La schizophrénie est un trouble mental débilitant qui se caractérise par des perturbations de la pensée, des émotions et de la cognition. Ces processus d’intégration fonctionnelle sont généralement associés à des oscillations bioélectriques cérébrales synchrones dans la bande de fréquence gamma (30-80 Hz), lesquelles sont aussi altérées chez des patients souffrant de schizophrénie. Ce travail de thèse vise à développer des méthodes et des outils pour étudier les mécanismes neuronaux sous-tendant les altérations de ces oscillations physiopathologiques. Pour ce faire, nous avons développé des modèles de rongeurs de laboratoire pour la schizophrénie. Nous avons démontré que des modifications génétiques ou pharmacologiques conduisent à des perturbations des oscillations gamma et que des médicaments antipsychotiques peuvent les moduler. / Schizophrenia is a debilitating mental disorder that is characterised by a breakdown in normal thought processes, blunted emotional responses and a variety of cognitive difficulties. Gamma frequency (30 – 80 Hz) oscillations are associated with many processes that are disrupted in people with schizophrenia memory, perception and attention. This thesis aimed to develop methods and tools to investigate the basic mechanisms that underlie the alterations in gamma frequency brain activity that are observed in patients suffering from schizophrenia. To do this we developed a variety of experimental animal models for schizophrenia. We successfully demonstrated that both genetic and pharmacological changes lead to alterations in gamma oscillations and that antipsychotic medications can modulate them.

La rétine a une physiologie rythmique contrôlée par une horloge circadienne dont la localisation et l’organisation sont peu connues chez les mammifères. Nous avons étudié in vitro l’horloge rétinienne du rat et de la souris grâce au suivi par bioluminescence des rythmes d’expression d’éléments de son mécanisme moléculaire, le gène Period1 et la protéine PERIOD2 respectivement. Nous avons montré que chacune des trois couches rétiniennes contient un oscillateur circadien fonctionnel, mais que la période de leurs oscillations est très rallongée par rapport à celle du tissu entier et dépend d’un couplage asymétrique entre les couches. Nous avons montré par pharmacologie que le glutamate, le GABA, la glycine et la dopamine ne sont pas indispensables à ce couplage, et que les caséine kinases 1δ et 1ε modulent largement la période de l’horloge rétinienne. Finalement, nous avons observé un couplage au niveau cellulaire également, qui met en jeu, au moins en partie, les jonctions communicantes. / The retina exhibits physiological rhythms that are under the control of a circadian clock whose location and organization are poorly understood in mammals. We studied the retina clock in rat and mouse through in vitro bioluminescence monitoring of the rhythmic expression of molecular elements of the clockwork: the Period1 gene and the PERIOD2 protein respectively. We showed that each of the three retinal layers harbors a functional circadian oscillator, which period is strikingly longer than in the whole retina and depends on asymmetric coupling between layers. We pharmacologically investigated the nature of the coupling signals and showed that glutamate, GABA, glycine and dopamine are dispensable. We nevertheless highlighted that casein kinases 1δ and 1ε strongly modulate the period of the retina clock. Finally, we observed that the retina clock also entails cell-to-cell coupling that involves at least partially gap-junctions.

La mesure récente de l'angle de mélange theta-13, à laquelle l'expérience Double Chooz contribue, a ouvert la voie aux futures expériences de la physique des neutrinos. Dans ce manuscrit, la caractérisation de certains bruits de l'expérience sont décrits. Les muons cosmiques qui s'arrêtent et se désintègrent dans le détecteur sont mal reconstruits, résultant en distorsion de la distribution temporelle des signaux laquelle peut être utilisée pour identifier ce type de fond. Les neutrons rapides créés par spallation par les muons cosmiques produisent de nombreux protons de recul qui peuvent entraîner un décalage dans la distribution temporelle des signaux et ainsi être identifiés. Ces distributions temporelles ont aussi été utilisées pour identifier la formation de l'état d'orthopositronium en observant et en mesurant un délai entre l'ionisation du positron et l'annihilation de celui-ci, pouvant permettre une séparation positron-électron. / The measurement of the theta-13 mixing angle, to which the Double Chooz experiment contributed, paves the way to future findings in neutrino physics. In this manuscript, we describe the characterization of some Double Chooz backgrounds. Cosmic muons that stop and decay in the detector are characterized by anisotropic emission of the scintillation light, causing the vertex to be poorly reconstructed. The resulting pulse shape distortion can be used to tag and remove such background. Fast spallation neutrons producing multiple recoil protons may produce a similar distortion in the pulse shape and can also be tagged. Pulse shapes are also used to identify the formation of ortho-positronium. The tagging of such electron-positron bound state is made possible by the induced distortion in the pulse shape due to the delay in the positron annihilation, and can be used for an electron-positron separation.

The effects of a non-zero background state on atmospheric dynamics is explored through simple models and observations. Firstly, we examine the effects of moisture gradients on the stability and propagation of Rossby waves in a mid-latitude -plane. We begin by a consistent derivation of the forced quasi-geostrophic equations on a -plane to understand the constraints placed by geostrophy on the time scale of condensation. We see that the presence of meridional gradients of moisture results in a slowdown of the waves. On the introduction of zonal gradients of moisture, the waves become unstable, and for certain parameters which are representative of the real atmosphere, they propagate eastward and mature on an intra-seasonal timescale. The mechanism of the in hence of moisture on waves is understood by thinking of condensation as providing an \equivalent" potential vorticity (PV) gradient which opposes the dynamical PV gradient. Secondly, we look at the effects of a mean background ow on the Matsuno-Gill response in the spherical shallow water system. The mean ow is prescribed to resemble the climatological upper tropospheric zonal wind structure in the atmosphere. As the strength of the ow increases, the equatorially trapped Matsuno-Gill response rst transforms into a poleward propagating Rossby wavetrain. As the strength of the mean ow reaches values similar to that observed in the atmosphere, the stationary wave response becomes a zonally oriented quadrupole structure. This structure bears a striking resemblance to the observed upper level structure of the Madden-Julian oscillation (MJO). The time evolution of this quadrupole structure is quick enough to be relevant on MJO timescales, and the structure is quite robust across a range of values for the drag coefficient. Finally, we look at the role played by low frequency variability in the Pacific in the recent expansion of the Hadley cell. We find that the dominant effect of the low frequency variability is a stationary dispersive Rossby wavetrain extending from the tropical Paci. We further find that most of the observed expansion of the Hadley cell can be accounted for by this low frequency variability. We nd that large scale changes such as the changes in the equator-pole temperature gradient or midlatitude static stability need not be invoked to understand the observed expansion.

La dynamique du déclenchement des avalanches dans un milieu granulaire lentement incliné passe par trois phases; (1) des petits réarrangements locaux et indépendants de grains (2) suivis de mouvements collectifs, successifs et quasi-périodiques, appelés 'précurseurs' (3) finissant par une avalanche. Cette dynamique peut dépendre de nombreux paramètres. Dans cette thèse, nous avons étudié, par des mesures optiques et acoustiques, la réponse du milieu granulaire soumis à une inclinaison lente de son container. Nous avons déterminé l'importance du choix de la puissance du signal acoustique sur nos mesures. Nous avons observé l'effet de l'état de surface des grains sur l'apparition des précurseurs et sur l'occurrence de l'avalanche. Nous avons réalisé des cycles d'inclinaison allant de -θ à +θ se terminant par une avalanche . Nous avons mis en évidence l'influence de l'angle du cycle θ sur les précurseurs et l'angle d'avalanche final. Nous avons aussi étudié des milieux granulaires soumis à des taux d'humidité comprises entre 40 et 96, par des mesures optiques surfaciques et latérales. Nous avons montré que les angles d'avalanche et l'apparition des premiers précurseurs dépendent de la taille des grains mais aussi de l'humidité. Cette dépendance est liée aux forces de cohésion qui sont relativement plus élevées à forte humidité et qui compensent la force de gravité pour des petits grains. Enfin, nous avons montré l'importance d'une diffusion homogène de l'humidité dans le milieu sur son comportement. L'impact de la mouillabilité des grains a été aussi abordé. / The dynamics of avalanche triggering in a slowly inclined granular medium passes through three phases; (1) small local and independent rearrangements of grains (2) followed by collective, successive and quasi-periodic movements, called 'precursors' (3) ending in an avalanche. This dynamic can depend on many parameters. In this thesis, we have studied, by optical and acoustic measurements, the response of the granular medium subjected to a slow inclination of its container. We determined the importance of choosing the power of the acoustic signal on our measurements. We observed the effect of the grain surface condition on the occurrence of precursors and the occurrence of the avalanche. We performed tilted cycles ranging from -θ to +θ ending in an avalanche. We have demonstrated the influence of the θ cycle angle on the precursors and the final avalanche angle. We have also studied granular media with moisture contents between 40 and 96%, by surface and lateral optical measurements. We have shown that the avalanche angles and the appearance of the first precursors depend on the grain size but also the humidity. This dependence is related to cohesive forces that are relatively higher at high humidity and that compensate for the force of gravity for small grains. Finally, we have shown the importance of a homogeneous diffusion of moisture in the environment on its behavior. The impact of grain wettability was also discussed.

This work deals with the power supply of wireless sensors. When using a wireless sensor is desirable application of alternative energy sources, because the primary cells or batteries may reduce the extent or length of service of the sensor itself. Ambient energy can be used as a suitable alternative source. This energy must be in an appropriate form, which allows its conversion to electric energy. These appropriate, already used types include: solar en., temperature gradient en., en. of flowing liquids, vibration, etc. The advantage of vibrations is its presence in almost all mechanical systems. One of the possibilities for using the vibration of machine systems for power supply wireless sensors is using the vibration power generator with oscillating component. The generator must be designed so that its resonance frequency coincides with the frequency of vibration in the machine system. This method can be used only if the machinery system vibrations at least partially constant. Another option is to use the vibrations caused by, for example, transit transport, or different step acting factor. In this case, it is desirable that the generator is designed with variable resonant frequency, which can partly be achieved, for example, integrating several oscillating component in the body of generator. After the general analysis of the problem, graduation theses will be concerned with the possibility of use of energy from the short damped oscillation and step impulse. Focusing on a proposal of multi-element structures.

On retrouve des contaminations d’aquifèr à l’arsenic dans touts les deltaï de l'Asie du Sud-Est, y compris dans le delta du Mékong, ce qui affecte la santé de millions de personnes. L’arsenic est très sensible aux fluctuations des conditions redox qui sont générés par les cycles alternés humides/secs pendant la saison de mousson. Une étude sur les caractéristiques géophysiques et chimiques du sol et des eaux souterraines dans le district de An Phu, dans le haut du delta du Mékong au Vietnam, suggère une forté contamination à l’As dans cette région. Les données chimiques et géophysiques indiquent une forte corrélation entre concentrations dans les eaux souterraines anoxiques et conductivité des sols. La liberation de l’arsenic est associée à la dissolution réductrice induih par des microorganisms des colloïdes et (oxyhydr)oxydes de fer dans des conditions d'oxydo-réduction oscillantes. La présence de bactéries sulforéductrices a le potentiel de stabiliser l’arsenic dans la phase solide et de l’atténuer dans la phase aqueuse par adsorption / désorption de l’arsenic sur les (oxyhydr)oxydes, et / ou sulfures de fer via la formation de complexes thiols. En raison de la teneur en pyrite élevée dans les sédiments, l'oxydation de la pyrite peut abaisser le pH et conduire à l'inhibition de la réduction microbienne du sulfate et aime empêcher la séquestration de l’arsenic dissous. Bien que le cycle biogéochimique de l’arsenic dans un système dynamique d’oxydoréduction soit une problématique complexe, il a été possible de renforcer notre compréhension de ce système / Aquifer arsenic (As) contamination is occuring throughout deltaic areas of Southeast Asia, including the Mekong Delta, and affects the health of millions of people. As is highly sensitive to fluctuations of redox conditions which are generated by the alternating wet-dry cycles during the monsoonal seasons. A survey of geophysical and chemical characteristics of soil and groundwater in the An Phu district, located in the vicinity of the Mekong Delta in Vietnam, shows the occurrence high As aqueous concentration in this region. Chemical and geophysical data indicate a strong positive correlation between As concentrations in the anoxic groundwater and conductivity of soils. In addition, mechanisms of As release are shown to be associated with colloidal and iron (oxyhydr)oxides which undergo microbial mediated reductive dissolution under redox oscilatting conditions. The presence of sulfate microbial reduction potentially stabilizes As in the solid phase and diminish As in the aqueous phase through the adsorption/desorption of As onto iron (oxyhydr)oxides and/ or sulfides with formation of thiols complexes in solid phase. Because of the high pyrite content in sediment, pyrite oxidation may drop in pH values, leads to inhibition of sulfate reducing bacteria and reduces sequestration of dissolved As. Although the biogeochemical cycling of redox sensitive species such as As in dynamic systems is challenging, it has been possible to strengthen our collective understanding of such system.

The objective of this research is to show that nonlinearity can be used to improve vibration absorption and suppression of unwanted vibrations in a main system due to external excitation. This was shown by investigating two systems a SDOF (with hardening nonlinearity) and a 2DOF (with softening nonlinearity). The aim of carrying out these investigations was to introduce a passive nonlinear system that can update itself and self-regulate to suppress undesired oscillations. To fulfil the desired gaol, various types of springs were considered and investigated. A commercially available spring called Mag-spring has been chosen and a function for its nonlinearity has been investigated. Mag-Spring is a newly invented spring which is designed to exhibit constant force at its operating range. However, this spring has a special non-linear behaviour before reaching to the constant force domain which is the main focus of the investigation presented in this thesis. The nonlinear behaviour of Mag-spring encouraged the idea that vibration design is possible by the advantages that can be gained from magnetic technology. The added benefit through this new Mag-spring, is that it solved some of the concerns assotiated with old available ones. The most concern norrowing the usage of magnetic springs, is the air gap between the two magnets, which make the attraction or repulsive force unstable through the spring’s working range. Linmot Company, introduced a solution to this concern by introducing a teflone that works as a bearing between the two magnets, which fixed the distance between them while they are sliding againest each other. In the first scenario of this study, a hardening nonlinear spring was added in parallel to a system with a single degree of freedom. The system will remain single degree of freedom as the spring was added in parallel without additional mass. The hardening spring shows low stiffness at low amplitude and high stiffness at higher amplitude. In this study, it was shown that nonlinearity affects the dynamic performance of a system and makes the natural frequency amplitude dependant. As the amplitude of vibration increases, consequently, stiffness increases and the natural frequency shifts away from the excitation frequency. For this investigation, a vibrating system with one degree of freedom has been built based on a mathematical model simulated and tested in Matlab software. Mag-spring was used to introduce the nonlinear stiffness to the system. Unbalance mass mounted to a disc fixed to a rotational machine has been used to create a forced vibration system with variable frequency. The response of the system with and without nonlinearity effect was monitored with an accelerometer. Simulation and experimental results showed that nonlinearity could shift the resonance frequency of the SDOF system by 10% (hardening of the system), without affecting the stiffness of the system at normal working condition. In the second scenario, a softening nonlinear spring was added as a vibration absorber to a system with a single degree of freedom, to make the system with two degree of freedom. The softening spring shows high stiffness at low amplitude and low stiffness at high amplitude. The rationale behind this is to introduce a spring which is hard at high frequency and soft at low frequency, which as a result will make the ratio √(k_a/m_a ) of the absorber follows the excitation frequency (ω) allowing the system to update itself and self-regulate providing vibration cancellation at more than one frequency value and widen the vibration cancellation range (ω_n2-ω_n1). It was shown that the Mag-spring could show a softening behaviour in a limited domain if its operating position is shifted. A program has been written to simulate the behaviour of all nonlinear system with two degree of freedom (nonlinear absorber). At this program, the maximum amplitude of each time domain was used to produce the frequency domain of the amplitude of the system. The amplitude of the vibration for a linear and a nonlinear absorber was compared. The results showed that the nonlinear absorber suppresses and reduces the vibration amplitude of the main system better than the linear absorbers with up to 60% reduction in magnification ratio and from 5% to 10% in widening the cancellation range (ω_n2-ω_n1). In the last scenario of this study, 4 different ideal softening stiffness curves were introduced based on theoretical methods. Their vibration response was calculated and compared to the nonlinear absorber (Mag-spring) and a linear absorber. This study shows that when nonlinearity is designed properly, it could provide a distinguished vibration cancellation response resulting more than 60% vibration cancellation improvement. This study demonstrated the possibility of developing a passive self-regulating tuned mass system involving the usage of nonlinearity. Nonlinearity will enhance the vibration cancellation by allowing the system to update itself and as a result will make the vibration absorption to be effective within a frequency range rather than single frequency unlike the classical tuned mass system. This study, to the best knowledge of the author, can be classified as an uncommon study in vibration systems investigations.

The dynamics of cell signalling are critical to cell fate decisions. Human Epidermal growth factor Receptors (HERs)-mediated Ras/Raf/MEK/ERK and PI3K/Akt signalling cascades relay extracellular signals from the plasma membrane to targets in the nucleus and cytoplasm and play pivotal roles in cell fate determination including proliferation, differentiation and cell survival. Both pathways, once activated, are further regulated by complex feedback loops which may exert either positive or negative effects on cascade components and can result in signalling oscillation. In this study, heregulin (HRG) - and epidermal growth factor (EGF)- stimulated oscillation of both p-ERK1/2 and p-Akt expression in breast cancer cell lines was demonstrated. The oscillation was cell line dependent and was observed in MCF-7 and MCF-7/HER2-18 cells but not in BT474 cells. The oscillation was augmented by cycloheximide implicating transcriptional involvement. Gene expression analysis identified 29 genes as possible candidates involved in the transcriptional feedback regulation. Apart from the feedback regulation, feedforward regulation was also observed. To expedite the analyses In-cell Western and Reverse Phase Protein Array (RPPA) assays were developed. A scheme of transcriptional feedback loops regulating the oscillation in the ERK1/2 pathway is proposed, including negative feedback loops to ERK1/2 from DUSPs, early positive and late negative feedback loops to MEK1/2 and positive feedback loops to HER-3 from AREG, HB-EGF, CYR61 and CTGF. Two HER-2-targeted inhibitory monoclonal antibodies were investigated – trastuzumab and pertuzumab. Trastuzumab not only inhibited the growth of HER-2 over-expressing MCF-7/HER2- 18 cells and BT474 cells but also that of EGF-driven MCF-7 cells which expressed low/moderate HER-2 levels. Pertuzumab blocked the growth of both MCF-7 and MCF-7/HER2-18 driven by either EGF or HRG. When used in combination with trastuzumab, pertuzumab had much more potent activity in inhibiting cell growth and signalling than either single drug. Trastuzumab and pertuzumab had opposing effects on immediate p-ERK1/2 signalling and trastuzumab’s effects on signalling could be mimicked by the PI3K inhibitor LY294002. PTPN13, a non-receptor type tyrosine protein phosphatase, is a proposed tumour suppressor in breast cancer. This was investigated as a candidate regulator of the signalling oscillation and although not observed as a transcriptional modulator of the oscillation, its high expression level was observed to be associated with cell growth inhibition in MCF-7/HER2-18 cells by trastuzumab. Moreover, immunohistochemical analysis of 121 clinical tumours which had received trastuzumab treatment revealed the correlation between the expression level of PTPN13 and the mutation status of PIK3CA. In conclusion, the observed oscillation may contribute to the elucidation of the complex regulation of signalling pathways, which is vital to the different cell fate decision made through the same core pathway. The synergy between trastuzumab and pertuzumab supports the clinical use of the combination treatment and suggested PI3K/Akt pathway as the major pathway in controlling tumour growth.

Dans la continuité des expériences SuperKamiokande et K2K, OPERA (Oscillation Project with Emulsion tRacking Apparatus), cherchera à confirmer l'oscillation des neutrinos dans le secteur atmosphérique. Utilisant une technique déjà employée dans CHORUS et DONUT, la chambre à brouillard d'émulsion (Emulsion Cloud Chamber (ECC)), cette expérience permettra la mise en évidence de l'oscillation nµ® nt par apparition de nt dans un faisceau pur de nµ.<br />L'expérience OPERA, avec ses ~100000 m2 d'émulsions nucléaires, nécessite l'utilisation de systèmes de scan automatiques ultra rapides. Les composantes optiques et mécaniques de ces systèmes ont été optimisées pour atteindre une vitesse de scan de ~20 cm2/heure par couche d'émulsion (44 μm d'épaisseur), tout en gardant une résolution sub-micrométrique.<br />Dans la première partie de mon travail de thèse, je me suis consacrée à l'optimisation des 4 systèmes de scan au sein de l'unique station de scan française basée à Lyon. Une étude expérimentale sur les performances d'un scan utilisant un objectif à sec a été également réalisée. Les résultats obtenus montrent que les performances d'un scan « à sec » sont similaires à celles d'un scan traditionnel utilisant un objectif à huile. <br />La deuxième partie de mon travail a consisté à valider la stratégie actuellement utilisée dans OPERA pour la localisation et la reconstruction des vertex de l'interaction des neutrinos, à l'aide d'un test sur faisceau dédié. Les résultats obtenus confirment définitivement que la stratégie proposée est bien adaptée à la recherche du lepton tau.