No description available.

This thesis proposes a method for the design of a real-time neuro-fuzzy trajectory generator for the robotic rehabilitation of patients with upper limb dysfunction due to neurological diseases. The system utilizes a fuzzy-logic schema to introduce compliance into the human-robot interaction, and to allow the emulation of a wide variety of therapy techniques. This approach also allows for the fine-tuning of system dynamics using linguistic variables. The rule base for the system is trained using a fuzzy clustering algorithm and applied to experimental data gathered during traditional therapy sessions. The compliance rule base is combined with a hybrid neuro-fuzzy compensator to automatically tune the dynamics of the system. The trajectory generator is packaged as a platform-independent solution to facilitate the rehabilitation of patients using multiple manipulator configurations.

This thesis proposes a method for the design of a real-time neuro-fuzzy trajectory generator for the robotic rehabilitation of patients with upper limb dysfunction due to neurological diseases. The system utilizes a fuzzy-logic schema to introduce compliance into the human-robot interaction, and to allow the emulation of a wide variety of therapy techniques. This approach also allows for the fine-tuning of system dynamics using linguistic variables. The rule base for the system is trained using a fuzzy clustering algorithm and applied to experimental data gathered during traditional therapy sessions. The compliance rule base is combined with a hybrid neuro-fuzzy compensator to automatically tune the dynamics of the system. The trajectory generator is packaged as a platform-independent solution to facilitate the rehabilitation of patients using multiple manipulator configurations.

L’étude de la neurotransmission et de la plasticité synaptique à l’échelle biomoléculaire dans des cellules vivantes nécessite des outils qui permettent la visualisation et la localisation d’une grande variété de protéines synaptiques ainsi que d’autres composantes. La transparence des neurones, la taille nanométrique des structures d’intérêt et leur compacité motivent le choix des modalités d’imagerie pouvant servir à étudier ces phénomènes. La microscopie à super-résolution en fluorescence produit des images ayant une résolution de localisation de l’ordre du nanomètre d’échantillons marqués. Toutefois, cette technique ne permet d’observer que les structures ayant été marquées. C’est pourquoi nous voulons la combiner à une technique ne nécessitant aucun marquage afin d’obtenir le plus d’information possible au sujet de la structure des échantillons. L’imagerie de phase quantitative est une technique sans-marquage qui utilise l’indice de réfraction comme agent de contraste intrinsèque pour cartographier en 3D le contenu cellulaire. Le but principal de ce projet est de concevoir et construire un montage de microscopie de phase quantitative et de l’intégrer à un microscope STED existant de façon à créer un nouveau système d’imagerie multimodale. La performance de ce système sera ensuite caractérisée et sa capacité à produire des images multimodales de synapses de cellules vivantes sera évaluée. Ce projet est un premier pas vers la création d’un outil qui pourrait permettre de simultanément mesurer de façon très précise la position de structures marquées en 2D et 3D et cartographier l’indice de réfraction des cellules en 3D afin de situer les structures marquées dans leur environnement. / The study of neurotransmission at the biomolecular level in live cells requires tools that allow the simultaneous visualisation and localization of a variety of neuronal proteins at their scale: the nanometric scale. In order to do so, an imaging approach offering high spatial and temporal resolution combined to low invasiveness is required. STED microscopy is an optical super-resolution fluorescence microscopy technique that produces images of labelled samples with a spatial resolution below 50 nm in living cells. However, since it is based on the detection of fluorescent molecules, labeling of the structures of interestis necessary and non-labeled structures are invisible for this type of microscope. Therefore, we want to combine it to a label-free optical microscopy technique to maximize the information that can be obtained about the global structure of the samples of interest: optical diffraction tomography (ODT). This approach uses refractive index as an intrinsic contrast agent to produce 3D maps of the cell’s internal contents.The main goal of this project is to design and build a quantitative phase imaging system and to integrate it onto an existing STED microscope to create a novel multimodal super-resolution imaging system. The performance of the microscope will then be characterized. This project is a first step towards the creation of a tool that could eventually allow simultaneous precise2D and 3D mapping of labelled structures and label-free 3D mapping of the sample’s refractive index to situate marked structures in their surroundings.

CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico / Esse trabalho propõe a modelagem e o controle neuro-fuzzy aplicados na estabilidade estática de um veículo de duas rodas do tipo pêndulo invertido, utilizando como método de otimização a evolução diferencial. Durante a fase de modelagem, determinam-se as incertezas relacionadas aos parâmetros e também à resposta do modelo neuro-fuzzy. Verifica-se que este é capaz de se ajustar satisfatoriamente aos dados extraídos experimentalmente do veículo. Na determinação do controlador neuro-fuzzy, testam-se três estratégias de ajuste de parâmetros, sendo duas delas propostas neste texto, e os resultados são comparados entre si e aos obtidos através de controladores clássicos, e verifica-se experimentalmente e por meio de testes estatísticos que as abordagens propostas apresentam grande capacidade de adaptação às restrições impostas à planta, garantindo a estabilidade estática e a eficiência energética do sistema. / This work proposes the neuro-fuzzy modeling and control applied to the static stability of a two-wheeled inverted pendulum vehicle, using differential evolution as optimization technique. During the modeling phase, the uncertainties related to the parameters and also to the neuro-fuzzy model response are determined. It is possible to verify that the neuro-fuzzy system is capable of satisfactorily adjusts to the data experimentally extracted from the vehicle. In the determination of the neuro-fuzzy controller, three strategies of parameter adjustment are tested, two of them being proposed in this text, and the results are compared between them and those obtained through classical controllers, and it is verified experimentally and through tests that the proposed approaches present a great capacity to adapt to the constraints imposed on the plant, guaranteeing the static stability and the energy efficiency of the system. / Dissertação (Mestrado)

This thesis challenges the restrictive definition of ‘gay’ used in legal discourse, argues for the adoption of a broader definition that is inclusive of more gay individuals, and demonstrates that the adoption of a broader definition would help frame gay rights debates in a way that is more acceptable to both progressives and conservatives. Current legal arguments for gay rights use ‘gay’ to refer almost solely to individuals that have exclusively—largely immutable—same-sex erotic desires. However, ‘gay’ should be understood to include a more diverse group of individuals. Thus, the current restrictive use of the term ‘gay’ either captures too many people or too few. Too many people, for conservatives, because gay rights are extended to many gay individuals that are not included in the restrictive definition. Too few people, for progressives, because the restrictive use of the term ‘gay’ doesn’t capture the entire gay community.

Opioid-based agents represent the cornerstone of analgesia in modern clinical practice. Additionally however opioids produce a range of unwelcome side-effects including immunomodulation. It has been suggested that this immunomodulation may result either as a direct effect of opioids on circulating immune cells or via a central action. Meanwhile studies show that classical opioid receptors are up-regulated in peripheral inflammation, while endogenous opioids are released from circulating immune cells producing local analgesia. Expression of opioid receptors on immune cells however remains contentious. This thesis has made a significant contribution to understanding the interaction between opioids and a neurovascularimmune axis by employing radioligand binding, flow cytometry and polymerase chain reaction techniques to make a systematic and detailed examination of the expression of the classical opioid receptors (MOP, DOP and KOP) and the non-classical opioid receptor (NOP) and the precursor for its endogenous ligand N/OFQ (ppN/OFQ) in the peripheral blood mononuclear cells (PBMCs) of healthy volunteers. Using these techniques we have shown (1) that naïve human PBMCs do not express classical opioid receptors, (2) that PCR techniques support the view that PBMCs do express gene transcripts for NOP and ppN/OFQ. In an additional clinical study during a profound vascular insult we have used quantitative PCR and radioimmunoassay techniques to follow the expression of the opioid receptors and native N/OFQ throughout a septic episode in patients admitted to the intensive care unit (ICU). Here we report for the first time an elevation in plasma N/OFQ concentration in non-survivors of sepsis requiring ICU admission, 3.0 [2.5 – 5.0]pg ml-1 in non-survivors vs. 1.0 [1.0 – 2.5]pg ml-1 in survivors (p=0.028). Similarly we are first in reporting an elevation in plasma N/OFQ following major abdominal surgery in septic patients. These findings lead us to suggest an amendment to the previously proposed neuroimmune axis to include the N/OFQ-NOP system.

Le vieillissement de la population est à l’origine de l’augmentation du nombre de personnes souffrant de démences, dont la plus fréquente est la maladie d’Alzheimer (MA). La MA est une maladie neurodégénérative incurable caractérisée par une atteinte progressive des fonctions cognitives, en premier lieu les fonctions mnésiques. Son diagnostic formel repose sur l’examen post-mortem du cerveau des patients. Il est basé sur la présence conjointe de deux lésions caractéristiques: des dépôts extracellulaires majoritairement composés de peptide amyloïde fibrillaire, résultat d’un clivage anormal du précurseur transmembranaire APP, et d’une dégénérescence neurofibrillaire ou pathologie tau, caractérisée par l’accumulation intra-neuronale de protéines tau hyper- et anormalement phosphorylées. Parallèlement à ces deux lésions se développe une réponse neuro-inflammatoire, notamment caractérisée par une augmentation du nombre et de l’activité des cellules microgliales et astrocytaires. Bien que les relations entre la pathologie amyloïde et la mise en place des processus neuro-inflammatoires aient fait l’objet d’intenses investigations, peu d’études se sont intéressés aux liens réciproques existants entre ces processus et la pathologie tau. A travers l’utilisation d’un modèle murin transgénique mimant le versant tau de la MA, la lignée THY-Tau22, un des objectifs de ma thèse a consisté à caractériser les différents aspects de leur réponse neuro-inflammatoire. Ces souris développent une pathologie tau hippocampique progressive associée à des altérations mnésiques. Les études transcriptomiques, biochimiques et histologiques réalisées ont mis en évidence une augmentation progressive de l’expression hippocampique de marqueurs de l’immunité innée mais également adaptative chez les souris THY-Tau22. Nous observons particulièrement l’établissement progressif de réactions microgliales et astrocytaires, une augmentation des niveaux de différentes chimiokines (CCL3, CCL4 et CCL5) conjointement à une infiltration parenchymateuse de lymphocytes T, en l’absence d’altération majeure de l’intégrité de la barrière hémato-encéphalique. Ces résultats mettent en exergue une corrélation entre le développement de troubles mnésiques et de la pathologie Tau hippocampique d’une part, et la présence d’une réponse neuro-inflammatoire d’autre part. La MA est une maladie multifactorielle dont la survenue est modulée par différents facteurs génétiques et environnementaux. Parmi les facteurs environnementaux mis en évidence par les études épidémiologiques, la consommation de caféine réduit notablement le risque de développer la MA. La caféine est une substance psychoactive dont les effets sont essentiellement médiés par le blocage des récepteurs adénosinergiques A1 et A2A, ces derniers étant particulièrement décrits pour moduler les processus neuroinflammatoires. Le rôle de ces récepteurs étant mal connus dans le contexte de la MA, et inconnu concernant ses relations à la pathologie Tau, la seconde partie de ma thèse a consisté à évaluer les effets de la caféine mais également d’un blocage spécifique des récepteurs A2A, par des approches génétiques et pharmacologiques, vis-à-vis des altérations comportementales, de la pathologie tau et de la réponse neuro-inflammatoire dans le modèle THY-Tau22. Les résultats obtenus démontrent que la caféine et le blocage spécifique des récepteurs A2A exercent des effets bénéfiques dans ce modèle de Tauopathie, avec une prévention des altérations mnésiques, une réduction de l’hyperphosphorylation de Tau et des effets anti-inflammatoires. Ces modifications sont associées à des effets bénéfiques en terme neurochimique et synaptique. L’ensemble de ces résultats démontrent pour la première fois un effet bénéfique de la caféine et du blocage des récepteurs A2A dans un modèle murin de tauopathie et suggèrent qu’un ciblage thérapeutique de ces récepteurs puisse être d’intérêt dans la MA. / Population ageing is a major risk factor for dementia, the most prevalent being Alzheimer disease (AD). AD is a neurodegenerative disorder characterized by a progressive cognitive decline, notably impacting memory functions. Its formal diagnosis is based on the post-mortem examination of AD patients’ brains and defined by the combination of two lesions: extracellular deposition of fibrillar amyloid peptide, resulting from the abnormal cleavage of transmembrane APP precursor, and neurofibrillary tangles, characterized by intraneuronal accumulation of hyper- and abnormal phosphorylated tau protein (Tau pathology). Besides these two lesions hallmarks, neuro-inflammatory processes, mainly defined by an increase of the number and the activity of microglial and astroglial cells, are considered as a third pathological component. Although the relationships between amyloid pathology and neuro-inflammatory processes had been the subject of intense investigations, few studies has been achieved with regards to tau pathology. As a first aim of this work, neuro-inflammatory processes associated with Tau pathology has been evaluated using a transgenic mouse model mimicking AD-like Tau pathology, THY-Tau22 strain.. These mice overexpress a mutated human tau protein under the control of a neuronal promoter and progressively hippocampal tau pathology associated to memory decline. Transcriptomic, biochemical and histological evaluations revealed a progressive increase several markers of both innate and adaptive immunity in the hippocampus of THY-Tau22 transgenic mice. We notably observed a progressive rise of microglial and astrogliale reactions, the overproduction of many chemokines (CCL3, CCL4, CCL5) in association with a parenchymatous infiltration of T cells, without major disruption of blood brain barrier (BBB). These results highlight a correlation between the establishments of memory alterations and hippocampal tau pathology on the one hand, and the occurrence of a neuro-inflammatory response on the other hand. AD is a multifactorial disorder whose occurrence depends on different genetic and environmental factors. Among the latter, epidemiological studies have shown that caffeine consumption significantly reduces the risk to develop AD. Caffeine is a psychoactive drug, whose effects are mainly ascribed to the blockade of A1 and A2A adenosinergic receptors, the latter beeing known to modulate neuro-inflammatory processes. The role of A2A receptors in AD is far from understood, and relationship with tau pathology currently unknown. The second part of my PhD aimed at evaluating effects of caffeine but also of a specific A2AR blockade, using genetic and pharmacological means, towards behavioural alterations, tau pathology and neuro-inflammatory processes in THY-Tau22 model. Results obtained demonstrate that caffeine and specific A2AR blockade lead to beneficial effects towards memory dysfunction, tau hyperphosphorylation and hippocampal neuro-inflammation. These improvements are associated with beneficial neurochemical and electrophysiological changes. Theses results demonstrate for the first time a beneficial effect of caffeine and A2A receptor blockade in a mouse model of tauopathy and support that therapeutic targeting of A2A receptors could be of interest in AD.

La neuro-inflammation induite par l'inflammation systémique ou générée en réponse à une lésion cérébrale aiguë a des conséquences cliniques néfastes : elle est mise en cause dans l'aggravation des lésions cérébrales aiguës chez l'homme, aussi bien chez l'adulte que chez l'enfant. La microglie est l'effecteur cérébral principal de cette réponse inflammatoire, et peut présenter selon les situations un profil neurotoxique ou, au contraire, anti-inflammatoire et régulateur. La compréhension des mécanismes d'activation microgliale et de leurs conséquences est capitale pour une meilleure prise en charge des malades. La première partie de ce travail de thèse s'intéresse aux conséquences de l'inflammation néonatale associée à la prématurité sur la réponse microgliale à l'âge adulte, face à de nouvelles agressions cérébrales que sont l'inflammation systémique et les lésions cérébrales aiguës. Dans un modèle murin d'inflammation néonatale, nous avons mis en évidence d'importantes modifications du transcriptome microglial une fois ces souris adultes. De plus, un stimulus inflammatoire à l'âge adulte modifie le profil d'activation microgliale, le pic des marqueurs pro-inflammatoires et immuno-régulateurs survenant plus précocement et intensément, démontrant l'existence d'une mémoire du système immunitaire inné cérébral. Ces modifications dans le profil d'activation microgliale s'accompagnent dans un modèle de lésion cérébrale excitotoxique d'une majoration de la taille des lésions de la substance blanche. Un traitement par mélatonine des souriceaux prévient cette aggravation. La deuxième partie de ce travail a consisté à caractériser in vitro le profil d'activation microgliale en réponse à une stimulation par HMGB1, une alarmine relarguée lors de la mort cellulaire et donc présente en cas de lésion cérébrale aiguë mais aussi de lésions extra-crâniennes associées. Nous avons montré que le profil d'activation microgliale dépend du type d'HMGB1 utilisé. Les microglies exposées à la forme recombinante de chez Sigma présentent un profil transcriptomique proinflammatoire mais une baisse des taux de cytokines sécrétées dans le milieu. Ces résultats mettent en évidence l'importance de l'inflammation et de l'activation microgliale dans le pronostic des lésions cérébrales et offrent la possibilité de mettre en place des stratégies neuroprotectrices innovantes / Neuroinflammation induced by systemic inflammation or generated in response to acute brain injury has adverse clinical consequences: it is implicated in exacerbation of acute brain injury in humans, for adults as well as for children. Microglia is the main effector of this cerebral inflammatory response, and may present, depending on the situation, a neurotoxic or - on the opposite - anti-inflammatory and regulating profile. To decipher the mechanisms of microglial activation and their consequences is essential for better management of patients.The first part of this thesis focuses on the consequences of neonatal inflammation associated with prematurity on the microglial response in adulthood, in case of new cerebral aggressions such as systemic inflammation or acute brain injury. Relying on a mouse model of inflammation of the preterm infant, we have demonstrated drastic modifications of the microglial transcriptome once these mice are adults. Moreover, when an inflammatory stimulus occurs in adulthood, the microglial activation profile is altered, the peak of pro-inflammatory and immuno-regulatory markers occurring earlier, demonstrating the existence of a memory of the cerebral innate immune system. These changes in the microglial activation profile are accompanied in a model of excitotoxic brain injury by an increase of the white matter lesion size. Melatonin treatment of mice prevents the happening of this worse outcome. In the second part of this thesis, we characterized the microglial activation profile in vitro, in response to stimulation by HMGB1, a damage associated molecular pattern released during cell death and therefore present in acute brain injuries but also in associated extra-cranial injuries. We have shown that the microglial activation profile depends of the kind of HMGB1 used. Microglia exposed to Sigma recombinant form have a proinflammatory transcriptomic profile but a lower release of cytokines in the culture medium. These results highlight the importance of inflammation and microglial activation in the prognosis of brain injuries and offer the opportunity to implement innovative neuroprotective strategies

Traditionally, the fuzzy rules for a fuzzy controller are provided by experts. They cannot be trained from a set of input-output training examples because the correct response of the plant being controlled is delayed and cannot be obtained immediately. In this paper, we propose a novel approach to construct fuzzy rules for a fuzzy controller based on reinforcement learning. Our task is to learn from the delayed reward to choose sequences of actions that result in the best control. A neural network with delays is used to model the evaluation function Q. Fuzzy rules are constructed and added as the learning proceeds. Both the weights of the Q-learning network and the parameters of the fuzzy rules are tuned by gradient descent. Experimental results have shown that the fuzzy rules obtained perform effectively for control.