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Modern wireless mobile communication technology has made noticeable improvements from the technologies in the past but is still plagued by poor power efficiency of power amplifiers found in today’s base stations. One of the factors that affect the power efficiency adversely comes from modern modulation techniques like orthogonal frequency division multiplexing which result in signals with high peak to average power ratio, also known as the crest factor. Crest factor reduction algorithms are used to solve this problem. However, the dominant method of hardware description for synthesis has been to start with writing register transfer level code which gives a very fixed implementation that may not be the optimal solution. This thesis project is focused on developing a peak cancellation crest factor reduction system, using a high-level language as the system design language, and synthesizing it using high-level synthesis. The aim is to find out if highlevel synthesis design methodology can yield increased productivity and improved quality of results for such designs as compared to the design methodology that requires the system to be implemented at the register transfer level. Design space exploration is performed to find an optimal design with respect to area. Finally, a few parameters are presented to measure the performance of the system, which helps in tuning it. The results of design space exploration helped in choosing the best possible implementation out of four different configurations. The final implementation that resulted from high-level synthesis had an area comparable to the previous register transfer level implementation. It was also concluded that, for this design, the high-level synthesis design methodology increased productivity and decreased design time. / Användning av högnivåsyntes för reduktion av toppfaktor Det har gjorts noterbara framsteg inom modern trådlös kommunikationsteknik för mobiltelefoni, men tekniken plågas fortfarande av dålig energieffektivitet hos förstärkarna i dagens basstationer. En faktor som påverkar energieffektiviteten negativt är om signaler har en stor skillnad mellan maximal effekt och medeleffekt. Kvoten mellan maximal effekt och medeleffekt kallas för toppfaktor, och en egenskap hos moderna moduleringstekniker, såsom ortogonal frekvensdelningsmodulering, är att de har en hög toppfaktor. Algoritmer för reducering av toppfaktor kan lösa det problemet. Den dominerande metoden för design av hårdvara är att skriva kod i ett hårdvarubeskrivande språk med abstraktionsnivån Register Transfer Level och sedan använda verktyg för att syntetisera hårdvara från koden. Resultatet är en specifik implementation som inte nödvändigtvis är den optimala lösningen. Det här examensarbetet är inriktat på att utveckla ett system för reducering av toppfaktor, baserat på algoritmen Peak Cancellation, genom att skriva kod i ett högnivåspråk och använda verktyg för högnivåsyntes för att syntetisera designen. Syftet är att ta reda på om högnivåsyntes som designmetod kan ge ökad produktivitet och ökad kvalitet, för den här typen av design, jämfört med den klassiska designmetoden med abstraktionsnivån Register Transfer Level. Verktyget för högnivåsyntes användes för att på ett effektivt sätt undersöka olika designalternativ för att optimera kretsytan. I rapporten presenteras ett antal parametrar för att mäta prestandan hos systemet, vilket ger information som kan användas för finjustering. Resultatet av undersökningen av designalternativ gjorde det möjligt att välja den bästa implementationen bland fyra olika konfigurationer. Den slutgiltiga implementationen hade en kretsyta som är jämförbar med en tidigare design som implementerats med hårdvarubeskrivande språk med abstraktionsnivån Register Transfer Level. En annan slutsats är att, för den här designen, så gav designmetoden med högnivåsyntes ökad produktivitet och minskad designtid.

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Suite à un infarctus du myocarde, la formation d’une cicatrice, nommée fibrose de réparation, représente un processus adaptatif et essentiel empêchant la rupture du myocarde. La cicatrice est constituée de myofibroblastes, de cellules vasculaires, de fibres sympathiques ainsi que de cellules souches neuronales cardiaques exprimant la nestine. Une perturbation au niveau de ces constituants cellulaires résulte en une formation maladaptative de la cicatrice et éventuellement, une diminution de la fonction cardiaque. La compréhension des événements cellulaires ainsi que les mécanismes sous-jacents participant à cette fibrose est alors d’une importance primordiale. Cette thèse est axée sur l’identification du rôle du système sympathique et des cellules souches neuronales cardiaques exprimant la nestine dans la formation de la cicatrice ainsi que leur interaction potentielle. Nos travaux examinent l’hypothèse que les cellules souches neuronales exprimant la nestine sont endogènes au cœur et que suite à un dommage ischémique, elles contribuent à la réponse angiogénique et à la réinnervation sympathique du tissu lésé. Les cellules souches neuronales exprimant la nestine sont retrouvées dans les cœurs de différentes espèces incluant le cœur infarci humain. Elles sont résidentes dans le cœur, proviennent de la crête neurale lors du développement et sont intercalées entre les cardiomyocytes n’exprimant pas la nestine. Suite à leur isolation de cœurs infarcis de rats, les cellules souches neuronales cardiaques prolifèrent sous forme de neurosphères et, dans des conditions appropriées in vitro, se différencient en neurones exprimant le neurofilament-M. Suite à un infarctus du myocarde, les niveaux de l’ARNm de nestine sont significativement augmentés au niveau de la région infarcie et non-infarcie. Nos résultats suggèrent que cette augmentation de l’expression de nestine dans la cicatrice reflète en partie la migration des cellules souches neuronales cardiaques exprimant la nestine de la région non-infarcie vers la région infarcie. Lors de la fibrose de réparation, ces cellules représentent un substrat cellulaire pour la formation de nouveaux vaisseaux et contribuent aussi à la croissance des fibres sympathiques dans la région infarcie. Finalement, nous démontrons que la formation de la cicatrice est associée à une innervation sympathique de la région infarcie et péri-infarcie. De plus, les fibres sympathiques présentes dans la région infarcie sont observées à proximité de vaisseaux de petits calibres. Ces données suggèrent indirectement que l’innervation de la cicatrice par les fibres sympathiques peut jouer un rôle dans la réponse angiogénique suite à un infarctus du myocarde. Suite à l’administration du corticostéroïde dexaméthasone, nous détectons un amincissement de la cicatrice, associé à une réduction significative des fibres sympathiques exprimant le neurofilament-M dans la région infarcie et péri-infarcie. La diminution de la densité de ces fibres par le dexaméthasone peut être reliée à une diminution de la prolifération des myofibroblastes et de la production de l’ARNm du facteur neurotrophique nerve growth factor. / GENERAL ABSTRACT Following myocardial infarction, scar formation represents an adaptive response required to heal the damaged myocardium and prevent cardiac rupture. Infarct healing requires the coordinated action of scar myofibroblasts, angiogenic cells, sympathetic fibres and nestin positive cardiac neural stem cells. A perturbation of one or more of the aforementioned events could lead to inadequate scar healing and further worsening of ventricular function. A better understanding of the cellular events and the underlying mechanisms involved in scar formation is of a primordial importance. The focus of the following studies consists of elucidating the role of the sympathetic system and cardiac neural stem cells during scar healing and their potential interaction. We tested the hypothesis that nestin positive neural stem cells are endogenous to the heart, contribute to angiogenesis and sympathetic innervation of the infarcted myocardium following ischemic injury. Nestin positive cardiac neural stem cells are found in a number of species including the infarcted human heart. Nestin positive cardiac neural stem cells represent a resident population in the heart, are derived from the neural crest and detected intercalated between nestin negative cardiac myocytes. Following their isolation from the infarcted rat heart, neural stem cells proliferate as a neurosphere and under appropriate in vitro conditions differentiate to a neurofilament-M immunoreactive neuron. Following myocardial infarction, nestin mRNA levels are significantly elevated in the viable left ventricle and infarct region. Our data further suggests that the increased expression of nestin in the infarct region reflects in part the migration of these neural stem cells from the viable myocardium. During cardiac wound healing, neural stem cells may represent a novel substrate for de novo blood vessel formation and further contribute to sympathetic fibre growth and innervation of the infarct region. Lastly, we demonstrate that scar formation and healing is associated with sympathetic fibre sprouting of the peri-infarct/infarct region. In addition, sympathetic fibres in the infarct region were detected in close proximity to small calibre blood vessels. These latter data indirectly suggest that innervating sympathetic fibres may play a role in angiogenesis during cardiac wound healing. Following the administration of the corticosteroid dexamethasone inadequate scar healing was observed and associated with a significant reduction of neurofilament-M immunoreactive fibres in the peri-infarct/infarct region. The loss of sympathetic fibre sprouting in the scar may be related to a dexamethasone-mediated suppression of myofibroblast growth and the concomitant reduction of nerve growth factor mRNA expression.

Bioimpedance spectroscopy is very useful in biomedical field as a safe and non-invasive technique. A stable and safe excitation current below than 0.5 mA for load impedances changing from 100 Ω to 10 kΩ in the full β-dispersion range from kHz up to 1 MHz is a big challenge for the design of the current source addressed by this thesis. For a good stability and high accuracy, the source should have a high output impedance. Different current source types in “current-mode approach” and “voltage-mode approach” were investigated and compared for usability in bioimpedance measurement systems. The “voltage-mode approach” with grounded load was proven to be more suitable and stable for biomedical measurements. Thereby the Tietze and the Howland circuit in dual configuration with negative feedback have shown the lowest error of the output current and the highest output impedance, where the improved Howland circuit in dual configuration with negative feedback is preferred because it has a simple structure, high accuracy and good stability. We suggest to improve the stability of the Howland circuit in dual configuration with negative feedback by introducing compensated operational amplifiers and to reduce stray capacitances at higher frequencies by adding gain compensation capacitor. We reach thereby an accuracy of 0.5% at low frequency and 0.9% at 1 MHz. With the realized accuracy of the designed voltage controlled current source, one decisive prerequisite for portable bioimpedance measurement system is achieved. In order to select the appropriate excitation signals for short measurement time, a comparative study of signals and their parameters was carried out. It leads to the selection of binary chirp signal as a suitable excitation signal due to its short measurement time about 100 μs, low crest factor lower than 2.8 and an energy efficiency higher than 54% in a very noisy signal. Simulation results show that the designed enhanced Howland current source excited by the binary chirp signal has low error and flatness in the whole range. / Die Bioimpedanzspektroskopie gewinnt aufgrund ihrer besonderen Eigenschaften als nicht-invasive, schonende Messmethode zunehmend an Bedeutung im biomedizinischen Bereich. Dabei ergeben sich besondere erausforderungen für den Entwurf der Stromquelle zur Realisierung eines stabilen und sicheren Anregungsstroms. Gefordert ist eine hohe Genauigkeit bis zu einem Maximalstrom von 0.5 mA in einem Frequenzbereich, der der β-Dispersion entspricht, von wenigen kHz bis hin zu 1 MHz. Die Stabilität muss bei variablen Lastimpedanzen im Bereich von 100 Ω bis 10 kΩ gewährleistet sein. Dafür muss die Stromquelle eine hohe Ausgangsimpedanz aufweisen. Diese Arbeit fokussiert auf den Entwurf von spannungsgesteuerten Stromquellen. Verschiedene Arten von Stromquellen wurden untersucht und verglichen. Der "Voltage-Modus-Ansatz" mit Masse-referenzierter Last hat sich als besser geeignet und stabiler für biomedizinische Messungen erwiesen. Die Tietze-Schaltung und diese Howland-Schaltung zeigen dabei die niedrigsten Fehler des Ausgangsstroms und die höchste Ausgangsimpedanz. Im direkten Vergleich besitzt die verbesserte Howland-Schaltung doch eine einfachere Struktur, höhere Genauigkeit und bessere Stabilität und wird daher gegenüber der Tietze-Schaltung bevorzugt. Um weitere Stabilitätsverbesserungen bei der Howland-Schaltung zu erreichen, werden zwei Maβnahmen vorgeschlagen. Zum einen werden kompensierte Operationsverstärker eingeführt und zum anderen wird der Einfluss von Streukapazitäten bei hohen Frequenzen minimiert indem die Verstärkung mit Kondensatoren kompensiert wird. Durch diese Maβnahmen wird eine Genauigkeit von 0.5% bei niedrigen Frequenzen und 0.9% bei 1 MHz ermöglicht. Mit dem neuen Entwurf der spannungsgesteuerten Stromquelle ist ein entscheidender Meilenstein für die Realisierung tragbarer Messsysteme der Bioimpedanz erreicht. Um eine kurze Messzeit zu realisieren wurde eine vergleichende Studie von Anregungssignalen und deren Signalparameter durchgeführt. Die Ergebnisse zeigen, dass binäre Chirp-Signale aufgrund der reduzierten Messzeit, des niedrigen Crest-Faktors unter 2.8 und hohe Energieeffizienz von mehr als 54% bei hohem Rauschlevel besonders geeignet sind. Simulationsergebnisse zeigen, dass die entwickelte Howland-Stromquelle zusammen mit einem binären Mehrfrequenzsignal den geringsten Amplitudenfehler im gesamten Frequenzbereich realisiert.

Os dispositivos de ancoragem temporária têm sido amplamente utilizados como auxiliares de ancoragem esquelética no tratamento de má oclusões mais severas. Para a instalação de mini parafusos na crista infrazigomática é necessário o conhecimento anatômico desta região e suas possíveis variações. Na literatura são descritos diferentes tipos faciais que diferem na predominância em relação ao padrão de crescimento facial vertical ou horizontal configurando conformações ósseas distintas. Com isso o objetivo deste estudo é avaliar se há diferença na espessura óssea na região de crista infrazigomática em cada o tipo facial. Para este estudo retrospectivo foi selecionada uma amostra composta por 86 tomografias computadorizadas por feixe cônico de indivíduos dos gêneros masculino e feminino, adultos, com idade entre 18 e 40 anos. As imagens foram avaliadas no software Dolphin® (versão 11.0, Dolphin Imaging and Manegement Solutions, Chatsworth, CA - EUA). As tomografias foram divididas em três grupos de acordo com o tipo facial, sendo: 24 do tipo facial Hiperdivergente, 30 do tipo facial Neutro e 32 do tipo facial Hipodivergente. Para atender aos objetivos do estudo, as medidas foram realizadas nas regiões entre segundo pré-molar e primeiro molar superior até região de raiz distal de segundo molar superior em alturas de 5 7, 9 e 11 mm a partir da crista alveolar. Os resultados mostraram que no grupo hiperdivergente os locais considerados seguros para a instalação dos mini parafusos foram entre primeiros e segundos molares superiores em 11 mm da crista alveolar, na região das raizes mesiais dos segundos molares superiores a partir de 9 mm da crista alveolar e em região das raizes distais dos segundos molares superiores em 11 mm da crista alveolar. No grupo neutro os locais considerados seguros para a instalação dos mini parafusos foram entre primeiro e segundo molar em 11 mm da crista alveolar do lado direito e em região das raizes mesiais dos segundos molares superiores em 11 mm da crista alveolar. Para o grupo hipodivergente observou-se como locais considerados seguros, entre primeiros e segundos molares superiores em 11 mm da crista alveolar e em região das raizes mesiais dos segundos molares superiores em 11 mm da crista alveolar. Baseados nos resultados obtidos consideramos que existe uma diferença de espessura entre os tipos faciais e que este fator deve ser considerado durante o planejamento para instalação de mini parafusos de ancoragem ortodôntica, no entanto para todos os grupos o local mais adequado é na região de raiz mesial dos segundos molares superiores em 11 mm da crista alveolar. / Temporary anchoring devices have been widely used as skeletal Anchorage in treatment of more severe malocclusions. The anatomical knowledge of this region and its possible variation are necessary for the installation of mini screws in the infrazygomatic crest. In the literature diferente facial types are described that differ in the predominance in relation to the vertical or horizontal facial growth pattern configuring different bone conformations. Therefore, the purpose os this study is to evaluate if there is difference in bone thickness in the region os the infrazigomatic crest in each facial type. For this retropective study, a sample composed fo 86 computed tomography scans of individuals of the masculine and feminine adults aged between 18 and 40 years, was selected. The images were evaluated in Dolphin® software (version 11.0, Dolphin Imaging and Manegement Solution, Chastworth, CA - USA). The CT scans were divided into three groups according to the facial type: 24 of the facial type Hyperdivergent, 30 of the facial type Neutral and 32 of the facial type Hipodivergent. To meet the study objectives, the measurements were performed in the regions between the second pre-molar and the first molar superior to the region of the upper second molar distal root at heights of 5, 7, 9 and 11 mm from the alveolar crest. The results showed that in the hyperdivergent group the sites that was considered safe for the installation of the mini screws were between the first and second maxillary molars in 11 mm of the alveolar crest, in the region of the mesial roots of the second maxillary molars from 9 mm of the alveolar crest and in the region of the distal roots of the second maxillary molars 11 mm from the alveolar crest. In the neutral group, the sites considered safe for the installation of mini screws were between the first and second molars in 11 mm of the alveolar ridge on the right side and in the region of the mesial roots of the maxillary second molars in 11 mm of the alveolar ridge. For the hypodivergent group, were considered safe places between the first and second maxillary molars were observed in 11 mm of the alveolar crest and in the region of the mesial roots of the maxillary second molars in 11 mm of the alveolar crest. Based on the results obtained, we consider that there is a difference in thickness between facial types and that this factor should be considered during planning for installation of mini orthodontic anchor bolts, however for all groups the most appropriate place is in the mesial root region of the upper second molars.

Neureguline (NDF, Heregulin, GGF ARIA, oder SMDF) sind EGF-ähnliche, extrazelluläre Signalmoleküle, die mit transmembranären Tyrosinkinaserezeptoren der ErbB-Familie interagieren. Neuregulin-1/ErbB Signale steuern während der Embryonalentwicklung und im adulten Organismus vielfältige zelluläre Prozesse, wie z. B. Proliferation, Migration und Differenzierung. In der vorliegenden Arbeit wurde die Rolle des Neuregulin-1/ErbB Signalsystems in der Entwicklung von Neuralleistenzellen und sich daraus entwickelnden Komponenten des peripheren Nervensystems (sympathisches Nervensystem und periphere Glia) untersucht. Neuregulin-1 Signale werden in Neuralleistenzellen und ihren Gliaderivaten durch ErbB2/ErbB3 Rezeptor-Heterodimere übertragen. Mit Hilfe von Mäusen mit gezielter Mutation (knock-out) des Neuregulin-1, ErbB2 oder ErbB3 Gens wurde gezeigt, daß Neuregulin-1/ErbB2/3 Signale die Migration sympathogener Neuralleistenzellen steuern. Mutante Tiere entwickeln daher eine hochgradige Hypoplasie des sympathischen Nervensystems. Neuregulin-1 Signale kontrollieren darüber hinaus die Entwicklung von Schwann Zellen. Die Unterbrechung des Neuregulin-1/ErbB2/3 Signalwegs in mutanten Mäusen führt zum Verlust von Schwann Zellen während der Embryogenese. Es wurde außerdem gezeigt, daß der Transkriptionsfaktor Sox10 die Expression von ErbB3 in Neuralleistenzellen kontrolliert. Sox10 und ErbB3 Mutanten besitzen daher übereinstimmende Defekte in der Neuralleistenzellentwicklung. Neben den ErbB3-abhängigen Funktionen von Sox10 wurde eine ErbB3-unabhängige Schlüsselfunktion von Sox10 bei der Differenzierung von Neuralleistenzellen zu peripherer Glia identifiziert. Das Neuregulin-1/ErbB2/3 Signalsystem und der Transkriptionsfaktor Sox10 besitzen also gemeinsam zentrale Funktionen in der Entwicklung peripherer Glia, steuern diesen Prozess aber über unterschiedliche Mechanismen und während unterschiedlicher Entwicklungsphasen. Sox10, ErbB2 und ErbB3 mutante Mäuse entwickeln neben dem Verlust von Schwann Zellen eine sekundäre Degeneration begleitender sensorischer und motorischer Neurone. Dies zeigt, daß periphere Glia Signale generiert, die essentiell sind für Integrität und Überleben begleitender Neurone. / Neuregulins (NDF, heregulin, GGF ARIA, or SMDF) are EGF-like growth and differentiation factors that signal through tyrosine kinase receptors of the erbB family. The neuregulin-1 proteins and their receptors play essential roles during embryonic development and in the adult. Functions of the neuregulin/erbB signaling system in developing neural crest cells and their derivatives (sympathetic nervous system, peripheral glial cells) were analyzed in mice with targeted mutations in the erbB2, erbB3, or neuregulin-1 genes. All three mutations cause severe hypoplasia of the primary sympathetic ganglion chain, and migration of sympathogenic neural crest cells to their target sites, where they differentiate into sympathetic neurons, depends on neuregulin-1 and its receptors. Neuregulin-1 signals are also essential for the development of Schwann cells. As a consequence, mice with targeted mutations in the neuregulin-1/erbB signaling system completely lack Schwann cells. Moreover, the HMG-box transcription factor sox10 is shown to control expression of erbB3 in neural crest cells. In accordance, sox10 and erbB3 mutant mice share phenotypes in the developing neural crest. Additionally, a novel, erbB3-independent developmental function of sox10 was identified: Sox10 is a key regulator for glial fate determination in undifferentiated neural crest cells. Thus, the transcription factor sox10 and the neuregulin-1/erbB signalling system both serve critical functions during development of peripheral glial cells. However, they act via different cellular mechanisms and during different developmental stages. At later developmental stages lack of peripheral glial cells in sox10, erbB2 and erbB3 mutant mice results in a severe degeneration of sensory and motor neurons. The comparison of the mutant phenotypes demonstrates, that peripheral glial cells generate essential signals for the survival and maintenance of accompanying neurons.

Numerous initiatives to improve our understanding of cancer biology have been lunched in different laboratories that aim to describe the interactome and gene-expression profile in different tumour cell line. It is now clear that the different strategies of cell migration observed in cancer are reminiscent of the different migratory strategies observed during embryo development. These similarities suggest that developmental program that has to be kept off after embryogenesis may be induced by spontaneous genetics modifications that produce tumour cells. In this study we went inside the genetic network/profile that controls how neural crest cells eventually switch on the migration program and how they are able to arise into different lines with the propose of getting new ideas on how to prevent dissemination of tumour cells or how to treat advanced tumour that have already spread. Neural progenitors of the dorsal neural tube that acquire the expression of specific neural crest determinants, delaminate from the neural tube and follow precise migratory pathways, to terminally differentiate into the various neural crest derivatives. Here we developed a novel resource for lineage trace and isolation of neural crest cells that allowed for a genome-wide expression screen in pre-migratory and migratory neural crest progenitors. We efficiently identified previously known neural crest specific genes. Expression profiling revealed new neural crest genes belonging to a wide range of cellular functions, with high representation of genes associated to cell motion. Additionally, we identified chick genes for which the human orthologues and/or paralogues are associated to Neuroblastoma formation. In my thesis we identified new genes specifically expressed in the developing neural crest, and proposed a revised genomic signature for the normal neural crest cells. Furthermore, mutations on some of these genes are markers for Neuroblastoma tumour formation. Thus we propose this as a valid screen to identify candidates genes that contribute to the characterization of the Neuroblastoma cancer stem cells, and thus to the identification of specific targets to design new therapeutic strategies. Getting in more detail into this genetic network, Wnt canonical signalling response has to been shown to be a key event in both cancer and neural crest cell development. Traditionally Wnt canonical pathway has been involved in neural crest induction process, but here we demonstrated that it is also critical for the onset migration of the neural crest cell. In fact, high levels of Wnt canonical activity prevents neural crest cell to delaminate and only through the inhibition of this activity mediate by dapper protein, neural crest cells can undergo into their normal migration pathways. If this process has an implication in cancer is still unknown, but Dapper expression proteins have been already associated to different types of cancer.