard device showed both Coulomb blockade (due to electron tunneling through either multiple QDs or single QD) and Fabry-Perot conductance oscillation at different gate bias regime. A 3-D electrostatic and 2-D eigenvalue coupled simulation was conducted to explain the observed conductance quantization. This model suggests that the nonuniform potential distribution in a thick NW dramatically modifies the confinement energies in the NW.

To study transport properties in single InAs nanowires (NW) with etched constrictions, a bunch of back-gated single InAs NW devices were made. The standard device contained a NW section with an etched constriction, placed between two pre-patterned side-gates. For comparison, devices either without etched constriction or without side-gates were also fabricated. Transport measurement results of three devices were presented and discussed. The device without side-gates exhibited Coulomb blockade due to electron tunneling through double quantum dots (QDs). The device without the etched constriction displayed conductance quantization. The standard device showed both Coulomb blockade (due to electron tunneling through either multiple QDs or single QD) and Fabry-Perot conductance oscillation at different gate bias regime. A 3-D electrostatic and 2-D eigenvalue coupled simulation was conducted to explain the observed conductance quantization. This model suggests that the nonuniform potential distribution in a thick NW dramatically modifies the confinement energies in the NW.

Magister Philosophiae - MPhil

xvi, 116 p. : ill. (some col.) A print copy of this thesis is available through the UO Libraries. Search the library catalog for the location and call number. / This dissertation focuses on low-dimensional electron transport phenomena in devices ranging from semiconductor electron 'billiards' to semimetal atomic clusters to gold nanoparticles. In each material system, the goal of this research is to understand how carrier transport occurs when many elements act in concert. In the semiconductor electron billiards, magnetoconductance fluctuations, the result of electron quantum interference within the device, are used as a probe of electron transport through arrays of one, two, and three connected billiards. By combining two established analysis techniques, this research demonstrates a novel method for determining the quantum energy level spacing in each of the arrays. That information in turn shows the extent (and limits) of the phase-coherent electron wavefunction in each of the devices. The use of the following two material systems, the semimetal atomic clusters and the gold nanoparticles, is inspired by the electron billiard results. First, the output of the simple, rectangular electron billiards, the magnetoconductance fluctuations, is quite generally found to be fractal. This research addresses the question of what output one might expect from a device with manifestly fractal geometry by simulating the electrical response of fractal resistor networks and by outlining a method to implement such devices in fractal aggregates of semimetal atomic clusters. Second, in gold nanoparticle arrays, the number of array elements can increase by orders of magnitude over the billiard arrays, all with the potential to stay in a similar, phase-coherent transport regime. The last portion of this dissertation details the fabrication of these nanoparticle-based devices and their electrical characteristics, which exhibit strong evidence for electron transport in the Coulomb-blockade regime. A sketch for further 'off-blockade' experiments to realize magnetoconductance fluctuations, i.e. phase-coherent electron phenomena, is presented. / Committee in charge: Jens Noeckel, Chairperson, Physics; Richard Taylor, Member, Physics; Heiner Linke, Member, Physics; David Strom, Member, Physics; James Hutchison, Outside Member, Chemistry