Particle transport method for convection-diffusion-reaction problems

Convective transport, both pure and combined with diffusion and reaction, can be observed in a wide range of physical and industrial applications, such as heat and mass transfer, crystal growth or biomechanics. The numerical approximation of this class of problemscan present substantial difficulties clue to regions of high gradients (steep fronts) of the solution, where generation of spurious oscillations or smearing should be precluded. This work is devoted to the development of an efficient numerical technique to deal with pure linear convection and convection-dominated problems in the frame-work of convection-diffusion-reaction systems. The particle transport method, developed in this study, is based on using rneshless numerical particles which carry out the solution along the characteristics defining the convective transport. The resolution of steep fronts of the solution is controlled by a special spacial adaptivity procedure. The serni-Lagrangian particle transport method uses an Eulerian fixed grid to represent the solution. In the case of convection-diffusion-reaction problems, the method is combined with diffusion and reaction solvers within an operator splitting approach. To transfer the solution from the particle set onto the grid, a fast monotone projection technique is designed. Our numerical results confirm that the method has a spacial accuracy of the second order and can be faster than typical grid-based methods of the same order; for pure linear convection problems the method demonstrates optimal linear complexity. The method works on structured and unstructured meshes, demonstrating a high-resolution property in the regions of steep fronts of the solution. Moreover, the particle transport method can be successfully used for the numerical simulation of the real-life problems in, for example, chemical engineering.

Dynamic Model of a Small Once-Through Boiler

In this study, a model for the unsteady dynamic behaviour of a once-through counter flow boiler that uses an organic working fluid is presented. The boiler is a compact waste-heat boiler without a furnace and it has a preheater, a vaporiser and a superheater. The relative lengths of the boiler parts vary with the operating conditions since they are all parts of a single tube. The present research is a part of a study on the unsteady dynamics of an organic Rankine cycle power plant and it will be a part of a dynamic process model. The boiler model is presented using a selected example case that uses toluene as the process fluid and flue gas from natural gas combustion as the heat source. The dynamic behaviour of the boiler means transition from the steady initial state towards another steady state that corresponds to the changed process conditions. The solution method chosen was to find such a pressure of the process fluid that the mass of the process fluid in the boiler equals the mass calculated using the mass flows into and out of the boiler during a time step, using the finite difference method. A special method of fast calculation of the thermal properties has been used, because most of the calculation time is spent in calculating the fluid properties. The boiler was divided into elements. The values of the thermodynamic properties and mass flows were calculated in the nodes that connect the elements. Dynamic behaviour was limited to the process fluid and tube wall, and the heat source was regarded as to be steady. The elements that connect the preheater to thevaporiser and the vaporiser to the superheater were treated in a special way that takes into account a flexible change from one part to the other. The model consists of the calculation of the steady state initial distribution of the variables in the nodes, and the calculation of these nodal values in a dynamic state. The initial state of the boiler was received from a steady process model that isnot a part of the boiler model. The known boundary values that may vary during the dynamic calculation were the inlet temperature and mass flow rates of both the heat source and the process fluid. A brief examination of the oscillation around a steady state, the so-called Ledinegg instability, was done. This examination showed that the pressure drop in the boiler is a third degree polynomial of the mass flow rate, and the stability criterion is a second degree polynomial of the enthalpy change in the preheater. The numerical examination showed that oscillations did not exist in the example case. The dynamic boiler model was analysed for linear and step changes of the entering fluid temperatures and flow rates.The problem for verifying the correctness of the achieved results was that there was no possibility o compare them with measurements. This is why the only way was to determine whether the obtained results were intuitively reasonable and the results changed logically when the boundary conditions were changed. The numerical stability was checked in a test run in which there was no change in input values. The differences compared with the initial values were so small that the effects of numerical oscillations were negligible. The heat source side tests showed that the model gives results that are logical in the directions of the changes, and the order of magnitude of the timescale of changes is also as expected. The results of the tests on the process fluid side showed that the model gives reasonable results both on the temperature changes that cause small alterations in the process state and on mass flow rate changes causing very great alterations. The test runs showed that the dynamic model has no problems in calculating cases in which temperature of the entering heat source suddenly goes below that of the tube wall or the process fluid.

Analysis of torque and speed ripple producing non-idealities of frequency converters in electric drives

Electric motors driven by adjustable-frequency converters may produce periodic excitation forces that can cause torque and speed ripple. Interaction with the driven mechanical system may cause undesirable vibrations that affect the system performance and lifetime. Direct drives in sensitive applications, such as elevators or paper machines, emphasize the importance of smooth torque production. This thesis analyses the non-idealities of frequencyconverters that produce speed and torque ripple in electric drives. The origin of low order harmonics in speed and torque is examined. It is shown how different current measurement error types affect the torque. As the application environment, direct torque control (DTC) method is applied to permanent magnet synchronous machines (PMSM). A simulation model to analyse the effect of the frequency converter non-idealities on the performance of the electric drives is created. Themodel enables to identify potential problems causing torque vibrations and possibly damaging oscillations in electrically driven machine systems. The model is capable of coupling with separate simulation software of complex mechanical loads. Furthermore, the simulation model of the frequency converter's control algorithm can be applied to control a real frequency converter. A commercial frequencyconverter with standard software, a permanent magnet axial flux synchronous motor and a DC motor as the load are used to detect the effect of current measurement errors on load torque. A method to reduce the speed and torque ripple by compensating the current measurement errors is introduced. The method is based on analysing the amplitude of a selected harmonic component of speed as a function oftime and selecting a suitable compensation alternative for the current error. The speed can be either measured or estimated, so the compensation method is applicable also for speed sensorless drives. The proposed compensation method is tested with a laboratory drive, which consists of commercial frequency converter hardware with self-made software and a prototype PMSM. The speed and torque rippleof the test drive are reduced by applying the compensation method. In addition to the direct torque controlled PMSM drives, the compensation method can also beapplied to other motor types and control methods.

The cell cycle–regulated genes of schizosaccharomyces pombe

Many genes are regulated as an innate part of the eukaryotic cell cycle, and a complex transcriptional network helps enable the cyclic behavior of dividing cells. This transcriptional network has been studied in Saccharomyces cerevisiae (budding yeast) and elsewhere. To provide more perspective on these regulatory mechanisms, we have used microarrays to measure gene expression through the cell cycle of Schizosaccharomyces pombe (fission yeast). The 750 genes with the most significant oscillations were identified and analyzed. There were two broad waves of cell cycle transcription, one in early/mid G2 phase, and the other near the G2/M transition. The early/mid G2 wave included many genes involved in ribosome biogenesis, possibly explaining the cell cycle oscillation in protein synthesis in S.pombe. The G2/M wave included at least three distinctly regulated clusters of genes: one large cluster including mitosis, mitotic exit, and cell separation functions, one small cluster dedicated to DNA replication, and another small cluster dedicated to cytokinesis and division. S. pombe cell cycle genes have relatively long, complex promoters containing groups of multiple DNA sequence motifs, often of two, three, or more different kinds. Many of the genes, transcription factors, and regulatory mechanisms are conserved between S. pombe and S. cerevisiae. Finally, we found preliminary evidence for a nearly genome-wide oscillation in gene expression: 2,000 or more genes undergo slight oscillations in expression as a function of the cell cycle, although whether this is adaptive, or incidental to other events in the cell, such as chromatin condensation, we do not know.

Aspects opératoires et péri-opératoires de la stimulation cérébrale profonde [Operative and perioperative aspects of deep brain stimulation].

La stimulation cérébrale profonde (SCP) nécessite l'implantation chirurgicale d'un système comprenant électrodes cérébrales et boîtier(s) de stimulation. Les noyaux cérébraux visés par la méthodologie stéréotaxique d'implantation doivent être visualisés au mieux par une imagerie à haute résolution. La procédure chirurgicale d'implantation des électrodes se fait si possible en anesthésie locale pour faire des mesures électro-physiologiques et tester en peropératoire l'effet de la stimulation, afin d'optimiser la position de l'électrode définitive. Dans un deuxième temps, le ou les générateur(s) d'impulsions sont implantés en anesthésie générale. La SCP pour les mouvements anormaux a une très bonne efficacité et un risque de complications graves faible quoique non nul. Les complications liées au matériel sont les plus fréquentes. Deep brain stimulation (DBS) requires the surgical implantation of a system including brain electrodes and impulsion generator(s). The nuclei targeted by the stereotaxic implantation methodology have to be visualized at best by high resolution imaging. The surgical procedure for implanting the electrodes is performed if possible under local anaesthesia to make electro-physiological measurements and to test intra-operatively the effect of the stimulation, in order to optimize the position of the definitive electrode. In a second step, the impulsion generator(s) are implanted under general anaesthesia. DBS for movement disorders has a very good efficacy and a low albeit non-zero risk of serious complications. Complications related to the material are the most common.

Decreasing fires in a Mediterranean region (1970-2010, NE Spain)

We analyse the recent evolution of fires in Catalonia (north-eastern Iberian Peninsula), a typical Mediterranean region. We examine a homogeneous series of forest fires in the period 1970-2010. During this period, more than 9000 fire events greater than 0.5 ha were recorded, and the total burned area was more than 400 kha. Our analysis shows that both the burned area and number of fire series display a decreasing trend. Superposed onto this general decrease, strong oscillations on shorter time scales are evident. After the large fires of 1986 and 1994, the increased effort in fire prevention and suppression could explain part of the decreasing trend. Although it is often stated that fires have increased in Mediterranean regions, the higher efficiency in fire detection could have led to spurious trends and misleading conclusions.

Hippocampal Theta-Phase Modulation of Replay Correlates with Configural-Relational Short-Term Memory Performance

Thereis now growing evidencethatthe hippocampus generatestheta rhythmsthat can phase biasfast neural oscillationsinthe neocortex, allowing coordination of widespread fast oscillatory populations outside limbic areas. A recent magnetoencephalographic study showed that maintenance of configural-relational scene information in a delayed match-to-sample (DMS) task was associated with replay of that information during the delay period. The periodicity of the replay was coordinated by the phase of the ongoing theta rhythm, and the degree of theta coordination during the delay period was positively correlated with DMS performance. Here, we reanalyzed these data to investigate which brain regions were involved in generating the theta oscillations that coordinated the periodic replay of configural- relational information. We used a beamformer algorithm to produce estimates of regional theta rhythms and constructed volumetric images of the phase-locking between the local theta cycle and the instances of replay (in the 13- 80 Hz band). We found that individual differences in DMS performancefor configural-relational associations were relatedtothe degree of phase coupling of instances of cortical reactivations to theta oscillations generated in the right posterior hippocampus and the right inferior frontal gyrus. This demonstrates that the timing of memory reactivations in humans is biased toward hippocampal theta phase

Catechol-O-methyltransferase, dopamine, and sleep-wake regulation.

NlmCategory="UNASSIGNED">Sleep and sleep disorders are complex and highly variable phenotypes regulated by many genes and environment. The catechol-O-methyltransferase (COMT) gene is an interesting candidate, being one of the major mammalian enzymes involved in the catabolism of catecholamines. The activity of COMT enzyme is genetically polymorphic due to a guanine-to-adenine transition at codon 158, resulting in a valine (Val) to methionine (Met) substitution. Individuals homozygous for the Val allele show higher COMT activity, and lower dopaminergic signaling in prefrontal cortex (PFC) than subjects homozygous for the Met allele. Since COMT has a crucial role in metabolising dopamine, it was suggested that the common functional polymorphism in the COMT gene impacts on cognitive function related to PFC, sleep-wake regulation, and potentially on sleep pathologies. The COMT Val158Met polymorphism may predict inter-individual differences in brain electroencephalography (EEG) alpha oscillations and recovery processes resulting from partial sleep loss in healthy individuals. The Val158Met polymorphism also exerts a sexual dimorphism and has a strong effect on objective daytime sleepiness in patients with narcolepsy-cataplexy. Since the COMT enzyme inactivates catecholamines, it was hypothesized that the response to stimulant drugs differs between COMT genotypes. Modafinil maintained executive functioning performance and vigilant attention throughout sleep deprivation in subjects with Val/Val genotype, but less in those with Met/Met genotype. Also, homozygous Met/Met patients with narcolepsy responded to lower doses of modafinil compared to Val/Val carriers. We review here the critical role of the common functional COMT gene polymorphism, COMT enzyme activity, and the prefrontal dopamine levels in the regulation of sleep and wakefulness in normal subjects, in narcolepsy and other sleep-related disorders, and its impact on the response to psychostimulants.

Identification of neuronal network properties from the spectral analysis of calcium imaging signals in neuronal cultures

Neuronal networks in vitro are prominent systems to study the development of connections in living neuronal networks and the interplay between connectivity, activity and function. These cultured networks show a rich spontaneous activity that evolves concurrently with the connectivity of the underlying network. In this work we monitor the development of neuronal cultures, and record their activity using calcium fluorescence imaging. We use spectral analysis to characterize global dynamical and structural traits of the neuronal cultures. We first observe that the power spectrum can be used as a signature of the state of the network, for instance when inhibition is active or silent, as well as a measure of the network's connectivity strength. Second, the power spectrum identifies prominent developmental changes in the network such as GABAA switch. And third, the analysis of the spatial distribution of the spectral density, in experiments with a controlled disintegration of the network through CNQX, an AMPA-glutamate receptor antagonist in excitatory neurons, reveals the existence of communities of strongly connected, highly active neurons that display synchronous oscillations. Our work illustrates the interest of spectral analysis for the study of in vitro networks, and its potential use as a network-state indicator, for instance to compare healthy and diseased neuronal networks.

How environmental sounds become meaningful

The term "sound object" describes an auditory experience that is associated with an acoustic event produced by a sound source. In natural settings, a sound produced by a living being or an object provides information about the identity and the location of the sound source. Sound's identity is orocessed alono the ventral "What" pathway which consists of regions within the superior and middle temporal cortices as well as the inferior frontal gyrus. This work concerns the creation of individual auditory object representations in narrow semantic categories and their plasticity using electrical imaging. Discrimination of sounds from broad category has been shown to occur along a temporal hierarchy and in different brain regions along the ventral "What" pathway. However, sounds belonging to the same semantic category, such as faces or voices, were shown to be discriminated in specific brain areas and are thought to represent a special class of stimuli. I have investigated how cortical representations of a narrow category, here birdsongs, is modulated by training novices to recognized songs of individual bird species. Dynamic analysis of distributed source estimations revealed differential sound object representations within the auditory ventral "What" pathway as a function of the level of expertise newly acquired. Correct recognition of trained items induces a sharpening within a left-lateralized semantic network starting around 200ms, whereas untrained items' processing occurs later in lower-level and memory-related regions. With another category of sounds belonging to the same category, here heartbeats, I investigated the cortical representations of correct and incorrect recognition of sounds. Source estimations revealed differential representations partially overlapping with regions involved in the semantic network that is activated when participants became experts in the task. Incorrect recognition also induces a higher activation when compared to correct recognition in regions processing lower-level features. The discrimination of heartbeat sounds is a difficult task and requires a continuous listening. I investigated whether the repetition effects are modulated by participants' behavioral performance. Dynamic source estimations revealed repetition suppression in areas located outside of the semantic network. Therefore, individual environmental sounds become meaningful with training. Their representations mainly involve a left-lateralized network of brain regions that are tuned with expertise, as well as other brain areas, not related to semantic processing, and occurring in early stages of semantic processing. -- Le terme objet sonore" décrit une expérience auditive associée à un événement acoustique produit par une source sonore. Dans l'environnement, un son produit par un être vivant ou un objet fournit des informations concernant l'identité et la localisation de la source sonore. Les informations concernant l'identité d'un son sont traitée le long de la voie ventrale di "Quoi". Cette voie est composée de regions situées dans le cortex temporal et frontal. L'objet de ce travail est d'étudier quels sont les neuro-mecanismes impliqués dans la représentation de nouveaux objets sonores appartenant à une meme catégorie sémantique ainsi que les phénomènes de plasticité à l'aide de l'imagerie électrique. Il a été montré que la discrimination de sons appartenant à différentes catégories sémantiques survient dans différentes aires situées le long la voie «Quoi» et suit une hiérarchie temporelle II a également été montré que la discrimination de sons appartenant à la même catégorie sémantique tels que les visages ou les voix, survient dans des aires spécifiques et représenteraient des stimuli particuliers. J'ai étudié comment les représentations corticales de sons appartenant à une même catégorie sémantique, dans ce cas des chants d'oiseaux, sont modifiées suite à un entraînement Pour ce faire, des sujets novices ont été entraînés à reconnaître des chants d'oiseaux spécifiques L'analyse des estimations des sources neuronales au cours du temps a montré que les representations des objets sonores activent de manière différente des régions situées le long de la vo,e ventrale en fonction du niveau d'expertise acquis grâce à l'entraînement. La reconnaissance des chants pour lesquels les sujets ont été entraînés implique un réseau sémantique principalement situé dans l'hémisphère gauche activé autour de 200ms. Au contraire, la reconnaissance des chants pour lesquels les sujets n'ont pas été entraînés survient plus tardivement dans des régions de plus bas niveau. J'ai ensuite étudié les mécanismes impliqués dans la reconnaissance et non reconnaissance de sons appartenant à une autre catégorie, .es battements de coeur. L'analyse des sources neuronales a montre que certaines régions du réseau sémantique lié à l'expertise acquise sont recrutées de maniere différente en fonction de la reconnaissance ou non reconnaissance du son La non reconnaissance des sons recrute des régions de plus bas niveau. La discrimination des bruits cardiaques est une tâche difficile et nécessite une écoute continue du son. J'ai étudié l'influence des réponses comportementales sur les effets de répétitions. L'analyse des sources neuronales a montré que la reconnaissance ou non reconnaissance des sons induisent des effets de repétition différents dans des régions situées en dehors des aires du réseau sémantique. Ainsi, les sons acquièrent un sens grâce à l'entraînement. Leur représentation corticale implique principalement un réseau d'aires cérébrales situé dans l'hémisphère gauche, dont l'activité est optimisée avec l'acquisition d'un certain niveau d'expertise, ainsi que d'autres régions qui ne sont pas liée au traitement de l'information sémantique. L'activité de ce réseau sémantique survient plus rapidemement que la prédiction par le modèle de la hiérarchie temporelle.

Sähkökäyttöjen kaapelivärähtelyt

Taajuudenmuuttajan kytkennän synnyttämä nopea jännitemuutos aiheuttaa pitkään moottorikaapeliin sähköisen värähtelyilmiön. Ilmiö on tullut erityisesti esille uusien nopeasti kytkevien puolijohdetehokytkimien ilmestyttyä markkinoille. Taajuudenmuuttajan lähtöön asennettu jännitteen nousunopeutta rajoittava suodin vähentää kaapelivärähtelyä, mutta riittävän pitkässä kaapelissa värähtely on voimakasta lähtösuotimesta huolimatta. Kaapelivärähtelyilmiön seurauksena moottorikaapelin taajuudenmuuttajan puoleiseen päähän syntyy voimakas virtavärähtely ja moottorin puoleiseen päähän voimakas jännitevärähtely. Sähkökäyttöjen vektorisäätöalgoritmit tekevät ohjauspäätöksiä moottorikaapelin taajuudenmuuttajan päästä tehtyjen virtamittausten perusteella. Säädön päätösväli on niin lyhyt, että kaapelin virtavärähtely ehtii häiritä säädön toimintaa. Tässä työssä on esitetty kaapelivärähtelyä kuvaava taajuudenmuuttajan lähtösuotimen huomioon ottava siirtofunktioperustainen matemaattinen malli. Mallin avulla kaapelivärähtelyilmiötä voi analysoida lineaarisen säätöteorian menetelmillä. Virtavärähtelyn moottorisäätöön tuomiin ongelmiin ratkaisuksi on esitetty virran mittasignaalin käsittelemistä analogisella ja digitaalisella suotimella. Simulointitulosten perusteella ratkaisua voidaan pitää toimivana. Lopuksi esitetään, kuinka avaruusvektoriteorian mukaista induktiomoottorimallia ja kaapelivärähtelymallia voidaan simuloida yhdessä.

Neuropathogenesis in glutaric aciduria type I and methylmalonic aciduria

Glutaric aciduria type-I (GA-I) and methylmalonic aciduria (MMA-uria) are two neurometabolic diseases manifesting in neonatal period and early childhood. They belong to the group of organic acidurias and are caused by defects in the catabolism of amino acids, leading to massive accumulation of toxic metabolites in the body and severe brain injury. Therapeutic strategies are mainly based on reversing catabolic state during metabolic crisis and dietary protein restriction that both aim to prevent extra production of toxic metabolites. Specific and neuroprotective treatments are missing because the mechanisms of brain damage in these diseases are only poorly understood. The principal objective of my work was to develop in vitro models for both diseases aiming at elucidation of toxic effects of the main metabolites accumulating in GA-I (glutaric acid (GA) and 3-hydroxy glutaric acid (3-OHGA)) and MMA-uria (methylmalonic acid (MMA), propionic acid (PA) and 2-methylcitric acid (2-MCA)) on developing brain cells, and to study the cellular pathways targeted by these deleterious effects in order to find new therapeutic potentials. We used re-aggregated embryonic rat brain cells in organotypic 3D cultures, which were exposed to toxic metabolites at different developing stages of the cultures. In parallel, we studied the cellular localization of the defected enzyme in GA-I, glutaryl-CoA dehydrogenase (GCDH), in the brain and peripheral tissues of rats in adulthood and during embryonic development. GCDH expression: GCDH showed a strong neuronal expression in embryonic central and peripheral nervous system. In the adult brain, GCDH expression was exclusively neuronal with the strongest signal in cerebral cortex and Purkinje cells. GCDH expression was homogenous in embryonic peripheral organs with high levels in intestinal mucosa at late stages. Strong GCDH expression was also observed in liver and intestinal mucosa and with lower intensity in muscles, convoluted renal tubules and renal collecting tubes in adult peripheral organs. GA-I and MMA-uria in vitro models: 3-OHGA (for GA-I) and 2-MCA (for MMA-uria) showed the most deleterious effects at early stages of the cultures with morphological and biochemical alterations and induction of cell death. 3-OHGA and 2-MCA caused astrocytic cell suffering reflected by astrocytic fiber loss and swelling and retardation in oligodendrocytic maturation and/or differentiation. High ammonium increase concomitant with glutamine decrease was observed in these cultures. Neurons were not substantially affected. Our studies revealed that brain-cell generated ammonia may play a role in the neuropathogenesis of these diseases. Thus, developing neuroprotective strategies that target ammonium toxicity in the brain of GA-I and MMA-uria patients might be important according to our findings. -- L'acidurie glutarique de type I (GA-I) et l'acidurie méthylmalonique (MMA-urie) sont deux maladies neurométaboliques se manifestant durant la période néonatale ou la petite enfance, et qui appartiennent aux aciduries organiques. Elles sont causées par des défauts dans le catabolisme des acides aminés, conduisant à une accumulation des métabolites toxiques dans le corps et aussi des lésions cérébrales sévères. Le traitement est limité à une prise en charge d'urgence pendant la crise métabolique et à une diète restreinte en protéines naturelles. Des traitements spécifiques, neuroprotecteurs manquent principalement parce que les mécanismes conduisant aux lésions cérébrales dans ces maladies sont peu connus. L'objectif principal de mon travail était d'élucider les effets toxiques des métabolites accumulés dans GA-I (l'acide glutarique (GA) et l'acide 3-hydroxyglutarique (3-OHGA)) et MMA-uria (l'acide méthylmalonique (MMA), l'acide propionique (PA) et l'acide 2-méthylcitrique(2-MCA) sur les cellules du cerveau ainsi que les voies cellulaires impliquées, dans le but de trouver de potentielles nouvelles stratégies thérapeutiques. Nous avons utilisé un modèle in vitro de cultures 3D de cellules de cerveau d'embryons de rat (en développement) en les exposant aux métabolites toxiques à différents stades de développement des cultures. En parallèle, nous avons étudié la localisation cellulaire de l'enzyme déficiente dans GA-I, la CoA-glutarly déshydrogénase (GCDH), dans le cerveau et les organes périphériques des rats adultes et pendant le développement embryonnaire. L'expression de GCDH: GCDH a montré une expression neuronale forte dans le système nerveux chez l'embryon et le cerveau adulte. L'expression était homogène dans les organes périphériques avec une forte expression dans l'intestin. Les modèles in vitro de GA-I et MMA-uria : 3-OHGA en modèle GA-I et 2-MCA en modèle MMA-uria ont montré les effets délétères les plus importants avec des altérations morphologiques des cellules et biochimiques dans le milieu de culture et l'induction de mort cellulaire non-apoptotique (3-OHGA) ou apoptotique (2-MCA). 3-OHGA et 2-MCA ont provoqué une souffrance astrocytaire avec perte des fibres et gonflement et un retard de maturation et/ou de différentiation des oligodendrocytes. Une augmentation importante d'ammonium avec une diminution concomitante de glutamine a été observée dans les cultures. Les neurones n'étaient pas vraiment affectés. Nos études ont révélé que l'ammonium généré par les cellules cérébrales pourrait jouer un rôle dans la neuropathogenèse de ces deux maladies. Par conséquent, développer des stratégies neuroprotectrices ciblant la toxicité de l'ammonium dans le cerveau des patients atteints de GA-I ou MMA-urie pourrait être très important selon nos résultats.

On the Analysis and Control of a Linear Synchronous Servomotor with a Flexible Load

Industry's growing need for higher productivity is placing new demands on mechanisms connected with electrical motors, because these can easily lead to vibration problems due to fast dynamics. Furthermore, the nonlinear effects caused by a motor frequently reduce servo stability, which diminishes the controller's ability to predict and maintain speed. Hence, the flexibility of a mechanism and its control has become an important area of research. The basic approach in control system engineering is to assume that the mechanism connected to a motor is rigid, so that vibrations in the tool mechanism, reel, gripper or any apparatus connected to the motor are not taken into account. This might reduce the ability of the machine system to carry out its assignment and shorten the lifetime of the equipment. Nonetheless, it is usually more important to know how the mechanism, or in other words the load on the motor, behaves. A nonlinear load control method for a permanent magnet linear synchronous motor is developed and implemented in the thesis. The purpose of the controller is to track a flexible load to the desired velocity reference as fast as possible and without awkward oscillations. The control method is based on an adaptive backstepping algorithm with its stability ensured by the Lyapunov stability theorem. As a reference controller for the backstepping method, a hybrid neural controller is introduced in which the linear motor itself is controlled by a conventional PI velocity controller and the vibration of the associated flexible mechanism is suppressed from an outer control loop using a compensation signal from a multilayer perceptron network. To avoid the local minimum problem entailed in neural networks, the initial weights are searched for offline by means of a differential evolution algorithm. The states of a mechanical system for controllers are estimated using the Kalman filter. The theoretical results obtained from the control design are validated with the lumped mass model for a mechanism. Generalization of the mechanism allows the methods derived here to be widely implemented in machine automation. The control algorithms are first designed in a specially introduced nonlinear simulation model and then implemented in the physical linear motor using a DSP (Digital Signal Processor) application. The measurements prove that both controllers are capable of suppressing vibration, but that the backstepping method is superior to others due to its accuracy of response and stability properties.

Tracking the ghost of coevolution in specific plant-insect interactions : the case of the pollination system between the globeflower Trollius europaeus and seven european Chiastocheta flies

This study aims at understanding the evolutionary processes at work in specialized species interactions. Prom the macroevolutionary perspective, coevolution among specialized taxa was proposed to be one of the major processes generating biodiversity. We challenge this idea from the theoretical and practical perspective and through a literature review and show that the major hypotheses linking coevolutionary process with macroevolutionary patterns do not necessarily predict lineage co diversification and parallel speciation, limit¬ing the utility of the comparative phylogenenetic approach for investigating coevolution¬ary processes. We also point to the rarity of observed long-term coevolutionary dynamics among lineages and propose that coevolution rather occurs in shorter timescales, followed by ecological fitting. Prom the empirical point, we focus on the nursery pollination interaction between the European globeflower Trollius europaeus (Ranunculaceae) and its associated Chiastocheta flies (Anthomyiidae; Diptera) as a model system of evolution and maintenance of special¬ized interactions. The flies are obligate parasites of the seeds, but also pollinate the plant - it was thus proposed that both species are mutually dependent. Contrasting with the paradigm used for two decades of research on this system, we show that the female fitness component of the plant is similar in the populations with and without Chiastocheta. The plant is thus not exclusively dependent on the flies for reproduction. We discuss this result in the context of the factors responsible for the evolution of mutualistic systems. Understanding the evolution of a biological system requires understanding of its phylo- genetic context. Previous studies showed large mismatch between mtDNA phylogeny and morphological taxonomy in Chiastocheta. By using a large set of RAD-sequencing loci, we delineate the species limits that are congruent with morphology, and show that the discordance is best explained by the scenario of mitochondrial capture among fly species. Finally, we examine this system from a phylogeographic perspective, and identify the lack of congruence in spatial genetic structures of the plant and associated insects across their whole geographic range. The flies show lower numbers of spatial genetic groups than the plant, indicating that not all of the plant réfugia were shared by all the fly species or that the migration dynamics homogenized some of the groups. The incongruence in spatial genetic patterns indicates that fly migrations were largely independent from the genetic background of the plant, following rather a scenario of resource tracking, without the signature of coevolutionary process at this scale. Indeed, while the flies require the plant to survive climatic oscillations, the opposite is not true. Eventually, we show that there is no phylogenetic signal of spatial genetic structures, meaning that neither histories nor life- history traits are shared among closely related species and that species are characterized by unique trajectories of their genes. -- Cette étude vise à comprendre les processus évolutifs à l'oeuvre au sein d'interactions en¬tre espèces spécialisées. Du point de vue macroévolutif, la coévolution entre les taxons spécialisée a été considérée comme l'un des principaux processus générateur de biodiversité. Nous contestons cette idée du point de vue théorique et pratique à travers une revue de la littérature. Nous montrons que les hypothèses majeures reliant les processus coévolutifs avec les patterns de diversité au niveau macroévolutif ne prédisent pas nécessairement la co- diversification des lignées et leur spéciation parallèle, ce qui limite l'utilité de l'approche de phylogénie comparative pour étudier les processus coévolutifs . Nous rappelons également le peu d'exemples de dynamique coévolutive à long terme et proposons que la coévolution se produit plutôt dans des intervalles courts, suivis d'ajustements écologiques. Du point empirique, nous nous concentrons sur l'interaction de pollinisation entre le Trolle d'Europe Trollius europaeus (Ranunculaceae) et ses pollinisateurs associés, du genre Chiastocheta (Anthomyiidae; Diptera) en tant que système-modèle pour étudier l'évolution et le maintien des interactions spécialisées. Les mouches sont des parasites obligatoires des semences, mais pollinisent également la plante. Il a donc été proposé que les deux espèces soient mutuellement dépendantes. Contrastant avec le paradigme utilisé pendant deux décennies de recherche sur ce système, nous montrons, que la composante de fitness femelle de la plante est similaire dans les populations avec et sans Chiastocheta. La plante ne dépend donc pas exclusivement de son interaction avec les mouches pour la reproduction. Nous discutons de ce résultat dans le contexte des facteurs responsables de l'évolution des systèmes mutualistes. Comprendre l'évolution d'un système biologique nécessite la compréhension de son con- texte phylogénétique. Des études antérieures ont montré, chez Chiastocheta, de grandes disparités entre les phylogénies obtenues à partir d'ADN mitochondrial et la taxonomie basée sur les critères morphologiques. En utilisant un grand nombre de loci obtenus par RAD-sequencing, nous traçons les limites des espèces, qui concordent avec les car¬actéristiques morphologies, et montrons que la discordance s'explique en fait par un scénario de capture mitochondriale entre espèces de mouches. Enfin, nous examinons le système d'un point de vue phylogéographique, et identi¬fions les incohérences entre structurations génétiques spatiales de la plante et des insectes associés dans toute leur aire de distribution géographique. Les mouches présentent un nombre de groupes génétiques inférieur à la plante, indiquant que tous les refuges de la plante n'étaient pas partagés par toutes les espèces de mouches ou que les dynamiques migratoires ont homogénéisés certains des groupes chez les mouches. Les différences ob¬servées dans les patrons de structuration génétique spatiale indique que les migrations et dispersions des mouches ont été indépendantes du contexte génétique de la plante, et ces dernières ont été uniquement tributaires de la disponibilité des ressources, sans qu'il n'y ait de signature du processus de coévolution à cette échelle. En effet, tandis que les mouches ont besoin de la plante pour survivre aux oscillations climatiques, le contraire n'est pas exact. Finalement, nous montrons qu'il n'y a pas de signal phylogénétique des structurations génétiques spatiales chez les mouches, ce qui signifie que ni l'histoire, ni les traits d'histoire de vie ne sont partagés entre les espèces phylogénétiquement proches et que les espèces sont caractérisées par des trajectoires uniques de leurs gènes.

Post-transcriptional regulation of circadian gene expression by miRNAs

La grande majorité des organismes vivants ont développé un système d'horloges biologiques internes, appelées aussi horloges circadiennes, contrôlant l'expression de gênes impliqués dans de nombreux processus moléculaires et comportementaux. Au cours de la dernière décennie, des analyses « microarray » et séquençages à haut débit sur divers tissus de mammifères, indiquent que jusqu'à 20% du transcriptome serait sous contrôle circadien. Il était jusqu'à présent admis que la majorité des ARNm ayant une accumulation rythmique était générée par une transcription qui était elle-même rythmique. Toutefois, de récentes études ont suggéré qu'une proportion considérable des ARNm cycliques serait en fait générée par des mécanismes post-transcriptionnelles, incluant une régulation par micro-ARN (miARN). Lorsque j'ai débuté mon travail de thèse, l'influence des miARN sur l'expression des gènes circadiens, au niveau pangénomique, était encore méconnue. Par l'utilisation d'un modèle murin, dont la biogenèse des miARN a été spécifiquement désactivée au niveau des cellules hépatiques (knockout conditionnel pour Dicer), je me suis donc intéressée au rôle que jouaient ces molécules régulatrices sur la rythmicité de l'expression génique dans le foie. Des séquençages sur l'ensemble du transcriptome révèlent que l'horloge interne du foie est étonnement résistante à la perte totale des miARN. Nous avons cependant trouvé que les miARN agissent de façon importante sur la régulation de l'expression des gènes contrôlés par l'horloge moléculaire. La corégulation par les miARN, affectant jusqu'à 30% des gènes transcrits de façon rythmiques, conduit ainsi à une modulation de phase et d'amplitude du rythme de l'abondance des ARNm. En revanche, seuls peu de transcrits dépendent uniquement des miARN pour la rythmicité de leur accumulation. Enfin, mon travail met en évidence plusieurs miARN spécifiques, qui semblent préférentiellement moduler l'expression des gènes cycliques et permet l'identification de voies hépatiques particulièrement sujettes à une double régulation par les miARN et l'horloge biologique interne. La première masse d'analyses a essentiellement porté sur le rôle que jouent les miARN au niveau de l'expression des gènes contrôlés par l'horloge interne. Dans deux études de suivi, je me suis penchée sur deux aspects supplémentaires et complémentaires de la manière dont les miARN et l'oscillation de l'expression des gènes interagissent. Dans les hépatocytes murins, spécifiquement privés de Dicer, je me suis demandée si un phénotype horloge avait pu être masqué, dû à un entraînement stable de l'horloge du foie par l'horloge maîtresse du cerveau. J'ai donc commencé une série d'expériences ambitieuses (impliquant la mesure de la rythmicité du foie in vivo, chez l'animal vivant) afin de déséquilibrer l'entrainement de l'horloge hépatique via l'utilisation d'un protocole nutritionnel spécifique. Les premiers résultats suggèrent que dans des conditions où l'animal subit une restriction alimentaire pendant la journée, les miARN sont importants dans la cinétique d'adaptation des organes périphériques à un nouvel horaire de sustentation. Dans une deuxième ligne de recherche, j'ai plus profondément étudié quels seraient les miARN responsables des rythmes post-transcriptionnels des ARNm, en utilisant le séquençage de « small » ARN sur 24h. L'analyse est en cours et se poursuivra après l'obtention de mon diplôme. De façon générale, mon travail révèle d'importants et nouveaux rôles des miARN dans la modulation de l'expression circadienne des gènes hépatiques. De plus, le set de données générées dans l'étude déjà publiée, peut dorénavant servir de ressource valable pour de prochaines investigations sur le rôle physiologique que les miARN jouent au niveau du foie. -- Most living organisms have developed internal timing systems, called circadian clocks, to drive the rhythmic expression of genes involved in many molecular and behavioral processes. Over the last decade, microarray analyses and high- throughput sequencing from various mammalian tissues have indicated that up to 20% of the transcriptome are under circadian control. It was generally assumed that the majority of rhythmic mRNA accumulation is generated by rhythmic transcription. However, recent studies have suggested that a considerable proportion of mRNA cycling may actually be generated by post-transcriptional mechanisms, including by microRNAs. When I started my thesis work, it was still unknown how miRNAs influence circadian gene expression in a genome-wide fashion. Using a mouse model in which miRNA biogenesis can be inactivated in hepatocytes (conditional Dicer knockout mouse), I have thus addressed the role that these regulatory molecules play in rhythmic gene expression in the liver. Whole transcriptome sequencing revealed that the hepatic core clock was surprisingly resilient to total miRNA loss. However, we found that miRNAs acted as important regulators of clock-controlled gene expression. Co- regulation by miRNAs, which affected up to 30% of rhythmically transcribed genes, thus led to the modulation of phases and amplitudes of mRNA abundance rhythms. By contrast, only very few transcripts were strictly dependent on miRNAs for their rhythmic accumulation. Finally, my work highlights several specific miRNAs that appear to preferentially modulate cyclic gene expression, and identifies pathways in the liver that are particularly prone to dual regulation through miRNAs and the clock. The first bulk of analyses mainly dealt with the role that miRNAs play at the level of rhythmic clock output gene expression. In two follow-up studies I further delved into two additional, complementary aspects of how miRNAs and gene expression oscillations interact. First, I addressed whether a core clock phenotype in the hepatocyte-specific Dicer knockout could have been masked due to the stable entrainment of the liver clock by the animals' master clock in the brain. I thus started a series of ambitious experiments (involving the in vivo recording of liver rhythms in live animals) to bring the stable entrainment of the liver clock out of equilibrium using specific feeding protocols. My first results suggest that under conditions when animals are challenged by food restriction to daytime, miRNAs are important for the kinetics of adapting to unusual mealtime in peripheral tissue. In a second line of research, I have more carefully investigated which miRNAs are responsible for post- transcriptional mRNA rhythms using small RNA sequencing around-the-clock. The analyses are ongoing and will be continued after my graduation. Overall, my work uncovered important and novel roles of miRNA activity in shaping hepatic circadian gene expression; moreover, the datasets collect in the published studies can serve as a valuable resource for further investigations into the physiological roles that miRNAs play in liver. -- L'alternance du jour et de la nuit dirige depuis longtemps la vie quotidienne des êtres humains et de la plupart des organismes sur terre. Ce cycle de 24 heures façonne beaucoup de changements comportementaux et physiologiques tels que la vigilance, la température corporelle et le sommeil. Les rythmes journaliers, appelés rythmes circadiens, sont dirigés par des horloges biologiques tournant dans presque chaque cellule du corps. Une structure dans le cerveau agit en tant qu'horloge maitresse pour synchroniser les horloges internes entre elles et en fonction des signaux de jour/nuit extérieurs. Dans les cellules "les gènes de l'horloge" sont activés et désactivés une fois par jour ce qui déclenche des cycles dans lesquels des protéines sont produites de manière circadienne. Ces rythmes protéiques sont spécialisés pour chaque tissu ou organe et peuvent les aider à réaliser leurs tâches quotidiennes. Les rythmes circadiens peuvent être générés d'autres manières n'impliquant pas directement les composants des gènes de l'horloge. Les ARN messagers (ARNm) sont des molécules intermédiaires dans la production de protéines à partir d'ADN. Dans le foie des souris jusqu'à 20% des molécules d'ARNm sont produites suivant des rythmes circadiens. Le foie réalise des tâches essentielles dans le contrôle du métabolisme incluant celui des hydrates de carbone, des graisses et du cholestérol. Un timing précis est important afin de traiter les substances nutritives correctement lors des repas il en résulte une variation des quantités de certains ARNm et protéines coïncidant avec les repas. Les microARNs constituent une autre classe de molécules ARN de très petite taille qui régulent l'efficacité de traduction des ARNm en protéines et la stabilité des ARNm. Lors de mon travail de thèse, j'ai exploré de manière approfondie l'influence de ces petits régulateurs sur les rythmes circadiens du foie de souris. Ces expériences qui impliquaient le "Knock-out" d'un gène essentiel à la production de microARNs montrent qu'au lieu de générer les rythmes des ARNm, les microARNs les ajustent pour répondre aux besoins spécifiques du foie comme assurer leur pic au bon moment de la journée. Le ciblage de microARNs spécifiques peut révéler de nouvelles stratégies pour rectifier ces rythmes lorsque par exemple les fonctions métaboliques ne fonctionnent plus normalement. -- The rising and setting of the sun have long driven the daily schedules of humans and most organisms on the earth. This 24-hr cycle shapes many behavioural and physiological changes, such as alertness, body temperature, and sleep. These daily rhythms, which are called circadian rhythms, are dictated by biological clocks that are ticking in almost every single cell of the body. A region in the brain acts as a master clock to synchronize the internal clocks with each other and with the outside light/dark cycles. In cells, "core clock genes" are turned on and off once per day, which triggers cycles that cause some proteins to be produced in a circadian manner. The protein rhythms are specialized to a particular tissue or organ, and may help them to carry out their designated daily tasks. However, circadian rhythms might also be produced by other ways that do not involve these core clock components. Messenger RNAs (mRNAs) are intermediate molecules in the production of proteins from DNA. In the mouse liver, up to 20% of mRNA molecules are produced in circadian cycles. The liver performs essential tasks that control metabolism-including that of carbohydrates, fats, and cholesterol. Precisely timing when certain mRNAs and proteins reach peaks and troughs in their activities to coincide with mealtimes is important for nutrients to be properly processed. Other RNA molecules called microRNAs, i.e. RNAs of very small size, regulate at which rate mRNA molecules are translated into proteins. In my thesis work, I have explored at the influence of these small regulators on circadian rhythms in the mouse liver in greater detail. These experiments, which involved "knocking out" a gene that is essential for the production of microRNAs, show that rather than generating the mRNA rhythms, the microRNAs appear to adjust them to meet the specific needs of the liver, such as ensuring that they peak at the right time-of-day. Targeting specific microRNA molecules may reveal new strategies to tweak these rhythms, which could help to improve conditions when metabolic functions go wrong.