Obwohl die künstliche bzw. mechanische Beatmung bei der Therapie von ALI / ARDS eine wichtige und bedeutende Rolle spielt, kann sie selbst eine akute Lungen-schädigung auslösen oder bestehende pulmonale Beeinträchtigungen verstärken. Zentraler Schädigungsmechanismus ist die alveoläre Überdehnung durch hohe Ti-dalvolumina. Selbst bei der Anwendung kleiner, protektiver Tidalvolumina in Lungen mit einem nur geringen Anteil belüfteter Alveolen kann es in diesen zu alveolärer Überdehnung kommen. Diese Überdehnung führt einerseits zu mechanisch induzier-te Apoptose sowie Nekrose und andererseits zu einer mechanisch induzierten Ver-änderung der Mediatorenfreisetzung hin zu einem pro-inflammatorischen Muster. Da der Transkriptionsfaktor NF-κB zahlreiche Mediatoren aktiviert bzw. von ihnen beeinf-lusst werden kann, nimmt er in diesem Geschehen eine ganz besondere Schlüssel-position ein. In der vorliegenden Arbeit wird der Hypothese nachgegangen, ob die NF-κB-Aktivierung bei der mechanischen Dehnung und dem daraus resultierenden inflam-matorischen Verhalten von pulmonalen Strukturzellen verändert wird und in wie weit ein Zusammenhang zwischen Dehnung, Zellschädigung und NF-κB besteht. Dafür wurden sowohl frisch isolierte alveoläre Ratten-Typ-II Zellen, Zellen der hu-man-alveolaren Epithelzelllinie A549 sowie Lungen- Fibroblasten der Zell-Linie Wi 38 untersucht. Alle drei Zellarten wurden auf einem speziellen elastischen Silikonboden von 6er-Well-Platten inkubiert, wo sie mit Hilfe des Flexercell-Stretch-Gerätes (FX 3000) als Zellmonolayer equibiaxial für 24 Stunden gedehnt wurden. Auch die zeitliche Abhängigkeit der NF-κB-Expression von der mechanischen Deh-nung wurde untersucht. Dabei konnte festgestellt werden, dass ein Zusammenhang zwischen NF-κB-Aktivierung, Zellschädigung und mechanischer Dehnung existiert. Wobei bei unter-schiedlichen Zellarten auch variierende Ergebnisse beobachtet werden konnten. Im Zusammenhang mit anderen aus unserer Forschungsgruppe und in der Literatur stammenden Erkenntnissen konnte so eine Verknüpfung zwischen NF-κB-Aktivierung, Zytokinfreisetzung und inflammatorischer pulmonaler Reaktion nachge-wiesen werden.

Introdução: o processo fisiológico de envelhecimento traduz-se em diversas alterações estruturais do sistema musculoesquelético. Estas, por sua vez, acarretam em modificações funcionais que se repercutem na dependência do senescente, determinando a diminuição da sua qualidade de vida. Das estratégias existentes para atenuar os efeitos da senescência o treinamento de potência tem sido apontado como preferido. Existem, contudo, indícios de que um treinamento baseado na potencialização da ação do ciclo alongamento-encurtamento seja uma melhor escolha. Hipóteses do estudo: pelos resultados obtidos em intervenções similares, hipotetiza-se que as participantes do protocolo de intervenção proposto apresentarão um aumento da densidade mineral óssea, do volume muscular, da capacidade funcional e melhora de alguns parâmetros biomecânicos da marcha, bem como da sua qualidade de vida. Objetivos: o objetivo geral do presente trabalho é, portanto, propor um modelo de treinamento fundamentado na potencialização da ação do ciclo alongamento-encurtamento e averiguar os seus efeitos em parâmetros selecionados da morfologia osteomuscular, capacidade funcional e qualidade de vida de idosas. Materiais e Métodos: 21 idosas sedentárias (66,9±4,2 anos) executaram o protocolo proposto durante 20 semanas, tendo os efeitos na densidade mineral óssea de fêmur, coluna, tíbia e rádio; efeitos na composição corporal, na força, no equilíbrio, na marcha, na flexibilidade e na qualidade de vida comparados aos efeitos obtidos pelo grupo controle (N=17, 65,0±3,4 anos), que não alterou o seu nível de atividade física. O protocolo de intervenção, composto por onze exercícios de força realizados com o intuito de potencializar a ação do ciclo alongamento-encurtamento, que apresentava duas modalidades de salto (salto vertical com contramovimento e drop jump), exigia a realização da fase concêntrica na maior velocidade possível. Resultados: quando comparado com o grupo controle, o grupo experimental apresentou alterações significantes (p<0,05) na densidade mineral óssea de coluna (g=1,06) e sua microarquitetura (g=0,80), na microarquitetura da tíbia (g=0,82), na força máxima (g=2,39) e potência (g=1,38) de extensores de joelho, na velocidade máxima de marcha (g=0,96), na flexibilidade de membros inferiores (g=1,05) e superiores (g=0,86) e no domínio Atividades passadas, presentes e futuras da qualidade de vida (g=1,08). Conclusão: os resultados apontam para a eficácia da proposta de intervenção, apresentando-se como uma nova estratégia para atenuar e até mesmo reverter algumas perdas estruturais e funcionais impostas pelo processo de envelhecimento / Introduction: the physiological aging process induces several structural changes in the musculoskeletal system. These, in turn, result in functional changes that are reflected in the senescent dependency, determining the reduction in their quality of life. Power training has been identified as ideal to mitigate the effects of aging. However, there are indications that an intervention based on the potentiation of the stretch-shortening cycle action is a better choice. Study hypotheses: the participants of the proposed intervention will increase their bone mineral density, muscle volume, functional capacity and will show some improvement in their gait, as well as in their quality of life. Purposes: the main objective of this study was to propose a training model based in the potentiation of the stretch-shortening cycle action and assess its effects on selected parameters of musculoskeletal morphology, functional capacity and quality of life of elderly women. Methods: 21 sendentary elderly women (66.9 ± 4.2 years) performed the proposed intervention protocol for 20 weeks and the effects on bone mineral density of the femur, spine, tibia and radio; effects on body composition, strength, balance, gait, flexibility and quality of life were compared to the effects obtained by the control group (N = 17, 65.0 ± 3.4 years) that did not change their level of physical activity. The program was composed by eleven strength exercises performed in order to enhance stretch-shortening cycle action, had two jump exercises (vertical jump with countermovement and drop jump) and had the concentric phase of the movements performed as fast as possible. Results: when compared to the control group the experimental group showed significant changes (p <0.05) in bone mineral density of the spine (g = 1.06) and its microarchitecture (g = 0.80), the microarchitecture of the tibia (g = 0.82), the knee extensors maximum force (g = 2.39) and power (g = 1.38), the maximum walking speed (g = 0.96), the lower (g = 1.05) and upper (g = 0.86) limbs flexibility and in the domain past, present and future activities of the quality of life (g = 1.08). Conclusion: the results point to the effectiveness of the proposed intervention, suggesting it as a new strategy to slow down and even reverse some structural and functional losses imposed by the aging process

Dans un contexte de diminution des émissions polluantes émises par les moteurs à combustion interne, le secteur des transports assiste à une amélioration des motorisations mais également à une diversification des carburants pour l’automobile. L’utilisation de ces différents carburants entraîne souvent un impact sur les performances de la combustion. Dans le cas du moteur à allumage commandé, la performance dépend du dégagement d’énergie, image de la vitesse de la combustion, soit du front de flamme consommant le mélange air-carburant. Or toute flamme en expansion est théoriquement soumise à des effets de courbure et de cisaillement, toutes deux contributions de l’étirement. La réponse à l’étirement étant propre à chaque type de mélange air-carburant (lié au carburant proprement dit, à la richesse du mélange, à la dilution …), ce travail de thèse est centré sur la compréhension de l’impact de l’étirement sur les performances des carburants dans les moteurs à allumage commandé. Pour cela, différents mélanges air-carburant similaires du point de vue des propriétés thermodynamiques et des vitesses fondamentales de combustion laminaire mais avec des sensibilités à l’étirement différentes ont été sélectionnés. Ces mélanges ont ensuite été étudiés dans différentes configurations expérimentales et à l’aide de différentes techniques de mesure: moteur monocylindre opaque et à accès optiques, chambre sphérique de combustion turbulente. Les résultats montrent que les propriétés de sensibilités à l’étirement déterminées en régime laminaire comme la longueur de Markstein et le nombre de Lewis sont indicatrices du comportement des mélanges en combustion turbulente, comme dans la chambre de combustion caractéristique des moteurs à allumage commandé, et sont des paramètres à prendre en considération afin de prédire les performances plus globales de ces carburants que ce soit expérimentalement qu’en simulation. / In a context of decreasing pollutant emissions, the transport sector is facing an improvement of engine concept as well as a fuel diversification. The use of these different fuels often involves an impact on the combustion performance itself. In the case of Spark ignition engine, the efficiency is a function of the released heat, image of the combustion speed, i.e. the flame front speed consuming the air-fuel mixture. It is well known that every expanding flame is submitted to flame curvature and strain rate which are both contributors to flame stretch. As the answer of each air-fuel mixture (i.e. the fuel itself, the equivalence ratio, the dilution …) is different to flame stretch, the objective of this work is to understand flame stretch impact on fuel performance in Spark-Ignition engines. To achieve this goal, different fuel-air mixtures with similar unstretched laminar burning speed and thermodynamic properties but different responses to stretch were selected. Those mixtures were then studied with different experimental devices with different measurement techniques: single-cylinder metallic and optical engines, turbulent combustion spherical vessel. Results show that flame stretch sensitivity properties such as Markstein length and Lewis number, determined in laminar combustion regime, are relevant parameters to describe the flame propagation in turbulent combustion as in the combustion chamber of the Spark-Ignition engine and need to be taken into consideration to evaluate global performance of these fuels, experimentally and also in modeling simulation.

De nos jours, la conception de moteurs à combustion interne à allumage commandé exige une consommation de carburant réduite et des émissions polluantes faibles, tout en conservant une performance adéquate. Le coût élevé des essais expérimentaux vient en faveur de l'utilisation de la simulation numérique pour l'évaluation de nouvelles définitions techniques. La modélisation phénoménologique zéro-dimensionnelle de combustion permet d'évaluer les différentes définitions techniques en tenant compte de différents aspects de de la combustion à allumage commandé comme la géométrie, la flamme laminaire et l'impact de la turbulence. Ces modèles calculent également la concentration des espèces de gaz d'échappement. Afin de créer un modèle de combustion, qui pourra décrire la physique de la combustion, les aspects principaux de la combustion pré-mélangée laminaire et turbulent sont identifiés. Trois versions de modèles de combustion typiques sont comparées en termes de description physique du processus de combustion. Le résultat de cette comparaison a indiqué le modèle le plus pertinent (le modèle de densité de surface de flamme). Ce modèle est retenu et il est complété avec la modélisation physique des plusieurs phénomènes qui affectent le taux de dégagement de chaleur. Ces phénomènes sont l’interaction flamme-paroi, les réactions post flamme et l’étirement de flamme. Enfin, le modèle proposé est validé pour plusieurs configurations techniques. Chaque configuration a un impact sur un paramètre spécifique de moteur. Cette analyse montre quels sont les intervalles de confiance et les limitations du modèle proposé. / Nowadays, the design of Spark Ignition internal combustion engines is focused on the reduction of fuel consumption and low pollutant emissions, while conserving an adequate output power. The high cost of experimental testing comes in favor of the use of numerical simulations for the assessment of engine technologies. Phenomenological Zero-Dimensional combustion models allow evaluating various technical concepts since they take into account various aspects of spark ignition combustion such as chamber geometry, laminar flame characteristics (thickness and speed) and the impact of turbulence. Such models also calculate species concentration of the exhaust gases. In order to create a zero-dimensional combustion model, which can be able to describe correctly the physics of combustion, the key aspects of laminar and turbulent premixed combustion are identified. Three versions of typical combustion models are compared in terms of physical description of the combustion process. The result of this comparison indicated the most physically pertinent mod-el (the Flame Surface Density model). This model is retained and is enhanced with physical modeling of the several phenomena, which affect the heat release rate. Those phenomena are the wall-flame interaction, post-flame reactions and flame stretch. Finally, the proposed model is validated for several engine configurations. Each configuration has an impact on a specific engine parameter. This analysis shows which are the confidence intervals and the limitations of the proposed model.

Ecological corridors play a key role in the ecosystem. The fragmentation of these systems often causes environmental destabilization, provoking direct impacts on associated biodiversity. One of the main reasons of fragmentation of such ecological corridors in water resources is the construction of dams that alter the natural water flow regime caused by the diversion of natural flow range thus emerging altered flow passages known as stretch of reduced flow (SRF). Fish that have migratory behavior use these corridors in spawning seasons for ecological succession. Thus, the understanding of this ecological succession is important for the conservation of the species. The Passo São João Hydroeletric Plant (UHE PSJ), constructed in the town of Roque Gonzales - RS by the Ijuí river, possesses a dam of 21 meters, which in the context is considered a potential fragmenting of the natural ecological corridor of the river. The present study aimed at assessing whether the SRF, which is 4 km long and emerged from the installation of this plant, presents any value as breeding or nursery area of the migratory fish. For this, monthly samples were collected in the spawning period between October 2013 and March 2014. In addition, a one-off collection of 24 h was performed in October 2014. Embarked and disembarked surface collections lasting 20 min each were carried out with support from a bongo net measuring 0.5 / 1.3 m x 0.5 mm of mesh. Shortly thereafter, a replica with the same duration and greater depth was conducted. A flow meter was coupled to the network in order to calculate the amount of water filtered. In all sampling points, measurements of pH, water temperature and the ambience, transparency of the water column, depth of collection and dissolved oxygen were taken. After collecting over 13 thousand m³ of filtered water, 25 larvae were registered. One larva of the species Prochilodus lineatus, one Pimelodus maculatus and one Leporinus sp. Still seven individuals classified at the level of order, four Siluriformes and three larvae of order Characiformes. All samples were preserved with formaldehyde 4%. Once the sample success of this study is characterized by periods of peak rainfall occurring in the months of October and November, extreme events such as long periods of rain and high temperatures may probably be directly influencing the reproductive cycle of fish. Given the present results, we can conclude that the SRF has value as a passage and migration area for both upstream and downstream migratory fish and their larvae. However, in view of the great buoyancy of this environment, the abiotic conditions, and the monthly samplings of this study, it was not possible to determine whether the SRF has been serving as a nursery or local for the spawn of the ichthyofauna. / Corredores ecológicos exercem papel fundamental no ecossistema. A fragmentação desses sistemas provoca muitas vezes a desestabilidade ambiental, ocasionando impactos diretos na biodiversidade associada. Uma das principais causas da fragmentação desses corredores ecológicos em recursos hídricos são as construções de barragens, alterando o regime hidrológico natural de escoamento, ocasionado pelo desvio da faixa de vazão natural, surgindo assim, trechos de vazão alterada, conhecidos como alça de vazão reduzida (AVR). Os peixes que possuem comportamento migratório utilizam esses corredores em épocas de piracema para sua sucessão ecológica, desta forma, o entendimento desta sucessão ecológica é importante para a conservação dessas espécies. A Usina Hidrelétrica Passo São João (UHE PSJ), instalada no município de Roque Gonzáles RS, junto ao rio Ijuí, possui uma barragem de 21 metros, sendo assim, considerada neste contexto uma possível fragmentadora do corredor ecológico natural do rio. O presente estudo teve por objetivo avaliar se a AVR, que possui 4 km de extensão e surgiu a partir da instalação dessa usina, apresenta algum valor como área de reprodução ou berçário dos peixes migradores. Para isso foram realizadas coletas mensais no período de piracema, entre outubro de 2013 e março de 2014 e ainda uma coleta pontual de 24h no mês de outubro de 2014. Com auxílio de rede do tipo Bongo de 0,5/1,3 m com malha 0,5 mm, foram realizadas as coletas de superfície embarcadas e não embarcadas com duração de 20 minutos cada, realizando, logo em seguida, uma réplica com mesmo tempo de duração em uma maior profundidade, na qual ainda foi acoplado na boca da rede, fluxômetro para calcular a quantidade de água filtrada. Em todos pontos amostrais, foram realizadas medidas de pH, temperatura da água e do ambiente, transparência da coluna d água, profundidade de coleta e oxigênio dissolvido. Após um esforço de coleta de mais de 13 mil m³ de água filtrada, foram registradas 25 larvas, sendo que destas, 15 não foi possível realizar a identificação. Uma larva da espécie Prochilodus lineatus, uma de Pimelodus maculatus e uma larva de Leporinus sp. Ainda 7 indivíduos classificados a nível de ordem, sendo eles 4 Siluriformes e 3 larvas da ordem Characiformes. Todas as amostras foram conservadas com formol 4%. Tendo em vista que o sucesso amostral deste estudo esteja caracterizado por períodos de pico de chuva ocorridos nos meses de outubro e novembro, ficou evidenciado que os eventos extremos, como grandes períodos de chuvas e temperaturas elevadas, estão influenciando diretamente no ciclo reprodutivo da ictiofauna. Diante dos resultados podemos concluir que a AVR, apresenta valor como área de passagem e migração tanto a montante, quanto a jusante, para os peixes migradores e para as larvas da ictiofauna. Porém, tendo em vista a grande variabilidade deste ambiente quanto às condições abióticas, e o esforço amostral mensal desse estudo, não foi possível definir se a AVR está servindo de berçário ou local de desova para a ictiofauna.

Made available in DSpace on 2014-06-11T19:22:52Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-04-17Bitstream added on 2014-06-13T20:09:59Z : No. of bitstreams: 1 papini_cb_me_rcla.pdf: 533751 bytes, checksum: 947e39c2977772360b0d7ec58b683ba9 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O objetivo desse estudo foi investigar associações entre nível, oferta de Atividade Física (AF) no trabalho e AF de lazer. Foi realizado um estudo transversal de base populacional. Participaram do estudo 864 trabalhadores com idade média e desviopadrão de 41 (± 13,4) anos, sendo 451 homens e 413 mulheres e eles responderam o Questionário Internacional de AF (versão longa– classificados em ativos e sedentários de acordo com o nível de AF de lazer), o Questionário baseado no modelo Transteorético (Estágios de Prontidão – classificados em fase de adoção e fase antecedentes), o Questionário sobre convênios e instalações para a prática de AF pela empresa e o Questionário sócio-demográfico. Para verificar as associações foi realizada a Regressão de Poisson no programa STATASE.10, obtendo a Razão de Prevalência (RP) com Intervalo de Confiança (IC - 95%). Como variáveis dependentes utilizamos o sedentarismo (nível de AF de lazer) e fase antecedentes (participação em AF de lazer). Para as variáveis independentes utilizamos: sexo, idade, índice de massa corporal (IMC), escolaridade, nível sócio-econômico, nível de AF no trabalho, oferta de ginástica laboral, participação na ginástica laboral e oferta de programas de condicionamento físico (PCF) através de convênios e instalações no local de trabalho. Os resultados indicam que os trabalhadores do sexo masculino são menos sedentários quando comparados com as trabalhadoras do sexo feminino. Para o sexo masculino, menor nível sócio-econômico está associado ao sedentarismo e a oferta de PCF oferecidos através de convênios está associada a níveis mais elevadosl de AF de lazer. Para o sexo feminino, maior IMC e menor nível sócio-econômico foram associados ao sedentarismo. Com relação a participação em AF de lazer o sexo feminino tem menos chances de estarem na fase de adoção... / The aim of this study was to investigate the associations between Physical Activity’s (PA) level and PA’s offer at worksite and Leisure time PA. The Population-based cross-sectional study was realized with 864 workers with average age and standard deviation 41 (± 13,4) years old, being 451 men and 413 women. They answered the International PA Questionnaire (long version – classified in activity and sedentary according to leisure time PA’s level), the Questionnaire based on Transteorethic Model (Stages of change – classified in adoption and antecedents phases), the Questionnaire about facilities and installations PA’s practice in the worksite and the demographic-status Questionnaire. The Poisson Regression in the STATASE.10 program, getting the Prevalence Ratio (PR) with Confident Interval (CI - 95%) was conducted to verify the associations between the variables. The dependents variables were the sedentarism (leisure time PA’s level) and antecedents phase (leisure time PA’s participation). For the independents variables were used: sex, age, body mass index (BMI), schooling level, social status, PA’s level in work, stretchbreak’s offer, stretch-break’s participation and fitness program’s (FP) through facilities and installations PA’s practice in the worksite. The results indicated that the male workers are less sedentary than female. For men the lower social status was associated with sedentarism and the FP facilities was associated with bigger leisure time PA’s level. For female, bigger IMC and lower social status were associates with sedentarism. About leisure time PA’s participation, the female has less chance to be in the adoption phase than male. The variables associated to leisure time PA’s participation for male are: bigger schooling and social status... (Complete abstract click electronic access below)

La dystrophie musculaire de Duchenne (DMD) est la conséquence de la perte de la dystrophine, protéine sous membranaire indispensable au maintien mécanique et fonctionnel du sarcolemme. Cette déficience augmenterait les influx cationiques par des microruptures de la membrane ou par la dérégulation de canaux tels que les canaux activés par l'étirement (SACs: Stretch-activated channel). Dans ce travail, les effets d'une stimulation mécanique ont été explorés sur des cardiomyocytes dans le contexte pathologique de la cardiomyopathie dilatée associée à la DMD. L'utilisation de fibres de carbone a permis de réaliser un étirement axial similaire aux conditions physiologiques de remplissage ventriculaire. Dans ces conditions, l'exploration de la topographie membranaire par la microscopie de conductance ionique à balayage n'a montré aucune évolution de la surface ni de lésion du sarcolemmel dans les conditions d'étirement. L'étude s'est donc focalisée sur l'activité de candidats moléculaires des SACs et plus particulièrement ceux appartenant à la famille des TRPs (Transient Receptor Potential) dans le dérèglement de l'homéostasie calcique induite par l'étirement. Les influx cationiques évalués par la technique d'extinction de fluorescence et l'étude de la concentration intracellulaire de Ca2+ ([Ca2+]i) grâce à la sonde Fluo8 montrent une implication des canaux TRPV2 et TRPCs. Les premiers semblent responsables d'une entrée cationique et d'une augmentation de [Ca2+]i importante dans les cardiomyocytes mdx. Les seconds, bien que responsables d'un influx, ne participeraient pas à l'augmentation de [Ca2+]i. Ces résultats révèlent que les canaux TRPV2 pourraient jouer un rôle important dans la dérégulation calcique observée dans les cardiomyocytes déficients en dystrophine. / Duchenne muscular dystrophy (DMD) is the consequence of the loss of dystrophin, a subsarcolemmal protein essential for mechanical and functional maintenances of the sarcolemma. This deficiency could increase cationic influxes by membrane microruptures or by dysregulation of channels such as stretch-activated channels (SACs). In this work, the effects of a mechanical stretch were explored on cardiomyocytes in the pathological context of dilated cardiomyopathy associated with DMD. Using carbon fibers, an homogenous axial stretch was performed to mimic physiological conditions of ventricular filling. In these conditions, exploration of membrane topography using the scanning ion conductance microscopy did not show any surface evolution or sarcolemma disruption in stretch condition. The study was thus focused on activity and identification of molecular candidates for SACs, especially the TRPs (Transient Receptor Potential) channels in the stretch-induced. Ca2+ homeostasis dysregulation. Cationic influxes assessed by Mn2+-quenching and assessment of the intracellular Ca2+ concentration ([Ca2+]i) using fluo-8 fluorescence demonstrated an involvement of TRPV2 and TRPCs channels. The first ones seem to be responsible for cationic entry and [Ca2+]i increase in mdx cardiomyocytes. The latter, though responsible for an influx, do not contribute to [Ca2+]i increase. These findings reveal that TRPV2 channels could play an important role in calcium dysregulation observed in dystrophin-deficient cardiomyocytes.

We report a Raman technique applicable for the in situ analysis of the development of hydrogen bonds in the liquid water‐rich phase just before the onset of gas hydrate formation. Herewith, the phase transition as well as the working principle of hydrate formation inhibitors and promoters can be analyzed.

Mechanical tension is an important regulator of cell proliferation, differentiation, migration and cell death. It is involved in the control of tissue architecture and wound repair and its improper sensing can contribute to cancer. The Hippo tumor suppressor pathway was recently shown to be involved in regulating cell proliferation in response to mechanical tension. The core of the pathway consists of the kinases MST1/2 and LATS1/2, which regulate the target of the pathway, the transcription co-activator YAP/ TAZ (hereafter referred to as YAP). When the Hippo pathway is inactive, YAP remains in the nucleus and promotes cell proliferation and stem cell maintenance. When the Hippo signaling pathway is turned on, MST1/2 phosphorylate and activates LATS1/2. LATS1/2 phosphorylates and inactivates YAP in the cytoplasm which is sequestered and degraded, stopping cell proliferation and promoting differentiation of stem cells. Mechanical forces are transmitted across cells and tissues through the cell-cell junctions and the actin cytoskeleton. However, the factors that connect cell-cell junctions to the Hippo signaling pathway were not clearly known. We identified a LIM domain protein called TRIP6 that functions at the adherens junctions to regulate the Hippo signaling pathway in a tension-dependent manner. TRIP6 responds to mechanical tension at adherens junctions and regulates LATS1/2 activity. Under high mechanical tension, TRIP6 sequesters and inhibits LATS1/2 at adherens junctions to promote YAP activity. Conditions that reduce tension at adherens junctions by inhibition of actin stress fibers or disruption of cell-cell junctions reduce TRIP6-LATS1/2 binding, which activates LATS1/2 to inhibit YAP. Vinculin has been shown to act as part of a mechanosensory complex at adherens junctions. We show that vinculin promotes TRIP6 inhibition of LATS1/2 in response to mechanical tension. Furthermore, we show that TRIP6 competitively inhibits MOB1 (a known LATS1/2 activator) from binding and activating LATS1/2. Together these findings reveal TRIP6 responds to mechanical signals at adherens junctions to regulate the Hippo signaling pathway in mammalian cells.

Thema: „Einfluß der zyklischen mechanischen Dehnung auf humane Gefäßzellen aus der Tunica media von der Vene, Arterie und Aorta“ Autor(en): Neubert D. [1],Mohr F.W.[2], Dhein S.[2] Institut(e): [1]Sana Kliniken Leipziger Land, Gefäßchirurgie, Borna, Germany, [2]Universität Leipzig, Herzzentrum, Klinik für Herzchirurgie, Leipzig, Germany Fragestellung: Verhalten humaner glatter Gefäßmuskelzellen unter der zyklischen mechanischen Dehnung im Zellkulturexperiment. Methodik: Es wurden erstmalig Veränderungen der Proteinexpressionen von α-SM Aktin, Prolyl- 4-Hydroxylase, Decorin und Kollagen I unter statischen Bedingungen und zyklischer mechanischer Dehnung beobachtet. Hierzu wurden die Zellen mittels Gewebeverdau aus nativen humanen Arterien, Aorta und Venen gewonnen. Die Experimente wurden mit Hilfe einer „Flexercell strain unit“ durchgeführt und die Zellkulturen unter Zellkulturbedingungen auf „Bioflex“-kollagenbeschichtete Platten einer Dehnung von 10%, 0.5 Hz, 24 und 96 Stunden ausgesetzt. Die Proteinanalyse erfolgte mittels Western Blot. Ergebnis: Es läßt sich folgern, dass eine abnehmende und fehlende zyklische mechanische Dehnung eine Phänotypänderung der arteriellen Gefäßzellen aus der Tunica media von kontraktilen hin zum sekretorischen und proliferativen Typ bewirkt. Konträr verhält es sich unter Vorliegen einer zyklischen mechanischen Dehnung wie der pulsatilen Wanddehnung. Hierbei wird in den arteriellen Gefäßzellen der kontraktile Phänotyp ausgebildet. In den Gefäßzellen der Venen konnte unter Zellkulturdehnung eine starke Zunahme der extrazellulären Matrix und die Begünstigung des sekretorischen und damit proliferativen Typs beobachtet werden. Schlussfolgerung: Bei fortschreitender Arteriosklerose einhergehend mit der Abnahme der Wandelastizität und dadurch reduzierter pulsatiler Stimuli ist eine zunehmende Zellproliferation und Synthese von extrazellulärer Matrix zu erwarten, welche folgend die Progredienz stenotischer Gefäßveränderungen bewirken würde. In diesem Kontext begünstigen möglicherweise die medizinischen minimalinvasiven Behandlungen mit Stentgraftmaterialien die Gefäßwandhyperplasie mit Ausbildung von Restenosen. In der Gefäßchirurgie häufig beobachteten Stenosierungen im Bereich der Gefäßnaht könnten durch den Verlust der Wandelastizität und hierdurch Reduktion der Wanddehnung im Bereich der Nahtlinie erklärt werden. Unter Annahme einer geringeren Gefäßwandelastizität bei erhöhten Gefäßwandtonus wären Beobachtungen zu protektiven Massnahmen wie auch medikamentöse Behandlungen im frühen Stadium der pAVK wie zum Beispiel durch Abnahme des peripheren Gefäßtonus mit peripheren Vasodilatatoren sinnvoll. Die unter Zellkulturdehnung beobachtete starke Zunahme der extrazellulären Matrix der glatten Muskelzellen der Vene sollte eine Erklärung für die höhere Stenoseneigung durch Gefäßwandhyperplasie und Hypertrophie in arterialisierten Venen sein. Der regulatorische Einfluß des pulsatilen Stimulus findet im Zusammenhang mit dem Verständnis des humanen Gefäßsystems und dessen Erkrankungen einschließlich der Reaktion in vivo auf medizinische Eingriffe noch wenig Anerkennung.