Les références de temps et de fréquence sont largement distribuées sur réseaux informatique et de communications, pour une large gamme d'applications scientifiques et industrielles. Poussé par une demande pour de meilleures performances, un certain nombre de nouvelles méthodes de transfert de temps et de fréquence sur des réseaux à fibres optiques ont été développées ces dernières années. Dans cette thèse, notre objectif est de développer une approche de transfert de temps et de fréquence multi-utilisateurs, compatible avec les réseaux de télécommunications et compétitive avec la distribution de temps par GNSS. Nous nous intéressons donc aux méthodes pour les réseaux à commutation par paquets, comme le NTP (Network Time Protocol) et le PTP (Precision Timing Protocol). Nous nous concentrons également sur les liaisons “unidirectionnelles”, où les signaux aller et retour entre les nœuds de réseau se propagent sur des fibres distinctes, non au sein d’une même fibre (liaisons “bidirectionnelles”). En particulier, nous utilisons une méthode appelée White Rabbit PTP (WR). Développée au CERN, basée sur PTP, utilisant l’Ethernet synchrone et d'autres techniques pour atteindre des performances élevées, WR réalise une stabilité du temps sous-nanoseconde pour la synchronisation d'instruments sur des réseaux à l'échelle de 10 km. Nous sommes particulièrement intéressés par l'extension de cette méthode pour la distribution de références au niveau régional ou national, sur des liaisons allant jusqu'à 1000 km.Nous étudions d’abord les performances de l'équipement réseau White Rabbit, en particulier le commutateur White Rabbit. Nous y apportons diverses améliorations : sur le verrouillage du commutateur grand maître à la référence externe, améliorant ainsi sa stabilité à court terme de plus d'un ordre de grandeur ; sur la bande passante de verrouillage du commutateur esclave ; et en augmentant le débit des messages PTP entre les commutateurs maître et esclave.Nous étudions ensuite les liaisons WR moyennes et longues distances. Nous construisons un lien unidirectionnel de 100 km en utilisant des bobines de fibres dans le laboratoire. Nous découvrons que la performance à court terme est limitée par la dispersion chromatique de la fibre, tandis que la performance à long terme est dégradée par le bruit thermique. Pour limiter l'effet de la dispersion chromatique sur les liaisons longue distance, nous proposons l'utilisation d'une approche en cascade. Nous réalisons un lien en cascade de 500 km, à nouveau avec des bobines de fibres. Nous utilisons le multiplexage en longueur d'onde dense pour construire ce lien par des passages multiples à travers des bobines plus courtes. Nous obtenons une stabilité de transfert de fréquence de 2 × 10-12 à une seconde de temps d'intégration et de 5 × 10-15 en un jour, limitée par le bruit thermique à long terme. Nous obtenons une stabilité temporelle de 5 ps à une seconde de temps d'intégration, diminuant jusqu'à un minimum de 1,2 ps à 20 secondes et restant inférieure à une nanoseconde pour des durées plus longues. Ces performances sont similaires à court terme, et deux ordres de grandeur meilleures à long terme, qu’un récepteur GPS de bonne qualité. Nous nous attendons à ce que les fluctuations thermiques et donc l'effet du bruit thermique des fibres soient réduits d'un facteur d'environ cinq pour les installations sur le terrain.Enfin, nous faisons des études préliminaires sur l'étalonnage en temps des liaisons WR. Le principal défi est de mesurer l'asymétrie de longueur optique entre les deux fibres utilisées pour le transfert des signaux aller et retour. Nous démontrons une technique d'échange de fibres, en utilisant une liaison suburbaine White Rabbit sur fibre noire. Nous décrivons et testons ensuite une nouvelle méthode variationnelle pour l'étalonnage, impliquant une méthode de mesure différentielle basée sur l'exploitation de deux liaisons WR à différentes longueurs d'onde sur la même liaison. / Time and frequency references are widely distributed over communications and computer networks, for a variety of scientific and industrial applications. Driven by a demand for improved performance, a number of new methods for time and frequency transfer over optical fiber-based networks have been developed in recent years. In this thesis our objective is to develop a scalable network time and frequency transfer approach, providing multi-user dissemination, compatible with large telecommunication networks and competitive with GNSS-based time distribution. Therefore we are concerned with methods for use in packet-based networks, like the Network Time Protocol (NTP) and Precision Timing Protocol (PTP). We also concentrate on “unidirectional” links, where the forward and backward signals between network nodes propagate over separate fibers, not within the same fiber (“bidirectional” links).In particular we use a method called White Rabbit PTP (WR). This is a novel technology developed at CERN, based on PTP while using Synchronous Ethernet and other techniques to achieve high performance. It demonstrates sub-nanosecond time stability and synchronization of arrays of instruments over 10 km scale networks. We are particularly interested in extending this method for large scale distribution of references at regional or national level, over links of up to 1000 km.We first study extensively the default performances and limitations of White Rabbit network equipment, in particular the White Rabbit switch. We make various improvements to its operation: on the locking of the grandmaster switch to the external reference, thus improving its short-term stability by more than an order of magnitude; optimizing the locking bandwidth of the slave switch; and increasing the PTP messaging rate between master and slave switches.We then study medium and long-distance WR links. We construct a 100 km, unidirectional link using fiber spools in the laboratory. We discover that the short-term performance is limited by chromatic dispersion in the fiber, while the long-term performance is degraded by the influence of temperature variations on the fiber. To limit the effect of chromatic dispersion for long-haul links, we propose the use of a cascaded approach. We realise a national scale, cascaded, 500 km link, again utilizing fiber spools. We use Dense Wavelength Division Multiplexing methods to construct this link by mutliple passages through shorter spools. We achieve a frequency transfer stability of 2 × 10−12 at one second of integration time and 5 × 10−15 at one day, limited by thermal noise in the long term. We achieve a time stability of 5 ps at one second of integration time, decreasing to a minimum of 1.2 ps at 20 seconds and remaining below one nanosecond for longer averaging times. These performances are similar in the short term, and two orders of magnitude better in the long term, than good quality GPS receivers. We expect thermal fluctuations and therefore the effect of fiber thermal noise to be suppressed by a factor of approximately five for installations in the field.Finally we make preliminary investigations of time calibration of WR links. The main challenge here is to measure the optical length asymmetry between the two fibers used for signal transfer in the forward and backward directions. We demonstrate a fiber swapping technique, using a mid range, suburban White Rabbit link over dark fiber. We then describe and test a new variational method for calibration, involving a differential measurement method based on operating two WR links at different wavelengths over the same optical fiber link.In conclusion, we demonstrate high performance, long haul White Rabbit links for time and frequency dissemination to multiple users. With the level of frequency transfer performance achieved, White Rabbit PTP provides a competitive and scalable technique for comparing industrial atomic clocks at regional and national scales.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

Many signaling pathways have been shown to be involved in the formation of the vascular system. Among them are the endothelial specific receptor families such as VEGF, Ang/Tie, as well as other signaling pathways such as semaphorins, which are also involved, in axonal guidance. It is known that the interaction between receptor tyrosine kinase, Tie2, VE-Cadherin, and VE-PTP mediate endothelial cell quiescence and adhesion. However, the structural basis of these interactions is not well understood. The aim of our study is to characterize the binding interactions between these players. Another important part of our study is describing the cross-talk between vasculature and nervous system by characterizing the Neuropilin/Plexin/Semaphorin system. VE-Cadherin along with neuropilins plays an essential role by directing VEGF signals to the appropriate location and coordinating the activation of downstream molecules. We characterize the interaction between Tie2, VE-PTP and VE-Cadherin by (FRET)-based proximity assay, fluorescence lifetime imaging, and co-immunoprecipitation assays. Our data showed a consistent localization of the protein and FRET signal for Tie2 and VE-PTP prior to ligand recognition. We showed the association between Tie2 and VE-Cadherin complex by co-immunoprecipatation. However, our FRET data was not consistent. The examination of VE-PTP and VE-Cadherin for association and localization of the protein showed a very unique, mutually exclusive localization of the protein. Our study of Neuropilin/Plexin/Semaphorin system showed changes in the protein localization, FRET signal and morphology upon stimulation of HEK293 cells expressing Nrp/plexin with Sema3D. In this system VE-Cadherin along with neuropilins plays an essential role by directing VEGF signals to the appropriate location and coordinating the activation of downstream molecules. The characterization of extracellular binding between Tie2, VE-PTP, and VE-Cadherin, will help to better understand the molecular mechanisms of normal and tumor angiogenesis to develop new anti-angiogeneic therapies.

Les glucides sont omniprésents dans la nature et jouent un rôle clé dans divers processus de reconnaissance moléculaire. Nous avons réalisé la conception et la synthèse de quatre types de dérivés glucidiques qui se divisent en 4 chapitres. Le le` chapitre est consacré à la synthèse d'analogues C glycosidiques de l'arbutine, une hydroquinone glycosylée, inhibiteur de la tyrosinase utilisé pour le blanchissement de la peau. Le 2è' chapitre concerne la synthèse d'analogues C glycosidiques de la vitamine E avec comme objectif d'améliorer ses propriétés antioxydants. Le 3e' chapitre est consacré à la synthèse des glycosides photolabiles pour la réalisation de glycopuces. Via l'ouverture régiosélective du 4,6 0 (o nitro)benzylidene des methyl glycopyranosides, suivie d'une C 4 épimerization, plusieurs 6 0 (o nitro)benzyl glycopyranosides ont été préparés. Enfin, le chapitre 4 est consacré à la synthèse des C glycosyl amino acides comme inhibiteurs potentiels de PTP 1B, cible potentielle pour le traitement du diabète de type II. Les résultats biologiques montrent que ces molécules inhibent l'enzyme avec IC50 de l'ordre de micromolaire.

Platelet-derived growth factor (PDGF) is a potent stimulator of cell growth, survival and motility. PDGF exerts its function by binding to specific tyrosine kinase receptors, initiating receptor auotphosphorylation and initiation of specific signaling pathways that regulates the cellular response. It is critical that these signals can be modulated and terminated, since over-activation of signaling pathways are often found in diseases, such as cancer. Protein tyrosine phosphatases (PTPs) counteract the tyrosine kinases by dephosphorylating proteins, thereby playing a crucial role in the control of signaling events. The aim of this thesis has been to study the regulation of PDGF receptor signaling by the T-cell protein tyrosine phosphatase (TC-PTP). In the first two studies, we demonstrated that loss of TC-PTP specifically redirected the PDGF β-receptor towards a rapid Rab4a-dependent recycling after ligand-induced internalization. Furthermore, we found that the sorting of activated PDGF β-receptor into the recycling pathway was dependent on sequential PKCα and Rab4a activation. Since the PDGF α-receptor did not recycle in the absence of TC-PTP, this study displays the first evidence of differences in trafficking of the PDGF receptor family members. PDGF β-receptor recycling was also induced by activating PKCα through the LPA receptor. The LPA-induced PDGF β-receptor recycling correlated with increased receptor phosphorylation and cell migration at low concentrations of PDGF-BB. The data suggests that PKCα activation could serve as a point of cross-talk between receptor families, regulating the duration and magnitude of PDGF β-receptor signaling. In the last study, we searched for novel substrates for TC-PTP downstream of the PDGF β-receptor, and identified the pyruvate kinase M2, PK-M2, as a possible substrate. PK-M2 is expressed in cells that proliferate rapidly, including tumor cells. Our data suggests that TC-PTP can interact with the glycolytic complex, affecting the activity of PK-M2 and hence, altering the glucose metabolism for proliferating tumor cells.

This paper presents an open system architecture with wireless network centric telemetry and data acquisition over UDP/IP. This networked solution was designed and developed for iron bird and helicopter rotor applications which present a significant challenge for data acquisition and telemetry. Traditionally slip rings were used for data transfer however these result in issues with low bandwidth, electrical noise, installation complexity, and high maintenance costs. This paper describes a networked system using standardized technologies and protocols that was used for data acquisition and recording of parameters such as vibration, strain, and video on DAQ installed on the rotating part. The acquired data was transmitted in real-time via the network-centric wireless telemetry link which was synchronized with a ground-based DAQ used for real time processing of the rotor data.

Overactivity of platelet-derived growth factor receptor (PDGFR) is a frequent event in many types of solid tumors. Therefore, it is of great importance to uncover the mechanisms that regulate PDGF/PDGFR signalling, to develop efficient inhibitors targeting this pathway. The first step of downregulation of PDGFR activity upon ligand binding is internalization; thus we investigated how endocytosis pathways affect PDGFR signaling. We showed that in Ras-transformed fibroblasts, the internalization of PDGFR is shifted from the routine clathrin-dependent endocytosis to macropinocytosis, which results in enhanced PDGFR activity and subsequent downstream signalling, promoting anchorage-independent growth. We were also interested in how intracellular trafficking regulates signalling attenuation of PDGFR. We found that His-domain containing protein tyrosine phosphatase (HD-PTP) positively regulates phosphorylation level of the ubiquitin-ligases c-Cbl and Cbl-b; consistently, silencing of HD-PTP led to a decreased level of PDGFR ubiquitination (paper II). Consequently, internalized PDGFR could not be sorted properly and escaped degradation. This resulted in enhanced activation of phospholipase C γ (PLCγ) and changed kinetics of signal transducer and activator of transcription (STAT) 3 signalling, which further increased colony formation of HD-PTP silenced cells in soft agar, indicating a tumor suppressor role of HD-PTP. Activation of PDGFR leads to stimulation of downstream pathways. We identified Fer kinase as a critical signal transducer downstream of PDGFR in a proteomic screen. We showed that Fer kinase is essential for PDGF-induced STAT3 activation; as a result (paper III), Fer depletion severely blunted the ability of PDGFR signalling to promote anchorage-independent growth in soft agar and delayed tumor initiation in a mouse model. The crosstalk between host and tumor plays a critical role in tumor progression. At present most anti-cancer drugs are targeting tumor cells; we were interested in how targeting tumor host cells affects the efficacy of anti-tumor therapy. We found that selective PDGFRβ inhibition in host cells exerted tumor inhibitory effects on growth and vascularization of tumors with autocrine PDGF signaling, whereas tumors lacking such stimulation show only minor response on tumor growth (paper IV). Meanwhile, we demonstrated that PDGF/PDGFRβ signalling promotes expression of NG2, a marker for pericytes.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

The purpose of the present study was to examine the effects of external laryngeal vibration on voice function. The current study was based on a recent pilot study using silicone vocal folds that demonstrated a decrease in phonation threshold pressure (PTP; cmH2O) when an external oscillation was applied to the vocal folds. Using a within-subjects experimental design, a custom external oscillatory device was fitted to the posterior portion of 12 excised pig larynges using a traditional benchtop phonation setup. For each larynx, phonation was elicited during 30 repeated trials, including 15 with and 15 without external oscillation. During the phonation trials, aerodynamic measures were collected. The outcome measure for this study was PTP, which has been established in the literature as being correlated with physiologic and self-perceived vocal effort. Furthermore, PTP is used routinely as an aerodynamic indicator of voice function, vocal efficiency, and the nature and severity of voice disorders. Although the aim was to quantify either positive (i.e., PTP decrease) or negative (i.e., PTP increase) effects of external oscillation on PTP, it was hypothesized that external oscillation would result in a reduction in average PTP values. The results of the study indicate that application of an external oscillatory device results in significantly lower PTP. These findings have important clinical implications for PTP signal acquisition and the potential use of external oscillation as a therapeutic tool to improve voice function.

This thesis is part of a larger series of studies being conducted by Kristine Tanner, PhD, Associate Professor in the Department of Communication Disorders at Brigham Young University (BYU). The larger project is funded by the National Institute on Deafness and Other Communication Disorders at the National Institutes of Health. This thesis primarily investigated the effects of combination inhaled corticosteroids (ICs) on aerodynamic measures of the voice. In recent years, an increase in the localized laryngeal side effects from IC treatment, including dysphonia, have been reported. This study employed a between-groups experimental design, with two groups of rabbit larynges having been exposed to either ICs or nebulized isotonic saline two times each day for eight weeks at The University of Utah. For this study, the independent variable is group condition (i.e., IC versus saline) and the dependent variables are two aerodynamic measurements made at the onset of phonation using a benchtop experimental setup, namely phonation threshold pressure (PTP; cmH2O) and phonation threshold flow (PTF; L/min). The results of this study indicate a significant difference in PTP and PTF between vocal folds treated with IC as compared to vocal folds treated with nebulized isotonic saline solution. Implications of this study suggest negative changes in the voice due to IC treatment.