Le cancer du sein est un problème majeur de santé publique qui touche 1 femme sur 5. Quatre-vingt percent des cancers sont hormono-dépendants et son traités par hormonothérapies qui cible les oestrogènes ou le récepteur des oestrogènes (ERa) et inhibent leurs effets tumorigènes. En parallèle de la voie génomique des oestrogènes, il existe une voie non génomique dans laquelle ERa recrute Src et PI3K à la membrane, et active des cacades de phosphorylation comme Akt, qui aboutit à la survie et la prolifération des cellules cancéreuses. Notre équipe a montré que la méthylation de l’arginine 260 par les oestrogènes, est un prérequis à la formation du complexe non génomique régulant la prolifération cellulaire. En 2012, l’équipe a montré que la signalisation non génomique des oestrogènes est activée dans les tumeurs mammaires agressives, représentant de nouvelles cibles thérapeutiques. Le crosstalk entre les oestrogènes et les facteurs de croissance impliquant des phosphorylations a été largement décrit. C’est pourquoi nous avons cherché si la méthylation d’ERa sur l’arginine 260 pouvait être impliquée dans ce crosstalk. Parmi plusieurs facteurs de croissance, nous avons mis en évidence que IGF-1 était le seul facteur capable d’induire la méthylation d’ERa de façon oestrogéno-indépendante. En effet, comme pour les oestrogènes, IGF-1 induit une méthylation rapide et transitoire par l’arginine méthyltransférase 1 (PRMT1), et la formation du complexe ERa/Src/PI3K. En utilisant plusieurs approches, nous avons obtenu des résultats intéressants, montrant que PRMT1 probablement via la méthylation d’ERa, joue un rôle crucial dans la signalisation d’IGF-1. D’autre part, nous avons montré qu’IGF1 phosphoryle ERa au niveau de son domaine de liaison à l’ADN, modulant l’interaction son interaction avec IGF-1R. De plus, l’analyse d’une cohorte de 440 tumeurs mammaires a mis en évidence que l’expression d’IGF-1 est corrélée à l’activation de la voie non-génomique des oestrogènes, renforçant les résultats obtenus in vitro et ouvrant de nouvelles perspectives thérapeutiques qui cibleraient les 2 voies de signalisation / Breast cancer is a major health problem currently affecting 1 out of 5 women. Seventy percent of breast cancers are hormone-dependent, and are treated by hormonal therapies targeting estrogen receptor and consequently the inhibition of its pro-tumorigenic effects. In parallel to the genomic estrogen signaling, non-genomic signaling has been described, where ERa recruits Src kinase and PI3K at the plasma membrane and thus activates downstream phosphorylation cascades like AKT, which in turn leads to survival and proliferation of cancer cells. Our team has found that estrogen-induced methylation of arginine 260 of ERa is a prerequisite for the formation of this non-genomic complex, regulating cell proliferation. In 2012, we have shown that this pathway is activated in aggressive breast tumors representing a new potential target for breast cancer therapy. Crosstalk between estrogen and growth factors signaling involving phosphorylation has been largely described. For this reason, we investigated if ERa R260 methylation could be involved in this crosstalk. Among several growth factors, we found that IGF-1 was the only one able to induce methylation of ERa in an estrogen-independent manner. Similarly to estrogen, IGF-1 induces a rapid and transient methylation of ERa by the Protein Arginine Methyltransferase (PRMT1) concomitant with the formation of ERa/Src/PI3K complex. Using several approaches, we found significant results showing that PRMT1 probably via ERa methylation plays a crucial role in IGF-1 signaling. Interestingly, we have recently found also that receptor tyrosine kinase IGF-1R phosphorylates the DNA binding domain (DBD) of ERa that could modulate the latter downstream signaling. In line with these results, we found on TMAs of a cohort of 440 breast tumors that IGF-1 expression is correlated with ERa non-genomic signaling. These results report new insight into estrogen and IGF-1 interference, which open new perspectives of combining therapies targeting the two pathways

This thesis is about ‘Dual View’ displays. These are displays that can show different images to different people. For example, the driver of a car could view a GPS map, whilst the passenger who looks at the display from a different angle, could watch a movie. This thesis describes some of the research that took the project from an idea to a refined product. Sharp’s first dual view display is prototyped, and problems such as crosstalk between the two views are seen. These problems are analysed and rectified to bring the device up to a high standard. In July 2005 Sharp used this technology to launch the world’s first dual view product. Since then a new design of dual view display has been investigated. This design is theoretically optimised and experimentally tested. The new design is shown to provide dual view with greater head freedom, greater efficiency, and lower crosstalk than the original parallax barrier design.

No description available.

Digital subscriber lines (DSL) have revolutionised the provision of high speed data over the ‘last mile’. Subscribers demand even more bandwidth and the penetration of the service is now nearly universal. While it is feasible to provide improved broadband services on the new very high speed DSL, such as VDSL2/3, one of the greatest challenges to further improvements in speed is the problem of crosstalk. Operating over the unused higher frequencies of the twisted pair network, this technology is subjected to electromagnetic coupling among the wires, limiting the DSL data rate and service reach. Crosstalk suppression methods such as zero-forcing or decision feedback mainly use block processing. However, to cope with the time-varying VDSL environment huge computational costs can be incurred. In contrast, adaptive processing approaches are much simpler and are more beneficial to track such a channel environment. An adaptive canceller uses a training sequence and the convergence speed depends on the number of crosstalk coefficients it has to estimate. In a populated DSL binder, only a few of the crosstalking neighbours to a particular user are significant. With the aim to reduce the computational complexity in such environments, this thesis introduces the concept of detection-guided adaptive crosstalk cancellation for DSL. We propose a least-squares test feature to detect and concentrate the adaptation only on the dominant crosstalking coefficients. In comparison to conventional adaptive cancellers, the cancellers proposed in this thesis demonstrate early convergence. Thus, by incorporating the test feature, these cancellers have to detect only the most significant canceller coefficients and therefore, the length of the training sequence is reduced. Together with enhanced adaptive cancellation with a low run-time complexity and improved convergence, the greatest advantage obtained here is in the bandwidth efficiency. While enhanced adaptive cancellation is a bandwidth-efficient approach, the frequent re-transmission of training sequences may still be required for a rapidly changing VDSL channel. Again, this can be a disadvantage in terms of bandwidth consumption. To overcome this difficulty, we propose fast-converging unsupervised cancellers with an aim to improve the bandwidth efficiency by not transmitting a training sequence. An added advantage obtained here is that this would enable Internet service providers to include multiple or improved broadband services within a single subscription. Certain properties of the DSL channel ensure the communication channel is properly conditioned. This ensures the basis vectors of the channel matrix are near-orthogonal and hence, the linear cancellers, such as zero-forcing perform near-optimally. However, this is not the case with wireless channels. We investigate user detection in wireless channels using the principle of lattice reduction. User detection can also be seen as a search for the closest vector point in the lattice of received symbols. Though a maximum likelihood (ML) detector facilitates optimal user-detection, it has exponential complexity. We identify that the closest vector problem can be cast as a non-linear optimisation problem. Using the periodicity of the maximum likelihood function, we first present a novel algorithm that approximates the ML function using the Taylor series expansion of a suitable cosine function. With the aim of minimising the approximation error, we represent the ML function as a Fourier Series expansion and later, propose another approximation using Jacobi theta functions. We study the performance of these approximations when subjected to a suitable unconstrained optimisation algorithm. Through simulations, we demonstrate that the newly-developed approximations perform better than the conventional cancellers, close to the ML and, importantly, converging in polynomial time.

Digital subscriber lines (DSL) have revolutionised the provision of high speed data over the ‘last mile’. Subscribers demand even more bandwidth and the penetration of the service is now nearly universal. While it is feasible to provide improved broadband services on the new very high speed DSL, such as VDSL2/3, one of the greatest challenges to further improvements in speed is the problem of crosstalk. Operating over the unused higher frequencies of the twisted pair network, this technology is subjected to electromagnetic coupling among the wires, limiting the DSL data rate and service reach. Crosstalk suppression methods such as zero-forcing or decision feedback mainly use block processing. However, to cope with the time-varying VDSL environment huge computational costs can be incurred. In contrast, adaptive processing approaches are much simpler and are more beneficial to track such a channel environment. An adaptive canceller uses a training sequence and the convergence speed depends on the number of crosstalk coefficients it has to estimate. In a populated DSL binder, only a few of the crosstalking neighbours to a particular user are significant. With the aim to reduce the computational complexity in such environments, this thesis introduces the concept of detection-guided adaptive crosstalk cancellation for DSL. We propose a least-squares test feature to detect and concentrate the adaptation only on the dominant crosstalking coefficients. In comparison to conventional adaptive cancellers, the cancellers proposed in this thesis demonstrate early convergence. Thus, by incorporating the test feature, these cancellers have to detect only the most significant canceller coefficients and therefore, the length of the training sequence is reduced. Together with enhanced adaptive cancellation with a low run-time complexity and improved convergence, the greatest advantage obtained here is in the bandwidth efficiency. While enhanced adaptive cancellation is a bandwidth-efficient approach, the frequent re-transmission of training sequences may still be required for a rapidly changing VDSL channel. Again, this can be a disadvantage in terms of bandwidth consumption. To overcome this difficulty, we propose fast-converging unsupervised cancellers with an aim to improve the bandwidth efficiency by not transmitting a training sequence. An added advantage obtained here is that this would enable Internet service providers to include multiple or improved broadband services within a single subscription. Certain properties of the DSL channel ensure the communication channel is properly conditioned. This ensures the basis vectors of the channel matrix are near-orthogonal and hence, the linear cancellers, such as zero-forcing perform near-optimally. However, this is not the case with wireless channels. We investigate user detection in wireless channels using the principle of lattice reduction. User detection can also be seen as a search for the closest vector point in the lattice of received symbols. Though a maximum likelihood (ML) detector facilitates optimal user-detection, it has exponential complexity. We identify that the closest vector problem can be cast as a non-linear optimisation problem. Using the periodicity of the maximum likelihood function, we first present a novel algorithm that approximates the ML function using the Taylor series expansion of a suitable cosine function. With the aim of minimising the approximation error, we represent the ML function as a Fourier Series expansion and later, propose another approximation using Jacobi theta functions. We study the performance of these approximations when subjected to a suitable unconstrained optimisation algorithm. Through simulations, we demonstrate that the newly-developed approximations perform better than the conventional cancellers, close to the ML and, importantly, converging in polynomial time.

Digital subscriber lines (DSL) have revolutionised the provision of high speed data over the ‘last mile’. Subscribers demand even more bandwidth and the penetration of the service is now nearly universal. While it is feasible to provide improved broadband services on the new very high speed DSL, such as VDSL2/3, one of the greatest challenges to further improvements in speed is the problem of crosstalk. Operating over the unused higher frequencies of the twisted pair network, this technology is subjected to electromagnetic coupling among the wires, limiting the DSL data rate and service reach. Crosstalk suppression methods such as zero-forcing or decision feedback mainly use block processing. However, to cope with the time-varying VDSL environment huge computational costs can be incurred. In contrast, adaptive processing approaches are much simpler and are more beneficial to track such a channel environment. An adaptive canceller uses a training sequence and the convergence speed depends on the number of crosstalk coefficients it has to estimate. In a populated DSL binder, only a few of the crosstalking neighbours to a particular user are significant. With the aim to reduce the computational complexity in such environments, this thesis introduces the concept of detection-guided adaptive crosstalk cancellation for DSL. We propose a least-squares test feature to detect and concentrate the adaptation only on the dominant crosstalking coefficients. In comparison to conventional adaptive cancellers, the cancellers proposed in this thesis demonstrate early convergence. Thus, by incorporating the test feature, these cancellers have to detect only the most significant canceller coefficients and therefore, the length of the training sequence is reduced. Together with enhanced adaptive cancellation with a low run-time complexity and improved convergence, the greatest advantage obtained here is in the bandwidth efficiency. While enhanced adaptive cancellation is a bandwidth-efficient approach, the frequent re-transmission of training sequences may still be required for a rapidly changing VDSL channel. Again, this can be a disadvantage in terms of bandwidth consumption. To overcome this difficulty, we propose fast-converging unsupervised cancellers with an aim to improve the bandwidth efficiency by not transmitting a training sequence. An added advantage obtained here is that this would enable Internet service providers to include multiple or improved broadband services within a single subscription. Certain properties of the DSL channel ensure the communication channel is properly conditioned. This ensures the basis vectors of the channel matrix are near-orthogonal and hence, the linear cancellers, such as zero-forcing perform near-optimally. However, this is not the case with wireless channels. We investigate user detection in wireless channels using the principle of lattice reduction. User detection can also be seen as a search for the closest vector point in the lattice of received symbols. Though a maximum likelihood (ML) detector facilitates optimal user-detection, it has exponential complexity. We identify that the closest vector problem can be cast as a non-linear optimisation problem. Using the periodicity of the maximum likelihood function, we first present a novel algorithm that approximates the ML function using the Taylor series expansion of a suitable cosine function. With the aim of minimising the approximation error, we represent the ML function as a Fourier Series expansion and later, propose another approximation using Jacobi theta functions. We study the performance of these approximations when subjected to a suitable unconstrained optimisation algorithm. Through simulations, we demonstrate that the newly-developed approximations perform better than the conventional cancellers, close to the ML and, importantly, converging in polynomial time.

[pt] O ruído interferométrico é um fator limitante cada vez mais importante nos sistemas óticos, principalmente nas ligações de longa distância em redes óticas transparentes. O presente trabalho analisa modelos para este tipo de ruído, dando um tratamento matemático novo para o modelo não-gaussiano. A teoria matemática é desenvolvida em detalhes e comrigor. O modelo gaussiano foi usado a fim de fazer previsões quanto aos valores de chão da taxa de erro de bits. Os dois modelos foram simulados em computador e comparados com os testes realizados em laboratório e os resultados são apresentados. / [en] The interferometric noise is becoming a serious limiting factor in optical systems,notably on long distance connections in transparent optical networks. The present work analyzes models for this kind of noise, giving a new mathematical treatment to the non-gaussian model. The mathematical theory is developed in detail and rigorously. The gaussian model was used in order to make predictions relative to bit error rate floors. Both models were simulated in computer and compared with the tests made in laboratory and the results are presented. / [es] EL ruido interferométrico es un factor limitante cada vez más importante en los sistemas ópticos, principalmente en las llamadas a larga distancia en redes ópticas transparentes. EL presente trabajo analiza modelos para este tipo de ruido, dando un nuevo tratamiento matemático para el modelo no gausiano. La teoría matemática es desarrollada en detalles y con rigor. EL modelo gausiano fue usado para efectuar previsiones de las cotas inferiores de la tasa de error de bits. Los dos modelos fueron simulados en computador y comparados con las priuebas de laboratorio y se presentan los resultados.

Master of Science / Department of Electrical Engineering / William B. Kuhn / Designers of mixed-signal systems must understand coupling mechanisms at the system, PC board, package and integrated circuit levels to control crosstalk, and thereby minimize degradation of system performance. This research examines coupling mechanisms in a RF-targeted high-resistivity partially-depleted Silicon-on-Insulator (SOI) IC process and applying similar coupling mitigation strategies from higher levels of design, proposes techniques to reduce coupling between sub-circuits on-chip. A series of test structures was fabricated with the goal of understanding and reducing the electric and magnetic field coupling at frequencies up to C-Band. Electric field coupling through the active-layer and substrate of the SOI wafer is compared for a variety of isolation methods including use of deep-trench surrounds, blocking channel-stopper implant, blocking metal-fill layers and using substrate contact guard-rings. Magnetic coupling is examined for on-chip inductors utilizing counter-winding techniques, using metal shields above noisy circuits, and through the relationship between separation and the coupling coefficient. Finally, coupling between bond pads employing the most effective electric field isolation strategies is examined. Lumped element circuit models are developed to show how different coupling mitigation strategies perform. Major conclusions relative to substrate coupling are 1) substrates with resistivity 1 kΩ·cm or greater act largely as a high-K insulators at sufficiently high frequency, 2) compared to capacitive coupling paths through the substrate, coupling through metal-fill has little effect and 3) the use of substrate contact guard-rings in multi-ground domain designs can result in significant coupling between domains if proper isolation strategies such as the use of deep-trench surrounds are not employed. The electric field coupling, in general, is strongly dependent on the impedance of the active-layer and frequency, with isolation exceeding 80 dB below 100 MHz and relatively high coupling values of 40 dB or more at upper S-band frequencies, depending on the geometries and mitigation strategy used. Magnetic coupling was found to be a strong function of circuit separation and the height of metal shields above the circuits. Finally, bond pads utilizing substrate contact guard-rings resulted in the highest degree of isolation and the lowest pad load capacitance of the methods tested.

No description available.

ABSTRACT Phosphorylation is a post-translational modification important for regulating protein activity and protein binding capacity. It is used in many different signaling pathways within the cell. Src Family Kinases and Protein Kinase A (PKA) are two prototyptical non-receptor tyrosine and serine/ threonine kinases, respectively, which are found in canonical signaling pathways. These two kinases are critical for signaling in essentially every cell of a multicellular organism, and are particularly important in development, cell migration and proliferation. Although both proteins have been intensely studied for many decades, an understanding of the molecular mechanisms which govern their regulation and the regulation that they effect on other proteins are still being elucidated. Fyn, like its related Src Family Kinase members, has previously been shown to be regulated by two tyrosine phosphorylation events at residues Y420 and Y531. Y420 is located in the kinase (Src Homology 1(SH1)) domain and it is a highly-characterized intermolecular autophosphorylation site that increases the activity of the kinase. Y531 is located near the C-terminus and is phosphorylated by C-terminal Src kinase (Csk). Phosphorylation of Y531 allows it to bind to R176 in the SH2 domain in an intramolecular fashion. In this conformation Fyn has only basal activity. Since these sites are essential for regulating the activity of the kinase, we hypothesized that four novel sites of tyrosine phosphorylation in Fyn could also importantly regulate the protein. Three of the novel sites lie in the SH2 domain, and one is located in the kinase domain. Mass spectrometry, in vitro kinase assays, as well as western blot analysis aided in uncovering that these novel Fyn phosphorylation sites fine tune the activity and substrate binding of the protein. PKA has been implicated in a multitude of signaling pathways and is particularly important in cell growth, proliferation, and migration. Fyn and PKA have classically been considered to be in separate signaling pathways. However, research over the past several decades has provided evidence that there is crosstalk that exists between the two pathways. The SFK Fyn and PKA can phosphorylate each other, thereby regulating each other's activity. Based on these data, we hypothesized the existence of downstream effectors of this relatively uncharacterized pathway. It was hypothesized that the presence of Fyn could lead to PKA activation and to differences in PKA binding partners. Through the use of co-immunoprecipitations, Stable Isotope Labeling of Amino Acids in Cell Culture (SILAC) and quantitative mass spectrometry, many proteins were found to increase their binding to PKA in the presence of Fyn. Several proteins were selected and further biochemically validated. These data suggest that the presence of Fyn could allow for PKA to more importantly interact with discrete pools of proteins within the cell to effectuate its signal transduction. Together these studies provide understanding on critical and fundamental processes by which all cells function.