Position sensing is one of the most important tasks in the industrial manufacturing of goods and materials. Position sensing can take on a variety of forms and is used in the measurement of a wide range of variables such as distance, speed, the number of revolutions per minute, orientation, identification, and in collision protection. Proximity sensors play a significant role and are used in a plethora of industries including agriculture, consumer goods, transportation, industrial processes, electrical services, medical, military and avionics. This research is aimed at improving the performance and manufacturability of inductive proximity sensors through the design and fabrication of coils using multilayer ceramic technologies common in the manufacturing of hybrid microelectronics components and circuits. As another alternative, multilayer structures utilizing polymer materials and fabrication techniques common to the printed circuit board (PCB) industry were also investigated. Manufacture of the coils utilizing ceramic and polymer materials and hybrid and PCB fabrication techniques would eliminate the problems of repeatability, and the placement and potting of the coil. The fabrication techniques also lend well to the mass production of the coils using techniques that are well established in the electronics industry. The overall result would be a planar inductor with high yield that is suitable for mass production. / Master of Science

Improved diagnosis, prognosis and disease follow-up is a fundamental procedure and a constant challenge in medicine.  Among the different molecular biomarkers, proteins are the essential regulatory component in blood; hence, by developing enhanced specific and sensitive molecular tools will gives great insight into the different processes in disease treatment.  In this thesis, we build on the proximity ligation assay to develop and apply new adaptable methods to facilitate protein detection. In paper I, I present a variant of the proximity ligation assay (we call PLARCA) using micro titer plate for detection and quantification of protein using optical density as readout in the fluorometer. PLARCA detected femtomolar levels of these proteins in patient samples, which was considerably below the detection threshold for ELISA. In paper II, we developed and adapted a new method into the in situ PLA methods for detection and identification of extracellular vesicles (EVs) using flow cytometry as readout (a method we call ExoPLA).  We identified five target proteins on the surface of the Evs and using three colors, we identified the EV using flow cytometer. In paper III, we aim to improve the efficiency of in situ PLA by creating and developing new designs and versions of the assay we called Unfold probes Through comparison of detection of protein using in situ PLA versus Unfold probes, we observed considerable decrease in non-specific signals, and also a lower detection threshold. In paper IV, we describe the development of a solid phase proximity extension (sp-PEA) assay for protein detection and quantification. We compared detection of IL-8, TNF-alpha, IL-10 and IL-6 using spPEA and PEA; spPEA demonstrations over 2 orders of magnitudes in the lower detection concentrations by decreased in background noise.

O objetivo desta tese é a proposição de uma classificação para organizar a perspectiva multidimensional da proximidade. Essa classificação organiza formas para medição, representação e análise das múltiplas dimensões da proximidade. Isto dado que ainda não foram utilizados indicadores suficientemente satisfatórios para medir as várias dimensões da proximidade e que a forma como as medidas são definidas podem influenciar os resultados inferênciais obtidos nos modelos estatísticos. Este estudo levantou as definições conceituais para a proximidade e as suas principais formas empíricas de medição e propõe uma organização que possibilita a escolha entre as diferentes possibilidades de indicadores e de outras técnicas para interpretação e análise dessas medidas. Com isso foi realizada uma aplicação com dados da interação Universidade-Empresa no Brasil. A análise avaliou tanto os limites do ganho com a proximidade quanto os mecanismos de complementariedade e de substituição entre as dimensões geográfica e cognitiva. O foco na proximidade cognitiva favoreceu a comparação entre diferentes formas para a sua medição. Comparação realizada na perspectiva geométrica com uso de Escalonamento Multidimensional (EMD) e Análise de Correspondência (AC). Os resultados mostram a importância que precisa ser dada na forma como as medidas são definidas e representadas já que as interpretações dos resultados inferênciais nos modelos estatísticos estão diretamente relacionadas com esse passo inicial. As contribuições com esse estudo são de natureza metodológica, porém de caráter prático para guiar estudos futuros a partir das técnicas organizadas. Dentro desse escopo, a tese visa que outras técnicas, ainda pouco exploradas se apresentem como alternativas de uso para a ampliação da literatura da área. Por fim, a própria classificação pode ser adaptada para incluir outras técnicas analíticas que incorporem dados não espaciais ou que lidam com dados de não proximidade. / The aim of this thesis is the proposition of a classification to organize the multidimensional perspective of proximity. This classification organizes forms for measurement, representation and analysis of the multiple dimensions of proximity. This is because satisfactory indicators have not yet been used to measure the proximity and that the way in which the measures are defined can influence the inferential results obtained in the statistical models. This study raised the conceptual definitions for proximity and its main empirical forms of measurement and proposes an organization that allows the choice between the different possibilities of indicators and other techniques for interpretation and analysis of these measures. Hence, an application with data of the University-Industry interaction in Brazil was performed. The analysis evaluated both the limits of the gain with proximity and the mechanisms of complementarity and substitution between the geographic and cognitive dimensions. The focus on cognitive proximity favoured the comparison between different ways of measuring it. Comparison carried out in the geometric perspective using Multidimensional Scaling and Correspondence Analysis. The results show the importance that must be given in the way the measures are defined and represented since the interpretations of the inferential results in the statistical models are directly related to this initial step. The contributions with this study are of a methodological nature, but of a practical nature to guide future studies from the techniques organized. Within this scope, the thesis aims that other techniques, still little explored are presented as alternatives of use for the broaden of the literature of the area. Finally, the classification itself can be adapted to include other analytical techniques that incorporate non-spatial data or that deal with non-proximity data.

Collisions between personnel on foot and heavy equipment or materials on a construction site can be characterized as a contact collision. These types of incidents are a common occurrence on a work site. Technology is needed to improve work zone safety by alerting workers that are in danger of collisions pro-actively and in real-time. Developing this technology may assist in collecting previously un-recorded data on "near-misses" (close-calls). An approach is presented in this paper that is based on wireless radio frequency technology to alert workers in real-time when they are in danger. Various experiments are described that have been conducted in order to gain better understanding of the technology's potential, including measuring equipment blind spots and alert (or safety) zones. Blind spots areas are measured for six common construction vehicles to help determine the required (or minimum) alert distance (safety zone) for the equipment. A computer program was developed in-house to automatically calculate the percentage of blind spots on 2-dimensional planes and in the overall 3-dimensional volume. The blind spots results directly indicate the necessary safety zones for the equipment. The proximity device results show that technology demonstrated the capability of collecting important safety data while pro-actively detecting hazardous situations and warning workers and equipment operators during imminent potential hazardous events. Furthermore, the presented research can lead to improve the overall safety performance in construction and elsewhere through improved learning and education by providing relevant information to decision makers at all levels.

O objetivo desta tese é a proposição de uma classificação para organizar a perspectiva multidimensional da proximidade. Essa classificação organiza formas para medição, representação e análise das múltiplas dimensões da proximidade. Isto dado que ainda não foram utilizados indicadores suficientemente satisfatórios para medir as várias dimensões da proximidade e que a forma como as medidas são definidas podem influenciar os resultados inferênciais obtidos nos modelos estatísticos. Este estudo levantou as definições conceituais para a proximidade e as suas principais formas empíricas de medição e propõe uma organização que possibilita a escolha entre as diferentes possibilidades de indicadores e de outras técnicas para interpretação e análise dessas medidas. Com isso foi realizada uma aplicação com dados da interação Universidade-Empresa no Brasil. A análise avaliou tanto os limites do ganho com a proximidade quanto os mecanismos de complementariedade e de substituição entre as dimensões geográfica e cognitiva. O foco na proximidade cognitiva favoreceu a comparação entre diferentes formas para a sua medição. Comparação realizada na perspectiva geométrica com uso de Escalonamento Multidimensional (EMD) e Análise de Correspondência (AC). Os resultados mostram a importância que precisa ser dada na forma como as medidas são definidas e representadas já que as interpretações dos resultados inferênciais nos modelos estatísticos estão diretamente relacionadas com esse passo inicial. As contribuições com esse estudo são de natureza metodológica, porém de caráter prático para guiar estudos futuros a partir das técnicas organizadas. Dentro desse escopo, a tese visa que outras técnicas, ainda pouco exploradas se apresentem como alternativas de uso para a ampliação da literatura da área. Por fim, a própria classificação pode ser adaptada para incluir outras técnicas analíticas que incorporem dados não espaciais ou que lidam com dados de não proximidade. / The aim of this thesis is the proposition of a classification to organize the multidimensional perspective of proximity. This classification organizes forms for measurement, representation and analysis of the multiple dimensions of proximity. This is because satisfactory indicators have not yet been used to measure the proximity and that the way in which the measures are defined can influence the inferential results obtained in the statistical models. This study raised the conceptual definitions for proximity and its main empirical forms of measurement and proposes an organization that allows the choice between the different possibilities of indicators and other techniques for interpretation and analysis of these measures. Hence, an application with data of the University-Industry interaction in Brazil was performed. The analysis evaluated both the limits of the gain with proximity and the mechanisms of complementarity and substitution between the geographic and cognitive dimensions. The focus on cognitive proximity favoured the comparison between different ways of measuring it. Comparison carried out in the geometric perspective using Multidimensional Scaling and Correspondence Analysis. The results show the importance that must be given in the way the measures are defined and represented since the interpretations of the inferential results in the statistical models are directly related to this initial step. The contributions with this study are of a methodological nature, but of a practical nature to guide future studies from the techniques organized. Within this scope, the thesis aims that other techniques, still little explored are presented as alternatives of use for the broaden of the literature of the area. Finally, the classification itself can be adapted to include other analytical techniques that incorporate non-spatial data or that deal with non-proximity data.

Comment l’individu devient-il touriste ? Cette recherche vise à comprendre l’expérience de la redécouverte de l’espace quotidien : peut-on s’attendre à être surpris ?Dans un contexte postmoderne dans lequel l’individu devient un personnage hybride (entre visiteur et résident, portant un regard à la fois simple et complexe sur le monde qui l’englobe), nous souhaitons répondre à la question suivante : (comment) est-il possible de vivre une expérience touristique dans la région où on réside ?La méthodologie utilisée repose sur quatre actions : écouter les professionnels du secteur touristique et culturel, identifier l’offre et les thématiques proposées, observer des visites guidées destinées notamment à un public local et accéder aux expériences des visiteurs.Par le biais d’une approche qualitative, nous visons à déterminer si la distance est une composante essentielle de l’expérience touristique. La ville de Barcelone (Espagne) constitue notre terrain d’études. Nous nous penchons sur la manière dont différentes expériences sont contextualisées, d’abord, dans la biographie de chaque visiteur interviewé et, ensuite, dans le cadre spatial et temporel où l’expérience a lieu. Les résultats obtenus approfondissent la compréhension de la condition du touriste et de la valorisation des espaces ordinaires comme des espaces permettant la redécouverte. / How do we become tourists? This research aims at understanding the experience of rediscovering the usual environment. Can we expect to be surprised?In a postmodern context where individuals become hybrid (they are at the same time residents and visitors, temporal and permanent inhabitants, in a simple and in a complex relationship with the world surrounding them), we raise the following question: (How) is it possible to enjoy a tourist experience in the region where we live?Our methodology rests on four actions: listening to the cultural and tourist sector, identifying the offer and the existing themes, observing guided tours especially conceived for locals and accessing to visitors’ experiences.Through a qualitative approach, we aim at ascertaining if the distance is indeed an essential component of tourist experiences. The case of the City of Barcelona will be analysed, especially how different experiences are contextualised, first, within the biography of each interviewed visitor and, second, within the spatial and temporal frame where these experiences are carried out. The results provide deeper understanding of the tourist condition and of the transformation of ordinary places into highlights from a rediscovery point of view.

Les mitochondries et le réticulum endoplasmique (RE) interagissent au niveau de points de contacts appelés « Mitochondria-Associated ER Membranes » (MAM), afin d'échanger du Ca2+ via le complexe TP3Rl/Grp75/VDACl et maintenir l'homéostasie énergétique. Bien que des dysfonctions mitochondriales, un stress du RE et des altérations de l'homéostasie du Ca2+ participent au développement de l'insulino-résistance, on ne sait pas si ce sont des facteurs indépendants ou s'ils sont inter-reliés par une altération des MAM. Mes travaux de thèse ont permis de mettre en évidence un nouveau rôle des MAM dans l'insulino-résistance hépatique. J'ai mis au point et validé la technique d'in situ PLA pour visualiser et quantifier les interactions mitochondrie-RE dans les cellules. J'ai montré que l'intégrité des MAM était nécessaire pour la signalisation de l'insuline dans le foie, et qu'un défaut d'intégrité des MAM était impliqué dans l'insulino-résistance hépatique. Des données préliminaires suggèrent qu'une altération des MAM est également associée à l'insulino-résistance musculaire. J'ai ensuite mis en évidence la présence de la protéine kinase B, une protéine clé de la signalisation de l'insuline, dans les MAM, et démontré que sa phosphorylation par l'insuline est altérée dans cette fraction dans le foie de souris diabétique. Enfin, j'ai participé à la mise en évidence l) de la présence de la cyclophilin D à l'interface des MAM régulant les échanges calciques entre les deux organites dans les cardiomyocytes et les hépatocytes, et 2) d'une régulation des MAM par le glucose dans le foie qui permet un contrôle de la dynamique et de la fonction mitochondriale au cours des transitions nutritionnelles. Par conséquent, mes travaux ont permis d'améliorer les connaissances actuelles sur les partenaires, la fonction et la régulation des MAM et de dévoiler les MAM comme une nouvelle cible pour moduler la signalisation de l'insuline et le métabolisme hépatique / Mitochondria-associated endoplasmic reticulum membranes (MAM) are functional domains between both organelles involved in Ca2+ exchange, through the voltage-dependent anion channel (VDAC)-1/glucose regulated protein 75 (Grp75)/inositol 1,4,5-triphosphate receptor (TP3R)-1 complex, and regulating energy metabolism. Whereas mitochondrial dysfunction, ER stress, and altered Ca2+ homeostasis are associated with altered insulin signalling, the implication of MAM dysfunctions in insulin resistance is unknown. During my PhD, my work has underlined a new role of MAM in hepatic insulin- resistance. T have developed a quantitative method called in situ Proximity Ligation Assay to visualise and quantify the interactions between ER and mitochondria. T have shown that MAM integrity is required for insulin signalling and that disruption of MAM is implicated in hepatic insulin resistance. Preliminary data also suggest that MAM alterations are also associated with muscle insulin resistance. T have also identified the presence of the protein kinase B (PKB), a key protein involved in metabolic effects of insulin, at the MAM interface, and demonstrated that its phosphorylation by insulin is altered in this fraction in liver of diabetic mice. Lastly, T have also participated to the identification of: 1) the presence of cyclophilin D (CypD) at MAM interface which regulates calcium transfer from ER to mitochondria in both cardiomyocytes and hepatocytes, and 2) a regulation of MAM by glucose in liver, which is involved in the regulation of mitochondria dynamics and function during nutritional transitions. Consequently, my work improved the knowledge on the composition, function and regulation of MAM, and highlighted MAM as a potential new target for the modulation of hepatic insulin action and metabolism

The focus of this study is the development and evaluation of a new partially supervised learning framework. This framework belongs to an emerging field in machine learning that augments unsupervised learning processes with some elements of supervision. It is based on proximity fuzzy clustering, where an active learning process is designed to query for the domain knowledge required in the supervision. Furthermore, the framework is extended to the parametric optimization of the kernel function in the proximity fuzzy clustering algorithm, where the goal is to achieve interesting non-spherical cluster structures through a non-linear mapping. It is demonstrated that the performance of kernel-based clustering is sensitive to the selection of these kernel parameters. Proximity hints procured from domain knowledge are exploited in the partially supervised framework. The theoretic developments with proximity fuzzy clustering are evaluated in several interesting and practical applications. One such problem is the clustering of a set of graphs based on their structural and semantic similarity. The segmentation of music is a second problem for proximity fuzzy clustering, where the aim is to determine the points in time, i.e. boundaries, of significant structural changes in the music. Finally, a time series prediction problem using a fuzzy rule-based system is established and evaluated. The antecedents of the rules are constructed by clustering the time series using proximity information in order to localize the behavior of the rule consequents in the architecture. Evaluation of these efforts on both synthetic and real-world data demonstrate that proximity fuzzy clustering is well suited for a variety of problems. / Digital Signals and Image Processing

Ziele wie eine hohe Auflösung und ein hoher Durchsatz sind bisher in der Elektronenstrahllithografie nicht gleichzeitig erreichbar; es existieren daher die Belichtungskonzepte Gaussian-Beam und Variable-Shaped-Beam (VSB), die auf Hochauflösung respektive Durchsatz optimiert sind. In dieser Arbeit wird der experimentelle Kreuzvergleich beider Belichtungskonzepte mit Hilfe chemisch verstärkter und nicht verstärkter Lacksysteme präsentiert. Als quantitativer Parameter wurde die Gesamtunschärfe eingeführt, die sich durch quadratische Addition der auflösungslimitierenden Fehlerquellen, also Coulomb-Wechselwirkungen (Strahlunschärfe), Lackprozess (Prozessunschärfe) und Proximity-Effekt (Streuunschärfe), ergibt. Für den Vergleich wurden wohldefinierte Prozesse auf 300 mm Wafern entwickelt und umfassend charakterisiert. Weitere Grundlage ist die Anpassung oder Neuentwicklung spezieller Methoden wie Kontrast- und Basedosebestimmung, Doughnut-Test, Isofokal-Dosis-Methode für Linienbreiten und Linienrauheit sowie die Bestimmung der Gesamtunschärfe unter Variation des Fokus. Es wird demonstriert, dass sich mit einer kleineren Gesamtunschärfe die Auflösung dichter Linien verbessert. Der direkte Vergleich der Gesamtunschärfen beider Belichtungskonzepte wird durch die variable Strahlunschärfe bei VSB-Schreibern erschwert. Da für die Bestimmung der Gesamtunschärfe keine Hochauflösung nötig ist, wird das Testpattern mit größeren Shots belichtet und induziert somit eine größere Gesamtunschärfe. Es wird gezeigt, dass die Prozessunschärfe den größten Anteil der Gesamtunschärfe stellt. Außerdem spielt die Streuunschärfe bei Lackdicken kleiner 100 nm und Beschleunigungsspannungen von 50 kV oder größer keine Rolle. / Up to now, targets like high resolution and high throughput can not be achieved at the same time in electron beam lithography; therefore, the exposure concepts Gaussian-Beam and Variable-Shaped-Beam (VSB) exist, which are optimized for high resolution and throughput, respectively. In this work, the experimental cross-comparison of both exposure concepts is presented using chemically amplified and non-chemically amplified resist systems. For quantification the total blur parameter has been introduced, which is the result of the quadratic addition of the resolution limiting error sources, like Coulomb interactions (beam blur), resist process (process blur) and proximity-effect (scatter blur). For the comparison, well-defined processes have been developed on 300 mm wafers and were fully characterized. Further basis is the adaption or the new development of special methods like the determination of contrast and basedose, the doughnut-test, the isofocal-dose-method for line widths and line roughness as well as the determination of the total blur with variation of the focus. It is demonstrated, that the resolution of dense lines is improved with a smaller total blur. The direct comparison of the total blur values of both exposure concepts is complicated by the variable beam blur of VSB writers. Since high resolution is not needed for the determination of the total blur, the test pattern is exposed with larger shots on the VSB writer, which induces a larger total blur. It is shown that the process blur makes the largest fraction of the total blur. The scatter blur is irrelevant using resist thicknesses smaller than 100 nm and acceleration voltages of 50 kV or larger.

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