L'hypertrophie bénigne de la prostate (HBP) est une pathologie qui affecte 50% des hommes dès l'âge de 60 ans et qui conduit à des troubles de la miction. L'HBP se caractérise par une hypertrophie exclusive ou composite de plusieurs compartiments tissulaires de la prostate que sont l'épithélium, le stroma et les fibres musculaires qui définissent respectivement les composantes glandulaire, fibreuse et musculaire de cette pathologie. Il a récemment été montré que les souris dépourvues en récepteurs nucléaires LXR (Liver‐X‐receptor) α (souris lxrα‐/‐) développent une hypertrophie de la prostate dont les signes histologiques évoquent une HBP de type fibreuse. Par ailleurs, un des traitements de l'HBP, vise à éteindre la signalisation androgénique en inhibant la conversion de la testostérone en son métabolite actif, la dihydrotestostérone (DHT). Le phénotype d'hypertrophie de la prostate pourrait donc également s'expliquer par une altération de la signalisation androgénique dans les souris lxrα‐/‐. Dans ce contexte, notre projet de recherche a été centré sur l'étude du rôle des LXR dans l'apparition de l'HBP dans sa composante glandulaire et l'analyse des relations moléculaires associant les signalisations dépendantes de LXRα et du récepteur des androgènes (AR) au sein de la prostate. Le phénotype d'HBP observé dans les souris lxrα‐/‐ résulte d'altérations importantes de l'homéostasie de l'épithélium qui miment la composante glandulaire : 1) une activité sécrétoire accrue ; 2) une altération des processus de sécrétion associée à une altération de l'expression des gènes codant des protéines du transport vésiculaire ; 3) une réponse altérée de certains gènes androgéno‐dépendants associée à une hypersensibilité aux androgènes ; 4) des modifications du réseau paracrine reliant le stroma et l'épithélium. Au final, ces travaux définissent LXRα comme un acteur clé de l'homéostasie prostatique et ouvrent des pistes intéressantes pour la compréhension de l'étiologie de l'HBP chez l'homme. Ces résultats montrent qu'il est possible de moduler la réponse androgénique de la prostate en ciblant LXRα. Ainsi, à plus long terme, l'activation pharmacologique de LXRα constitue une piste potentielle dans le traitement de l'HBP.

Submitted by Marco Antônio de Ramos Chagas (mchagas@ufv.br) on 2017-05-12T11:09:27Z No. of bitstreams: 1 texto completo.pdf: 1226647 bytes, checksum: 9e3237bb24db4758f26f774a630a1f7e (MD5) / Made available in DSpace on 2017-05-12T11:09:27Z (GMT). No. of bitstreams: 1 texto completo.pdf: 1226647 bytes, checksum: 9e3237bb24db4758f26f774a630a1f7e (MD5) Previous issue date: 2002-10-15 / Conselho Nacional de Desenvolvimento Científico e Tecnológico / A proteína SBP (Sucrose Binding Protein) foi inicialmente identificada pela sua capacidade de se ligar a sacarose e parece estar envolvida na via de translocação de sacarose em plantas superiores. Nesta investigação, foram isolados de uma biblioteca genômica de soja, propagada em λZAPII, dois clones genômicos, que correspondem às formas alélicas do gene SBP2. O número de cópias gênicas da família SBP foi estimado por Southern blot e por FISH (Fluorescence in situ Hibridization), utilizando o cDNA SBP e o clone genômico SBP2 como sondas, em lâminas com núcleos interfásicos de soja. O padrão de hibridização demonstrou a existência de dois pares de genes homólogos, com razão de hibridização diferente, representando os dois genes distintos, SBP e SBP2. Para investigar a funcionalidade da sequência do promotor SBP2, aproximadamente 2,0 quilobases da região 5’ foram sequenciadas e fusionadas aos genes repórteres GUS (beta-glucuronidase) e GFP (Green Fluorescent Protein) e analisados em plantas de tabaco transgênicas. Os ensaios histoquímicos demonstraram que ambos os promotores exibem expressão tecido- específica. Estes resultados foram confirmados pela fluorescência tecido- específica da expressão de GFP. Consistente com seu envolvimento no transporte de sacarose a longa distância, os promotores SBP2 dirigiram a expressão dos genes repórteres com alta especificidade para o floema de todos os órgãos analisados, como meristema, caule, folha e raiz. Entretanto, altos níveis de expressão foram observados predominantemente no meristema e em folhas- dreno. Foi também demonstrado que o promotor SBP2 é regulado de modo dependente da forma e da concentração de açúcar disponível no meio de cultura de células de tabaco transgênico em suspensão. Deleções no promotor SBP2 foram feitas para a identificação de regiões contendo elementos regulatórios em cis. Ensaios histoquímicos com plantas transgênicas contendo as construções quiméricas com as deleções do promotor demonstraram que o padrão tecido-específico do gene SBP2 é coordenado pela interação entre elementos regulatórios positivos e negativos. A região contida entre as posições -2000 até -490 possui elementos positivos que potencializam a expressão no floema, uma vez que a deleção dessa região causou um decréscimo substancial na atividade do promotor. A deleção adicional do promotor até a posição -364 restaurou a atividade do promotor em todos os tecidos analisados. Como conseqüência, a atividade quantitativa de GUS foi muito superior àquela observada para o promotor intacto. Estes resultados indicam a presença de um elemento silenciador, na região delimitada pelas posições -489 a -364. Além disso, a região de -363 a -132 possui um elemento positivo, responsável pela expressão no meristema radicular, uma vez que a deleção deste fragmento silencia a expressão de GUS no meristema radicular. O padrão de expressão tecido- específico, das construções quiméricas das deleções do promotor, se correlaciona com a distribuição dos elementos DOF na seqüência do promotor, em associação com os elementos O2 e GCN4. Coletivamente, estes resultados mostram que o promotor SBP representa uma poderosa ferramenta biotecnológica útil para o direcionamento da expressão de genes alvos para o tecido vascular de plantas de soja e tabaco transgênicas. / Tese importada do Alexandria, apresenta somente resumo em português.

Patienten mit einer dekompensierten Leberzirrhose besitzen ein hohes Risiko bakterielle Infektionen zu entwickeln. Besonders häufig kommt es dabei zu einer spontan bakteriellen Peritonitis, wobei die Letalität bis heute noch immer bei bis zu 50 % liegt. Ein wesentlicher Grund für das generelle Infektionsrisiko besteht in der Zirrhose-assoziierten systemischen Immunparalyse als Folge einer andauernden Immunstimulation. Es ist allerdings ungeklärt warum bei Patienten mit Leberzirrhose die SBP die häufigste Infektion ist, wohingegen Patienten mit malignem Aszites dafür nicht empfänglich sind. Daher war das Ziel dieser Arbeit, die Funktionseinschränkung von PMNs im Aszites von Patienten mit Leberzirrhose zu evaluieren und dafür die Fähigkeit zur Phagozytose und stimuliertem oxidativen Burst in Aszites- und korrespondierenden Blutproben zu untersuchen.

We consider diagonal-norm classical summation-by-parts (SBP) operators us-ing the simultaneous approximation term (SAT) method of imposing boundaryconditions. We derive a formula for the inverse of these SBP-SAT discretizationmatrices. This formula is then used to show that it is possible to construct a secondorder accurate SBP-SAT operator using only seven grid points.

Low frequency acoustic room behaviour can be approximated using numerical methods. Traditionally, music studio control rooms are built with complex geometries, making their eigenmodes difficult to predict mathematically. Hence, a summation-by-parts method with simultaneous-approximation-terms is derived to approximate the time dependent acoustic wave equation in three dimensions. The derived model is limited to rectangular prismatic rooms but planned to be expanded to handle complex geometries in the future. Semi-reflecting boundary conditions are used, corresponding to tabulated reflection and absorption properties of real. walls. Two speakers are modeled as omnidirectional point sources placed on a boundary, to mimic common studio setups. Through tests and examination of eigenvalues of the matrices in the method, conditions for stability and reflection coefficients are derived. Simulations of sound pressure distribution produced by the model correlate well to room mode theory, suggesting the model to be accurate in the application of predicting low frequency acoustic room behaviour. However, the convergence rate of the model turns out to be lower than expected when point sources are introduced. Future steps towards applying the model to real music studio control rooms include modeling the walls as changes in density and wave speed rather than boundaries of the domain. This would potentially allow more complex geometries to be modeled within a larger, rectangular domain.

Background Major incidents are characterized by a lack of resources compared to an overwhelming number of casualties, requiring a prioritization of medical treatment. Triage algorithms are an essential tool for prioritizing the urgency of treatment for patients, but the evidence to support one over another is very limited. We determined the influence of blood pressure limits on the diagnostic value of triage algorithms, considering if pulse should be palpated centrally or peripherally. Methods We used a database representing 500 consecutive HEMS patients. Each patient was allocated a triage category (T1/red, T2/yellow, T3/green) by a group of experienced doctors in disaster medicine, independent of any algorithm. mSTaRT, ASAV, Field Triage Score (FTS), Care Flight (CF), “Model Bavaria” and two Norwegian algorithms (Nor and TAS), all containing the question “Pulse palpable?”, were translated into Excel commands, calculating the triage category for each patient automatically. We used 5 blood pressure limits ranging from 130 to 60 mmHg to determine palpable pulse. The resulting triage categories were analyzed with respect to sensitivity, specificity and Youden Index (J) separately for trauma and non-trauma patients, and for all patients combined. Results For the entire population of patients within all triage algorithms the Youden Index (J) was highest for T1 (J between 0,14 and 0,62). Combining trauma and non-trauma patients, the highest J was obtained by ASAV (J = 0,62 at 60 mmHg). ASAV scored the highest within trauma patients (J = 0,87 at 60 mmHg), whereas Model Bavaria (J = 0,54 at 80 mmHg) reached highest amongst non-trauma patients. FTS performed worst for all patients (J = 0,14 at 60 mmHg), showing a lower score for trauma patients (J = 0,0 at 60 mmHg). Change of blood pressure limits resulted in different diagnostic values of all algorithms. Discussion We demonstrate that differing blood pressure limits have a remarkable impact on diagnostic values of triage algorithms. Further research is needed to determine the lowest blood pressure value that is possible to palpate at a peripheral artery compared to a central artery. Conclusion As a consequence, it might be important in which location pulses are palpated according to the algorithm at hand during triage of patients.

Background Major incidents are characterized by a lack of resources compared to an overwhelming number of casualties, requiring a prioritization of medical treatment. Triage algorithms are an essential tool for prioritizing the urgency of treatment for patients, but the evidence to support one over another is very limited. We determined the influence of blood pressure limits on the diagnostic value of triage algorithms, considering if pulse should be palpated centrally or peripherally. Methods We used a database representing 500 consecutive HEMS patients. Each patient was allocated a triage category (T1/red, T2/yellow, T3/green) by a group of experienced doctors in disaster medicine, independent of any algorithm. mSTaRT, ASAV, Field Triage Score (FTS), Care Flight (CF), “Model Bavaria” and two Norwegian algorithms (Nor and TAS), all containing the question “Pulse palpable?”, were translated into Excel commands, calculating the triage category for each patient automatically. We used 5 blood pressure limits ranging from 130 to 60 mmHg to determine palpable pulse. The resulting triage categories were analyzed with respect to sensitivity, specificity and Youden Index (J) separately for trauma and non-trauma patients, and for all patients combined. Results For the entire population of patients within all triage algorithms the Youden Index (J) was highest for T1 (J between 0,14 and 0,62). Combining trauma and non-trauma patients, the highest J was obtained by ASAV (J = 0,62 at 60 mmHg). ASAV scored the highest within trauma patients (J = 0,87 at 60 mmHg), whereas Model Bavaria (J = 0,54 at 80 mmHg) reached highest amongst non-trauma patients. FTS performed worst for all patients (J = 0,14 at 60 mmHg), showing a lower score for trauma patients (J = 0,0 at 60 mmHg). Change of blood pressure limits resulted in different diagnostic values of all algorithms. Discussion We demonstrate that differing blood pressure limits have a remarkable impact on diagnostic values of triage algorithms. Further research is needed to determine the lowest blood pressure value that is possible to palpate at a peripheral artery compared to a central artery. Conclusion As a consequence, it might be important in which location pulses are palpated according to the algorithm at hand during triage of patients.

Induced seismicity (earthquakes caused by injection or extraction of fluids in Earth's subsurface) is a major, new hazard in the United States, the Netherlands, and other countries, with vast economic consequences if not properly managed. Addressing this problem requires development of predictive simulations of how fluid-saturated solids containing frictional faults respond to fluid injection/extraction. Here we present a numerical method for linear poroelasticity with rate-and-state friction faults. A numerical method for approximating the fully coupled linear poroelastic equations is derived using the summation-by-parts-simultaneous-approximation-term (SBP-SAT) framework. Well-posedness is shown for a set of physical boundary conditions in 1D and in 2D. The SBP-SAT technique is used to discretize the governing equations and show semi-discrete stability and the correctness of the implementation is verified by rigorous convergence tests using the method of manufactured solutions, which shows that the expected convergence rates are obtained for a problem with spatially variable material parameters. Mandel's problem and a line source problem are studied, where simulation results and convergence studies show satisfactory numerical properties. Furthermore, two problem setups involving fault dynamics and slip on faults triggered by fluid injection are studied, where the simulation results show that fluid injection can trigger earthquakes, having implications for induced seismicity. In addition, the results show that the scheme used for solving the fully coupled problem, captures dynamics that would not be seen in an uncoupled model. Future improvements involve imposing Dirichlet boundary conditions using a different technique, extending the scheme to handle curvilinear coordinates and three spatial dimensions, as well as improving the high-performance code and extending the study of the fault dynamics.

Aerodynamic shape optimization and multidisciplinary optimization algorithms have the potential not only to improve conventional aircraft, but also to enable the design of novel configurations. By their very nature, these algorithms generate and analyze a large number of unique shapes, resulting in high computational costs. In order to improve their efficiency and enable their use in the early stages of the design process, a fast and robust flow solution algorithm is necessary. This thesis presents an efficient parallel Newton-Krylov-Schur flow solution algorithm for the three-dimensional Navier-Stokes equations coupled with the Spalart-Allmaras one-equation turbulence model. The algorithm employs second-order summation-by-parts (SBP) operators on multi-block structured grids with simultaneous approximation terms (SATs) to enforce block interface coupling and boundary conditions. The discrete equations are solved iteratively with an inexact-Newton method, while the linear system at each Newton iteration is solved using the flexible Krylov subspace iterative method GMRES with an approximate-Schur parallel preconditioner. The algorithm is thoroughly verified and validated, highlighting the correspondence of the current algorithm with several established flow solvers. The solution for a transonic flow over a wing on a mesh of medium density (15 million nodes) shows good agreement with experimental results. Using 128 processors, deep convergence is obtained in under 90 minutes. The solution of transonic flow over the Common Research Model wing-body geometry with grids with up to 150 million nodes exhibits the expected grid convergence behavior. This case was completed as part of the Fifth AIAA Drag Prediction Workshop, with the algorithm producing solutions that compare favourably with several widely used flow solvers. The algorithm is shown to scale well on over 6000 processors. The results demonstrate the effectiveness of the SBP-SAT spatial discretization, which can be readily extended to high order, in combination with the Newton-Krylov-Schur iterative method to produce a powerful parallel algorithm for the numerical solution of the Reynolds-averaged Navier-Stokes equations. The algorithm can efficiently solve the flow over a range of clean geometries, making it suitable for use at the core of an optimization algorithm.

Aerodynamic shape optimization and multidisciplinary optimization algorithms have the potential not only to improve conventional aircraft, but also to enable the design of novel configurations. By their very nature, these algorithms generate and analyze a large number of unique shapes, resulting in high computational costs. In order to improve their efficiency and enable their use in the early stages of the design process, a fast and robust flow solution algorithm is necessary. This thesis presents an efficient parallel Newton-Krylov-Schur flow solution algorithm for the three-dimensional Navier-Stokes equations coupled with the Spalart-Allmaras one-equation turbulence model. The algorithm employs second-order summation-by-parts (SBP) operators on multi-block structured grids with simultaneous approximation terms (SATs) to enforce block interface coupling and boundary conditions. The discrete equations are solved iteratively with an inexact-Newton method, while the linear system at each Newton iteration is solved using the flexible Krylov subspace iterative method GMRES with an approximate-Schur parallel preconditioner. The algorithm is thoroughly verified and validated, highlighting the correspondence of the current algorithm with several established flow solvers. The solution for a transonic flow over a wing on a mesh of medium density (15 million nodes) shows good agreement with experimental results. Using 128 processors, deep convergence is obtained in under 90 minutes. The solution of transonic flow over the Common Research Model wing-body geometry with grids with up to 150 million nodes exhibits the expected grid convergence behavior. This case was completed as part of the Fifth AIAA Drag Prediction Workshop, with the algorithm producing solutions that compare favourably with several widely used flow solvers. The algorithm is shown to scale well on over 6000 processors. The results demonstrate the effectiveness of the SBP-SAT spatial discretization, which can be readily extended to high order, in combination with the Newton-Krylov-Schur iterative method to produce a powerful parallel algorithm for the numerical solution of the Reynolds-averaged Navier-Stokes equations. The algorithm can efficiently solve the flow over a range of clean geometries, making it suitable for use at the core of an optimization algorithm.