The Accelerator Test Facility (ATF2) at KEK, Japan, aims to experimentally verify the local chromaticity correction scheme designed to achieve a vertical beam size of 37 nm. The facility is a scaled down version of the final focus design proposed for the future linear colliders. In order to achieve this goal, high precision tuning methods and orbit correction techniques are being developed. Experimental studies were planned and undertaken in order to discover and compensate for sources of emittance growth in the extraction region of ATF2. Global Single Value Decomposition (SVD)-based orbit correction algorithms have been developed and optimised for the ATF2 extraction line and final focus. A novel method known as the 'rotation matrix' method has been developed for the spot-size tuning of ATF2 in order to achieve a nanometre-scale beamsize. The tuning algorithms used at ATF2 will provide an important input for future linear colliders (including the International Linear Collider (ILC) and Compact Linear Collider (CLIC)).

No description available.

La construction d'un futur collisionneur linéaire e+/e− est prévue pour obtenir des mesures précises (à l'échelle du T eV ) qui seraient complémentaires de celles obtenues du LHC. Un des défis de ce collisionneur linéaire sera de focaliser le faisceau à des tailles transverses nanométriques au point d'interaction, afin d'obtenir une importante luminosité de quelques 10^−34 cm^2 s^−1 . Les deux projets de collisionneur linéaire (ILC et CLIC) requièrent un système de distribution du faisceau partageant le même schéma de correction de chromaticité locale dans le système de focalisation finale. ATF2 à KEK (Japon), une implémentation de ce schéma mis à l'échelle en énergie, utilise le faisceau extrait d'ATF, qui est un des meilleurs anneaux d'amortissement au monde. Les objectifs d'ATF2 sont de prouver la faisabilité et la stabilité du système de focalisation finale et de définir et tester les procédures de corrections expérimentales. Les tailles nominales du faisceau au point d'interaction sont de 3µm horizontalement et 37nm verticalement. Le travail de thèse a commencé avant la mise en service et en couvre la première année à KEK. Au début, nous avons observé que les BPMs 'stripline' ne fonctionnaient pas correctement, nous avons donc examiné leurs comportements en détail. Le problème a été caractérisé puis résolu plus tard, en 2010, en changeant l'électronique. Nous avons alors développé une procédure efficace pour vérifier la modélisation de la ligne de faisceau, en comparant les mesures des matrices de transfert aux prédictions du modèle calculé en direct. Après avoir obtenu un bon accord, nous avons pu tester avec succès l'algorithme de correction de trajectoire que nous avions développé, réduisant la différence entre les mesures obtenues par les BPMs et les valeurs cibles jusqu'à 0.5mm horizontalement et 0.2mm verticalement. Nous avons aussi développé avec succès un algorithme pour reconstruire les fluctuations de la trajectoire du faisceau pour chaque paquet avec une résolution inférieure au micron. Cette reconstruction détermine aussi les fluctuations en énergie, permettant un ajustement général de la fonction de dispersion sur la longueur de la ligne de faisceau avec une précision de quelques millimètres, dominé par les erreurs systématiques provenant des matrices de transfert et des incertitudes sur les facteurs d'échelles des BPMs. Une méthode simple et robuste de réglage de la taille du faisceau à l'IP utilisant des déplacements de sextupoles a aussi été étudiée en simulation. Les performances indiquent que, en faisant quelques hypothèses sur le niveau d'erreur du faisceau, la convergence à 20% de la taille nominale devrait être possible en 8 heures avec une probabilité de 80%. Les premiers résultats expérimentaux de telles méthodes de réglages de la taille du faisceau sont actuellement en cours pour 2010 et 2011.

L'étude détaillée des distributions transverses du halo du faisceau est importante du point de vue des pertes de faisceau et du contrôle du bruit de fond dans ATF2 et les futurs collisionneurs linéaires (FLC). Un nouveau type de capteur diamant sous vide (DSv) déplacable, avec quatre pistes, a été conçu et développé pour la mesure des distributions transverses du halo du faisceau et la détection du spectre des électrons de recul Compton après le point d'interaction (IP) d'ATF2, qui est un prototype à basse énergie (1.3 GeV) de la section de focalisation finale pour les projets de collisionneurs linéaires ILC et CLIC.Cette thèse présente les études du halo du faisceau et des électrons de recul Compton, ainsi que la caractérisation, les études de performance et les tests des capteurs diamant (DS), tant sur PHIL, un photo-injecteur à basse énergie (<10 MeV) au LAL, que sur ATF2. Les résultats des premières mesures du halo du faisceau, utilisant des wire scanner (WS) et un DSv, sur ATF2 sont également présentés et comparés dans cette thèse.Des simulations utilisant Mad-X et CAIN ont été réalisées afin d'estimer le nombre d'électrons composant le halo du faisceau ainsi que le nombre d'électrons de recul Compton. Les résultats des simulations ont indiqué qu'une grande gamme dynamique, supérieure 10⁶ , est nécessaire pour une mesure simultanée du cœur du faisceau, du halo du faisceau et des électrons de recul Compton. Un DSv mono-cristallin, fabriqué par CVD (Chemical Vapor Deposition), a été développé dans ce but.Avant l'installation du capteur diamant, une première tentative de mesure du halo du faisceau a été effectuée en 2013, en utilisant les wire scanners (WS) actuellement installés sur ATF2. En raison de leur dynamique limitée de ~10³ , la distribution du halo du faisceau a été mesurée seulement jusqu'à ~±6σ dans la ligne d'extraction (EXT). Un paramétrage des distributions mesurées du halo du faisceau a montré que les distributions mesurées sont cohérentes avec des mesures faites précédemment, en 2005, sur l'ancienne ligne faisceau d'ATF. Durant ces mesures, une distribution asymétrique du halo vertical du faisceau a été observée pour la première fois en utilisant le WS situé après l'IP, son origine est actuellement sous investigation en utilisant le DSv.Des études pour caractériser des capteurs diamants de dimensions 4.5x4.5x0.5 mm³ ont été réalisées en utilisant des sources α et β. Les paramètres de transport des porteurs de charge (durée de vie, vitesse de saturation, etc.) ont été obtenus en utilisant la technique des courants transitoires (TCT). Par ailleurs, la linéarité de la réponse du DS a été testée sur PHIL avec différentes intensités de faisceau après la fenêtre de sortie de d'accélération. Un signal maximum de 10⁸ électrons a été mesuré, avec une réponse linéaire jusqu'à 10⁷ électrons. Des études similaires de la linéarité ont été faites pour le DSv sur ATF2. Nous avons pu y exploiter avec succès, pour la première fois une gamme dynamique de ~10⁶ , permettant de mesurer simultanément le cœur du faisceau (~10⁹ électrons) et le halo du faisceau (~10³ électrons). Le pick-up électromagnétique induit par le passage du cœur du faisceau et des effets de saturation, qui sont les limitations empêchant actuellement le DSv d'atteindre une gamme dynamique supérieure à 10⁶ , ont également été identifiés et étudiés.Les premières mesures de la distribution horizontale du halo, en utilisant le DSv, ont été effectuées jusqu'à ~±20σx , et ont permis de prouver que le halo du faisceau est collimaté par les ouvertures de la ligne ATF2. Une distribution horizontale du halo compatible avec les paramétrages de 2005 et 2013 a été confirmée. La possibilité de détecter les électrons de recul Compton a été étudiée. Différentes solutions pour accroître la sensibilité des mesures ont été proposées. / The investigation of beam halo transverse distributions is an important issue for beam losses and background control in ATF2 and in Future Linear Colliders (FLC). A novel in vacuum diamond sensor (DSv) scanner with four strips has been designed and developed for the investigation of beam halo transverse distributions and also for the diagnostics of Compton recoil electrons after the interaction point (IP) of ATF2, a low energy (1.3 GeV) prototype of the final focus system for ILC and CLIC linear collider projects. This thesis presents the beam halo and Compton recoil electrons studies as well as the characterization, performance studies and tests of the diamond sensors (DS) both at PHIL, a low energy (<10 MeV) photo-injector at LAL, and at ATF2. First beam halo measurement results using wire scanners (WS) and DSv at ATF2 are also presented and compared in this thesis. Simulations using Mad-X and CAIN were done to estimate the rate of the beam halo and Compton recoil electrons. Simulation results have indicated that a large dynamic range of more than 10⁶ is needed for a simultaneous measurement of the beam core, beam halo and Compton recoil electrons. A single crystalline Chemical Vapor-Deposition (sCVD) based DSv was developed for this purpose. Prior to the diamond detector installation, first attempt of beam halo measurements have been performed in 2013 using the currently installed WS. With a limited dynamic range of ~10³ , the beam halo distribution was measured only up to ~±6σ in the extraction (EXT) line. Parametrizations of the measured beam halo distribution showed a consistent distribution with previous measurements done in 2005 at the old ATF beam line. Meanwhile, an asymmetric vertical beam halo distribution was observed for the first time using the post-IP WS, the origin of which is currently under investigation using the DSv.Studies to characterize DS pads with dimensions of 4.5x4.5x0.5 mm³ were carried out using the α and β sources. Charge carrier transport parameters (lifetime, saturation velocity etc.) were obtained using the transient-current technique (TCT). Furthermore, the linearity of the DS response was tested at PHIL with different beam intensities in air: a maximum signal of 108 electrons was measured with a linear response up to 10⁷ electrons. Similar linearity studies were done for the DSv at ATF2, where we have successfully demonstrated and confirmed for the first time a dynamic range of ~10⁶ by a simultaneous beam core (~10⁹ e-) and beam halo (~10³ e-) measurement using the DSv. Present limitations due to signal pick-up and saturation effects, which prevent the DSv from reaching a dynamic range higher than 10⁶ , were also studied.First measurements of the horizontal beam halo distribution using the DSv were performed up to ~±20σx, where the beam halo was proved to be collimated by the apertures. Horizontal beam halo distributions consistent with the 2005 and 2013 parametrizations were confirmed. The possibility of probing the Compton recoil electrons has been investigated and different ways to increase their visibility have been proposed.

Despite intense research efforts, the repair of large bone defects is still not satisfactory and remains a major challenge in Orthopaedic Surgery. In this context bone tissue engineering has emerged as a promising strategy. However, one of the fundamental principles underlying tissue engineering approaches is that newly formed tissue must maintain sufficient vascularization to support its growth. Thus an active blood vessel network is an essential pre-requisite for scaffold constructs to integrate within existing host tissue. Currently, great efforts are made to address this problem employing transplantation of vascular cells and loading of appropriate biological factors. Endothelial progenitor cells (EPCs) are a heterogeneous subpopulation of bone marrow mononuclear progenitor cells with potential for differentiation to the endothelial lineage and thus vasculogenic capacity. However, clinical studies reported that with the increase of age, increased susceptibility to apoptosis and accelerated senescence may contribute to the numerical and functional impairments observed in EPCs, which may lead to a reduced angiogenic capacity and an increased risk of vascular disease. Hence attention has increasingly been paid to enhance mobilization and differentiation of EPCs for therapeutic purposes. A large body of evidence indicates that in Traditional Chinese Medicine (TCM) a plethora of herbs and herbal extracts are effective in the treatment of vascular diseases such as chronic wounds, diabetic retinopathy and rheumatoid arthritis. Thus, it seems rational to explore these medicinal plants as potential sources of novel angiomodulatory factors. In this thesis we demonstrated that treatment with TCM herbal extracts promote cell growth, cell migration, cell-matrix and capillary-like tube formation of BM-EPCs. Among these TCM extracts, Salidroside (SAL) and Icariin (ICAR) incubation increased VEGF and nitric oxide secretion, which in turn mediated the enhancement of angiogenic differentiation of BM-EPCs. A mechanic evaluation provided evidence that SAL stimulates the phosphorylation of Akt, mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase (p70S6K), as well as phosphorylated ERK1/2, which is associated with the cell migration and tube formation. Furthermore, a pilot in vivo study showed that SAL has the potential to enhance bone formation in a murine femoral critical-size bone defects model. Another new finding of the present study is that hydrogen peroxide (H2O2)-induced cytotoxicity is counteracted by TCM extracts. We found that SAL, Salvianolic acid B (SalB) and ICAR significantly abrogated H2O2-induced cell apoptosis, reduced the intracellular level of reactive oxygen species (ROS) and nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) expression, and restored the mitochondrial membrane potential of BM-EPCs. Our data suggest that this protective effect of SalB is mediated by the activation of mTOR, p70S6K, 4EBP1, and by the suppression of MKK3/6-p38 MAPK-ATF2 and ERK1/2 signaling pathways after H2O2 stress. In addition, the investigation also demonstrates that ICAR owns the ability to inhibit apoptotic and autophagic programmed cell death via restoring the loss of mTOR and attenuation of ATF2 activity upon oxidative stress. Based on the outcomes of the present work, we propose SAL, SalB and ICAR as novel proanigiogenic and cytoprotective therapeutic agents with potential applications in the fields of systemic and site-specific tissue regeneration including ischaemic disease and extended musculoskeletal tissue defects.

Despite intense research efforts, the repair of large bone defects is still not satisfactory and remains a major challenge in Orthopaedic Surgery. In this context bone tissue engineering has emerged as a promising strategy. However, one of the fundamental principles underlying tissue engineering approaches is that newly formed tissue must maintain sufficient vascularization to support its growth. Thus an active blood vessel network is an essential pre-requisite for scaffold constructs to integrate within existing host tissue. Currently, great efforts are made to address this problem employing transplantation of vascular cells and loading of appropriate biological factors. Endothelial progenitor cells (EPCs) are a heterogeneous subpopulation of bone marrow mononuclear progenitor cells with potential for differentiation to the endothelial lineage and thus vasculogenic capacity. However, clinical studies reported that with the increase of age, increased susceptibility to apoptosis and accelerated senescence may contribute to the numerical and functional impairments observed in EPCs, which may lead to a reduced angiogenic capacity and an increased risk of vascular disease. Hence attention has increasingly been paid to enhance mobilization and differentiation of EPCs for therapeutic purposes. A large body of evidence indicates that in Traditional Chinese Medicine (TCM) a plethora of herbs and herbal extracts are effective in the treatment of vascular diseases such as chronic wounds, diabetic retinopathy and rheumatoid arthritis. Thus, it seems rational to explore these medicinal plants as potential sources of novel angiomodulatory factors. In this thesis we demonstrated that treatment with TCM herbal extracts promote cell growth, cell migration, cell-matrix and capillary-like tube formation of BM-EPCs. Among these TCM extracts, Salidroside (SAL) and Icariin (ICAR) incubation increased VEGF and nitric oxide secretion, which in turn mediated the enhancement of angiogenic differentiation of BM-EPCs. A mechanic evaluation provided evidence that SAL stimulates the phosphorylation of Akt, mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase (p70S6K), as well as phosphorylated ERK1/2, which is associated with the cell migration and tube formation. Furthermore, a pilot in vivo study showed that SAL has the potential to enhance bone formation in a murine femoral critical-size bone defects model. Another new finding of the present study is that hydrogen peroxide (H2O2)-induced cytotoxicity is counteracted by TCM extracts. We found that SAL, Salvianolic acid B (SalB) and ICAR significantly abrogated H2O2-induced cell apoptosis, reduced the intracellular level of reactive oxygen species (ROS) and nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) expression, and restored the mitochondrial membrane potential of BM-EPCs. Our data suggest that this protective effect of SalB is mediated by the activation of mTOR, p70S6K, 4EBP1, and by the suppression of MKK3/6-p38 MAPK-ATF2 and ERK1/2 signaling pathways after H2O2 stress. In addition, the investigation also demonstrates that ICAR owns the ability to inhibit apoptotic and autophagic programmed cell death via restoring the loss of mTOR and attenuation of ATF2 activity upon oxidative stress. Based on the outcomes of the present work, we propose SAL, SalB and ICAR as novel proanigiogenic and cytoprotective therapeutic agents with potential applications in the fields of systemic and site-specific tissue regeneration including ischaemic disease and extended musculoskeletal tissue defects.

Chez les mammifères, l'environnement est un puissant régulateur de l'expression des gènes. Par exemple, en fonction de l'alimentation, la disponibilité en nutriments, en particulier en acides aminés, est responsable de l'induction de l'expression d'un certain nombre de gènes. Ainsi, des mécanismes moléculaires sont mis en jeu de façon à permettre la détection de ces variations et d'y répondre de façon appropriée. Lorsque l'un des neuf acides aminés essentiels vient à manquer, on observe une augmentation de la transcription de certains gènes. Cette activation de la transcription requière d'une part l'accumulation du facteur de transcription ATF4 et d'autre part la phosphorylation du facteur de transcription ATF2. La voie ATF4 a été identifiée et relativement bien décrite. En revanche les éléments régulateurs de la voie de signalisation en amonts du facteur ATF2 restent inconnus. Le but de ma thèse était donc de déterminer les différents intermédiaires responsables de la phosphorylation d'ATF2 en réponse à une carence en acides aminés. J'ai ainsi montré qu'une carence en acides aminés provoque la mise en jeu d'un module MAPK composé de MEKK1>MKK7>JNK2 contrôlant la phosphorylation d'ATF2 sur les résidus thréonine 69 et 71. J'ai montré que ce module est régulé en amont par deux GTPases Cdc42+Rac1 et par la protéine Gα12. Enfin, j'ai démontré l'impact de cette nouvelle voie de signalisation sur la transcription AARE-dépendante du gène ATF3 en réponse à une carence en acides aminés.

Oral submucous fibrosis (OSF) is a debilitating irreversible fibrotic condition of the oral cavity. It is characterized by inflammation and ultimately results in trismus. Patients face difficulty in speaking, swallowing and chewing due to restricted mouth opening (trismus). This disease is also categorized as an oral premalignant disorder (OPMD). Recent reports cite a conversion rate of 10% from OSF to oral squamous cell carcinoma (OSCC). Epidemiological studies and case reports over the years have correlated the habit of chewing areca nut (Areca catechu) to the manifestation of OSF. It is a major cause of concern in the South and South East Asian parts of the world where areca nut is cultivated and routinely consumed. There are an estimated 700 million areca nut chewers around the globe with 0.5% of the population in the Indian subcontinent being affected by OSF due to this habit. Previous studies have reported differential gene expression profile and up regulation of the pro-fibrotic transforming growth factor-β (TGF-β) pathway in OSF. However, detailed molecular mechanisms for the pathogenesis of this disease are still unclear despite our knowledge about the etiological agent (areca nut) responsible for its progression. Therefore, to gain insights into the etiopathogeneses of OSF, following objectives were undertaken:  To study the gene expression changes induced by areca nut and pro-fibrotic cytokine TGF-β in primary fibroblast cells, and their implications in OSF.  To elucidate the mechanism of TGF-β signal activation in epithelial cells by areca nut. Fibroblast cells are the effectors in all fibrotic disorders. Therefore, it is essential to study the response of this cell type in fibrosis. With prior knowledge of the activation of TGF-β pathway in OSF and the etiological agent of this disease being areca nut; we wanted to study the differential gene response of fibroblasts to these two agents. For this purpose, human primary gingival fibroblasts (hGF) were used as a model system to study the global gene expression profile regulated by areca nut and/or TGF-β. hGF cells were treated with sub-cytotoxic dose of areca nut (5 µg/ml) with and without TGF-β (5 ng/ml) for 72 hours and microarray was performed. The results revealed 4666 genes being differentially regulated by areca nut in hGF cells while TGF-β regulated 1214 genes. Both of them together differentially regulated 5752 genes. 413 genes which were commonly regulated by areca nut and TGF-β were observed to have enhanced regulation with a combined treatment of areca nut, together with TGF-β. This result pointed towards the potential role of both areca nut and TGF-β in modulating fibroblast response. To further assess the role of areca nut in OSF manifestation, we first compared the transcriptome profile induced by it in epithelial cells with fibroblast cells. Areca nut was found to induce differential response in these two cell types which corroborates with the disease pathology wherein; epithelial atrophy is observed and conversely fibroblasts are proliferative. To extend these observations we compared the areca nut induced profile in epithelial cells with OSF differential profile and found that a majority of the genes regulated by areca nut which were common with OSF are regulated by TGF-β. Similarly, areca nut and TGF-β regulated profile in fibroblast cells overlapped significantly with OSF profile. Additionally, areca nut and TGF-β treatment positively enriched matrix associated and metabolic pathways among others which are reported to be differentially regulated in OSF. These observations also highlighted the importance of combined actions of areca nut and TGF-β in OSF manifestation. To test the physiological importance of combined actions of areca nut and TGF-β in the context of OSF; activation of fibroblasts by these treatments was assessed. Treatment of fibroblasts with areca nut and TGF-β enhanced the expression of myofibroblast markers αSMA and γSMA with a concomitant increase in the contractile property when compared to areca nut or TGF-β treatment alone. Further, we observed that areca nut did not regulate any of the TGF-β ligands or receptors in fibroblasts, whereas it induced TGF-β2 in epithelial cells. Therefore, this invoked a possible epithelial-mesenchymal interaction that may exist in OSF pathogenesis. To test this possibility in-vitro, epithelial cells were treated with areca nut and the secretome of these cells was put on hGF cells to study the regulation of fibrosis associated genes. This treatment enhanced the regulation of fibroblast activation markers (αSMA and γSMA) as compared to direct areca nut treatment. This increase in regulation was abrogated when induction of TGF-β2 was compromised in epithelial cells. Similar results were obtained for the regulation of other genes (TGM-2, THBS-1, EDN1, LOXL3, PLOD2, TMEPAI, TGFBI, CTGF, BMP1, LMIK1). Therefore, we concluded that TGF-β which is secreted in response to areca nut by epithelial cells influences fibroblasts in combination with areca nut to enhance fibrosis response. Furthermore, the secretome of untreated epithelial cells was found to down regulate the basal expression of fibrosis related genes in fibroblasts, invoking a role for epithelial secretome in regulating the fibrosis progression. Our data highlighted the importance of TGF-β’s influence on fibroblast response in OSF, but the mechanism for the regulation of this cytokine was not known. Areca nut did not induce TGF-β ligands in fibroblast as discussed above, but previous data from our group had reported areca nut mediated up regulation of TGF-β2 in epithelial cells. Therefore, we further elucidated the mechanistic details for this induction using immortalized keratinocytes (HaCaT and HPL1D) and correlated these in OSF tissues. The kinetics of the induction of TGF-β signaling by areca nut (5 µg/ml) in epithelial cells was established. Areca nut induced TGF-β2 transcript, protein and activated the canonical signaling (pSMAD2/3) at 2 hours post treatment, which persisted till 24 hours. The regulation of TGF-β2 mRNA at 2 hours was dependent on active transcription but was independent of protein translation whereas the activation of signaling (pSMAD2) required both transcription and translation at this time point. This warranted probing for the role of TβR-I in the activation of TGF-β signal by areca nut. A small molecule inhibitor was used to abrogate the kinase activity of TβR-I. Areca nut induced TGF-β2 mRNA at 2 hours even in the presence of TβR-I inhibitor whereas the induction was compromised at 24 hours although the activation of SMAD2 at both 2 and 24 hours was compromised in the presence of TβR-I. This result signified that induction of TGF-β signaling was dependent on the TβR-I activity at early and late time points, but the transcription of the ligand was independent of the receptor activity at early time point. These results indicated the activation of some other pathway by areca nut which could regulate the transcription of TGF-β2 and thereby activate TGF-β signaling in epithelial cells. To explore this possibility, a panel of pathway inhibitors was used and only JNK inhibitor compromised areca nut induced TGF-β2 mRNA and pSMAD2. The results were corroborated by transient knockdown of JNK1 and JNK2. Further, JNK was phosphorylated at 30 minutes to 2 hours by areca nut treatment on epithelial cells. This activation was found to be independent of TβR-I activity. In good correlation, activated JNK1/2 was also detected in OSF tissues and was not detectable in normal tissues. Since JNK activation was found to be a pre-requisite for areca nut induced TGF-β signal activation; we further explored the mechanism of JNK activation by areca nut itself. Areca nut mediated activation of JNK was found to be dependent on muscarinic acid receptor, Ca2+/CAMKII and ROS. Inhibition of these significantly compromised areca nut induced pJNK. In line with this, inhibition of muscarinic acid receptor activity, CAMKII and ROS also abrogated areca nut mediated induction of TGF-β2 mRNA and pSMAD2. The regulation of TGF-β signaling by areca nut in epithelial cells was dependent on transcription, and JNK activity was essential for this. We further sought to explore transcription factors which were regulated by JNK and therefore could possibly induce TGF-β2 promoter activity. ATF2 and c-Jun transcription factors were found to be induced at 30 minutes by areca nut and this up regulation also persisted till 24 hours. Further, activation of both ATF2 and c-Jun was dependent on JNK but independent of TβR-I activity. Moreover, areca nut treatment induced translocation of these phoshorylated transcription factors in the nucleus of epithelial cells. Additionally, pATF2 and p-c-Jun were enriched on TGF-β2 promoter after 2 hours of treatment by areca nut. To investigate the importance of this enrichment and regulation of TGF-β signal activation by areca nut, we transiently knocked down these proteins and studied the regulation of TGF-β2. Areca nut induced TGF-β2 mRNA and pSMAD2 was abrogated upon ATF2 and c-Jun knockdown, implicating JNK mediated activation of ATF2 and c-Jun in areca nut induced TGF- β signaling. To explore the significance of this mechanism in OSF, immunohistochemical staining for pATF2 and p-c-Jun was performed on OSF and normal tissues. Both the transcription factors were found in the nuclei of OSF tissues whereas their expression was not detected in normal tissues. This expression also correlated with the previously reported activation of SMAD2 in OSF tissues by our group. Hence, ATF2 and c-Jun were observed to be important in areca nut mediated TGF-β signaling in OSF. In conclusion, the work described in this thesis provides mechanistic details into OSF etiopathogenesis. Combined actions of areca nut and TGF-β induced a response in fibroblasts akin to OSF. Our results advocate a role for epithelial secreted factors in influencing fibroblast response in both normal and disease (OSF) conditions. Further, importance of TGF-β in OSF has been elucidated in terms of enhancing the fibroblast response to areca nut. We have also elucidated the mechanism for areca nut mediated activation of TGF-β signaling and have identified the contribution of JNK/ATF2/Jun axis in this process. This work can impact the management of oral submucous fibrosis by providing newer targets for treatment.

L’exploration d’une nouvelle physique à l’échelle d’énergie des « Tera electron Volt » (TeV) nécessite de collisionner des leptons dans de grands accélérateurs linéaires à grande luminosité. Ces collisionneurs linéaires requiert une taille de faisceau à l’echelle nanométrique au Point d’Interaction (IP).Parmi les multiples effets participant à la degradation de la luminosité, la correction de la chromaticité, l’effet du rayonnement synchrotronique et la correction des erreurs dans la ligne sont parmi les trois effets à maîtriser afin de réduire la taille du faisceau dans la Section Finale de Focalisation (FFS).Cette these propose un nouveau schéma de correction de la chromaticitè que l’on appelera “non-entrelacé”, appliqué ici au projet CLIC. Lors de l’implementation de cette nouvelle methode, il a été mis en evidence que le probléme principal est la dispersion de deuxième ordre au Doublet Final (FD), qui traverse un sextupole utilisé pour annuler les composantes géometriques restantes.L’effet du rayonnement peut être evalué par méthode de tracking des particules ou par des approximations analytiques. Afin d’inclure ces effets du rayonnement et les paramétres optiques de la ligne pendant la conception et le processus d’optimisation, l’effet Oide et le rayonnement dû aux aimants dipolaires ont été etudiés.Le résultat analytique du rayonnement synchrotronique dans les aimants dipolaires fut generalisé dans les cas avec alpha et dispersion non-nulles à l’IP. Cette généralisation est utilisée pour améliorer le code de simulation PLACET.Le rayonnement dans les aimants quadripolaires finaux imposent une limite à la taille verticale minimale du faiceau, connu comme l’effet Oide. Celui-ci est uniquement important à 3 TeV, donc deux possibilités sont explorées pour atténuer sa contribution dans la taille du faisceau : doubler la longueur et réduire le gradient du dernièr quadripole (QD0), ou integrer une paire d’aimants octupolaires, un en amont et un en aval du QD0.Une partie des exigences du FFS pour les nouveaux collisionneurs linéaire à leptons est testée expérimentalement dans l’« Accelerator Test Facility » (ATF). La réduction de la taille du faisceau d’électrons en utilisant le schéma local de correction de la chromaticité est explorée dans une extension de la ligne originale, appellé ATF2, oú deux buts furent fixés : atteindre 37 nm de taille verticale du faisceau à l’IP, et stabiliser de l’ordre du nanomètre la position verticale du faisceau à l’IP. Depuis 2014, une taille de 44 nm avec un nombre de particules d’environ 0.1 × 10^10 par paquet est atteint de manière regulière.Des cavités radio-frequence seront utilisées pour la stabilisation du faisceau, et également pour détecter le déplacement/les fluctuations du faisceau au dehors la marge tolerable pour le systéme de mesure, ainsi que des erreurs non detectées dans l’optique.Un set de trois cavités furent installées et sont utilisées pour mesurer la trajectoire du faiceau dans la région de l’IP, fournissant ainsi des informations pour reconstruire la position et l’angle à l’IP. Les specifications pour l’optique nominale d’ATF2, i.e. 1 nm de résolution sur 10 μm de gamme dynamique à un nombre de particules de 1.0 × 10^10 par paquet, n’ont pas encore été atteint.La meilleur résolution atteinte jusqu’ici correspond à 50 nm pour 0.4 × 10^10 particules par paquet, où le bruit de l’éléctronique impose une limite de 10 nm par cavité sur la résolution. La gamme dynamique est de 10 μm à 0.4 × 10^10 particules par paquet et 10 dB d’attenuation du signal des cavités, nécéssitant de mettre l’électronique à niveau. Le test du système d’asservissement pour stabiliser le faisceau a atteint une réduction de la fluctuation jusqu’a 67 nm, compatible avec la résolution des cavités. / The exploration of new physics in the “Tera electron-Volt” (TeV) scale with precision measurements requires lepton colliders providing high luminosities to obtain enough statistics for the particle interaction analysis. In order to achieve design luminosity values, linear colliders feature nanometer beam spot sizes at the Interaction Point (IP).Three main issues to achieve the beam size demagnification in the Final Focus Section (FFS) of the accelerator are the chromaticity correction, the synchrotron radiation effects and the correction of the lattice errors.This thesis considers two aspects for linear colliders: push the limits of linear colliders design, in particular the chromaticity correction and the radiation effects at 3 TeV, and the instrumentation and experimental work on beam stabilization in a test facility.A new chromaticity correction scheme, called non-interleaved, is proposed to the local and non-local chromaticity corrections for CLIC. This lattice is designed and diagnosed, where the main issue in the current state of lattice design is the non-zero second order dispersion in the Final Doublet (FD) region where a strong sextupole is used to correct the remaining geometrical components.The radiation effect can be evaluated by tracking particles through the lattice or by analytical approximations during the design stage of the lattices. In order to include both, radiation and optic parameters, during the design optimization process, two particular radiation phenomena are reviewed: the Oide effect and the radiation caused by bending magnets .The analytical result of the radiation in bending magnets in was generalized to the case with non-zero alpha and non-zero dispersion at the IP, required during the design and luminosity optimization process. The closed solution for one dipole and one dipole with a drift is compared with the tracking code PLACET, resulting in the improvement of the tracking code results.The Oide effect sets a limit on the vertical beamsize due to the radiation in the final quadrupole. Only for CLIC 3 TeV this limit is significant, therefore two possibilities are explored to mitigate its contribution to beam size: double the length and reduce the QD0 gradient, or the integration of a pair of octupoles before and after QD0.Part of the requirements of the FFS for new linear accelerators are tested in The Accelerator Test Facility (ATF). The beam size reduction using the local chromaticity correction is explored by an extension of the original design, called ATF2 with two goals: achieve 37 nm of vertical beam size at the IP, and the stabilization of the IP beam position at the level of few nanometres. Since 2014 beam size of 44 nm are achieved as a regular basis at charges of about 0.1 × 10^10 particules per bunch.A set of three cavities (IPA, IPB and IPC), two upstream and one downstream of the nominal IP and on top of separate blocks of piezo-electric movers, were installed and are used to measure the beam trajectory in the IP region, thus providing enough information to reconstruct the bunch position and angle at the IP. These will be used to for beam stabilization and could detect beam drift/jitter beyond the tolerable margin and undetected optics mismatch affecting the beam size measurements. The specifications required of 1 nm resolution over 10 μm dynamic range at 1.0 × 10 10 particules per bunch with the ATF2 nominal optics have not been yet achieved.The minimum resolution achieved is just below 50 nm at 0.4 × 10^10 particules per bunch with a set of electronics impossing a noise limit on resolution of 10 nm per cavity. The dynamic range is 10 μm at 10 dB attenuation and 0.4 × 10^10 particules per bunch, indicating the need to upgrade theelectronics. The integration to the ATF tuning instruments is ongoing. Nonetheless, feedback has been tested resulting in reduction of beam jitterdown to 67 nm, compatible with resolution.