Este estudo investiga o sucesso no processo de bilinguismo português/japonês de seis jovens retornados do Japão. Como sucesso no bilinguismo, entendemos pelo caso em que o indivíduo, mesmo após uma longa permanência no Japão e vivência no sistema escolar japonês, tenha conseguido após o seu retorno no Brasil, manter o domínio na lingua japonesa e possuir uma proficiência linguísitica em português suficiente para seu ingresso no ensino superior brasileiro. O referencial teórico sobre bilinguismo foi baseado nos estudos de Skutnabb-Kangas (2008); Cummins (1984); Baker (1993); Nakajima (2010). Foram realizadas entrevistas semiestruturadas presenciais e online, sendo analisados os seguintes três domínios na trajetória de vida desses colaboradores que, baseados em uma auto-avaliação, foram divididos em 2 grupos bilíngues dominantes em português e bilingues dominantes em japonês : (1) ambiente linguístico no Japão (2) atitudes dos colaboradores com os estudos da L1 e L2 e (3) ambiente linguístico no Brasil. O estudo comprovou que o apoio de familiares e de terceiros constitui um fator importante na motivação dos estudos, bem como na superação de desafios surgidos na adaptação linguística e cultural. Foi também observado que os colaboradores de ambos os grupos tiveram que investir na aprendizagem da língua por um longo período para o desenvolvimento da proficiência linguística acadêmica ALP (Cummins, 2001; 2011) até o ingresso na faculdade. Em relação à rede de apoio formal, foram verificadas as seguintes ações para minimizar os problemas relacionados ao não domínio da língua japonesa no contexto de imigração no Japão: ingresso em escola pública de região com alta concentração de brasileiros, ingresso em faculdade japonesa por programa especial para retornados e ingresso em escola brasileira ações essas realizadas pelos colaboradores do grupo dominantes em português. Por outro lado, os do grupo dominantes em japonês utilizaram as seguintes medidas para facilitar a adaptação linguística e escolar no Brasil: ingresso em escola privada com curso curricular de japonês, ingresso em escola técnica e ingresso em escola pública estadual. Em ambos os grupos foi observada a frequência em cursos preparatórios pré-vestibular. Concluiu-se que o uso dessas redes de apoio formais infuenciou positivamente no desenvolvimento da ALP dos colaboradores. / The study herein aims to investigate success in the process of Portuguese/Japanese bilingualism of six youngsters returned from Japan. In our view, successful bilingualism happens in those cases in which even after a long stay in Japan along with an experience with the Japanese school system, the individual has managed to keep his mastery of the Japanese language after returning to Brazil, and be proficient enough in Portuguese so as to be admitted to Brazilian higher education. The theoretical framework on bilingualism was based on studies of Skutnabb-Kangas (2008); Cummins (1984); Baker (1993); Nakajima (2010). Both in-person and online semi-structured interviews have been conducted focusing on three aspects in the life trajectory of interviewees who, based on self-evaluation, have been divided into two groups: Portuguese-dominant bilinguals, and Japanese-dominant bilinguals: (1) linguistic environment in Japan (2) attitude of interviewees with the study of both L1 and L2; and (3) linguistic environment in Brazil. The study has proved that support both from family and others is key to generate motivation for studies, as well as to foment the overcoming of problems arising from both linguistic and cultural adaptation. It has also been observed that interviewees in both groups had to invest on language learning for a long period of time to develop academic linguistic proficiency ALP (CUMMINS, 2001; 2011) until they were admitted to college. As for the formal support network, the following actions aiming at alleviating problems concerning nonmastering of Japanese language in the context of Japanese immigration in Japan have been taken: admission to a public school in an area with a high concentration of Brazilian people; admission to a Japanese college by means of a program specially designed for returned, and admission to a Brazilian school, being all those actions taken by interviewees in the Portuguese-dominant group. On the other hand, those in the Japanese-dominant group have taken the following measures to facilitate linguistic and school adaptation in Brazil: admission to a private school with Japanese language in the syllabus, admission to a technical school, and admission to a state public school. Attendance to college entrance examination prep courses has been observed in both groups. it has been concluded that the use of those formal support networks has had a positive impact on the development of ALP of interviewees.

The average cost of operating a queueing network depends on several factors such as the complexity of the network and the service policy used. Approximate linear programming (ALP) is a method that can be used to compute an accurate lower bound on the optimal average cost as well as generate policies to be used in operating the network. These average cost solutions and policies are dependent on the type of basis function used in the ALP. In this paper, the ALP average cost solutions and policies are analyzed for twelve networks with four different types of basis functions (quadratic, linear, pure exponential, and mixed exponential). An approximate bound on the optimality gap between the ALP average cost solution and the optimal average cost solution is computed for each system, and the size of this bound is determined relative to the ALP average cost solution. Using the same set of networks, the performance of ALP generated policies are compared to the performance of the heuristic policies first-buffer-first-served (FBFS), last-buffer-first-served (LBFS), highest-queue-first-served (HQFS), and random-queue-first-served (RQFS). In general, ALP generated average cost solutions are considerably smaller than the simulated average cost under the corresponding policy, and therefore the approximate bounds on the optimality gaps are quite large. This bound increases with the complexity of the queueing network. Some ALP generated policies are not stabilizing policies for their corresponding networks, especially those produced using pure exponential and mixed exponential basis functions. For almost all systems, at least one of the heuristic policies results in mean average cost less than or nearly equal to the smallest mean average cost of all ALP generated policies in simulation runs. This means that generally there exists a heuristic policy which can perform as well as or better than any ALP generated policy. In conclusion, a useful bound on the optimality gap between the ALP average cost solution and the optimal average cost solution cannot be computed with this method. Further, heuristic policies, which are more computationally tractable than ALP generated policies, can generally match or exceed the performance of ALP generated policies, and thus computing such policies is often unnecessary for realizing cost benefits in queueing networks. / text

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No description available.

Calcific aortic valve disease (CAVD) is the most common cause of aortic valve failure and replacement in the elderly population, affecting 25% of the population over 65 years of age. Current pharmacological approaches for preventing the onset and progression of calcific aortic valve disease have not shown consistent benefits in clinical studies. Differentiation of valvular interstitial cells (VICs) into osteoblast–like cells is an integral step in the calcification process. Although clinical evidence suggests hypertension as a potential candidate contributing to the development of CAVD, the underlying molecular mechanisms that cause de-differentiation remain unclear. The present study investigates the role of elevated cyclic pressure in modulating osteoblast differentiation pathways in VICs in vitro. We used a combination of systems biology modeling and pathway-based analyses to identify novel genes and molecular mechanisms that are activated in valve tissue during exposure to elevated pressure conditions. Our results show that elevated pressure induces a gene expression pattern in valve tissue that is considerably similar to that seen in CAVD, underlining the key role of hypertension as an initiating factor in the onset of pathogenesis. In addition, our analysis revealed a set of genes that was not previously known to be regulated in valve tissue in a pressure dependent manner. Currently, the molecular mechanisms involved in CAVD and their associations with changes in local mechanical environment are poorly understood, and thus a better understanding of the cell based process mediating CAVD progression will improve our ability to develop potential medical therapies for this disease.

Zu den Eigenschaften eukaryotischer Zellen gehört ihre Kompartimentierung, welche durch die Abtrennung verschiedener Reaktionsräume durch Lipiddoppelschichten erreicht wird. Verschiedene Vesikel-Transportwege verbinden diese Kompartimente miteinander, einer dieser Wege in der Hefe Saccharomyces cerevisiae ist der sogenannte ALP-Weg. Dieser gehört zu den biosynthetischen Wegen, über die neue Proteine an ihren Bestimmungsort gebracht werden, in diesem Falle die Vakuole. Ausgehend vom Golgi-Apparat werden die Vesikel dieses Weges mit Hilfe des Adaptorproteinkomplexes-3 (AP-3) gebildet. Ein weiteres Protein, das eine spezifische Funktion in diesem Weg übernimmt, ist Vps41. Ein aktuelles Modell beschreibt seine Funktion in der Aufnahme der Vesikel an der Vakuole. Es konnte gezeigt werden, das Vps41 mit der sogenannten ear-Domäne von Apl5, einer Untereinheit des AP-3- Komplexes, interagiert. In dieser Arbeit konnte ich nachweisen, dass die Interaktionsstelle im Vps41 innerhalb einer konservierten PEST-Domäne liegt. Eine Deletion dieser Domäne beeinflußte die Funktion des Proteins im ALP-Weg jedoch nicht die in der homotypischen Vakuolenfusion und im CPY-Weg. Eine weitere Eingrenzung des deletierten Bereiches zeigte, dass die PEST-Domäne eine Sequenz enthält, die einem Di-Leucin- Sortierungssignal ähnlich ist. Dieses konnte ich als minimal notwendigen Bereich für die Wechselwirkung mit der Apl5-ear-Domäne bestimmen. Meine Daten zeigen, dass dieser Bereich des Proteins notwendig ist für das Docking der AP-3-Vesikel an der Vakuole. Weiterhin konnte ich eine kompetitive Bindung von Liposomen und Apl5 an die N-terminale Hälfte von Vps41 zeigen. Zusammengefasst und mit aktuellen Veröffentlichungen in Zusammhang gebracht, ergänzen meine Daten das Modell der Funktion von Vps41 in der Vesikelaufnahme an der Vakuole: Vps41 wird durch die Rab-GTPase Ypt7, als deren Effektorprotein, an späte Endosomen gebunden. An dieser stark gekrümmten Membran taucht ein kürzlich identifiziertes ALPS (amphipathic lipid packing sensor)-Motiv im Vps41 in die Membran des Organells ein und zieht so den N-terminalen Bereich mit der Bindestelle für die AP-3-Vesikel an die Oberfläche des Organells wodurch eine verfrühte Fusion der AP-3-Vesikel mit dem Endosom verhindert wird. Erst nach der Reifung zur Vakuole wird die PEST-Domäne für die Bindung an Apl5 verfügbar, da sich die Membrankrümmung ändert. Zusätzlich wird das ALPS-Motiv phosphoryliert, so dass dieses nicht mehr in die Membran eintauchen kann. Erst jetzt ist eine Interaktion zwischen Apl5 und Vps41 und damit eine Fusion der AP-3-Vesikel mit der Vakuole möglich. Der zweite Teil dieser Arbeit beschäftigt sich mit der Protonentranslokation durch den Fo-Teil der ATP-Synthase aus Escherichia coli. Durch Mutagenese wurden ATP-Synthasen hergestellt, in denen die beiden für den Protonentransport essentiellen Aminosäurereste D61 in der Untereinheit c und R210 in der Untereinheit a in der α-Helix in der sie liegen, entweder einzeln oder beide zusammen, um je eine Helixwindung nach oben oder unten verschoben wurden. Dies führt zu einer Verlängerung bzw. Verkürzung der Protonenzu- und austrittskanäle. Durch die Untersuchung der Funktionalität dieser ATPasen auf sowohl aktives und passives Protonenpumpen, als auch ATP-Synthese konnte ich zeigen, daß die Position der beiden essentiellen Aminosäurereste cD61 und aR210 zueinander nicht entscheidend ist. Werden beide Reste in die gleiche Richtung verschoben, so daß ihre Position zueinander gleich bleibt, kommt es unabhängig von der Richtung immer zu einem kompletten Funktionsverlust. Weiterhin läßt sich aus meinen Daten folgern, daß die Position des Restes aR210 in der Mitte der Membran wichtig ist. Beim Verschieben des Restes auf die Position 206 (a-up) geht die gesamte Funktion des Fo-Teiles verloren, während das Verschieben auf die Position 214 (a-down) zu einem passiven Ausströmen der Protonen durch den Fo-Teil führt. Die Position des Restes cD61 in der Membran ist flexibler. Obwohl die Repositionierung des Aspartats auf die Position 57 (c-up) jegliche Funktionalität des Fo-Teiles beeinträchtigt, ermöglicht ein Verschieben auf die Position 65 (c-down) aktives und passives Protonenpumpen, sowie die Synthese von ATP.

Between 1983 and 1996, the environment emerged to become a major political issue in Australia to which a series of national public policy decisions was directed. In examining these policies, this thesis argues that the association of environmentalism with the politics of policy-making reflected the primary role played by the Australian Labor Party as the major political party in Government at that time. It reflected the Labor Government’s primary role in determining the nature and direction of the debate between 1983 and 1996. Of particular importance was a period in which the Labor Government sought to undertake institutional innovation in order to contain the environmental debate within the institutionalised policy-making process - a period described here as the ‘Accordist’; phase of Labor’s management of the environmental debate. The thesis challenges theoretical approaches that argue that relations between social democratic trade union based parties and the environmental movement have the potential to tend toward mutual antagonism. It also challenges the argument that environmentalism, as a manifestation of the ‘new politics’, necessarily involves a qualitative transformation of politics associated with new social movements. Rather, the thesis argues that the debate in Australia went beyond simply addressing controversial specific issues when they arose, to instead become an examination of the capacity for agencies and departments to incorporate environmental values into their decision-making, and about ways in which competing interest group demands could be reconciled through newly created government-led forums. (For complete abstract open document)

Primary sclerosing cholangitis (PSC) is a rare chronic liver disease characterized by inflammation and fibrosis of the biliary ducts, resulting in cholestasis and eventually liver failure. No effective treatment is currently available and most patients ultimately require liver transplantation in order to survive. The underlying mechanisms of the disease is poorly understood but a range of hypotheses exist, many of which recognize and grapple with PSC's close relationship with inflammatory bowel disease. Most agree genetics is involved, predisposing for an imbalance in 1) bile acid metabolism, 2) immune response and/or 3) gut microbiota. This literature study aims to describe and elucidate recent progress in the field of pharmacotherapy, as it relates to PSC and our current understanding of the disease. Covered in this study is a total of seven randomized, controlled trials, published between 2015-2022, and available through the medical database/search engine PubMed. Endpoints of particular note are ALP and ELF. ALP, or alkaline phosphatase, is an enzyme found in the liver. Rising levels of ALP in the blood stream is indicative of liver damage. ELF, or Enhanced Liver Fibrosis, is a blood test measuring markers of fibrosis, useful in assessing and staging fibrosis in chronic liver disease. Drugs included in this literature study are aldafermin, cilofexor, fenofibrate, norUrsodeoxicholic acid, obeticholic acid, simtuzumab and vancomycin. With the exception of aldafermin and simtuzumab, all showed promise as ALP reducing agents, in general lowering levels with 15-40 percent. In the case of fenofibrate, a reduction of 65 percent was observed. Of the drugs measured against ELF, only aldafermin produced a statistically significant reduction in fibrosis markers. At the time being it is not entirely clear what to make of the results, due to uncertainties surrounding ALP as a prognostic marker. To what extent ALP predicts transplantation free survival is still a matter of debate. Although considerable efforts have been made to further our understanding of PSC, much is yet to be solved. With regards to pharmacotherapy, the field is experiencing somewhat of a renaissance, showcased by the dozen on-going randomized, controlled trials on a plethora of potential PSC substances. Thus, the search for an effective therapy against PSC goes on.

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Indiana University-Purdue University Indianapolis (IUPUI) / Introduction: Regenerative endodontic procedures are an effective treatment option for immature teeth with infected necrotic pulps to allow for healing and potential continued root development, yet challenges to ideal treatment outcomes remain. Consistent development of root length and width of dentin remains a challenge, as does development of the pulp-dentin complex. Previous in vitro studies have assessed the role of different growth factors and bioactive molecules in combination with scaffolds to potentially facilitate continued development of the pulp-dentin complex using dental pulp stem cells (DPSCs). The proline-rich tyrosine kinase 2 (Pyk2) is linked with osteoblast activity and the regulation of bone mass. Further, the Pyk2 inhibitor PF-4618433 (PF-46) has been shown in previous studies to enhance osteoblast activity and mineral deposition in vitro. However, whether Pyk2 targeting promotes the osteogenic differentiation of DPSCs remains unknown. Objective: The purpose of this study was to investigate the effect of a Pyk2 inhibitor, PF-46, on the proliferation, differentiation, and mineralization of human DPSCs. Materials and Methods: Human DPSCs were cultured in 24-well plates with α-MEM with 10% FBS, and containing 0 μM (vehicle control) or 0.1 μM, 0.3 μM, or 0.6 μM PF-46. Fresh media and treatments were replaced every 2-3 days. After 1 day incubation, cytotoxic effects were evaluated by using an MTS proliferation assay. After 4 days of treatment, direct cell counting was performed. To induce osteogenic differentiation, ascorbic acid and β-glycerol phosphate were added to the culture media and the DPSCs were cultured with PF-46 for 14 days. Then, an alkaline phosphatase (ALP) assay and mineral deposition assay were performed. Differences between treatment groups were analyzed by a one-way ANOVA followed by pair-wise tests conducted using Tukey’s multiple comparisons procedure with a 5% significance level. Results: The 0.6 μM PF-46 group had a significantly higher cell count, ALP activity and mineral deposition when compared to 0 μM PF-46. The 0.1 and 0.3 μM PF-46 groups also had significantly higher ALP activity compared to the 0 μM PF-46 group after 14 days of incubation. There was a general trend of increased differentiation and mineral deposition as the concentration of PF-46 increased from 0.1 μM to 0.6 μM. Conclusion: There was a general concentration-dependent increase in cell count, differentiation, and mineral deposition by human DPSCs as the concentration of PF-46 increased from 0 μM up to 0.6 μM, with the highest activity observed with 0.6 μM PF-46. Although further research is needed, these results suggest that strategies that target Pyk2 may potentially be used to improve the osteogenic differentiation of DPSCs to aid endodontic regeneration.