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Capacité de modèles in vitro de complexité différente à prédire les réponses toxiques pulmonaires observées in vivo après exposition aiguë à des nanoparticules de TiO2 et de CeO2 / Predicting the in vivo pulmonary toxicity induced by acute exposure to TiO2 and CeO2 nanoparticules by using in vitro methodsLoret, Thomas 20 March 2017 (has links)
Les nanoparticules (NPs) représentent un danger potentiel pour la santé des travailleurs et du grand public, notamment en cas d’exposition par voie respiratoire. Si une NP est évaluée in vivo comme toxique chez l’animal, cela peut inciter à prendre des mesures pour réduire l’exposition de l’Homme à celle-ci, avant qu’il y ait des conséquences sanitaires graves. Les études in vivo sont donc d’une importance capitale afin de diminuer les potentiels risques sanitaires des NPs pour l’Homme. Néanmoins, dans un contexte de réduction du nombre d’animaux utilisés et compte tenu du nombre important de NPs existantes et de leur grande diversité physico-chimique, la toxicologie a besoin de modèles alternatifs, comme le in vitro, permettant de prédire de manière fiable les potentiels effets pulmonaires chez l’Homme. Des progrès importants ont été faits pour développer des modèles in vitro pulmonaires plus physiologiques et des méthodes d’exposition permettant de simuler l’inhalation de NPs in vitro. Cependant, des incertitudes existent quant à la capacité de ces nouveaux modèles in vitro à prédire les réponses observées in vivo dans les poumons après exposition à des NPs. Dans ce contexte, l’objectif de ce travail a été d’évaluer la capacité de plusieurs méthodes in vitro, de complexité différente, à prédire les effets toxiques observés in vivo chez le rat après exposition aiguë (24h) pulmonaire à des NPs métalliques faiblement solubles de TiO2 et de CeO2. Dans un premier temps, des expérimentations in vitro ont été effectuées afin d’évaluer si exposer des cellules alvéolaires à l’interface air-liquide (ALI) à des aérosols de NPs de TiO2 et de CeO2, générait des résultats différents par rapport à des expositions classiques à des suspensions en submergé. Dans un second temps, des expérimentations in vivo par aspiration intratrachéale ont été réalisées afin de comparer les réponses toxiques pulmonaires in vitro avec celles obtenues in vivo. Pour comparer les réponses pulmonaires in vivo et in vitro, des référentiels de dose similaires, notamment la masse par unité de surface ou par macrophage, ont été utilisés. Après 24h d’exposition, des réponses biologiques significatives (inflammation principalement) ont été observées in vitro à des doses inférieures à l’ALI par rapport au submergé. Nous avons par ailleurs souligné la nécessité de prendre en compte les doses réellement déposées sur les cellules ainsi que le débit de dose pour effectuer les comparaisons entre les deux méthodes d’exposition in vitro utilisées. Nous avons ensuite comparé les résultats in vitro avec ceux obtenus in vivo. Nous avons constaté que la méthode ALI générait des résultats plus prédictifs du in vivo, en termes de niveau d’activation des réponses toxiques à 24h. Finalement, nous avons établi un classement des quatre NPs utilisées dans notre étude et celles-ci ont été classées similairement in vivo et in vitro et quelle que soit la méthode utilisée in vitro. Nous avons par ailleurs montré l’importance de considérer la surface active des NPs pour établir ce classement. En conclusion, notre approche nous a permis de mieux évaluer le fossé existant entre le in vivo et le in vitro. Nos résultats soulignent l’intérêt d’utiliser des méthodes in vitro plus réalistes et plus proches de la physiologie humaine dans le but de modéliser les potentiels effets indésirables des NPs pour l’Homme. Cela ouvre des perspectives quant à l’utilisation et au développement de méthodologies in vitro de plus en plus représentatives des conditions d’exposition in vivo. / Nanoparticles (NPs) represent a potential danger for workers and public, especially after inhalation. When a NP is shown toxic for the lungs in vivo in animals, this can incite regulators to implement measures to reduce human exposure risks. The in vivo studies are thus of utmost importance in reducing the potential health risks for humans. However, in a context of a diminution in the number of animals used in experimentations and considering the high number of NPs used and their physicochemical diversity, there is an urgent need for alternative methods, like the in vitro, which could be used to predict the potential health effects of NPs in human. Many progresses have been made recently to develop more physiological cell models and exposure methods simulating the inhalation of NPs in vitro. Nevertheless, uncertainties remain regarding the capacity of these new in vitro methods to predict the biological responses observed in vivo into the lungs after exposure to NPs. In this context, the aim of our study was to assess the ability of several in vitro methods, differing in complexity, to predict the adverse responses observed in vivo in rat lungs after acute exposure (24h) to several metallic and poorly soluble TiO2 and CeO2 NPs. For this, in vitro experimentations were first performed to assess if exposing alveolar cells in monoculture or in co-culture at the ALI interface to aerosols of NPs, generated different results compared to classic exposure in submerged conditions to suspensions. In a second step, rats were exposed by intratracheal aspiration of NP suspensions to compare the biological responses in vitro to those obtained in vivo. To compare the pulmonary responses in vivo and in vitro, similar dose metrics were selected, including the mass per surface unit or per macrophage. After 24h of exposure, significant biological responses (mostly inflammation) were observed at lower doses at the ALI compared to in submerged conditions. Moreover, we highlighted the necessity to take into account the deposited dose on the cells and the timing of the dose delivery in order to compare the two exposure methods used in vitro. When we compared the responses in vitro to those observed in vivo, we noticed that the ALI methods generated more predictive results than the submerged one, in term of biological activation levels after 24h of exposure. Finally, a ranking of the four NPs used in our study was provided and the NPs were ranked similarly both in vivo and in vitro and whatever the exposure method used in vitro. We also showed the importance of the surface area when ranking the poorly soluble NPs. In conclusion, the gap existing between the in vivo and the in vitro has been evaluated in our study. Our results highlighted the relevance of using more realistic in vitro exposure methods to model the potential adverse effects of NPs for human. This brings perspectives about using and developing in vitro methods mimicking more closely the in vivo exposure conditions.
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Les images du cerveau : epistémologie de l'usage de l'imagerie cérébrale en sciences cognitives / Images of brain, philosophy of brain imaging in cognitive scienceGaillard, Maxence 19 October 2015 (has links)
Cette thèse d’épistémologie et d’histoire des sciences cognitives est consacrée à son niveau le plus général au problème de l’instrument scientifique, parent pauvre de la réflexion sur l’investigation scientifique, et se concentre à titre particulier sur le développement des techniques d’imagerie cérébrale fonctionnelle et leur introduction dans le domaine cognitif au cours des années 1980-1990. Un choix motivé notamment par la nouveauté et l’importance de ce nouvel instrument, dont l’émergence est régulièrement comparée à celle du télescope au moment de la Révolution scientifique du XVIIe siècle. La première partie est ainsi consacrée à une analyse générale de l’instrument scientifique et des problèmes essentiels qu’il soulève. Elle propose un certain nombre d’hypothèses en réponse, et en examine les enjeux théoriques. La deuxième partie défend une interprétation historique de l’émergence des deux technologies d’imagerie fonctionnelle que sont la tomographie par émission de positons et l’imagerie par résonance magnétique fonctionnelle. En reprenant dans le détail certains éléments d’invention et de diffusion de ces techniques, elle montre notamment l’intrication des procédures de validation des instruments et des divers mécanismes scientifiques et sociétaux qui poussent à les développer puis à les utiliser. A la lumière des analyses théoriques et générales de la première, et sur la base de l’interprétation historique de la seconde, la troisième partie est dédiée à l’examen des implications de ces nouvelles technologies d’imagerie sur l’évolution du champ des sciences cognitives et de la reprise de leurs résultats dans d’autres domaines, tant scientifiques que technologiques ou pratiques. A ce double égard, elle défend la thèse générale que l’introduction de l’imagerie agit beaucoup moins comme un facteur de résolution de certaines questions que comme un facteur de déplacement de la problématique et de l’impact théorique et sociétal des sciences cognitives. / At a general level, this dissertation in philosophy and history of cognitive science is devoted to the underestimated problem of scientific instruments. It is focused on some functional brain imaging techniques introduced in the field of cognitive studies during the 1980’s and 1990’s, the impact of such new technologies being sometimes compared to an instrumental revolution, in a way similar to the impact of the invention of the telescope on post-Galilean astronomy. The first part consists in a philosophical and historical analysis of the notion of scientific instrument. In this regard, some issues are raises and some hypotheses are formulated. The second part presents an interpretation of the historical emergence of Positron Emission Tomography and functional Magnetic Resonance Imaging. Dealing with details of the invention and circulation of those techniques, it shows in particular the entanglement of the validation procedures of instruments with the various scientific and societal mechanisms driving to their development and use. Taking its roots in the general analysis of the first part and the historical interpretation of the second part, the third part looks into the impact of the new functional brain imaging technologies on the evolution of cognitive science and the diffusion of its results in other domains. Concerning both cognitive science and larger aspects, it is argued that brain imaging is less a factor of resolution of specific questions than a factor of shifting in the problematics and the theoretical and societal significance of cognitive science.
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Les dynamiques de création contemporaine du Yuju à Taiwan : de la sauvegarde du patrimoine à l’expérimentation esthétique / The dynamics of contemporary creation of Yuju in Taiwan : from safeguarding of heritage to aesthetic experimentationMartin, Eléonore 18 November 2015 (has links)
Le Yuju 豫剧(traduit de manière impropre par « opéra du Henan ») est une forme spectaculaire chinoise chantée et codifiée, dite « traditionnelle », en provenance du Henan. Sa présence puis son maintien depuis plus de soixante ans dans le sud de Taiwan sont surprenants. Le Yuju est arrivé à Taiwan en 1949 avec le gouvernement et l’armée nationaliste battant en retraite face aux communistes. Depuis, le Yuju est toujours présent au répertoire d’une seule compagnie taïwanaise, la compagnie Henan bangzi : Taiwan Yuju 河南梆子:台灣豫劇. Les relations politiques entre la Chine continentale et Taiwan dictent la politique intérieure de l’île depuis 1949. Une indigénisation du régime et de la population réfugiée succède alors à une forte politique de sinisation où les arts classiques chinois étaient favorisés au détriment de la culture locale. Désormais, au contraire, la dimension multiculturelle est encouragée pour construire une identité taiwanaise propre. L’environnement taiwanais, pris dans cette tourmente politique, est a priori hostile au développement et à l’épanouissement du Yuju sur l’île. Ainsi pour la compagnie Henan bangzi : Taiwan Yuju, la question de la survie est fondamentale et il est essentiel pour elle de se constituer un public. Aussi nous interrogerons-nous sur les différentes stratégies mises en place par la compagnie depuis son arrivée à Taiwan (1953) jusqu’à aujourd’hui, pour assurer sa pérennité et attirer de nouveaux publics. Dans ce contexte spécifique, nous analyserons les différentes orientations esthétiques choisies par la compagnie, de la promotion des arts traditionnels à l’expérimentation esthétique. / The Yuju 豫劇 (improperly translated as "Henan Opera") is a comprehensive performing art from Henan, a province located in the central part of China. It blends stylized action, singing, dialogue and mime, to represent a story or depict different characters. It is often considered as a “traditional performing art”. Its presence and its preservation for more than sixty years in the southern Taiwan are quite surprising. The Yuju arrived in Taiwan in 1949 with the government and the Nationalist army retreating from the communist’s expansion in the mainland. Since then, the Yuju is always played by a unique Taiwanese company named Henan bangzi: Taiwan Yuju company 河南 梆子: 台灣 豫劇. Since 1949, internal politics of the island is largely determined by relations with Mainland China. An indigenization of both, the regime and the refugee population, comes up following a strong policy of bringing Taiwan under Chinese rule and culture. At that time, Chinese classical arts were favoured far beyond local culture. Nowadays, the multicultural aspect of the Taiwan society is encouraged in order to develop a specific Taiwanese identity. Such political context in Taiwan should be significantly hostile to the development of Yuju on the island. Thus, the survival of the Henan bangzi: Taiwan Yuju Company is fundamental and the company have to look for new audiences. Hence, we shall analyse what strategies the company implemented from its arrival in Taiwan in1953 till today, ensuring its sustainability while attracting new audiences. In this specific context, we shall analyse the different aesthetic directions chosen by the company from the promotion of traditional arts to aesthetic experimentation.
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Reducing remodularization complexity through modular-objective decouplingChern, Rick 11 1900 (has links)
This dissertation defines "modular-objective coupling", and shows that programming language designs which imply reduced modular-objective coupling reduce complexity of remodularizations--behaviour-preserving restructurings for which the only intended goals are to change program source code structure.
We explicitly distinguish between two points of view on program structure: modular structure--the structure of a program as a set of static text documents, and objective structure--the structure of a program as a dynamic computational model during execution. We define modular-objective coupling as the degree to which changes in modular structure imply changes to objective structure, for a given programming language.
We use the term remodularization to refer to any behaviour-preserving source code restructuring, for which the only intended goal is to change modular structure. We argue that programming languages with strong modular-objective coupling introduce accidental complexity into remodularizations, by requiring complex objective structure changes to achieve intended modular structure changes. Our claim is that a programming language design which implies reduced modular-objective coupling reduces remodularization complexity in the language.
To validate this claim, we first present SubjectJ, a subject-oriented programming system that extends Java. The design of Java implies strong modular-objective coupling, while SubjectJ is designed for reduced modular-objective coupling. We then perform a series of remodularization case studies comparing Java and SubjectJ. Our results suggest that remodularizations are less complex in SubjectJ. / Science, Faculty of / Computer Science, Department of / Graduate
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An Experimental Facility for Studying Heat Transfer in Supercritical FluidsJiang, Kai January 2015 (has links)
A state-of-art research facility has been built at the University of Ottawa, which is suitable for thermalhydraulic experiments in support of the development of the Canadian Supercritical-Water-Cooled Reactor (SCWR). The facility is a recirculating flow loop, using carbon dioxide as a medium and having three different test sections, two tubes with inner diameters of 8 and 22 mm, respectively, and a three-rod bundle. The loop can operate within ranges of pressure, temperature, heat flux and mass flux, which are of interest to the current SCWR design. The present thesis includes a comprehensive description of the facility. It also documents the procedure and results of its commissioning, as well as some preliminary measurements that have been collected so far. It is intended to provide an insight to the design of the facility and its functionality and to serve as a reference for future research activities. A number of tests performed by previous researchers in other facilities were replicated and nearly identical results were obtained. It was demonstrated that the design of the facility is sound and its performance is adequate within the intended ranges of operation conditions. It is expected that the results obtained in this facility will make a significant contribution to the understanding of supercritical heat transfer and pressure losses in the SCWR context.
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Analyse expérimentale et modélisation du comportement non linéaire thermomécanique de cloison en plaques carton-plâtre-carton, vissées et soumise à des charges thermiques et mécaniques / Experimental analysis and modeling of nonlinear thermomechanical behavior for partition wall with plates cardboard-plasterboard-cardboard, screwed and subjected to thermal and mechanical chargeDo, Thanh Trung 08 December 2011 (has links)
Dans le cadre de ce travail nous étudions le comportement thermomécanique d'une cloison légère faite de plaques carton-plâtre-carton (CPC) vissées sur une ossature métallique. Cette étude consiste d'une part à mener une analyse expérimentale pour identifier les propriétés thermiques, mécaniques et thermomécaniques des différents constituants de la cloison, et d'autre part, à développer un modèle analytique et un modèle numérique robuste du comportement thermomécanique non linéaire de cloisons légères soumises à un incendie naturel. Pour une modélisation robuste, nous avons d'une part développé un modèle du comportement thermomécanique de l'assemblage par vissage, et d'autre part développé un modèle global de la cloison légère en combinant, le modèle thermomécanique non linéaire du vissage, le modèle du comportement thermomécanique d'une plaque CPC et le modèle de l'ossature métallique. Comme il existe une grande variabilité dans les résultats expérimentaux, les incertitudes doivent être prises en compte. Pour ce faire, nous avons proposé d'utiliser un modèle probabiliste du comportement de l'assemblage par vissages / In this research, we study the thermomechanical behavior of a light partition wall made of carton-gypsum-carton (CGC) plates screwed to a metallic frame. This study consist firstly, to conduct an experimental analysis in order to identify the thermal, mechanical and thermomechanical propeties of the differents components of the light partition wall, and secondly, to develop an analytical model and a robust numerical model of nonlinear thermomechanical behavior of the partition walls subjected to natural fire. For a robust model, firstly, we developped a model of the thermomechanical behavior of the assembly by screws, and then developped a global model of the light partition wall by combining the nonlinear thermomechanical model of the assembly by screws, the model of the thermomechanical behavior of a CGC plate and model of the metal frame. As there is important variability in experimental results, the uncertainties must be taken into account. To do this, we proposed to use a probabilistic model of the behavior of the assembly by screw
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Expert Explanations of Protein-Folding and Dynamics Research: Implications for Biochemistry InstructionKathleen Jeffery (6391091) 15 May 2019 (has links)
Recent calls in education have emphasized the critical need for
curricula in the sciences to support student development of the general and
disciplinary-specific practices that are relevant to modern scientific research
and careers, as well as foundational scientific knowledge that reflects recent
advances. In this regard, the life sciences, including biochemistry, have been
under pressure to develop curricula that reflect current research knowledge and
practices, and that develop student competence in areas such as experimentation
and visualization. In contrast to these calls, biochemistry textbooks, and
instruction based on them, seldom discuss how disciplinary knowledge is
combined with experimental work or other disciplinary resources to investigate
and communicate about biochemical phenomena. This is of great concern given
that graduates entering life science careers must be able to reason with relevant
disciplinary knowledge, utilize experimental research methods, and navigate
data representations in order to solve research problems. It is therefore
crucial for biochemistry instruction to expose students to the ways in which
expert scientists navigate and reason with disciplinary resources in cutting-edge
scientific research on topics such as protein folding and dynamics, the focus
of this project. Thus, this dissertation aims to fill a gap in our
understanding of how expert research scientists explain protein-folding and
dynamics research, and how that research knowledge can be used to inform the development of instructional
materials in this crucially important area of biochemistry. To address this
goal, we explore three overarching research questions: How can we model experts’ explanations of their research related to
protein folding and dynamics? (RQ1); How do experts use representations to
explain their protein-folding and dynamics research? (RQ2); and How can we use
expert research to inform the design and implementation of instructional
materials aimed at developing biochemistry students’ understanding of protein-folding
and dynamics? (RQ3). To address these research questions, we first collected and analyzed
interview data from four experts to explore the nature of their research
explanations. This data was used to develop a model (i.e. the MAtCH model) of
how experts integrate theoretical knowledge with their research context, methods,
and analogies when explaining how phenomena operate (RQ1). In doing so, we also
established how the experts use and combine explanatory models depending on the
phenomena discussed and their explanatory aims, as well as how they explain
thermodynamic and kinetic concepts relevant to protein folding in ways that
align with their experimental research methods. We then examined selected representations
from the expert interviews to explore how experts use language and representations
to create meaning when explaining their research (RQ2). In comparing these to
representations from biochemistry textbooks, analysis of the data indicated
that textbooks generally explain ‘what is known’ but seldom explain ‘how it is
known,’ whereas the experts use a combination of language, multiple
representations, and gestures to explain how experimental research methods can
provide evidence for phenomena. From this analysis, suggestions were made
regarding the design of instructional materials to support discussion of experimental
research methods and student interpretation of representations in classroom
activities. In the final study, these suggestions were used in combination with
additional analysis of expert research to inform the development anticipated
learning outcomes (ALOs) and the design of instructional materials aimed at
developing biochemistry students’ understanding of protein folding and dynamics
(RQ3). The materials focus on the use of hydrogen-deuterium exchange mass
spectrometry (HDX-MS) to study changes in protein structure due to denaturation
and interactions with other molecules. The instructional materials were piloted
in an undergraduate biochemistry course for the health sciences, and the nature
of students’ understandings were explored. Our
findings suggest that research practice – including research context,
experimental methods, and representations – influences reasoning and
explanation, providing additional evidence of the importance of developing
discursive literacy in science students. To that end, a major implication of
this work is that student knowledge of experimentation and representation may
be a critical component of developing functional scientific understanding. Each
of the studies contained in this dissertation therefore suggests ways in which
practitioners may use our findings to modify instruction and instructional
materials so that they are more aligned with expert practices. In order to
teach students how scientific research underpins factual knowledge in biochemistry,
future research should continue to explore experts’ use of disciplinary
resources and ways of thinking in order to inform teaching and learning
strategies and materials that can support the development of students’
disciplinary literacy.
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Automatisation et amélioration de performances d'application pick & place multi-robots / Automation and improvement of performance of multi-robot pick & place applicationsHumbert, Gaël 25 April 2016 (has links)
Cette thèse s'inscrit dans le domaine de l’emballage et du conditionnement. À notre connaissance, dans le monde industriel et académique, il n'existe pas d'outils de simulation qui prennent en compte toutes les étapes du cycle de développement afin d'aider au dimensionnement et à l'amélioration des performances d'application pick & place multi-robots. Il existe des outils performants répondant à un seul besoin mais aucun logiciel répondant à tous. L'objectif de ces travaux est le développement d'une méthodologie utilisable, à l'aide d’un unique outil logiciel, tout au long du cycle de création d’une application pick & place. Dans un premier temps, la cinématique des différents robots ainsi que leur environnement sont abordées. Dans un second temps, les stratégies de commande, permettant le travail individuel et collaboratif des robots, sont développées. En dernier lieu, le transfert du programme de la simulation à l'expérimentation est effectué de façon automatisée. A chaque étape, une phase de tests est initiée. Des tests comportementaux pour vérifier le fonctionnement des robots et leur interaction avec leur environnement sont effectués. Des essais en simulation des différents algorithmes sont réalisés suivant différentes configurations d'applications pick & place. Enfin, la comparaison entre les résultats obtenus en simulation et en expérimentation montre la pertinence de la démarche proposée. / This work belongs to the field of packaging. To best of our knowledge, in industrial and academic context, there are no digital tools that take into account all the steps of the development cycle to assist in the sizing and in the improvement of performance of multi-robots pick & place applications. The aim of these works is the development of a methodology usable, using a single software tool, throughout the creation cycle of a pick & place application. Firstly, kinematics of different robots and their environment are addressed. Secondly, control laws for individual and collaborative work of robots are developed. Finally, the transfer of the program from simulation to experimentation is carried out. At each step, a testing phase is initiated. Behavioral tests to check the robots operation and their interaction with their environment are performed. Simulation tests of the different algorithms are carried out according different configurations of pick & place application. Finally, a comparison between the result in simulation and in experimentation shows the relevance of the proposed approach.
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Développement de nouvelles méthodes de mesure du frottement transversal entre fibres / Development of new measurement methods of transversal friction between fibersGassara, Houssem Eddine 13 December 2016 (has links)
Le comportement mécanique des structures fibreuses, particulièrement le comportement transverse de filés de fibres et de mèches multi-filamentaires est tributaire entre autre du contact et glissement inter fibre. La connaissance de loi de comportement en compression transverse est un verrou scientifique de taille lors de la modélisation numérique du comportement mécanique de structures fibreuses. La mesure des propriétés frictionnelles des fibres, dont les dimensions transversales sont en général très faibles, est une entreprise très délicate. Le contact et le mouvement relatif entre deux fibres, malgré leurs complexités peuvent être résumés par trois cas simples, schématisés ci-dessous. Il existe dans la littérature scientifique un certain nombre d’études et de dispositifs sur le contact et le frottement interfibre, mais ils se concentrent tous sur les cas A et B, rien ne permet pour l’instant de modéliser et de mesurer le frottement interfibre dans la configuration C. Or, c’est bien dans cette dernière configuration que se produisent les mouvements interfibre lors de la compression transversale des filés ou mèches multi-filamentaire. De nouveaux dispositifs expérimentaux ont été conçus et développés afin de caractériser le frottement transversal entre fibres. / The mechanical behavior of fibrous structures, particularly the transverse behavior of spun yarns and multi-filament strands is among others dependent on contact and inter fiber slippage. Knowledge of law of transverse compression behavior is a relatively important lock at numerical modeling of fibrous structures’ mechanical behavior. Measuring of frictional properties of very thin fibers is not easy because of very low levels of normal and tangential interfiber forces developed during the fiber contact. The contact and relative motion between two fibers, despite their complexity, can be summarized by three simple cases shown above. In scientific literature, there are a number of studies and experimental devices on interfiber contact and friction, but they all focus on the A and B cases; nothing is proposed unfortunately in the experimental literature on the t-t friction measurement type (case (c) in Figure above). However, it is in this configuration that the inter fiber movements occur during transverse compression of yarns or multi-filament strands. New experimental devices have been designed and developed in order to characterize the transversal friction between fibers.
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Ethanol Tolerance in the Rat Neurohypophysis: a DissertationKnott, Thomas K. 01 January 2001 (has links)
One of the main components underlying drug addiction is the emergence of tolerance. Although its development is a complex issue, and is believed to have both psychological and physiological connotations, it is clear that some physiological change must occur that would enable an organism to withstand drug concentrations lethal to a naïve system. The purpose of this thesis was to identify and study a physiological mechanism, whose characteristics were altered due to chronic exposure to ethanol.
Vasopressin (AVP), whose primary function is to control water balance, release from the neurohypophysis is suppressed by an acute ethanol challenge. Therefore, I hypothesized; 1) that chronic ethanol exposure would reduce the normal suppression of AVP release during an acute ethanol challenge and 2) that the ion channels that are acutely sensitive to ethanol, involved in the control of AVP release, would exhibit a change in their ethanol sensitivity and characteristics.
To study the hypothesis, I utilized the neurohypophysis from rats chronically exposed to ethanol and yoked controls to determine whether chronic exposure would modify the acute ethanol sensitivity of the neurohypophysial vasopressin release mechanism. I examined whether the long-term ethanol exposure affected the suppression of vasopressin release from either or both the intact neurohypophysis and the isolated neurohypophysial terminals. In addition, I investigated how chronic exposure affected two types of potassium channels, the ethanol sensitive large conductance Ca+2-activated (BK) channel and the fast inactivating (IA) channel known to be insensitive to physiologically relevant concentrations of ethanol.
I was able to establish that chronic ethanol exposure reduced the suppression of vasopressin release by an acute ethanol challenge from both the intact neurohypophysis and the isolated neurohypophysial terminals. In addition, I discovered that oxytocin release was affected similarly. I concluded from this data that chronic exposure to ethanol affected a general mechanism, which controlled hormone release from the neurohypophysis, and that this mechanism could be isolated to the neurohypophysial terminals.
I also used electrophysiological techniques to study ion channel characteristics of both the BK and IA potassium channels. I found that in naïve rats, BK channels were potentiated and IA channels insensitive to physiological relevant concentrations of ethanol. But in chronic ethanol-exposed rats the BK channels exhibited a reduced sensitivity to ethanol while IA channels were inhibited. In addition, the current density of the BK channel was significantly reduced. These results show that at least one characteristic of each potassium channel has been modified. This suggests that chronic exposure can not only modify the ethanol sensitivity of ion channels known to be ethanol-sensitive, but also those believed to be relatively insensitive. Therefore, since modifications in these channels have previously been shown to alter the duration and frequency of action potentials, I conclude that these ethanol-induced modifications play a role in the modified hormone release patterns observed in the chronically exposed rats.
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