Una línia de transmissió three-line-microstrip consisteix en tres pistes paral·leles practicades sobre la cara d'un dielèctric amb un pla de massa inferior. La propagació en aquesta línia es pot descriure en termes de tres modes fonamentals anomenats ee, oo i oe. Tot i que aquests modes són ortogonals interaccionen entre sí a qualsevol transició, discontinuïtat o asimetria. En el pla d'una transició o asimetria es genera un intercanvi d'energia o conversió modal en el que prenen part tots els modes.En aquest treball s'analitza la conversió modal que s'origina en un conjunt de transicions i asimetries construïdes sobre línies three-line-microstrip. L'estudi es realitza aplicant la tècnica de l'anàlisi multimodal. L'ús d'aquesta tècnica permet la deducció d'una sèrie de models multimodals (un per a cada transició) que proporcionen una anàlisi simple, rigorosa i quantitativa d'aquest fenomen.La validesa d'aquest estudi es verifica de manera experimental. Els bons resultats obtinguts demostren que els models multimodals proposats prediuen de manera precisa el comportament de les transicions. Aquest fet permet el seu ús per analitzar circuits o estructures constituïts per trams de tres pistes acoblades. En el cas d'aquesta tesi, han estat aplicats als camps de l'EMC i de les microones. Pel que fa a l'EMC, s'ha realitzat un estudi de l'acoblament i la integritat del senyal en configuracions de PCB amb trams de tres pistes acoblades. Aquest estudi ha permès identificar les transicions i asimetries en aquests circuits com a possibles fonts d'interferència i de degradació dels senyals ja que la conversió modal es pot interpretar com a un procés d'interferència que involucra tots els senyals presents. Pel que fa a les microones, s'ha realitzat una anàlisi multimodal de filtres spurline. Aquesta anàlisi ha permès desenvolupar dues noves estructures, la principal característica de les quals és la seva compacitat que, a diferència d'altres estructures similars, s'aconsegueix permetent la presència d'un nou mode en el procés de ressonància. L'ús dels models multimodals per a l'anàlisi d'aquestes estructures ha permès una interpretació clara i senzilla del seu funcionament així com el desenvolupament d'una sèrie de regles de disseny que permeten un ajust fàcil i ràpid de certs paràmetres dels filtres com ara la freqüència central i l'ample de banda. / Una línea de transmisión three-line-microstrip consiste en tres pistas paralelas practicadas sobre la cara de un dieléctrico con un plano de masa inferior. La propagación en esta línea se puede describir en términos de tres modos fundamentales llamados ee, oo i oe. Aunque estos modos son ortogonales interaccionan entre se en cualquier transición, discontinuidad o asimetría. En el plano de una transición o asimetría se genera un intercambio de energía o conversión modal en el que toman parte todos los modos.En este trabajo se analiza la conversión modal que se origina en un conjunto de transiciones i asimetrías construidas sobre líneas three-line-microstrip. El estudio se realiza aplicando la técnica del análisis multimodal. El uso de esta técnica permite la deducción de una serie de modelos multimodales (un per a cada transición) que proporcionan un análisis simple, riguroso i cuantitativo de este fenómeno.La validez de este estudio se verifica de manera experimental. Los buenos resultados obtenidos demuestran que los modelos multimodales propuestos predicen de manera precisa el comportamiento de las transiciones. Este hecho permite su uso para analizar circuitos o estructuras constituidos por tramos de tres pistas acopladas. En esta tesis doctoral, han sido aplicados a los campos de la EMC i de las microondas. En el primero de ellos, se ha realizado un estudio del acoplamiento y la integridad de la señal en configuraciones de PCB con tramos de tres pistas acopladas. Este estudio ha permitido identificar las transiciones y asimetrías en estos circuitos como posibles fuentes de interferencia y de degradación de las señales ya que la conversión modal se puede interpretar como a un proceso de interferencia que involucra todas las señales presentes. En el campo de las microondas, se ha realizado un análisis multimodal de filtros spurline. Este análisis ha permitido desarrollar dos nuevas estructuras, cuya principal característica es su compacidad que, a diferencia de otras estructuras similares, se consigue permitiendo la presencia de un nuevo modo en el proceso de resonancia. El uso de los modelos multimodales para el análisis de estas estructuras ha permitido una interpretación clara i sencilla del su funcionamiento así como el desarrollo de una serie de reglas de diseño que permiten un ajuste fácil i rápido de ciertos parámetros de los filtros como por ejemplo la frecuencia central y el ancho de banda. / A three-line-microstrip transmission line consists of three parallel coupled strips printed on a grounded dielectric substrate. The propagation in this line can be described in terms of three fundamental modes, namely the ee, oo and oe modes. These modes are orthogonal and propagate independently unless a transition or asymmetry is present in the line. Any transition or asymmetry will generate an energy exchange or modal interaction among all the propagating modes. In this work, the modal interaction of a set of transitions and asymmetries in three-line-microstrip transmission lines is analyzed. The study is carried out by using the multimodal analysis. By means of this technique a set of multimodal circuit models (one for each transition) is derived. These models provide a simple and a quantitative interpretation of the modal interaction.The proposed multimodal analysis is experimentally validated. The obtained results show that the derived multimodal models accurately predict the behavior of the transitions. Due to this fact, they can be used for the analysis of circuits and structures composed of three-coupled-strip sections. In this work, the models have been applied to both the EMC and microwave fields. In the former, they have been employed to study the cross-talk and signal-integrity problems in PCB configurations involving tree-coupled-trace sections. The performed analysis has shown that transitions and asymmetries in these circuits must be considered as a source of interference and signal degradation since the modal interaction can be interpreted as an interference process that involves all the present signals. In the latter, a multimodal analysis of spurline filters has been performed. This study has allowed the derivation of two new filter structures whose main feature is their compactness, which, in contrast to other analogous filters, is achieved by allowing the presence of an additional mode in the resonance process. The use of the multimodal models for the analysis of these structures has permitted both a simple interpretation of the filter operation and the derivation of a set of design rules which allows a rapid fine tuning of some filter parameters such as the center frequency and the bandwidth.

The existence of hydrodynamically developed, laminar Viscoelastic Secondary Flows (VSFs) of non-Newtonian fluids in straight ducts of non-circular cross-section was proposed in the 1950's. VSFs have since been observed sporadically, and only once with a velocimetric technique. Using axial and transverse full flow-field velocity-position raster maps made with Rheological Nuclear Magnetic Resonance (Rheo-NMR), Newtonian and non-Newtonian fluid flows were quantified in Hagen-Poiseuille and Power Law contexts, over more than two orders of magnitude of flow rate, in ducts of circle, square, triangle, and pentagon cross-section. VSF was reliably and repeatedly observed to occur at between one part in 130 and one part in 600 of the primary axial flow velocity. Velocity measurements ranged from <10 µm/s to approximately 30 cm/s, suggesting a velocity dynamic range >3E4 without optimization. To obtain VSF flow direction information, a novel flow directional phantom was developed and characterized. Aqueous solutions of Polyethylene Oxide (PEO), Viscarin GP-109NF, Viscarin GP-209NF (V209), Hyaluronan (HA) in a Phosphate-Buffered Saline-like solvent, and an aqueous Polyethylene Glycol/PEO-based Boger fluid were investigated. Axial data was corroborated with related data gathered by an independent method. Basic simulations corroborated the VSF observations. Duct hydraulic diameters (>= 1.6 mm) approached the micro-channel regime. VSF detections in HA --- synovial fluid's principal component --- and V209 were novel, as were observations of some artifacts which were subsequently characterized and corrected. The detection of VSF in HA represents the first experimental evidence suggesting that its second normal stress (N_2) is comparable to that of better-characterized fluids. In the first application of a new VSF-based method, a particular Boger fluid's constant viscosity and, in the square duct, its lack of VSF were used with established criteria to suggest that the fluid's N_2 approached zero. The development of a rudimentary, but versatile and inexpensive home-built velocimetric spectrometer is detailed, as are several new components. An exhaustive VSF literature review is included. The remarkable transverse velocimetric ability of Rheo-NMR in both optically opaque and transparent system is highlighted, suggesting that perhaps the technique might represent, in both micro-channels and conventional ducts, the gold-standard in flow velocimetry.

La majorité des individus exposés au virus de l’hépatite C (VHC) développent une infection chronique. Une réponse immunitaire adaptative forte et soutenue est associée avec la guérison spontanée du VHC, mais les mécanismes sous-jacents demeurent mal définis. Le rôle des cellules NK et des cellules dendritiques (DC) dans la guérison spontanée du VHC est encore méconnu. Les cellules NK sont la population effectrice la plus importante de l’immunité innée car elles tuent les cellules infectées et sécrètent diverses cytokines. Les DC reconnaissent des agents infectieux et elles sont les premières à initier et réguler l’immunité adaptative. Les cellules NK et les DC interagissent également entre elles afin de réguler l’immunité innée et adaptative. L’hypothèse du projet de doctorat est que l'activité des cellules NK pendant la phase aiguë de l'infection par le VHC module la fonction des DC afin que ces dernières puissent générer une réponse immunitaire adaptative capable d'éliminer le VHC. Le premier objectif était d’établir une corrélation entre l'activité des cellules NK et l'évolution de l'infection au VHC. Nous avons observé une augmentation de la cytotoxicité, mais une diminution de la sécrétion de cytokines par les cellules NK chez les patients chroniques et qui ont résolu spontanément pendant la phase aiguë en comparaison aux contrôles non infectés, démontrant alors une dissociation entre ces deux fonctions. Nos résultats suggèrent que les cellules NK sont activées pendant la phase aiguë indépendamment de l’évolution de l’infection. Le deuxième objectif était d’établir une corrélation entre le phénotype et la fonction des DC, et l'évolution de l'infection. Nous avons d’abord observé que les DC plasmacytoïdes de tous les patients infectés ont un phénotype plus immature que les contrôles, et que ce phénotype est plus prononcé chez les patients ayant résolu spontanément. De plus, en réponse à des stimulations, nous avons observé que pendant la phase aiguë précoce, les DC myéloïdes (mDC) de tous les patients infectés indépendamment de l’évolution de l’infection produisent davantage de cytokines en comparaison aux contrôles. Cependant, cette hyperréactivité n’est pas soutenue au cours de l’évolution chronique. Le troisième objectif était d’établir une corrélation entre les interactions NK/DC et l’évolution de l’infection. Nous avons étudié la capacité des cellules NK à lyser les DC potentiellement tolérogéniques, ainsi que la capacité des DC matures à activer les cellules NK, et nous avons observé aucune différence entre les patients infectés et les contrôles. Finalement, nous avons démontré pour la première fois la capacité des DC immatures à inhiber la fonction des cellules NK. En conclusion, nous avons démontré que les cellules NK sont activées pendant la phase aiguë de l’infection par le VHC indépendamment de l’évolution de l’infection. De plus, la capacité des cellules NK à éliminer les DC potentiellement tolérogéniques est intacte. Finalement, les mDC sont hyperréactives pendant la phase aiguë de l’infection, mais cette hyperréactivité n’est pas soutenue avec la persistance de l’infection. Cette perte d’hyperréactivité des mDC ne semble pas affecter la capacité des DC à activer les cellules NK, mais elle pourrait jouer un rôle dans l’inefficacité de l’immunité adaptative à éliminer le VHC. / The majority of individuals exposed to the hepatitis C virus (HCV) develop a chronic infection. It is known that a strong and sustained adaptive immune response is associated with the spontaneous clearance of HCV, however the underlying mechanisms are not well defined. The role of natural killer (NK) cells and dendritic cells (DCs) during the spontaneous resolution of HCV remains unknown. NK cells are the primary effector population of the innate immune response which are able to kill infected cells and secrete various cytokines. On the other hand, DCs are the first cell type to initiate and regulate adaptive immunity after recognizing infectious pathogens. NK cells and DCs can also interact reciprocally to further regulate innate and adaptive immunity. Our hypothesis is that NK cell activity during acute HCV will modulate DC function to prime a highly efficient adaptive immune response resulting in viral clearance. The first aim of my project was to establish a correlation between NK cell activity and the outcome of HCV infection. We observed increased NK cell cytotoxicity, but decreased cytokine secretion during acute HCV in patients with chronic evolution as well as spontaneous resolution, further demonstrating a dissociation between these two NK cell functions. Our results suggest that NK cells are activated during acute HCV infection regardless of infection outcome. The second aim was to establish a correlation between DC phenotype, function and the outcome of infection. We observed that plasmacytoid DCs (pDCs) from all HCV-infected patients have a more immature phenotype as compared to negative controls, yet this is more pronounced in spontaneous resolvers. Furthermore, we observed that during the early acute phase, myeloid DCs (mDCs) from all HCV-infected patients, regardless of outcome, have increased production of cytokines as compared to un-infected controls in response to stimulation. However, this hyperresponsiveness of mDCs is not sustained with chronic evolution. The third aim was to establish a correlation between the NK/DC cross-talk and infection outcome. We studied the capacity of NK cells to kill potentially tolerogenic DCs, as well as the capacity of mature DCs to activate NK cells, and we observed no major differences between different stages of HCV infection and un-infected controls. However, we obtained unprecedented data which suggests that immature DCs have the capacity to inhibit NK cell function. In conclusion, our results demonstrate that NK cells are activated during acute HCV infection regardless of its outcome. Furthermore, the capacity of NK cells to kill potentially tolerogenic DCs is intact for all groups of patients. Finally, mDCs are hyperresponsive during acute HCV, but this hyperresponsiveness is not sustained with persistence of viremia. The loss of mDC hyperresponsiveness does not seem to affect the capacity of DCs to activate NK cells, but might play a role in the capacity of DCs to prime a highly efficient adaptive immune response resulting in viral clearance.

No description available.

Mapping of the human genome has been instrumental in understanding diseasescaused by changes in single genes. However, disease mechanisms involvingmultiple genes have proven to be much more elusive. Their complexityemerges from interactions of intracellular molecules and makes them immuneto the traditional reductionist approach. Only by modelling this complexinteraction pattern using networks is it possible to understand the emergentproperties that give rise to diseases.The overarching term used to describe both physical and indirect interactionsinvolved in the same functions is functional association. FunCoup is oneof the most comprehensive networks of functional association. It uses a naïveBayesian approach to integrate high-throughput experimental evidence of intracellularinteractions in humans and multiple model organisms. In the firstupdate, both the coverage and the quality of the interactions, were increasedand a feature for comparing interactions across species was added. The latestupdate involved a complete overhaul of all data sources, including a refinementof the training data and addition of new class and sources of interactionsas well as six new species.Disease-specific changes in genes can be identified using high-throughputgenome-wide studies of patients and healthy individuals. To understand theunderlying mechanisms that produce these changes, they can be mapped tocollections of genes with known functions, such as pathways. BinoX wasdeveloped to map altered genes to pathways using the topology of FunCoup.This approach combined with a new random model for comparison enables BinoXto outperform traditional gene-overlap-based methods and other networkbasedtechniques.Results from high-throughput experiments are challenged by noise and biases,resulting in many false positives. Statistical attempts to correct for thesechallenges have led to a reduction in coverage. Both limitations can be remediedusing prioritisation tools such as MaxLink, which ranks genes using guiltby association in the context of a functional association network. MaxLink’salgorithm was generalised to work with any disease phenotype and its statisticalfoundation was strengthened. MaxLink’s predictions were validatedexperimentally using FRET.The availability of prioritisation tools without an appropriate way to comparethem makes it difficult to select the correct tool for a problem domain.A benchmark to assess performance of prioritisation tools in terms of theirability to generalise to new data was developed. FunCoup was used for prioritisationwhile testing was done using cross-validation of terms derived fromGene Ontology. This resulted in a robust and unbiased benchmark for evaluationof current and future prioritisation tools. Surprisingly, previously superiortools based on global network structure were shown to be inferior to a localnetwork-based tool when performance was analysed on the most relevant partof the output, i.e. the top ranked genes.This thesis demonstrates how a network that models the intricate biologyof the cell can contribute with valuable insights for researchers that study diseaseswith complex genetic origins. The developed tools will help the researchcommunity to understand the underlying causes of such diseases and discovernew treatment targets. The robust way to benchmark such tools will help researchersto select the proper tool for their problem domain. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 5: Manuscript. Paper 6: Manuscript.</p>

Die vorliegende Arbeit beschäftigt sich mit dem Konzept der radial nicht-oszillierenden, zeitlich stabilen ultrakurzen Bessel ähnlichen Strahlen oder "Nadelstrahlen" ("needle beams"), die zu einer Klasse von optischen hochlokalisierten Wellenpaketen generalisiert werden. Hierbei wird die Theorie über das räumlich-zeitlichen Ausbreitungsverhaltens von nicht auseinanderdriftenden Nadelstrahlen mit Pulsdauern von kleiner als 10 fs näher diskutiert. Dies wird durch eine systematische Darstellung der Methoden zur Generierung und Detektierung von lokalisierten Wellen komplettiert, die ein optischen Drehmoment tragen. Für die Erzeugung von HLWs kommen räumliche Lichtmodulatoren zum Einsatz, die ein flexibles Zuschneiden von Wellenpaketen mit der Dauer weniger Zyklen des EM-Feldes erlauben. Es wird gezeigt, dass solche optischen Pulse sich über beträchtliche Entfernungen ausbreiten, ohne dass sich dabei signifikant der Strahldurchmesser vergrößert oder der Puls zeitlich verbreitert. In variabler Weise werden verschiedene geometrische (z.B. ringförmige) Lichtverteilungen erzeugt. Anwendungspotential findet sich insbesondere in den Techniken der räumlichen Pulsformung und Diagnostik. Als besonders wichtiger Ansatz ist der Zeit-Wellenfront-Sensor zu erwähnen, welcher die nichtlineare, mehrkanalige Autokorrelation, die Wellenfrontdetektion mittels nichtdiffraktiver Teilstrahlen nach dem Shack-Hartmann-Prinzip und eine adaptive Funktionalität miteinander vorteilhaft verbindet. Das enorme Potential solcher Ansätze wird durch die hohe Genauigkeit orts-, winkel- und zeitabhängiger Rekonstruktionen der Wellenpakete nachgewiesen. Darüber hinaus ermöglicht das räumliche Kodieren und anschließende Verfolgen der Teilstrahlen eine wesentliche Verbesserung der Identifikation relevanter Parameter von Verteilungsfunktionen. Schließlich werden erste Schritte zur experimentellen Generation von optischen "light bullets" mit ganzzahligen und fraktalen orbitalen Drehmomenten präsentiert. / This thesis deals with the concept of radially non-oscillating, temporally stable ultrashort-pulsed Bessel-like beams or "needle pulses", which are an example of a highly localized wave packet (HLW). HLWs are the closest approximation of linear-optical light bullets and provide specific benefits compared to conventional Gaussian-like light bullets. The spatio-temporally nonspreading propagation behavior of few-cycle needle beams of less than 10 fs duration will be theoretically discussed in detail. An overview of the generation and detection of localized waves carrying an orbital angular momentum is also given. High fidelity spatial light modulators are used for the generation of HLWs. The flexible tailoring of few-cycle wave packets at near-infrared wavelengths is reported. It is shown that such pulses propagate over a huge depth of focus, neither significantly changing their spot size or nor the pulse duration. Variable geometrical distributions like circular disks, rings, or bars of light are shaped and exploited as building blocks for structures of higher complexity. Another section of the thesis emphasizes the numerous potential applications of related techniques for an optimized two-dimensional spatial pulse shaping and diagnostics (reduce ambiguities) based on localized waves. As a particularly important example, time-wavefront sensing is used to combine nonlinear multichannel autocorrelation with Shack-Hartmann wavefront sensing by means of localized sub-beams and adaptive functionality. The capabilities of such devices are illustrated by the results of angular and temporal mapping of few-cycle wave packets. Moreover, spatial encoding and subsequent tracking of individual sub-beams, even at incident angles of up to 50°, enables to significantly improve the spot recognition. Finally, first steps towards the generation of optical light bullets carrying integer or non-integer orbital angular momenta are presented.