Le cancer du sein est une maladie impactant le système immunitaire dont le rôle évolue au cours de la tumorigénèse, allant de la détection et l'élimination des cellules transformées (immunosurveillance) à la promotion du développement tumoral (immunosubversion). Les efforts déployés pour définir de nouvelles stratégies thérapeutiques ont révélé que rétablir l'immunité anti-tumorale chez les patientes permettrait d'améliorer leur pronostic. Durant ma thèse, nous avons mis en évidence l'existence de signaux activateurs et inhibateurs des pDC dans les cancers du sein, qui confèrent aux pDC un rôle dans l'immunosurveillance et dans l'échappement immunitaire du cancer du sein respectivement. Nous avons ainsi montré que le TGF-beta et le TNF-alpha sont impliqués dans l'inhibition fonctionnelle des TApDC en réprimant l'expression et l'activation d'IRF-7. Dans un second temps, nous avons montré i) la présence de complexes [ADN-LL37] produits par les neutrophiles dans les tumeurs et capables d'induire la production d'IFN-alpha par les pDC, ii) l'expression des gènes associés aux IFN-I dans les tumeurs de sein et iii) un rôle majeur de la voie des IFN-I dans l'immunosurveillance des tumeurs mammaires chez la souris. De plus, des données préliminaires chez la souris suggèrent que les pDC participent à l'immunosurveillance anti-tumorale in vivo. Les travaux présentés dans ce manuscrit apportent de nouvelles données sur le rôle des pDC dans l'immunosurveillance des cancers du sein et ouvrent sur de nouvelles stratégies d'immunothérapie anti-tumorale ciblant les pDC / Breast cancer are disease impacting immune system whose play role during tumorigenesis, to detect and eliminate malign cells (immunosurveillance) or promote tumoral development (immunosubversion). Efforts to define new therapeutic strategies revealed that restoring anti-tumor immunity in patients would improve their prognosis. During my thesis, first, we demonstrated the existence of stimulatory and inhibitory signals of pDCs in the breast, which give the pDCs a role in immunosurveillance and immune escape of breast cancer, respectively. We showed that TGF-beta and TNF-alpha are involved in the functional inhibition of TApDC repressing IRF-7 expression and activation. Secondly, we showed i) the presence of [DNA LL37] complex produced by neutrophils in tumors that can induce the production of IFN-alpha by pDCs, ii) the expression of type I IFN associated genes in breast tumors and iii) a major role of IFN-I pathway in immunosurveillance of mammary tumors in mice. In addition, in mice, preliminary data suggest that pDC could play a role in anti-tumor immunosurveillance in vivo. The work presented in this thesis provide new data on the role of pDCs in immunosurveillance of breast cancers, and open new anti-tumor immunotherapy strategies targeting pDCs

Cette thèse porte sur la conception d'algorithmes adaptatifs pour des communications sans fil dans un contexte multi-antennes en émission et en réception (MIMO) et en environnement tunnel pour les métros. La technologie MIMO permet de répondre aux besoins de haut débit et de qualité de transmission. Dans les tunnels, ces performances sont réduites en raison de la corrélation spatiale. Dans cette thèse, nous avons étudié les algorithmes de précodage MIMO, qui utilisent la connaissance du canal (CSI) à l'émetteur. Généralement, ces algorithmes nécessitent un lien retour pour transmettre la CSI. Afin de minimiser la perte d'efficacité spectrale due au lien retour, nous avons choisi des précodeurs issus de la littérature qui réduisent le débit sur le lien retour. Nous avons réalisé une chaîne de simulation complète et réaliste afin d'évaluer les performances de ces précodeurs en tenant compte de plusieurs niveaux de quantité et de qualité de la CSI. Les simulations ont été réalisées dans des canaux théoriques et mesurés. Nous avons aussi évalué l'impact du bruit impulsif caractéristique de l'environnement ferroviaire. Nous proposons une borne supérieure théorique de la probabilité d'erreur du précodeur max-dmin dans des environnements décorrelés en présence du bruit impulsif modélisé par une loi de Cauchy ainsi qu'un récepteur adapté à ce bruit. La caractérisation du canal de propagation MIMO en tunnel a aussi permis d'obtenir une connaissance fine des caractéristiques du canal de en fonction de la position dans le tunnel. Ainsi, nous avons donc proposé un précodeur basé sur la connaissance de la matrice de corrélation et étudié la possibilité de supprimer le lien retour. / This thesis focuses on the design of adaptive algorithms for wireless communications in a multiple input multiple output (MIMO) design for subway tunnel environment. MIMO system meet the requirement of high capacity and robustness. However, these performance decreased due to the spatial correlation in tunnels. In this thesis, we studied precoding MIMO algorithms that use the channel state information (CSI) at the transmitter. Generally, these algorithms require feedback from receiver. To minimize the loss of spectral efficiency due to the reverse link, we selected from the literature precoder that reduce the feedback. We conducted a complete and realistic simulation system to evaluate the performance of these precoders taking into account several levels of quantity and quality of the CSI. For simulation, we used both theoretical and measured channels. We also assessed the impact of impulsive noise measured in the railway environment. By assuming a Cauchy law, We propose a receiver and a theoretical upper bound of the error probability of max-dmin precoder in uncorrelated environments. Finally, we proposed a precoder based on knowledge of the correlation matrix and studied the possibility of removing the return link thanks to the knowledge of the channel statistiques based on the localization in the tunnel.

O transporte de α-metil glicosídio ( α-MG) em Saccharomyces cerevisiae foi recentemente reportado como transporte ativo, do tipo simporte de &$945;-MG com H+ mediado pela permease Agt1p. A cepa AP77-11B (cepa selecionada em nosso laboratório) 14C-α-MG pelo mecanismo descrito como difusão facilitada porque não existe co-transporte de H+ durante o transporte de α-MG. Os genes HXT1-HXT17 pertencem à família dos transportadores de hexoses em Saccharomyces cerevisiae. Então, nós decidimos investigar a possibilidade que o transporte de α-MG poderia ser mediado pelos transportadores de hexoses. Nós demonstramos que cepa MC966A (tipo selvagem), KY73 (isogênica com MC966A mas deletada nos HXT1-7), BSY08 (isogênica com KY73 com o AGT1 deletado), BSY09 (isogênica com MC966A com o AGT1 deletado) e a EBY.VW4000 (hxt1-17 agt1 gal2-null), não cresceram em α-MG como fonte de carbono. Além disso, estas cepas não transportaram α-MG por difusão facilitada quando as células foram cultivadas em meio com maltose, levando-nos a concluir que os transportadores de hexoses não estavam envolvidos no transporte de α-MG. Nós observamos que a cepa AP77-11B apresentou alta atividade de α-metilglicosidase periplásmica quando as células foram cultivadas em α-MG. Esta atividade enzimática foi ensaiada usando um método descrito primeiramente para invertase periplásmica, no qual as células eram incubadas com fluoreto de sódio, um inibidor da enolase, antes da incubação com α-MG. Então, a glicose produzida durante a hidrólise do -MG poderia ser determinada. A atividade extracelular só está presente em células cultivadas em -αMG. Células de-reprimidas não mostraram atividade de alpha-metilglicosidase. Os parâmetros cinéticos determinados para α-metilglicosidase, indicaram que esta enzima tem baixa afinidade para o alpha-MG. Além do mais, a atividade específica da alpha-metilglicosidase periplásmica aumentou ao longo da curva de crescimento em α-MG. Os resultados reportados mostraram que existem duas vias de utilização de α-MG em Saccharomyces cerevisiae. Uma via é mediada pela Agt1p, responsável pelo transporte ativo de α-MG. Na outra via, a α -metilglicosidase é secretada para o espaço periplásmico das células. Então, a glicose produzida pela hidrólise do α-MG é transportada pelos transportadores de hexoses por difusão facilitada. / Alpha-Methyl glucoside ( alpha-MG) transport in Saccharomyces cerevisiae was previously reported to be an active transport, a H+ -symport mediated by the Agt1p permease. Strain AP77-11B (a strain obtained in our laboratory) takes up 14C- alpha-MG by a mechanism which was ascribed to be facilitated diffusion since there is no H+-cotransport during the alpha-MG uptake. The HXT1-HXT17 there is no H genes belong to a family of hexose transporters in Saccharomyces cerevisiae. Therefore, we decided to investigate the possibility that -MG transport could be mediated by hexose transporters. We demonstrated that strains MC966A (w.t.), KY73 (isogenic to MC966A but hxt1-hxt7-null), BSY08 (isogenic to KY73 with AGT1 deleted), BSY09 (isogenic to MC966A with AGT1 deleted) and even strain EBY.VW4000 (hxt1-hxt17 agt1 gal2-null), were not able to grow on alpha-MG as the sole carbon source. Moreover, none of them presented alpha-MG transport by facilitated diffusion when the strains were grown on maltose leading us to conclude that the HXT glucose transporters were not involved in alpha-MG transport. We found that strain AP77-11B displayed a high periplasmic alpha-methylglucosidase activity when cells were grown on alpha-MG. This enzymatic activity was assayed using a method first described for periplasmic invertase in which cells were incubated with sodium fluoride, an inhibitor of enolase, prior to the incubation with alpha-MG. Then the glucose produced during alpha-MG hydrolysis could be accurately measured. The extracellular activity was present only in cells grown on alpha-MG. Glucose derepressed cells did not show periplasmic alpha-methylglucosidase activity.

Cette thèse a pour objet l'étude des éléments radioactifs qui peuvent altérer le bon fonctionnement des composants électroniques au niveau terrestre. Ces éléments radioactifs sont appelés émetteurs alpha. Intrinsèques aux composants électroniques, ils se désintègrent et émettent des particules alpha qui ionisent la matière du dispositif électronique et déclenchent des SEU (Single Event Upset). Ces travaux visent à évaluer la fiabilité des circuits digitaux due à cette contrainte radiative interne aux composants électroniques. Dans ce but, tous les émetteurs alpha naturelles ou artificielles susceptibles de contaminer les matériaux des circuits digitaux ont été identifiés et classés en deux catégories : les impuretés naturelles et les radionucléides introduits. Les impuretés naturelles proviennent d'une contamination naturelle ou involontaire des matériaux utilisés. Afin d'évaluer leurs effets sur la fiabilité, le SER (Soft Error Rate) a été déterminé par simulations Monte-Carlo pour différents nœuds technologiques dans le cas de l'équilibre séculaire. Par ailleurs, avec la miniaturisation des circuits digitaux, de nouveaux éléments chimiques ont été suggérés ou employés dans la nanoélectronique. Les radionucléides introduits regroupent ce type d'élément naturellement constitué d'émetteurs alpha. Des études basées sur des simulations Monte-Carlo et des applications analytiques ont été effectués pour évaluer la fiabilité des dispositifs électroniques. Par la suite, des recommandations ont été proposées sur l'emploi de nouveaux éléments chimiques dans la nanotechnologie. / This work studies radioactive elements that can affect the proper functioning of electronic components at ground level. These radioactive elements are called alpha emitters. Intrinsic to electronic components, they decay and emit alpha particles which ionize the material of the electronic device and trigger SEU (Single Event Upset).This thesis aims to assess the reliability of digital circuits due to this internal radiative constraint of electronic components. For that, all alpha-emitting natural or artificial isotopes that can contaminate digital circuits have been identified and classified into two categories: natural impurities and introduced radionuclides.Natural impurities result from a natural or accidental contamination of materials used in nanotechnology. To assess their effects on reliability, the SER (Soft Error Rate) was determined by Monte Carlo simulations for different technology nodes in the case of secular equilibrium. Besides, a new analytical approach was developed to determine the consequences of secular disequilibrium on the reliability of digital circuits.Moreover, with the miniaturization of digital circuits, new chemical elements have been suggested or used in nanoelectronics. The introduced radionuclides include this type of element consisting of natural alpha emitters. Studies based on Monte Carlo simulations and analytical approches have been conducted to evaluate the reliability of electronic devices. Subsequently, recommendations were proposed on the use of new chemical elements in nanotechnology.

The master´s thesis presents the problems of EEG biofeedback and its application to relax people. The first part discusses the properties of EEG signal , the requirements of the standard EEG and also distribusion signal into different frequency bands. The main essence of the work is the design and realization of Alfa Monitor – a device for relaxation , that for implamanting EEG biofeedback uses acoustic form and sensing of electrical activity of brain in the region of alpha waves. The second half of the work is t focused on circuit design, using integrated circuits with component values of relevant calculations . Further, it analyzes the practical implementation of alfa monitor. The last chapter is devoted to the testing the functionality of this device.

La stimulation transcrânienne par courant alternatif (tACS) est une technique de stimulation non invasive du cerveau qui est d’un intérêt croissant, entre autres pour ses effets sur les ondes cérébrales intrinsèques. Par opposition à la stimulation transcranienne par courant direct (tDCS), la tACS permet l’administration d’un courant sinusoïdal ajusté à la fréquence endogène individuelle d’un individu. Les oscillations cérébrales constituant la bande de fréquence alpha (8-12 Hz) sont parmi les plus étudiées en raison de leurs associations variées avec les fonctions et états cérébraux. Un nombre important d’études ont montré l’efficacité de la tACS de diverses façons pour augmenter la puissance de l’activité EEG dans la bande de fréquence alphal’onde alpha. Cependant, l’hétérogénéité des paramètres de stimulation, particulièrement l’intensité, rend l’implémentation de nouveaux protocoles ardue. En effet, il n’y a actuellement aucun consensus sur les paramètres optimaux de stimulation pour moduler l’activité EEG dans la bande de fréquence alphal’onde alpha. Ce projet a pour but de documenter l’impact différentiel de contrôler les caractéristiques de stimulation tACS, soit l’intensité, la fréquence et le site (antérieur ou postérieur) de stimulation. À cette fin, 20 participants en santé ont pris part à notre étude, chacun soumis à 4 conditions de stimulation tACS, échelonnées sur 2 jours (2 blocs par jour). Pour chaque condition expérimentale, la stimulation tACS a été administrée de façon continue via 2 électrodes pendant 20 minutes. Deux conditions actives de tACS ont été réalisées aux sites PO7-PO8 (Système International EEG 10-10), l’une à Fréquence Alpha Individuelle (IAF) et l’autre à Fréquence Theta Individuelle (ITF), qui ont été prédéterminées par une session EEG, au repos et les yeux ouverts, de 5 minutes a priori. Deux conditions de stimulation ont été effectuées avec les électrodes de stimulation positionnées aux sites F3F4 (Système International EEG 10-20), à IAF ou à intensité SHAM (montée de courant 15 secondes seulement). L’intensité de stimulation a été ajustée en respectant le degré de confort de chaque participant, selon une échelle standardisée de désagréabilité (≤ 40 sur 100), et ne pouvait excéder 6 mA. La seconde séance journalière était exécutée 180 minutes après la première séance de tACS. Afin d’évaluer les niveaux de fatigue, les participants ont eu à réaliser une tâche psychomotrice de vigilance (PVT) durant la tACS. Toutes les conditions ont été contrebalancées. Les résultats suggèrent que la tACS ajustée à IAF a été plus efficace que les conditions ITF et SHAM afin d’augmenter la puissance alpha. Pour les deux sites de stimulation IAF tACS, l’augmentation de puissance spectrale la plus importante a été obtenue en tACS antérieure; par contre cette augmentation est distale et spécifique aux générateurs alpha, en pariéto-occipital. Pour ce qui est du montage tACS postérieur, l’augmentation alpha est observée pour les deux régions cérébrales, frontale et postérieure, tout en démontrant un effet d’augmentation préférentiel sur la puissance alpha, versus les autres bandes de fréquence theta et beta. Cette étude propose une évidence préliminaire que la tACS ajustée à IAF à plus hautes intensités est bien tolérée et démontre que l’optimisation de la technique peut avoir un impact prometteur dans le domaine. / Transcranial alternating current stimulation (tACS) is a non-invasive brain stimulation technique increasingly used for its modulating effect on intrinsic brain oscillations. In comparison to transcranial direct current stimulation (tDCS), tACS allows the administration of a sinusoidal current adjusted to one’s endogenous measured frequency. Oscillations within the alpha band range (8-12 Hz) are among the most studied, given their various associations with brain functions and states. A number of studies have proven to be effective in increasing alpha power using tACS through diverse methods. However, the heterogeneity of stimulation parameters, notably the intensity, makes it difficult to implement new tACS protocol. Indeed, there is currently no consensus on optimal stimulation parameters to modulate the alpha rhythm. The current project aimed to document the differential impact of controlling for key tACS stimulation characteristics, namely the stimulation intensity, the stimulation frequency and the stimulation site (anterior or posterior). To this end, we conducted a study, in which 20 healthy participants underwent four different tACS conditions conducted over two non-consecutive days (2 blocks per day). In each experimental condition, tACS stimulation was continuously delivered via two electrodes for a total duration of 20 minutes. Two active tACS conditions were administered at electrode sites PO7-PO8 (10-10 International System) at either the Individual’s Alpha Frequency (IAF) or at the Individual’s Theta Frequency (ITF), which were a priori determined via a 5-minute pre-stimulation EEG recording with eyes open at rest. Two stimulation conditions were performed with stimulating electrodes positioned over F3-F4 electrode sites, at IAF or sham intensity (ramp-up of 15 seconds). The stimulation intensity was set according to the participant’s own rating of unpleasantness on a standardized unpleasantness scale (≤ 40 out of 100) and could not exceed 6 mA. The second tACS condition was administered 180 minutes after the first tACS condition. To assess for fatigue levels, participants were asked to perform a psychomotor vigilance task (PVT) during tACS. All conditions were counterbalanced. Results suggest that alpha tACS stimulation adjusted to IAF was effective in increasing alpha power. Of the two stimulating sites, anterior alpha tACS stimulation induced greatest increases in alpha power, maximal when set to IAF, although specific to alpha generators’ site. Posterior alpha tACS stimulation showed overall increase both over frontal and posterior brain areas. These effects persisted at the 60-minute recording for the anterior tACS only. The current pilot study provides preliminary evidence that posterior tACS stimulation adjusted to IAF at higher intensities is well tolerated and shows potential as an effective brain stimulation technique to increase posterior alpha power.

DNA replication is a fundamental process in all living organisms. It is a semi- discontinuous process in which the leading strand is synthesized continuously and the lagging strand is synthesized discontinuously as short Okazaki fragments (OF). The initiation of DNA synthesis requires DNA polymerase α (Pol α/primase) in complex with the primase to form a complex of four subunits. Pol α/primase is the only enzyme that can perform de novo DNA synthesis on single-stranded DNA. The catalytic subunit of the primase (PRIM1) synthesizes RNA primers that are approximately nine nucleotides long. The synthesized RNA primers are then passed intramolecularly to the polymerase active site (POLA1), which is thought to be mediated by the C-terminal domain of the primase large subunit (PRIM2-C) to synthesize dNTPs of approximately 20 nucleotides. The aim of this project was to optimize the expression and purification of Pol α/primase. The insect codon optimized POLA1 was C-terminally Strep tagged and transposed into the baculovirus genome. The other subunits of Pol α/primase, POLA2, PRIM1 and PRIM2 were cloned and expressed in E. coli cells. The cell lysates from Sf9 insect cells and E. coli cells were then mixed and purified by immunoaffinity chromatography and size-exclusion chromatography. This helped us achieve a pure Pol α/primase containing all the four subunits with a good total yield. The identity of all the protein bands were verified by mass spectroscopy. Furthermore, the protein demonstrated primer extension activity on multiple primer/template substrates. We also characterized the effect of the human replication protein A (RPA) on the DNA polymerization activity of Pol α/primase.

Anesthesia affects the central nervous system and can suppress cardiovascular activity. In this study, we compared two anesthetics, urethane and alpha-chloralose, to better understand their effect on sympathetic control of blood pressure, as well as how they would affect baroreceptor response and blood pressure in adult rats. To do this we performed baroreceptor tests in adult rats under isoflurane anesthesia and then either urethane (I.V. 1.25 g/kg, n=2) or alpha-chloralose (100 mg/kg, n=2). We found that baroreceptor responses were not significantly different between urethane or alpha-chloralose anesthesia. However, significant depression of baseline blood pressure occurred under alpha-chloralose anesthesia compared with urethane. Additionally, we observed significant elevation of baseline renal sympathetic nerve activity (RSNA) occurred under urethane anesthesia. Ultimately, our findings suggest that both urethane and alpha-chloralose provided sufficient induction of anesthesia without significantly modifying baroreceptor response. However, since urethane significantly raised baseline sympathetic nerve activity, it should be avoided in studies where raised sympathetic activity could confound with the test results. alpha-chloralose significantly lowered baseline blood pressure by nearly 30%, and its use should be avoided in studies where lowered blood pressure may confound the results.

The thesis deals with the HKSp α integral, which is generalization of the HKS integral, its properties and the concepts of ordinary oscillation and p-oscillation, which are needed for the construction of the integral. This integral is non-absolutely convergent and more general than the Lebesgue integral. This thesis is based on recent results in the theory of integrals and its goal is to introduce this integral to a wide readership interested in mathematical analysis. 1

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