A população indígena Guarani desde tempos imemoriais ocupa tradicionalmente as Bacias do Rio Paraguai, Paraná e Uruguai e seus afluentes, ou seja, a grande Bacia do Prata. A região da Bacia do Paraná na Tríplice Fronteira entre Brasil, Paraguai e Argentina é denominada pelos Guarani como sendo uma parcela do Tekoa Guassu (conjunto de várias aldeias Guarani ou Aldeia Grande). Ali possuem o direito de permanecer, reconhecido legalmente desde a época colonial portuguesa e pelas sucessivas constituições brasileiras. No decorrer do século XX com a instalação de empreendimentos estatais brasileiros na região do oeste paranaense, os Guarani foram esbulhados de suas terras desaparecendo assim, inúmeras aldeias. Instalou-se um processo de desconstrução do território indígena. Grande parte da população indígena foi expulsa para o Paraguai, concentrando-se junto às aldeias ali existentes, localizadas na fronteira com o Brasil. Apesar das pressões, uma única população Guarani conseguiu resistir no Brasil. Trata-se dos habitantes da antiga aldeia do Ocoy-Jacutinga. Em 1973, ela teve a maior parte de suas terras ocupadas pelo INCRA, visando reassentar colonos retirados do Parque Nacional do Iguaçu. Em 1982 a parte restante do território indígena, foi totalmente inundada com a construção da Usina Hidrelétrica de Itaipu. Somente parte dos indígenas foram compulsoriamente reterritorializados para a Terra Indígena Avá-Guarani do Ocoy. A transferência da população, legalmente deveria ser de todo o agrupamento indígena, para terras de igual extensão e ambientalmente semelhantes à anterior, e ainda seu uso deveria ser exclusivo. Ocoy apresenta dimensões diminutas, menores que a anterior e ambientalmente comprometida. É sobreposta à Área de Preservação Permanente do reservatório da Usina Hidrelétrica de Itaipu, terras em que, antes, constituía-se parte de Glebas de Colonos, os quais não foram indenizados pelo INCRA. Dada a insuficiência de terras e os problemas sociais decorrentes das superposições, os Guarani sofrem toda sorte de impactos sociais, ambientais, econômicos e sanitários. Tentativas de reterritorialização por parte dos indígenas foram reprimidas pelo Estado. Encontram-se acuados e necessitam de terras em ambiente adequado para sua reprodução física e cultural. Para esta solução, é preciso descartar falsas versões, que atribuem à emigração de indivíduos Guarani provenientes do Paraguai, a existência de excesso demográfico no Ocoy. Esta assertiva vem sendo utilizada, impedindo e mascarando a resolução do problema fundiário. O crescimento demográfico no Ocoy é semelhante ao de qualquer aldeia da etnia. Na verdade, não é a população indígena que é excessiva, mas o território onde foi reassentada que se apresenta insuficiente e inadequado desde a sua instalação no local. Tal situação é fruto de histórico descumprimento das leis pelos poderes Executivo e Judiciário federais, favorecendo grupos de poder locais. / Traditionally, since memorable times, the Paraguay, Paraná and Uruguay Bays and their tributaries, known as the greater Prata Bay, have been occupied by the Guarani Indian population. The Paraná Bay in the triple border between Brazil, Paraguay and Argentina is identified by part of the Guarani as Tekoa Guassu (a cluster of many Guarani villages or Big Village). Their right to live there is legally recognized by the consecutive Brazilian Constitutions since Portuguese Colonial Times. During the 20th century the Guarani were evicted from their lands due to the Brazilian governments enterprises in the west region of the Paraná State which caused the disappearance of countless villages. It initiated a process of dissipating the Indian Territory. Great part of the Indian population was pushed to Paraguayan lands in the border with Brazil where other villages already existed. In spite of that, one Guarani population, the inhabitants of the old village known as Ocoy-Jacutinga managed to resist in Brazilian territory. However, in 1973, the majority of its lands was occupied by INCRA, to resettle colonists that were withdrawn from Iguaçu National Park. In 1982 the remaining part of the Indian Territory was completely flooded with the construction of Itaipu Hydroelectric Power Plant. Only part of the Indians were compulsorily relocated to the Indian Land of Avá-Guarani do Ocoy. Legally the transference of that population should be for whole Indian group to lands of the same extension and environmentally similar to the previous ones with exclusive occupation. Ocoy, conversely, presents diminutive dimensions, smaller than the preceding one and environmentally impaired. It is overlaped by the Area of Permanent Preservation of Itaipu Hydroelectric Power Plant reservoir; lands that were previously part of the colonist areas, which were not reimbursed by INCRA. Due to the small quantity of land and the social problems developed by the overlapping, the Guarani Indians suffer all kinds of social, environmental, economic and sanitary impact. Indian resettlement attempts were restrained by the State. They are cornered and need the land in a proper environment for their physical and cultural reproduction. For a solution to that matter, it is necessary to throw away false versions that attribute emigration of Guarani Indians from Paraguay due to demographic excess in Ocoy. The use of such statement is an impediment to the resolution for the land property problem. The demographic growth in Ocoy is similar to any other of its ethnic villages. Actually, it is not the Indian population that is excessive but the place where they were resettled that is insufficient and inadequate from the start. Those circunstances are a consequence of the historical unbinding of the law from the Brazilian Judiciary and Executive Federal Institutions on behalf of local power groups.

Cancer, a global epidemic, is a major cause of morbidity and mortality affecting populations in all nations and regions. Breast cancer (BC) is the second most common cancer in the world and the most fatal malignancy affecting women both in the developed and developing countries. Even with the improvement in overall survival of BC patients due to early detection and advancement with systematic therapy, triple negative breast cancer (TNBC), an aggressive subtype of BC still remains a major challenge as it lacks targetable receptors. Chemotherapy is the main treatment for TNBC. However, de novo and acquired resistance to conventional anticancer drugs is a major limitation and cause of therapeutic failure. Cancer stem cells (CSCs) are believed to be responsible for chemoresistance and tumour relapse. My study demonstrates that hypoxia is involved in the development and maintenance of these CSCs traits in TNBC, as cells grown in hypoxia are significantly resistant to several first line anti-BC drugs. Hypoxia-induced activation of nuclear factor kappa B (NFB) and hypoxia inducible factors (HIFs) also play pivotal roles in chemoresistance. Forced expression of NFB and HIFs by transfection with p65 subunits of NFB and HIF1α and 2α subunits induced CSCs characters and resistance to a range of anticancer drugs in TNBC cell lines. My study also indicated a positive loop between the activation of NFB and HIFs. Therefore development of novel medicine to interfere the pathways of hypoxia and NFB may efficaciously target CSCs and reverse chemoresistance which will be of clinical significance for TNBC treatment. iv Disulfiram (DS) is a commercially available anti-alcoholism drug. Recent studies demonstrate that it is highly cytotoxic in a wide range of cancer types and potentially repurposed as an anticancer drug. The anticancer mechanisms of DS were investigated in this study. The results from my study indicate that the cytotoxicity of DS is copper (Cu) dependent with a biphasic manner. The instant cytotoxic phase is induced by the extracellular reactive oxygen species (ROS) generated by the reaction between DS and Cu. The delayed killing is caused by the complex diethyldithiocarbamate (DDC) and Cu (DDC-Cu), the final product of the reaction. The cytotoxicity of both phases needs the intact DS. However, due to the extremely short half-life of DS in the bloodstream, the anticancer efficacy of DS has been severely hampered in vivo and in patients. Nanotechnology-based drug delivery system is a rapidly evolving and expanding interdisciplinary field involving in an amalgamation of chemistry, engineering, biology and medicine. In the last part of my study, I have successfully encapsulated DS into polymeric micelle (PM) nanoparticles. The half-life of PM encapsulated DS (PM-DS) was extended to over 3 hours in horse serum. The PM-DS showed strong anticancer efficacy. Therefore this nano-enabled DS may be able to translate DS into cancer therapeutics in the future.

A significant racial disparity in breast cancer mortality exists among women in the United States. Triple-negative breast cancer (TNBC) is a breast cancer phenotype that may explain, in part, this disparity between white and African American women. The objective of this study was to determine the predictors of survival in TNBC and non-triple-negative breast cancer (NTNBC) patients. Data on 168,756 female patients with a diagnosis of invasive breast cancer in the Surveillance Epidemiology and End Results (SEER) program were stratified based on breast cancer receptor phenotypes in this retrospective longitudinal cohort study design. Multiple logistic regressions were used for exploring predictors of treatment which showed that not receiving surgery as standard treatment was associated (odds ratio: 95% CI) with TNBC (OR 1.151: 1.042, 1.177), uninsured (OR 3.552: 3.206, 3.937) and African American (OR 1.804: 1.702, 1.912) while not receiving radiation was associated with TNBC (OR 1.151: 1.113, 1.190), uninsured (OR 1.318; 1.217, 1.429). Cox’s hazard models were used, regressing age, race, ethnicity, marital status, health insurance status, histological tumor grade, and treatment status on survival time, the outcome measure. Analysis revealed that the mean survival time is lower for TNBC [15.60 (± 10.29)] months compared with NTNBC [16.01 (± 10.18)] (p < 0.0001), a difference though small is statistically significant. The independent determinants of survival in TNBC were: young age at diagnosis [(β = 0.033, HR 1.033 (1.026, 1.041)]; being African American [(β = 0.182, HR 1.200 (1.117, 1.289)], being married [(β = - 0.362, HR 0.697 (0.658, 0.737)]; higher tumor histological grades [β = 1.034, HR 2.812 (2.159,3.661)]; uninsured [(β = 0.541, HR 1.717 (1.481, 1.992)]; no surgery [(β = 2.156, HR 8.633 (8.152, 9.143)], or no radiation treatment [(β = 0.489, HR 1.630 (1.535,1.73)]. African American race, uninsured status, higher grade at diagnosis, inadequate treatment are independent predictors of poor survival among breast cancer patients; importantly, TNBC had a lower survival than that of NTNBC patients. A higher proportion of TNBC patients had a diagnosis at younger age, with higher tumor grade and was of the African American race. The survival disparity in African American patients may be partially explained by disproportionately higher TNBC cases among them, as well as, rates of not receiving standard treatments.

Recent approaches in depression therapeutics include triple reuptake inhibitors, drugs that target three monoamine systems. Using in vivo electrophysiological and microdialysis techniques, the effects of 2- and 14-day treatments of escitalopram, nomifensine and the co-administration of these two drugs (TRI) were examined in male Sprague-Dawley rats. Short- and long-term TRI administration decreased NE firing and had no effect on DA neurons. Normal 5-HT firing rates were maintained after 2-day TRI administration compared to the robust inhibitory action of selective serotonin reuptake inhibitors (SSRIs). Escitalopram treatment enhanced the tonic activation of the 5-HT1A receptors given the increase in firing observed following WAY100635 administration. Nomifensine treatment enhanced tonic activation of the α2–adrenoceptors following idazoxan administration. TRI treatment caused a robust increase in extracellular DA levels that was in part mediated by a serotonergic contribution. Therapeutic effects of the drugs examined in this study may be due to the enhancement of 5-HT, NE and/or DA neurotransmission.

This thesis investigated the views, opinions and experiences of children, young people and parents of mental health services and Triple P parent training using qualitative methods. It is divided into four separate papers, the first three written as standalone journal papers. Paper 1 is a systematic review and synthesis of qualitative studies exploring children’s views and opinions of mental health services. The review used specific databases, a search of qualitative journals and a general Internet search to identify relevant studies. The paper utilized inclusion/exclusion criteria and a quality appraisal assessment. Fifteen studies meeting inclusion and quality criteria were identified exploring the experiences of 378 children and young people aged between 5 and 16 years, from a range of countries. The review then involved synthesising the findings of these studies to generate several overarching themes. Themes that emerged were; the stigma of mental health difficulties; alliance making and breaking properties; the physical location of services; consent and confidentiality; preferences for creative therapies and a recognition of therapeutic stages. Paper 2 is an original research study that explored the experiences of parents of Triple P parent training. Eight parents were interviewed using a semi-structured protocol. Data were analysed using Interpretative Phenomenological Analysis. Emergent themes were; a search for a cause; the stigma of parenting difficulties; the destruction and recreation of family life and a shift in perspective. Paper 3 explores the views and opinions of children whose parents have recently undertaken Triple P parent training. This qualitative study used ‘In My Shoes’, a computer assisted interview tool, to explore the experiences of eleven children from England aged between five and sixteen years. Children’s data were analysed using Thematic Analysis. Children’s themes were; a search for a cause; changes in life brought about by Triple P and wider difficult life circumstances. Parents and children’s narratives broadly agreed though children talked about being smacked before Triple P and parents did not comment about chastisement. The final section of the thesis was a critical appraisal of the literature review, research study and research process as a whole, including methodological reflections, implications for future research and clinical practice, and the researcher’s personal reflections in undertaking the research.

We investigate the effect of thermal expansion and gravity on the propagation and stability of flames in inhomogeneous mixtures. We focus on laminar flames in the simple configuration of an infinitely long channel with rigid porous walls in order to understand the effect of inhomogeneities on these fundamental structures. The first part of the thesis is concerned with premixed flames propagating against a prescribed parallel (Poiseuille) flow and subject to thermal expansion. We show that in a narrow channel (corresponding to a relatively thick flame), if the Peclet number is fixed and of order unity, a premixed flame propagating against a parallel flow is governed by the equation for a planar premixed flame with an effective diffusion coefficient. The enhanced diffusion is shown to correspond to Taylor dispersion, or shear-enhanced diffusion. Several important applications of the results are discussed. One of the topics of relevance is the bending effect of turbulent combustion. The results of our analysis show that, for a large flow intensity, the effective propagation speed of the premixed flame for depends only on the Peclet number (which is equal to the Reynolds number if the Prandtl number is unity). This mimics the behaviour of the turbulent premixed flame when the effective propagation speed is plotted versus the turbulence intensity for fixed values of the Reynolds number. The second part of the thesis is concerned with triple flames, subject to thermal expansion and buoyancy. A study is undertaken to investigate the stability of a diffusion flame subject to these effects, which gives rise to a problem analogous to the classical Rayleigh--B\'nard convection problem. A linear stability analysis in the Boussinesq approximation is performed, which leads to analytical results showing that the Burke-Schumann flame is unstable if the Rayleigh number is above a critical value which is determined. Numerical results confirm and complement the analytical results. A full numerical investigation of the effects of gravity and thermal expansion on triple flames propagating in a direction perpendicular to the direction of gravity is then carried out. This configuration does not seem to have received dedicated attention in the literature. It is found that the well-known monotonic relationship between the propagation speed $U$ and the flame-front thickness $\epsilon$, which exists in the constant density case when the Lewis numbers are of order unity or larger, persists for triple flames undergoing thermal expansion. Under strong enough gravitational effects, however, the relationship is no longer found to be monotonic, exhibiting hysteresis if the Rayleigh number is large enough. Finally, the initiation of triple flames from a hot two-dimensional ignition kernel is investigated. Particular attention is devoted to the energy required for ignition and the transient evolution of triple flames after initiation. Steady, non-propagating, two-dimensional solutions representing "flame tubes" are determined; their thermal energy is used to define a minimum ignition energy for the two-dimensional triple flame in the mixing layer. The transient behaviour of triple flames following "energy-increasing" or "energy-decreasing" perturbations to the flame tube solutions is described in situations where the underlying diffusion flame is either stable or unstable.

This thesis investigates the municipality of Linkopings role in the development project Ebbepark. How an innovative business-environment can facilitate trilateral networks in the Triple-Helix. The thesis aims to compare intentions and outcome of the development project. The theory of the Triple-Helix constitutes the theoretical framework, of which the study relates to. With the use of a thematic analysis of qualitative data gathered from interviews, an insight is given to government officials own beliefs and convictions about Ebbepark. An additional document analysis of the development projects visionary- and general plan, generates an understanding of the projects initial intentions. A tangible difference in outcome, is Linkopings University involvement in Ebbepark. Initially the plan was to establish a physical presence in order to strengthen the innovative space. The University decided to centralize their operations on campus, which can be seen as limiting in regard to facilitating the Triple-Helix. / Studien undersöker hur Linköpings kommun har arbetet med projektet Ebbepark och hur en organisationsöverskridande samverkan, s.k.Triple-Helix, kan faciliteras. Uppsatsen ämnar undersöka och besvara hur projektets initiala intentioner skiljer sig från utfallet av Ebbepark. Teorin för Triple-Helix utgör det teoretiska ramverk som studien förhåller sig till. En tematisk analys av intervjuer ger insyn till tjänstemäns egna övertygelser angående projektet. Kompletterande dokumentanalys av projektets förarbete skapar förståelse för visionerna och Ebbeparks helhetsplan. Ett exempel på skillnader mellan planerade intentioner och utfallet, är Linköpings universitets roll. Från att vara engagerade om en fysisk närvaro i Ebbepark för ökat innovationsskpande, till att centralisera sin verksamhet inom campusområdet. Det leder till en minskad akademisk närvaro, något som kan minska möjligheterna för en Triple-Helixsamverkan.

archives@tulane.edu / Triple negative breast cancers (TNBCs) are clinically and biologically aggressive, with higher recurrence and metastasis rates compared to other subtypes. Acquisition of a mesenchymal and migratory cell phenotype is consequential process that promotes metastasis. There are no clinically approved small molecule targeted therapies for TNBC; kinases are effective drug targets in cancer research. Although some kinases are known to regulate the mesenchymal phenotype, a large subset of the human kinome is understudied. There are many approaches to discovering novel kinase targets in cancer. Here, a phenotypic screen approach is described to identify understudied kinases using the Published Kinase Inhibitor Set (PKIS). Initial screens using TNBC cell lines (MDA-MB-231, BT549 and MDA-MB-157) identified 36 hits representative of twelve kinase inhibitor chemotypes based on reversal of the mesenchymal cell morphology. Our hits were further prioritized based on gene expression changes of the epithelial marker E-cadherin and migratory behavior. Active compounds were confirmed to reverse EMT on transcript and protein levels with qRT-PCR and Western blot. When pharmacologically similar compounds were more closely examined, different effects on cancer biology were observed (‘active’ versus ‘inactive’ compounds). Based on these observations, a kinase array was employed to compare both the active and inactive compounds to demonstrate how to identify candidate kinases responsible for the EMT reversal. Using this screening approach, small molecule inhibitors from the PKIS library (GSK346294A, GSK448459A, GSK237700A) were identified that were pharmacologically similar that reversed the mesenchymal phenotype in TNBC. These compounds have different biological effects in TNBC, despite having similar pharmacophores. Differential effects of the PKIS compounds on transwell migration, gene (qRT-PCR) and protein (Western blot) expressions, and mammosphere formation in TNBC cells was observed. In follow-up in vivo studies, our most active compound (GSK346294A) suppressed tumorigenesis and metastasis. RNA-sequencing confirmed downregulated pathways induced by GSK346294A treatment in TNBC cells included EMT, cytoskeletal rearrangement and cell cycle regulation. Because these compounds have different off-target activities, this approach can be used to identify candidate unique kinases responsible for the observed effects. NEK5 was one of these kinases candidates. NEK5 function remains understudied in cancer, and even more understudied in breast cancer. This study is the first, to our knowledge, to describe the function of NEK5 in breast cancer, specifically its roles in acquisition of a mesenchymal and migratory cell phenotype. Overexpression of NEK5 promotes a migratory and mesenchymal phenotype, and knockdown with a shRNA construct suppresses this migratory behavior. Data obtained using both qRT-PCR of the knockdown and overexpression cell lines, and follow-up RNA sequencing, revealed NEK5 regulates the PLAU/PAI-1/SRC axis. Furthermore, a role for NEK5 in resistance to SRC-targeting anticancer agents is demonstrated. The work described here demonstrates the utility of a novel approach to identify understudied kinases in cancer, and characterization of these kinases has potential impact in other metastatic diseases not limited to breast cancer. / 1 / Margarite Matossian

This study investigates the relationship between three visual representations (two-dimensional, three-dimensional fixed, and three-dimensional rotatable) of multidimensional data, and the subjects' ability to make predictions based on the data. Output of a momentum accounting system was simulated and graphics were rendered based on that information. An interactive computer program was developed and used to administer the laboratory experiment and collect the results. Subjects made prediction decisions based on the graphics produced for four companies. The companies were stratified based on size (high or low) and growth patterns (high or low). Each subject made predictions for one type representation for each of the four companies. Because of inconsistencies of the sample distributions for the different representations, nonparametric analyses were used to examine the data. The subjects using the three-dimensional data that could be rotated were found to provide the most accurate predictions. No differences between the treatments were found based on the subject's visual acuity, as measured by the Visual Vividness Imagery Questionnaire (VVIQ). The subjects using the two-dimensional representations were found to take the least amount of time for their predictions. / Ph. D.

A key component of defense acquisition programs operating using the Integrated Defense Acquisition, Technology, and Logistics Life Cycle Management System is the reliance on the triple constraints of cost, schedule, and performance. While the use of Modeling and Simulation tools and capabilities is prevalent and well established in the Research and Development, Analysis, and Training domains, acquisition programs have been reluctant to use Modeling and Simulation in any great depth due to inaccessibility of tools, Subject Matter Experts, and implications to cost and schedule. This presents a unique Simulation Management challenge which requires an in-depth understanding of the technical capabilities available within an organization, their applicability to support immediate needs, and the flexibility to utilize these capabilities within the programmatic environment to provide a value added service. The focus of this dissertation is to study the use of Modeling and Simulation in the Defense arena, and to review the applicability of Modeling and Simulation within programmatic acquisition environments which are constrained by cost, schedule, and performance. This research draws comparisons between Modeling and Simulation to other Process Improvement initiatives, such as Lean and Six Sigma, and reviews case studies involving the application of Modeling and Simulation within triple constrained environments. The development of alternate scenarios allows cost benefit analysis to be conducted for each scenario and alternate scenario, developing a case for whether or not the application of Modeling and Simulation within the triple constrained environment delivered any consequential benefit to the acquisition process. Observations are made regarding the level of Modeling and Simulation as applied within each case study, and generalized recommendations are made for the inclusion of cost benefit iv analysis methodologies for analyzing proposed Modeling and Simulation activities within acquisition programs. Limitations and shortcomings of the research activity are discussed, along with recommendations for potential future work in the Simulation Management field, both with respect to the specific case studies reviewed in this study and the general field.