Steric regulation of tandem calponin homology domain actin-binding affinity.

Tandem calponin homology (CH1-CH2) domains are common actin-binding domains in proteins that interact with and organize the actin cytoskeleton. Despite regions of high sequence similarity, CH1-CH2 domains can have remarkably different actin-binding properties, with disease-associated point mutants known to increase as well as decrease affinity for F-actin. To investigate features that affect CH1-CH2 affinity for F-actin in cells and in vitro, we perturbed the utrophin actin-binding domain by making point mutations at the CH1-CH2 interface, replacing the linker domain, and adding a polyethylene glycol (PEG) polymer to CH2. Consistent with a previous model describing CH2 as a steric negative regulator of actin binding, we find that utrophin CH1-CH2 affinity is both increased and decreased by modifications that change the effective "openness" of CH1 and CH2 in solution. We also identified interface mutations that caused a large increase in affinity without changing solution "openness," suggesting additional influences on affinity. Interestingly, we also observe nonuniform subcellular localization of utrophin CH1-CH2 that depends on the N-terminal flanking region but not on bulk affinity. These observations provide new insights into how small sequence changes, such as those found in diseases, can affect CH1-CH2 binding properties

Aspectos jurídicos e implicações da repercussão geral como pressuposto de admissibilidade do recurso extraordinário

Os nuances jurídicos afetos à repercussão geral como pressuposto de recurso extraordinário perfazem o objeto nuclear deste trabalho. Desde a concepção do instituto pela emenda constitucional nº 45 de 2004 até os fenômenos processuais decorrentes de seu julgamento, estudada previamente a figura do recurso extraordinário, serão pesquisados o escorço histórico, bases normativas, panorama ensejador, características e processamento do instituto. Quanto aos aspectos procedimentais, o foco residirá nas consequências jurídicas do manejo da repercussão geral enfatizando-se o sobrestamento de recursos nos órgãos de origem durante o julgamento do leading case pelo Supremo Tribunal Federal. Destaca-se a questão da sucumbência às partes daquelas demandas sopesadas, imposta por ocasião de decisão desfavorável no julgamento por amostragem pelo STF, podendo ser compreendida como hipótese indevida de mitigação do direito de ação. Nesse ponto, será discorrida a possibilidade de se contemplar o amicus curiae como instrumento hábil àqueles sucumbentes para que possam reverter eventuais ônus gerados pela decisão paradigma

Optimization of Tensor Controlled-Source Electromagnetic Exploration Methods: Case Study from Trachyte Mesa Intrusion, Henry Mountains, Utah

The Henry Mountains in Utah are home to several small igneous intrusions from the Late Oligocene to Early Miocene. One of the most critical small satellite bodies to the main intrusions of the Henry Mountains is the Trachyte Mesa intrusion. What is interesting about the Trachyte Mesa intrusion is that geologist and geophysicist are able to observe outcrops on the surface of Earth in order to characterize the mesa. An important question that is continuously being researched about this area concerns the emplacement of these intrusions. Scientist believe that by understanding the internal structure of these intrusions, answers regarding the emplacement of these intrusions will appear. There has been debate, however, regarding this internal structure. The main dispute is between two structural geologists who have competing ideas regarding Trachyte Mesa after conducting magnetic surveys in the area. Sven Morgan (2008) has concluded that the Trachyte Mesa intrusion internal structure is based on a sheet magma stacking model. Whereas Paul Wetmore (2009) believes that the mesa took the shape of the surrounding rock structures. In order to shed further light upon this dilemma, the original aim of the project was to conduct a tensor control-source electromagnetic characterization survey of the area and produce a model of the Trachyte Mesa intrusion. Due to several complications with responses from the equipment, the aim of the project was modified. The new goal is to discover the cause of the unusual signals from the equipment, whether it be from equipment malfunctions or the resistive environment present at Trachyte Mesa. With the extensive testing of equipment, a controlled-source electromagnetic survey process that will pave the way for future projects using the same methodology will also be established

Bridging Gaps: Urban Planning for Coexistence

Urban planning as a discipline has been continuously evolving in the past decades, aiming to become the response to diverse issues through transdisciplinarity, innovation, creativity and justice. As a result of an ever- accelerating pace of life, we constantly witness worldwide transitions and turbulences, from environmental crises to socio-economic struggles, that challenge cities, regions, and the nature of the planning discipline itself. Climate change and both natural and man-made disasters render territories fragile and force humans and species to migrate, while the growing urban population requires solutions for sustainable transformation for life in the city and beyond. In this context of increasing uncertainty, the planning discipline attempts to suggest ways forward, yet often lacks in providing tangible examples of how to bridge theory and practice. Within this framework, the conference focuses on the predominant discontinuities that currently characterise the planning field. Those are articulated into two directions of discussion that are in dialogue with and between each other: the urban-rural divide (Track 1 and Track 2) and the academia-practice divide (Track 3 and Track 4). The conference aims to create space for these dialogues to emerge, and to ultimately bridge these gaps by reflecting on our role as researchers, on our position towards, and in relationship with, society and on the effectiveness of practice. The questions that arise are timely and crucial, contemplating on the complexities inherent in a perpetual endeavour for coexistence between humans, species and the environment (Track 5). How can planning reinvent itself? How can we reconcile a holistic perception of territories? Which theories, strategies and methods should planning adopt so as to contribute to a better future for the human and natural species? Which are the tools and practices that will ensure human well-being and coexistence with the world

The Mechanoregulation of the Actin Cytoskeleton

The actin cytoskeleton is essential for maintaining mechanical integrity of cells and tissues and for providing structural support during dynamic processes including migration, endocytosis and cytokinesis. From a molecular perspective, it consists of (1) actin monomers polymerized in double helical filamentous structures and (2) an ensemble of regulatory proteins that regulate shape and function of actin structures. From a mechanics perspective, the cytoskeleton is a dynamic entity that can generate force while being subject to various load perturbations. Though molecular understanding of actin networks is extensive, our understanding of how molecular signaling is converted to force output and how force input feeds back into molecular activity remains limited. The goal of this dissertation is to investigate how the interplay between molecular and mechanical attributes of the actin cytoskeleton results in desired cellular activity and physiological phenotypes. We first focus on the leading edge of migrating cells where nucleation of branched actin structures is involved in membrane protrusion. In chapter 2, we investigate the effect of the biochemical composition of these structures on the observed dynamic properties of network growth. To do so, we reconstitute branched actin network assembly using a minimal set of essential proteins (i.e. nucleation promoting factors, ARP2/3 and capping proteins) and evaluate their role over a broad range of concentrations. We find that in the absence of opposing force, changes in the nanomolar range of soluble protein concentration significantly modulates architectural and kinetic properties of nucleating actin structures. In cells, branched actin networks do not just transmit forces in the form of protrusion but also resists opposing load imposed by the membrane and other physical barriers. In chapter 3, we use atomic force microscopy to study the impact of external force on the biochemical composition and mechanical properties of reconstituted branched actin structures. Interestingly, we find that mechanical loading alters network density and composition, which in turn modulates its bulk mechanical properties and renders it stiffer, more powerful and efficient. Central to assembly and function of actin networks is the activity of actin binding proteins. We next extend our investigation to ask whether forces on actin filaments can influence actin binding protein (ABP) localization and activity in the cytoskeleton. Despite sharing the same cytoplasm, ABPs in cells spatially segregate and differentially regulate actin structures. In the context of the leading edge of migrating cells, cofilin binds and severs filaments in the lamellipodia, whereas tropomyosin is secluded as it binds and stabilizes filaments in the lamellum. In chapter 4, we hypothesize that these proteins are mechanosensitive and show that cofilin preferentially binds to network structures subject to compression whereas tropomyosin favors relaxed structures. Lastly, in chapter 5, we explore the sensitivity of calponin homology domain-containing proteins to the mechanical state of actin filaments. We focus our study on wild type and mutated versions of the utrophin actin binding domain, which is used as a universal actin marker. Using a multiscale biophysical approach, we show that mutant utrophin can selectively bind highly stressed actin filaments in vitro and in cells. We use this mutant to develop a ratiometric actin mechanosensor for mapping physiological forces in-vivo which provides a new tool for exploring mechanoregulation of cellular processes. Overall, the findings in this dissertation provide direct evidence for the importance of mechanical perturbations in regulating structure and function of the actin cytoskeleton

Les télévisions au Liban aujourd'hui

Cette recherche décrit le paysage télévisuel au Liban qui reflète l image des identités politico-communautaires. Que regarde le public libanais ? Deux enquêtes quantitatives auprès d un échantillon représentatif de 1439 personnes de tous bords vont montrer que le téléspectateur se réfugie auprès de la chaîne qui représente sa communauté religieuse et/ou ses convictions politiques. Quel est le contexte politique au Liban et dans quelle mesure chaque parti, clan féodal ou confession ont eu leur mot à dire dans la régularisation du paysage audiovisuel ? Quelles sont ces chaînes et quels sont les objectifs de leur propriétaire ? L assassinat du Premier ministre Rafic Hariri et la division des Libanais entre les blocs de 14-Mars et de 8-Mars a conduit à une division similaire des médias. La diffusion par satellite de la LBC et de Future TV a rendu à Beyrouth sa place primordiale dans la production de programmes de divertissement avec des présentatrices à la Jennifer Lopez , un savoir-faire à la libanaise et un professionnalisme dans l adaptation des émissions comme Star Ac et Super Star. Ces deux chaînes à puissance médiatique transnationale font vibrer les cœurs dans les ménages arabes et caressent leurs rêves les plus fous. En audience, elles sont ainsi parmi les premières chaînes au Moyen-Orient. Tandis qu Al-Manar occupe une place notoire à côté des autres chaînes panarabes tout info.La grille des programmes de chaque chaîne est étudiée : elle est envahie par des feuilletons égyptiens, syriens, mexicains ou turcs et des programmes femmes et satiriques. Une place proéminente est accordée aux JT et émissions politiques au détriment de la culture, de la jeunesse, de l économie et des émissions francophonesPARIS-CUJAS-BU Droit (751052119) / SudocSudocFranceF

Incidence des itinéraires culturaux (fertilisation foliaire azotée, irrigation et hauteur de haie végétale, sur la composition azotée des baies de Vitis vinifera en climat méditerranéen)

Compte tenu des changements climatiques, la vigne dans les régions méditerranéennes est de plus en plus soumise à des conditions de sécheresse estivale prononcée provoquant des contraintes hydriques plus ou moins intenses. L absorption d azote, extrêmement dépendante de l eau du sol, peut être très réduite, voire bloquée, entraînant une résonance importante sur la composition des baies, en particulier au niveau de la concentration en azote avec des conséquences sur la fermentescibilité des moûts. Ce travail comporte une étude très fine de la composition azotée des baies dans leurs différents compartiments tout au long du cycle végétatif. A la lumière des résultats, des solutions sont proposées, permettant d assurer la qualité des raisins issus de vignes soumises à des conditions de contrainte hydrique sévère, parmi lesquelles la fertilisation foliaire azotée apparaît comme un moyen efficace. Notre travail met en évidence l effet améliorateur, sur la composition azotée des baies de plants de Vitis vinifera, de pulvérisations foliaires d azote à différents niveaux de contrainte hydrique : les effets dose , stade d apport et ceux de l interaction croisée dose-stade d apport sont explorés. L effet de l interaction alimentation hydriquehauteur de haie foliaire est également étudié. D une manière générale, la fertilisation foliaire affirme son efficacité dans toutes les expérimentations et révèle que plus la carence azotée ou hydrique est marquée, plus l effet de la fertilisation foliaire est important. L apport à véraison, par rapport aux autres stades de développement, est le plus approprié pour améliorer la teneur des baies en azote. Dès la dose de 10 kg N/ha apportée à cette période clé, les carences azotées des moûts sont enrayées. Ce travail contribue à la connaissance de la distribution de l azote apporté par voie foliaire, de l évolution de certains acides aminés comme la glutamine et l arginine ainsi que du métabolisme et de la remobilisation de l azote dans la vigne durant la maturation. Nous révélons aussi l incidence de la fertilisation foliaire azotée, de l irrigation et de la hauteur de haie foliaire sur la synthèse des précurseurs d arômes en particulier ceux du sulfure de diméthyle.MONTPELLIER-BU Pharmacie (341722105) / SudocSudocFranceF

Optimization of catheter’s implementation in the mold, in the case of vaginal HDR brachytherapy treatment

Background: The purpose of this study was to evaluate and compare results obtained in high dose rate (HDR) brachytherapy treatment of vaginal cancer. Different catheters distributions inside the custom mold were explored. The difference between those distributions is the position of the posterior catheter located near the rectum in the actual custom mold applicator used in different hospitals, each one having a catheter displacement of 0.5 which is equal to the length of a step position. The best catheters distribution offering an optimal dose distribution: better coverage of the clinical target volume (CTV), while reducing the dose received by organs at risk (OARs), were discussed. Materials and methods: A group of 60 patients treated with HDR brachytherapy, alone or in combination with external radiotherapy, was investigated. A custom mold is normally used for HDR brachytherapy vaginal cancer treatment. Three different geometrical positions of the catheters (G1, G2 and G3) and, consequently, 3 different dosimetries were simulated out for each patient on the CT images, using the Oncentra planning system. The coverage of the CTV was studied. Results: The average volume treated was 30.46 cc (min = 9.8 cc, max = 70.86 cc). The total prescribed dose, including external and internal radiotherapy, was 80 Gy. We evaluated conformity index (CI), dose homogeneity index (DHI) and conformality index (COIN) indices for the three implantation geometries to reach the same coverage criteria of the CTV. The D2cc parameter allowed the evaluation of the dose received by the OARs. For the rectum, a dose reduction of 9.67% (range 0.29–32.86) was obtained with the second geometry of implantation compared to 10.14% (range 1.43–28.33) with the third geometry. For the bladder, the second geometry of implantation showed a better preservation for this organ [15.93% (range 0.86–58.71) vs. 8.35% (range 0.33–30.43) with the third geometry]. The sigmoid was more protected using the second plan of implantation as well [6.33% (range 0.14–40.71) for the second implantation compared to 5.95% (range 0.33–36) for the third implantation]. Conclusions: G2 and G3 catheters’ distribution, having catheter position farther from the mold wall and so from the vaginal wall compared to the catheter position applied showed a better protection for the OARs while giving the same prescribed dose for the CTV