Orientador: Fernando Jose Von Zuben / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia Eletrica e Computação / Made available in DSpace on 2018-08-11T19:03:12Z (GMT). No. of bitstreams: 1 Coelho_GuilhermePalermo_M.pdf: 2968179 bytes, checksum: bbea7c9c565907f86eee09155421bfa3 (MD5) Previous issue date: 2006 / Resumo: O uso da abordagem ensembles tem sido bastante explorado na última década, por se tratar de uma técnica simples e capaz de aumentar a capacidade de generalização de soluções baseadas em aprendizado de máquina. No entanto, para que um ensemble seja capaz de promover melhorias de desempenho, os seus componentes devem apresentar bons desempenhos individuais e, ao mesmo tempo, devem ter comportamentos diversos entre si. Neste trabalho, é proposta uma metodologia de criação de ensembles para problemas de classificação, onde os componentes são redes neurais artificiais do tipo perceptron multicamadas. Para que fossem gerados bons candidatos a comporem o ensemble, atendendo a critérios de desempenho e de diversidade, foi aplicada uma meta-heurística populacional imuno-inspirada, denominada opt-aiNet, a qual é caracterizada por definir automaticamente o número de indivíduos na população a cada iteração, promover diversidade e preservar ótimos locais ao longo da busca. Na etapa de seleção dos componentes que efetivamente irão compor o ensemble, foram utilizadas seis técnicas distintas e, para combinação dos componentes selecionados, foram adotadas cinco estratégias. A abordagem proposta foi aplicada a quatro problemas de classificação de padrões e os resultados obtidos indicam a validade da metodologia de criação de ensembles. Além disso, foi verificada uma dependência entre o melhor par de técnicas de seleção e combinação e a população de indivíduos candidatos a comporem o ensemble, assim como foi feita uma análise de confiabilidade dos resultados de classificação / Abstract: In the last decade, the ensemble approach has been widely explored, once it is a simple technique capable of increasing the generalization capability of machine learning based solutions. However, an ensemble can only promote performance enhancement if its components present good individual performance and, at the same time, diverse behavior among each other. This work proposes a methodology to synthesize ensembles for classification problems, where the components of the ensembles are multi-layer perceptrons. To generate good candidates to compose the ensemble, meeting the performance and diversity requirements, it was applied a populational and immune-inspired metaheuristic, named opt-aiNet, which is characterized as being capable of automatically determining the number of individuals in the population at each iteration, promoting diversity and preserving local optima through the search. In the component selection phase, six distinct techniques were applied and, to combine these selected components, five strategies were adopted. The proposed approach was applied to four pattern classification problems and the obtained results indicated the validity of the methodology to synthesize ensembles. It was also verified a dependence of the best pair of selection and combination techniques on the population of candidates to compose the ensemble, and it was made an analysis of the confidence of the classification results / Mestrado / Engenharia de Computação / Mestre em Engenharia Elétrica

O crescente desenvolvimento na indústria de transporte tornou-se um tema de pesquisa em diversos países, uma vez que as obras de arte especiais até então construídas não foram projetadas para as elevadas cargas atualmente transportadas. Mostra-se necessária uma reavaliação de como a ação do carregamento móvel é levada em consideração. Dessa forma, elaborou-se um estudo de normas e códigos de diversos países sobre o tema. Definem-se algumas combinações de veículos de cargas (CVCs) e analisam-se as conseqüências e a viabilidade do tráfego das mesmas. Essa análise é realizada através da comparação dos esforços solicitantes provocados pelas CVCs e pelos veículos previstos por normas em diversos sistemas estruturais e por meio da verificação da capacidade portante de um projeto típico. Objetivando-se encontrar uma solução que se adequasse à realidade brasileira, é elaborado um estudo sobre como outros países vêm tratando a questão das combinações de veículos de cargas especiais. Ao final do trabalho, constata-se a existência de CVCs que, apesar de atenderem às exigências estabelecidas pelo Conselho Nacional de Trânsito (CONTRAN), são incompatíveis com a as pontes da malha viária nacional. / The increasing development in the transport industry has become a research topic in several countries, once the bridges constructions built to date were not originally designed to support the ever increasing heavy loads nowadays being transported. It is thus necessary a re-evaluation of how the action of live loading is taken in consideration. A study of the codes and specifications of several countries is elaborated. It is defined some cases of combinations of special load vehicles (CVCs) and it is analyzed the consequences and viability of their traffic. This analyses is done by comparing the efforts caused by the CVC\'s to the other normative vehicles in various structural systems and by the verification of the strength capacity of a typical project. In order to find a solution in accordance with the Brazilian reality, a study is elaborated on how other countries manage the combinations of special load vehicles issue. Among other conclusions of this research, it is worth noting that there are CVC\'s that attend the standards established by the National Council of Transportation (CONTRAN) but are not compatible with the bridges of national roads.

O gênero Mallodeta Butler, exclusivamente neotropical, contava, no início deste estudo, com seis espécies: M. clavata (Walker) (espécie-tipo), M. sortita (Walker), M. consors (Walker), M. sanguipuncta Druce, M. cubana Gaede e M. simplex Rothschild. Estas espécies, mais Phoenicoprocta parthenii (Fabricius), outrora também considerada integrante daquele gênero, foram estudadas quanto às suas relações filogenéticas. A hipótese de monofiletismo de Mallodeta não foi corroborada, sendo as espécies historicamente associadas ao gênero doravante consideradas pertencentes a três clados: (i) Mallodeta, composto unicamente por sua espécie-tipo; (ii) Rezia Kirby gen. reval., composto por R. sortita comb. nov., R. consors comb. nov. e R. sanguipuncta, além de R. cardinale (Hampson), R. erythrarchos (Walker) comb. nov., R. cruenta (Perty) comb. nov. e R. hanga (Herrich-Schäffer) comb. nov., previamente tratadas em Cosmosoma Hübner; (iii) Antilleana gen. nov., composto por A. parthenii comb. nov., A. jamaicensis (Schaus) comb. nov., A. capistrata (Fabricius) comb. nov. e A. carminata (Hampson) comb. nov., todas anteriormente alocadas em Phoenicoprocta Druce. Dentre as conclusões taxonômicas, M. simplex foi tratada como sin. nov. de M. clavata, Glaucopis (Erruca) deyrolii Walker, 1854 sin. nov. de Rezia sortita, Laemocharis ignicolor Ménétriés sin. nov. de Rezia erythrarchos e M. cubana sin. nov. de A. capistrata. Todas as espécies tratadas no presente estudo foram redescritas, ilustradas e tiveram sua distribuição geográfica elucidada. / At the beginning of this study the genus Mallodeta Butler, exclusively neotropical, comprised six species: M. clavata (Walker) (type species), M. sortita (Walker), M. consors (Walker), M. sanguipuncta Druce, M. cubana Gaede and M. simplex Rothschild. These species besides Phoenicoprocta parthenii (Fabricius), formerly considered part of Mallodeta, had their phylogenetic relationships elucidated. The monophyly of Mallodeta was not corroborated, and the species historicaly associated to it should be considered, from now on, belonging to three different clades: (i) Mallodeta, composed exclusively by its type species; (ii) Rezia Kirby rev. gen, comprising R. sortita n. comb., R. consors n. comb. and R. sanguipuncta, plus R. cardinale (Hampson), R. erythrarchos (Walker) n. comb., R. cruenta (Perty) n. comb. and R. hanga (Herrich-Schäffer) n. comb., previously treated in the genus Cosmosoma Hübner; (iii) Antilleana n. gen., comprised by A. parthenii n. comb., A. jamaicensis (Schaus) n. comb., A. capistrata (Fabricius) n. comb. and A. carminata (Hampson) n. comb., formerly treated in Phoenicoprocta Druce. Among taxonomic conclusions we discovered M. simplex to be a n. syn. of M. clavata, Glaucopis (Erruca) deyrolii Walker, 1854 n. syn of Rezia sortita, Laemocharis ignicolor Ménétriés n. syn of Rezia erythrarchos and M. cubana n. syn. of A. capistrata. All species studied were redescribed, illustrated and had their geographical distribution elucidated.

Submitted by Geandra Rodrigues (geandrar@gmail.com) on 2018-10-24T12:50:06Z No. of bitstreams: 1 taisdemedeirospedreira.pdf: 1862768 bytes, checksum: 0c6ee31fd9be772b5b609051a207f61f (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2018-11-23T12:17:19Z (GMT) No. of bitstreams: 1 taisdemedeirospedreira.pdf: 1862768 bytes, checksum: 0c6ee31fd9be772b5b609051a207f61f (MD5) / Made available in DSpace on 2018-11-23T12:17:19Z (GMT). No. of bitstreams: 1 taisdemedeirospedreira.pdf: 1862768 bytes, checksum: 0c6ee31fd9be772b5b609051a207f61f (MD5) Previous issue date: 2018-09-05 / As previsões a curto prazo da carga elétrica (de algumas horas até alguns dias à frente) são essenciais para o planejamento, controle e operação dos sistemas de energia, tanto por por razões técnicas quanto financeiras. Como não é possível estocar grandes quantidades, torna-se indispensável um maneira eficaz de programar a produção da energia para que ela atenda a demanda. Por conta disso, uma grande literatura desenvolveu-se sobre o assunto. Devido à complexidade das séries de carga e à dependência não-linear destas carga em relação a diversas variáveis exógenas, os sistemas de previsão mais frequentemente propostos em trabalhos recentes são aqueles baseados em algoritmos complexos de inteligência computacional. No entanto, métodos lineares simples ainda são muito comumente usados, por si sós ou em combinação com técnicas não-lineares. Um desses métodos é o de Holt-Winters-Taylor, que é uma adaptação do conhecido método de amortecimento exponencial de Holt-Winters para que múltiplas sazonalidades possam ser modelados concomitantemente. Este trabalho implementa três variantes deste método HWT e analisa seus desempenhos em duas séries de dados reais de carga. Verificou-se que uma combinação linear dessas variantes nitidamente supera o método HWT original e fornece previsões precisas, com um baixo custo computacional. / Short-term load forecasts (forecasts for horizons ranging from a few hours to a few days ahead) are essential for the planning, controling and operation of energy systems, both for technical and financial reasons. Since it is not feasible to store energy in large quantities, an efficient way to forecast energy demand becomes indispensable. Because of this, a large literature has developed on the subject. Due to the complexity of load series and the nonlinear relationship of the load with exogenous variables, the most frequently proposed forecasting systems in recent papers are those based on complex algorithms of computational intelligence. However, simple linear methods are still very frequently used, either alone or in combination with non-linear techniques. One of these methods is Holt-Winters-Taylor (HWT), which is an adaptation of the well-known Holt-Winters exponential smoothing method, modified so that multiple seasonalities can be modeled at the same time. In this paper, we implement three variants of this HWT method and analyze their performances over two sets of actual load data. We found that a linear combination of these variants clearly outperforms the original HWT method, and provides accurate forecasts at a low computational cost.

Abstract—Background: Software Process Improvement (SPI) maturity models have been developed to assist organizations to enhance software quality. Agile methodologies are used to ensure productivity and quality of a software product. Amongst others they are applied in Small and Medium – sized Enterprises (SMEs). However, little is known about the combination of Agile methodologies and SPI maturity models regarding SMEs and the results that could emerge, as all the current SPI models are addressed to larger organizations and all these improvement models are difficult to be used by Small and Medium – sized firms. Combinations of these methodologies could lead to improvement in the quality of the software products, better project management methodologies and organized software development framework. Objectives: The aim of this study is to identify the main Agile methodologies and SPI maturity models applied in SMEs, the combinations of these methodologies, and the results that could emerge. Through these combinations, new software development frameworks are proposed. What is more, the results of this study can be used as a guide with the appropriate combination for each SME, as a better project management methodology or as improvement in the current software engineering practices. Methods: A Systematic Literature Review was conducted, resulting in 71 selected relevant papers ranging from 2001 to 2013. Besides, a survey has been performed from June 2013 to October 2013, including 49 participants. Results: Seven Agile methodologies and six different SPI maturity models were identified and discussed. Furthermore, the combination of eight different Agile methodologies and Software Process Improvement maturity models is presented, and as well as their benefits and drawbacks that could emerge in Small and Medium – sized firms. Conclusion: The majority of the Agile methodologies and SPI maturity models are addressed to large or very large enterprises. Thus, little research has been conducted for SMEs. The combinations of the Agile methodologies and SPI maturity models are usually performed in experimental stages. However, it has been observed that such type of combination could present numerous benefits, which can also be applicable in SMEs as well. The combinations that are most common are the CMMI and XP, CMMI and Scrum, CMMI and Six Sigma, and the PRINCE2 and DSDM. / 0034-636835645

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Candida species are the most common etiologic agent of opportunistic fungal infections. Candida albicans is the most frequent species in candidiasis, however species of non-albicans species have emerged increasingly in hospitals in which the use of azoles as a prophylactic or therapeutic is common. C. glabrata is the species most relevant in this scenario, causing infections with high morbidity and mortality due to high rates of resistance to antifungal azoles, especially fluconazole, and reduced sensitivity to amphotericin B and echinocandins. The remarkable resistance of these species to antifungal agents requires the search for new therapeutic options. An alternative is the combination of drugs with different mechanisms of action. This study aimed to evaluate the in vitro susceptibility of Candida glabrata to conventional antifungal agents (amphotericin B, ketoconazole, itraconazole, fluconazole and voriconazole), and these associations with non-antifungal drugs (chlorpromazine, linezolid, minocycline, sulfamethoxazole, tacrolimus and diphenyl diselenide). Two groups of clinical isolates of C. glabrata were evaluated. The first group consists of fluconazole-sensitive clinical isolates (FS) (n = 30) and the second, derivative of the first, fluconazole-resistant clinical isolates (FR) (n = 30). Based on protocol M27-A3 (CLSI, 2008), the checkerboard method. In isolation, MICs (Minimum Inhibitory Concentration) for fluconazole ranged from 0.25 to ≥ 64.00 μg/mL (FS) and 64.00 to 256.00 μg/mL (FR); for amphotericin B ranged from 0.06 to 0.50 μg/mL (FS) and 0.03 to 0.50 μg/ mL (FR); for itraconazole 0.50 to 8.00 μg/ mL (FS) and 1.00 to 16.00 μg/mL (FR); for ketoconazole 0.13 to 2.00 μg/mL (FS) and 0.50 to 16.00 μg/mL (FR); for voriconazole 0.13 to 4.00 μg/mL (FS) and 1.00 to 16.00 μg/mL (FR). The combinations of tacrolimus with azoles showed significant synergism rates; for the group FS tacrolimus + ketoconazole (43%), tacrolimus + itraconazole (43%), tacrolimus + voriconazole (37%); for the group FR ketoconazole + tacrolimus (77% ) tacrolimus + itraconazole (73%), tacrolimus + voriconazole (63%). Linezolid combined with ketoconazole and voriconazole showed high rates of synergism against the FR group, 76.67% and 70%, respectively. Minocycline + amphotericin B obtained 46.67% (FS) and 36.67% (FR) of synergism; chlorpromazine + amphotericin B was synergistic for 40% of the FR. Chlorpromazine combined to azoles showed high rates of antagonism for resistant group, 76.67%, 70% and 80% for ketoconazole, itraconazole and voriconazole, respectively, for the sensitive group combinations had higher rates of indifference. Sulfamethoxazole evidenced a higher percentage of indifferent interactions associated with all tested antifungals, 70% (FS), 73.34% (FR) associated to ketoconazole, 60% (FS), 43.34% (FR) associated to itraconazole, 56.67% (FS), 66.67% (FR) ins association with voriconazole, 86.66% (FS), 80% (FR) associated to amphotericin B. Synergistic (76.66%) and indifferent (23.34%) interactions were observed for diphenyl diselenide + amphotericin B combination for the sensitive group. Diphenyl diselenide + fluconazole combination demonstrated indifferent (50%) and antagonistic (40%) interactions for sensitive group, whereas synergistic interactions were observed in 10% of the isolates. The most significant associations deserve in vivo evaluation in order to verify their potential in the treatment of infections caused by C. glabrata. / Candida spp é o mais frequente agente etiológico de infecções fúngicas oportunistas. Candida albicans é a espécie mais isolada nas candidíases, no entanto espécies de Candida não-albicans têm emergido de forma crescente nas unidades hospitalares em que o uso de azólicos de forma profilática ou terapêutica é frequente. C. glabrata é uma das espécies mais relevantes neste cenário, causando infecções com alta morbidade e mortalidade, devido às altas taxas de resistência frente aos antifúngicos azólicos, em especial ao fluconazol, e a reduzida sensibilidade a anfotericina B e equinocandinas. A marcante resistência desta espécie aos antifúngicos impõe a busca por novas possibilidades terapêuticas. Uma alternativa é a combinação entre fármacos com distintos mecanismos de ação. Este estudo objetivou avaliar a suscetibilidade in vitro de C. glabrata a antifúngicos convencionais (anfotericina B, fluconazol, cetoconazol, itraconazol e voriconazol) e associações destes, com fármacos e compostos não-antifúngicos (clorpromazina, linezolida, minociclina, sulfametoxazol, tacrolimus e disseleneto de difenila). Foram avaliados dois grupos de isolados clínicos de C. glabrata. O primeiro grupo composto de isolados sensíveis ao fluconazol (FS) (n=30) e o segundo, derivado do primeiro, isolados clínicos resistentes ao fluconazol (FR) (n=30). Com base no protocolo M27-A3 (CLSI, 2008), pelo método de checkerboard. Isoladamente, as CIMs (Concentrações Inibitórias Mínimas) para o fluconazol variaram de 0,25 - ≥64,00 μg/mL (FS) e 64,00 - 256,00 μg/mL (FR); para anfotericina B variaram de 0,06 - 0,50 μg/mL (FS) e 0,03 - 0,50 μg/mL (FR); para o itraconazol 0,50 - 8,00 μg/mL (FS) e 1,00 - 16,00 μg/mL (FR); para cetoconazol 0,13 - 2,00 μg/mL (FS) e 0,50 - 16,00 μg/mL (FR); para voriconazol 0,13 - 4,00 μg/mL (FS) e 1.00 - 16.00 μg/mL (FR). As combinações de tacrolimus com azólicos apresentaram consideráveis taxas de sinergismo; para o grupo FS tacrolimus + cetoconazol (43%), tacrolimus + itraconazol (43%), tacrolimus + voriconazol (37%). Para o grupo FR tacrolimus + cetoconazol (77%), tacrolimus + itraconazol (73%), tacrolimus + voriconazol (63%). Linezolida associada ao cetoconazol e ao voriconazol apresentou altas taxas de sinergismo frente ao grupo FR, 76,67% e 70%, respectivamente. Minociclina + anfotericina B obteve 46,67% (FS) e 36,67% (FR) de sinergismo; clorpromazina + anfotericina B foi sinérgica para 40% do grupo FR. Clorpromazina combinada aos azólicos apresentou altas taxas de antagonismo para o grupo resistente, 76,67%, 70% e 80% para cetoconazol, itraconazol e voriconazol, respectivamente; para o grupo sensível as combinações com clorpromazina tiveram maiores taxas de indiferença. Interações sinérgicas (76,66%) e indiferentes (23,34%) foram observadas na combinação de anfotericina B e disseleneto de difenila para o grupo sensível. A combinação de disseleneto de difenila com fluconazol apresentou indiferença (50%) e antagonismo (40%) para o grupo sensível, 10% dos isolados apresentaram sinergismo. Sulfametoxazol apresentou um maior porcentual de interações indiferentes, associado a todos os antifúngicos testados frente aos dois grupos, 70% (FS), 73,34% (FR) associado ao cetoconazol, 60% (FS), 43,34% (FR) associado ao itraconazol, 56,67% (FS), 66,67% (FR) na associação com voriconazol, 86,66% (FS), 80% (FR) associado à anfotericina B. As associações de maior relevância merecem avaliação in vivo, a fim de verificar o potencial das mesmas no tratamento de infecções por Candida glabrata.

Abstract Applying the principles of user-centered development (UCD) in software development practice is not straightforward. In technology-push type software product development it is not clear how to match the new product innovation to the future needs of potential future users. Intensive collaboration between different organizational functions becomes essential. UCD provides valuable tools and practices as learning mechanisms both for users and for the company. The purpose of cross-functional interaction is to iteratively define the best possible market for the emerging new product. This study investigates cross-functional interaction during the early phases of a new software product. The roots of UCD are in traditional software engineering (SE). However, in a software product company it is necessary to take a broader new product development (NPD) perspective. The results indicate that the early phases of software NPD are actually a collaborative learning process in which representations of the new product are built iteratively, increasing multidisciplinary knowledge related to the evolving shared object of development. The cross-functionally shared object is more than the new software product. It is an emerging new vision for the whole new business area. Both the product and its users-customers-market develop iteratively. Traditionally this is considered to happen through communication within a cross-functional NPD team. Rather than one cross-functional team effort, software NPD seems to be a network of cross-functional activities. Furthermore, in software NPD practice the development of the new business unit may actually overlay the more established business organization. This has not been visible enough, and part of the problems with cross-functional interaction may be due to confusion between these two activity systems during every-day practices. Different mediating representations of the multidimensional object knowledge become crucial. The study starts with a summary of a three-year process improvement effort in one case company, providing the basis for theoretical reflections and analytical generalizations. SE and NPD literature is reviewed to situate the case within current theoretical understanding. The findings are synthesized using concepts from cultural-historical activity theory. This study will hopefully provoke the rethinking of some of the current taken-for-granted issues related to the management of new emerging software product businesses.

The Electrospray (ES) technique is a promising particle generation method for drug delivery due to its capabilities of producing monodisperse PLGA composite particles with unique configurations and high drug encapsulation efficiency. In the dissertation work, the coaxial dual capillary ES was used to generate drug-loaded core-shell PLGA particles to study the effects of particle filling materials, drug loading locations and particle shell thicknesses on the resultant in vitro release behaviors of the hydrophilic and/ or hydrophobic model drugs. Through release profile characterization of drug-loaded PLGA particles (particle size: 400 nm and 1 μm), it was confirmed that the co-encapsulation of Budesonide (BUD, the hydrophobic small-molecule model drug) and Theophylline (THY, the hydrophilic small-molecule model drug) in the particle cores is the most effective drug loading strategy for extended release of the fixed combined BUD and THY. Particles composed of PLGA fillers with lower molecular weights and with greater shell layer thicknesses could release THY in a well controlled fashion. On the other hand, a slower release rate of Bovine Serum Albumin (BSA, the protein model drug) from PLGA particles with greater shell thickness was also observed. Sequential release of BSA and Paclitaxel (PTX, the hydrophobic small-molecule anti-cancer model drug) was achieved by the 400-nm PLGA (Mw: 7,000-17,000 g/mol, LA/GA: 50/50) particles with potential biopharmaceutical applications in cancer therapy.

Allogeneic hematopoietic stem cell transplantation (allo-HCT) has been a successful cellular therapy for patients suffering from hematological malignancies for many decades; however, the beneficial effects of graft-versus-leukemia (GVL) are classically offset by graft-versus-host disease (GVHD). GVHD occurs when major and/or minor human leukocyte antigen (HLA) mismatches between donor and recipient cause rapid expansion and activation of donor effector T cells (Teffs) resulting in end organ damage to the recipient’s epithelial tissues. Given the lymphoproliferative nature of this disease, the standard treatment option is broad immunosuppression, which can result in primary disease relapse, steroid refractory GVHD, and/or opportunistic infection. A more targeted therapy that can selectively suppress GVH responses with maintained GVL responses would achieve the optimal goal of allo-HCT. Regulatory T cells (Tregs) both natural (nTregs) or induced (iTregs) could be potential cellular therapies for the treatment of GVHD, given their innate suppressive function. Initial clinical trials using nTregs have yielded positive results; however, nTreg cellular therapy has been cumbersome due to the necessity for large scale ex vivo expansion given their low yield within an apheresis product and non-specific suppression. Conversely, iTregs can be generated from naïve T cells thus decreasing ex vivo culture times and can be educated with specific antigen thus providing targeted suppression, but a consensus on their efficacy for GVHD therapy has not been reached. Therefore, we investigated the efficacy of antigen specific iTreg therapy for the prevention of GVHD while maintaining GVL responses. In Chapter 2, we evaluated the effectiveness of monoclonal HY-specific iTregs in GVHD attenuation. We chose HY as a target antigen because it is a naturally processed, ubiquitously expressed minor mismatch antigen carried by only male donors/recipients cited to increase GVHD prevalence when donor and recipient are sex-mismatched. Utilizing HY-transgenic mice in which all T cells recognize HY antigen exclusively, we generated HY specific iTregs which effectively attenuating GVHD in male, but not female recipients in three murine bone marrow transplantation (BMT) models (major mismatch, parent to F1, and miHAg mismatch). We found HY specific iTregs lost stability in female recipients but remained stable and suppressive in male recipients suggesting expression of HY antigen was required for their suppressive function and stability. GVL responses were not compromised with the addition of HY specific iTregs in recipient mice using a pre-established tumor model. Thus, HY-specific iTregs can be generated and suppress GVHD in an antigen-dependent manner while sparing the GVL effect. In Chapter 3, we extend our findings in Chapter 2, which provided proof of principle that antigen specific iTregs effectively control GVHD; however, this therapy has a limited translational potential. Therefore, we generated alloreactive CD4 and CD8 iTregs and evaluated GVHD attenuation and GVL preservation in either full or haplo-MHC mismatched BMT models. We found alloreactive CD4 iTregs significantly suppress lethal GVHD, but completely abrogated the GVL effect against aggressive tumors. Conversely, alloreactive CD8 iTregs moderately attenuated GVHD and possessed direct cytotoxicity against tumor cells. Therefore, to rescue the impaired GVL effect mediated by CD4 iTregs, we established a combinational therapy with CD8 iTregs. Indeed we found combination CD4 and CD8 iTreg therapy significantly suppressed GVHD while sparing GVL responses compared to either CD4 or CD8 singular therapy. Mechanistically, this was achieved by potent suppression of both CD4 and CD8 Teffs coupled with preserved cytolytic molecule expression by both CD8 iTregs and Teffs. Taken together, we propose antigen specific iTreg therapy can effectively attenuate GVHD while preserving GVL responses. We further uncovered unique characteristics of CD4 and CD8 iTregs that can be exploited to achieve the optimal cellular therapy following allo-HCT.

This thesis is an analysis of the use of combined concepts of covenant and priesthood in some late Second Temple period Jewish and Jewish-Christian texts. In this thesis I investigate 1 and 2 Maccabees, Dead Sea Scrolls, and Hebrews, to see the various ways in which these Second Temple compositions have articulated the combined concepts of covenant and priesthood on the basis of their treatment of various biblical and extra-biblical traditions. The elaborate articulations of the combined concepts of covenant and priesthood in these texts partly reflect the concern of the Second Temple Jewish authors: how significant the priestly institutions and priesthood were, not only in terms of cultic matters, but also in terms of political and identity concerns. By means of this study, I hope to demonstrate that the combined concept of covenant and priesthood is necessary for a better understanding of some Second Temple texts.