INTRODUÇÃO: O bócio é um termo genérico usado para descrever o aumento no volume da glândula tireoide que pode estar associado à formação de múltiplos nódulos, o chamado bócio multinodular. Camundongos transgênicos tireoide específicos com depleção do Pten ou aumento de expressão do Dream, dois importantes genes que têm sido implicados nas vias de sinalização das células foliculares, apresentam desenvolvimento de bócio. Em humanos, uma larga porcentagem de pacientes com doença de Cowden apresentam bócio ou outras anormalidades tireoidianas associadas a mutações germinativas no PTEN. OBJETIVO: O objetivo desse estudo foi investigar a expressão dos genes PTEN e DREAM em tecido hiperplásico tireoidiano, bem como mutações germinativas e somáticas no PTEN e mutações somáticas no DREAM, em pacientes portadores de bócio multinodular, com a finalidade de avaliar o papel destes genes na etiologia do bócio. MÉTODOS: Foram investigados 60 pacientes com bócio multinodular (54 mulheres). A extração do DNA genômico foi realizada a partir de tecido hiperplásico da tireoide e do sangue periférico dos pacientes enquanto o RNA foi obtido apenas do tecido glandular. A quantificação relativa do RNA mensageiro do PTEN e do DREAM foi avaliada pelo método de 2-??Ct utilizando o GAPDH como normalizador em dados produzidos pela PCR em tempo real. A alta e a baixa expressão de PTEN e DREAM foram definidas, respectivamente, por valores de quantificação superiores a 2.0 e inferiores a 0.5 em comparação a um pool comercial de RNA de tireoide normal de humanos. Análise de mutação foi realizada por amplificação da região codificante dos genes PTEN e DREAM pela PCR convencional seguida por sequenciamento automático (RQ = quantificação relativa; x? = média e DP = desvio padrão). RESULTADOS: Foi observada alta expressão do PTEN em 58,3% dos pacientes portadores de bócio (x RQ = 3,81; DP = 2,26) enquanto apenas dois casos apresentaram baixa expressão (x? RQ = 0,34; DP= 0,09). Nos 38,3% casos restantes foi observada expressão normal de PTEN (x? RQ = 1,35; DP = 0,35). Em relação ao gene DREAM, alta e baixa expressão foram observadas em 33,3% (x RQ = 6,07; DP = 5,02) e 15,0% (x RQ = 0,30; DP = 0,10) dos pacientes com bócio respectivamente, enquanto pouco mais da metade dos casos (51,6%) teve expressão normal RQ = 1,12 ; DP = 0,40). A Análise de mutações do PTEN e do DREAM revelaram apenas polimorfismos intrônicos, previamente descritos no banco de dados do NCBI, tanto nos DNA de sangue e/ou de tecido hiperplásico. CONCLUSÕES: Nossos resultados demonstraram uma expressão aumentada de PTEN em bócio multinodular, sugerindo que este pode estar hiperexpresso, ou pelo menos tem sua expressão mantida, nesta hiperplasia benigna da tireoide. Alterações na sequência gênica codificante do PTEN não foram observadas. Na análise mutacional e de expressão do DREAM não foram encontradas alterações que pudessem ser relacionadas à patogênese de bócio em humanos / BACKGROUND: Multinodular goiter is a clinicopathological entity characterized by an increased volume of the thyroid gland with formation of nodules. A high proliferative status of thyroid follicular cells and goiter were observed in mutants mice with specifically deleted Pten or Dream overexpression in thyrocytes. In humans, a large percentage of patients with Cowden disease have goiters or other thyroid abnormalities associated with germ-line PTEN mutations. OBJECTIVE: The aim of this study was to investigate the tissue expression of PTEN and DREAM, as well as germ-line and somatic PTEN mutations and somatic DREAM mutations, in patients with multinodular goiter to evaluated the role of these genes in goitrogenesis. METHODS: We investigated 60 multinodular goiter patients (54 females). Genomic DNA was extracted from both patients\' hyperplastic thyroid tissue and peripheral blood whereas RNA was obtained only from glandular tissue. Relative quantification of PTEN and DREAM messenger RNA was evaluated using 2-Ct method normalized to GAPDH expression on data produced by real-time PCR. PTEN and DREAM over and lower expression were respectively defined by value > 2.0-fold and < 0.5-fold relative to a commercial pool of normal human thyroid RNA. Mutations analyses were performed by amplification of PTEN and DREAM coding region by PCR followed by automatic sequencing. RQ = relative quantification; x = average; SD = standard deviation. RESULTS: We observed a high expression of PTEN in 58.3% of multinodular goiter patients (RQ x = 3.81; SD = 2.26) and only two cases with lower expression (RQ x = 0.34; SD = 0.09). In the remaining 38.3% of patients expression of PTEN was normal (RQ x = 1.35; SD = 0.35). For the DREAM, over and lower expression were observed in 33.3% (RQ x = 6.07; SD = 5.02) and 15.0% (RQ x = 0.30; SD = 0.10) of patients respectively, whereas 51.6% had normal expression (RQ x = 1.12; SD = 0.40). Regarding PTEN and DREAM mutations analysis, only previously described intronic polymorphisms were observed in DNA from blood and/or thyroid hyperplastic tissue. CONCLUSIONS: Our results demonstrated that PTEN expression is higher in multinodular goiter suggesting that this gene is overregulated (or at least has its expression maintained) in this benign hyperplastic thyroid lesions. No evidence for the involvement of DREAM in goitrogenesis was observed in our cohort of multinodular goiter patients

This master’s thesis is divided into two logical parts. The first part contains theory of calculation of steady state and short-circuits conditions within 110 kV distribution network. Newton’s method and short-circuit current calculation is also explained here. It also deals with classification and aftereffects of transient performance occurring in power networks. The second part contains practical calculation of steady flow and short-circuit conditions at parallel operation of transformers T403 and T402 in 400/110 kV transformer stations Sokolnice and Otrokovice. This calculation is done with program used by system operators called SINAUT Spectrum and consequently analyzed. This part also contains brief description of substations from this region.

The master Thesis deals with indirect air heating in air handling units. In the theoretical part of the thesis the categories of heat exchangers are defined according to their positioning in ventilation system, used material and type of heat transfer fluid. To the issue of calculating heat exchanges through heat exchangers and description of different kinds of regulation of primary heat transfer fluid is dedicated a separate chapter. The experimental part of the thesis deals with determining performance of current air heat exchanger at set thermal gradient with various heat transfer fluids. In the calculating part of the Thesis, based on measured values, are suggested two possible solutions for use of technological waste heat. Final evaluation of particular solutions was based on the criterion of efficiency usage and implementation investment costs.

Hyperexcitabilité est l'un des changements les plus importants observés dans de nombreuses maladies neuro-dégénératives telles que la sclérose latérale amyotrophique (SLA) et la maladie d'Alzheimer. De nombreuses recherches études se sont concentrées sur la réduction de l'hyperexcitabilité, soit en inactivant les canaux sodiques ce qui va réduire la génération de potentiels d'action, soit en prolongeant l'ouverture des canaux potassiques ce qui va qui ramener la membrane à son état de repos et réduire l’activité des neurones. Ainsi, pour cibler l'hyperexcitabilité, il faut tout d’abord comprendre les différents aspects de la fonction des canaux ioniques au niveau. Les objectifs des travaux présentés dans cette thèse consistent à déterminer le mécanisme d'inactivation dans les canaux potassiques Shaker. Les canaux Shaker Kv s'inactivent rapidement pour culminer le potentiel d'action et maintenir l'homéostasie des cellules excitables. L'inactivation de type N est causée par les 46 premiers acides aminés situés de l'extrémité N-terminale du canal, encore appelé, peptide d'inactivation (IP). De nombreuses études mutationnelles ont caractérisé l'inactivation de type N au niveau fonctionnel, cependant, la position de l'IP à l'état de repos et leur transition lors de l'inactivation est encore débattue. L'objectif de la première étude consiste à évaluer le mouvement des IP pendant leur inactivation à l'aide de la fluorométrie en voltage imposé. En insérant un acide aminé non naturel, la 3-[(6-acétyl-2-naphtalényl) amino]-L-alanine (Anap), qui est sensible aux changements d'environnement, nous avons identifié séparément les mouvements de la boule et de la chaîne. Nos données suggèrent que l'inactivation de type N se produit dans un mouvement biphasique en libérant d'abord le IP, ce qui va bloquer le pore du côté cytoplasmique. Pour affiner davantage la position de repos des IP, nous avons utilisé le transfert d'énergie de résonance à base de lanthanide et le métal de transition FRET. Nous proposons que le IP se situe dans la fenêtre formée par le canal et le domaine T1, interagissant avec les résidus acides-aminés du domaine T1. Dans notre deuxième étude, nous avons montré que le ralentissement de l'inactivation de type N observé dans la première étude est causée par une expression élevée des canaux Shaker. En effet, l'extrémité C-terminale du canal interagit avec les protéines d'échafaudage associées à la membrane pour la formation d'amas. Nous avons aussi montré qu'en tronquant les quatre derniers résidus C-terminaux impliqués dans la formation des amas, nous empêchons également le ralentissement de la cinétique d'inactivation dans les canaux Shaker. Nous avons également démontré que l'inactivation lente de type N n'est pas affectée par l'accumulation des cations potassiques [K+] externe ou toute diaphonie entre les sous-unités voisines. Cette étude élucide non seulement la cause du ralentissement de l'inactivation, mais montre également que les canaux modifient leur comportement en fonction des conditions d'expression. Les résultats trouvés au niveau moléculaire ne peuvent donc pas toujours être extrapolés au niveau cellulaire. / Hyperexcitability of neurons is a major symptom observed in many degenerative diseases such as ALS and Alzheimer’s disease. A lot of research is focused on reducing hyperexcitability, either by inactivating sodium channels that will reduce the generation of action potentials, or by prolonging the opening of potassium channels which will help to bring the membrane back to resting state and thus, reduce firing frequency of neurons. At the molecular level, it is important to understand different aspects of ion channel function to target hyperexcitability. The aim of this thesis was to investigate in two projects the inactivation mechanism in Shaker potassium channels. Shaker Kv channels inactivate rapidly to culminate the action potential and maintain the homeostasis of excitable cells. The so-called N-type inactivation is caused by the first 46 amino acids of the N-terminus of the channel, known as the inactivation peptide (IP). Numerous mutational studies have characterized N-type inactivation functionally, however, the position of the IP in the resting state and its transition during inactivation is still debated. The aim of the first project was to track the movement of IP during inactivation using voltage clamp fluorometry. By inserting an unnatural amino acid, 3-[(6-acetyl-2-naphthalenyl) amino]-L-alanine (Anap), which is sensitive to changes in environment, we identified the movements of ball and chain separately. Our data suggests that N-type inactivation occurs in a biphasic movement by first releasing the IP, which then blocks the pore from the cytoplasmic side. To further narrow down the resting position of the inactivation peptide, we used Lanthanide-based Resonance Energy transfer and transition metal FRET. We propose that the inactivation peptide is located in the window formed by the channel and the T1 domain, interacting with the acidic residues of the T1 domain. In a follow-up study, we explored the reason underlying slow inactivation kinetics observed during the study of N-type inactivation in the first project. High expression of Shaker channels results in slowing of the N-type inactivation. The C-terminus of the channel interacts with membrane associated scaffold proteins for cluster formation. In this study, we have shown that by truncating the last four C-terminal residues involved in cluster formation, and hence preventing channel clustering, we also prevent slowing of the inactivation kinetics in Shaker channels. We also showed that slow N-type inactivation is not affected by accumulation of external [K+] or any crosstalk between the neighboring subunits. The second project not only elucidates the cause of the inactivation slow-down but illustrates that the channels alter their behavior dependent on the expression conditions. Results found on the molecular level can thus not always be extrapolated to the cellular level.

<p>During cognitive tasks, synchronicity of neural activity varies and is correlated with performance. However, there may be an upper limit to normal synchronised activity – specifically, epileptogenic activity is characterized byexcess spiking at high synchronicity. An epileptic seizure has a complicated course of events and I therefore focused on the synchronised activity preceding a seizure (fast ripples). These high frequency oscillations (200–1000 Hz) have been identified as possible signature markers of epileptogenic activity and may be involved in generating seizures. Moreover, a range of ionic currents have been suggested to be involved in distinct aspects of epileptogenesis. Based on pharmacological and genetic studies, potassium currents have been implicated, in particular the transient A–type potassium channel (KA). Our first objective was to investigate if KA could suppress synchronized input while minimally affecting desynchronised input. The second objective was to investigate if KA could suppress fast ripple activity. To study this I use a detailed compartmental model of a hippocampal CA1 pyramidal cell. The ion channels were described by Hodgkin–Huxley dynamics.</p><p>The result showed that KA selectively could suppress highly synchronized input. I further used two models of fast ripple input and both models showed a strong reduction in the cellular spiking activity when KA was present. In an ongoing in vitro brain slice experiment our prediction from the simulations is being tested. Preliminary results show that the cellular response was reduced by 30 % for synchronised input, thus confirming our theoretical predictions. By suppressing fast ripples KA may prevent the highly synchronised spiking activity to spread and thereby preventing the seizure. Many antiepileptic drugs down regulate cell excitability by targeting sodium channels or GABA–receptors. These antiepileptic drugs affect the cell during normal brain activity thereby causing significant side effects. KA mainly suppresses the spiking activity when the cell is exposed to abnormally high synchronised input. An enhancement in the KA current might therefore be beneficial in reducing seizures while not affecting normal brain activity.</p>

<p>The purpose of this thesis was to investigate the possibility of power flow control, on a section of a railway grid fed by rotary converters, using an extra feeding line. Two possible solutions for the power flow control were examined. The first using a series reactance in connection to each converter station and the second by changing the tap changer level of the transformer between the converter station and the feeding line.</p><p>In the two models a distance, comparable to the distance between Boden and Häggvik, in Stockholm, was used. The simulations were performed using the software SIMPOW.</p><p>The results from the performed simulations show that series reactances, under the stated conditions, can essentially improve the power flow. To implement this air coils with inductances in the approximate size of 10 to 45 mH could be used. Further, the tap changer levels of the transformer may be used, for individual converter stations, as a way to control the reactive power flow.</p>

The purpose of this thesis was to investigate the possibility of power flow control, on a section of a railway grid fed by rotary converters, using an extra feeding line. Two possible solutions for the power flow control were examined. The first using a series reactance in connection to each converter station and the second by changing the tap changer level of the transformer between the converter station and the feeding line. In the two models a distance, comparable to the distance between Boden and Häggvik, in Stockholm, was used. The simulations were performed using the software SIMPOW. The results from the performed simulations show that series reactances, under the stated conditions, can essentially improve the power flow. To implement this air coils with inductances in the approximate size of 10 to 45 mH could be used. Further, the tap changer levels of the transformer may be used, for individual converter stations, as a way to control the reactive power flow.

I denna uppsats studeras idén om allmänintresset i den fysiska planeringen. Allmänintresset har setts vara det som legitimerar offentlig planering, som en norm för praktiserande planerare, eller ett sätt att utvärdera planer. Det är även något som förordas i plan- och bygglagstiftningen (PBL). Trots detta är det ett begrepp som är mycket vagt definierat. Detta har lett till diskussioner inom den akademiska plandebatten om begreppet angående dess innehåll men också dess användbarhet. Trots att det har riktats kritik mot begreppet finns det ändå en stark tilltro till begreppet hos aktiva planerare, då det är allmänintresset som motiverar planering som verksamhet.  Uppsatsen handlar om att studera olika syner på allmänintresset, vilka intressen som formuleras som allmänna, och hur det påverkar planeringen.   Uppsatsen är utformad som en fallstudie, där det studerade fallet är en detaljplan för kvarteret Seminariet i Uppsala kommun. Metod för datainsamling är dokumentstudier där detaljplanen, samrådsredogörelse, inkomna yttrande, utlåtanden samt överklaganden ingår. En kvalitativ textanalys har genomförts på detta empiriska material. Det teoretiska perspektivet har formulerats utifrån uppsatsens forskningsöversikt. En övergripande teoretisk dimension har kunnat identifierats samt centrala aspekter utifrån olika förhållningssätt och planeringsideal.   Den genomförda studien i uppsatsen visar att det i praktiken finns skilda uppfattningar mellan olika aktörer om allmänintresset, dess konkreta innehåll men också hur det ska tillgodoses. Kritiska sakägare anser att de representerar en betydande majoritet av uppsalaborna samt deras intressen och därmed allmänintresset. Samtidigt anser kommunen att de kan representera hela kommunen, och intressena inom kommunen då kommunpolitikerna är folkvalda representanter. De kommunala intressena hävdar de är allmänintresset. Dessa olika uppfattningar leder till konflikter i planprocessen, där ena sidan vill se mer direktdemokratiskt inflytande i planprocessen och att konsekvenserna ska bedömas utifrån sakägarnas samlade intressen. Den andra sidan anser att konflikten löses inom politiken, medborgardeltagande är inte direktdemokratisk utan ska förbättra beslutsunderlaget och underlätta implementeringen av planförslaget. De förtroendevalda är demokratisk valda för att kunna ta denna typ av beslut om vad som är bäst för kommunen med detta synsätt.   Beslutsmakten över markanvändningen ligger främst hos de förtroendevalda, planerarna arbetar nära politiken och utåt sett ger de intrycket av att stå för samma ställningstaganden. Konflikten tyder på att det inte finns en gemensam bild över hur planeringen går till, vad medborgarnas möjlighet till inflytande är och vad som anses ingå i allmänintresset i den aktuella lokala kontexten. Studien visar att planerarna verkar ta en relativt konservativ och rationell roll. Detta överensstämmer inte med vad mycket av den forskning på ämnet som finns menar. I en stor del av forskningen framstår det som att den kommunikativa eller den nyliberala diskursen skulle ha fått mycket mer utrymme i planeringen och att dessa skulle ha influerat synen på allmänintresset i en högre utsträckning. Problematiken med det svårhanterliga begreppet underlättas av det som belyses i uppsatsen, nämligen att det finns ett par kritiska principer som kan använda för att förstå underliggande politiska ställningstaganden i formuleringen och hanteringen av allmänintresset.

During cognitive tasks, synchronicity of neural activity varies and is correlated with performance. However, there may be an upper limit to normal synchronised activity – specifically, epileptogenic activity is characterized byexcess spiking at high synchronicity. An epileptic seizure has a complicated course of events and I therefore focused on the synchronised activity preceding a seizure (fast ripples). These high frequency oscillations (200–1000 Hz) have been identified as possible signature markers of epileptogenic activity and may be involved in generating seizures. Moreover, a range of ionic currents have been suggested to be involved in distinct aspects of epileptogenesis. Based on pharmacological and genetic studies, potassium currents have been implicated, in particular the transient A–type potassium channel (KA). Our first objective was to investigate if KA could suppress synchronized input while minimally affecting desynchronised input. The second objective was to investigate if KA could suppress fast ripple activity. To study this I use a detailed compartmental model of a hippocampal CA1 pyramidal cell. The ion channels were described by Hodgkin–Huxley dynamics. The result showed that KA selectively could suppress highly synchronized input. I further used two models of fast ripple input and both models showed a strong reduction in the cellular spiking activity when KA was present. In an ongoing in vitro brain slice experiment our prediction from the simulations is being tested. Preliminary results show that the cellular response was reduced by 30 % for synchronised input, thus confirming our theoretical predictions. By suppressing fast ripples KA may prevent the highly synchronised spiking activity to spread and thereby preventing the seizure. Many antiepileptic drugs down regulate cell excitability by targeting sodium channels or GABA–receptors. These antiepileptic drugs affect the cell during normal brain activity thereby causing significant side effects. KA mainly suppresses the spiking activity when the cell is exposed to abnormally high synchronised input. An enhancement in the KA current might therefore be beneficial in reducing seizures while not affecting normal brain activity.

The demand for high-power converters are surging due to applications like renewable energy, motor drives and grid-interface applications. Typically, these converters’ power ranges from tens of kilowatts (kW) to several megawatts (MW). To reach such high power levels the converter voltage ratings must increase, as the current ratings cannot be reached by the available devices or because the system losses become excessive. To address this, two strategies can be utilized: multilevel topologies (e.g. Multilevel Modular Converter or Flying Capacitor Multilevel Converter) and high voltage switches. For medium voltage applications, the most commonly employed switches are the IGBT and the IGCT. Both are silicon-based technology and are limited to a rated voltage of 6.5 kV and 4.5 kV, respectively. Often, these devices switching frequency are limited to less than 1 kHz. To expand the frontiers of medium voltage converters and to demonstrate the capabilities of wide band gap devices in medium voltage, a 7-level 13.8 kV AC 22 kV DC 1.1 MW flying capacitor multilevel converter based on 10 kV SiC MOSFET with 2.5 kHz switching frequency was designed and constructed. Given the complexity of a multilevel topology, the high voltage levels, and the critical nature of the loads, a failure in a high-power converter can incur significant costs, long service downtime, and safety risks to personnel. Hence, understanding the failure modes of these converters is essential for designing protections and mitigation strategies to prevent or reduce the risks of failures. Furthermore, the adoption of 10 kV SiC MOSFET introduces additional challenges in terms of protection. Despite their well-known benefits, these devices exhibit shorter energy withstanding time compared with their silicon counterpart, and increased insulation stress resulting from the high dv/dt imposed by the fast-switching transient at higher voltages. In this context, a failure mode analysis was conducted for the converter aforementioned. The analysis examined the fault dynamics and evaluated the protections schemes at the converter level. The study identified a failure mechanism between cells, so called Cell Short- Circuit Fault (CSCF), capable of damaging the entire phase-leg. In response, a protection scheme based on TVS (Transient Voltage Suppression) diodes was designed to prevent extremely imbalanced cell voltages and failure propagation. Because of the high electric field intensity environment of the converter, an FEA (Finite Element Analyses) simulation is performed to verify and control the electric field (E-field) intensity within the protection module itself and in the converter assembly. Next, the protection module insulation design was successfully verified in a Partial Discharge (PD) experiment. In sequence, an experimental verification utilizing an equivalent circuit based on the fault model demonstrated the efficacy of the protection module. Waveforms extracted while the converter was operating showing the protection module acting during a fault are presented and analyzed. Finally, the influence of the protection module in the switching of the 10 kV SiC MOSFET was evaluated via a double pulse test (DPT), revealing negligible effects on the converter performance. / Center of Power Electronics Systems (CPES) Department of Energy (DoE) / Master of Science / Due to governmental policies and market opportunities renewable energy (e.g. solar and wind energy) is increase its share in the electricity generation in the US and around the world. This scenario poses challenges regarding the stability of the grid and variation in the generation along the day. One of the alternatives to alleviate the problem is to use highpower converters that provides a interface between grid and manufacturing plants. This type of converter have bidirectional capabilities and can store the energy generated by solar farms during the day and return it to the grid at night for example. Moreover, it can provide grid support capabilities in terms of variation of frequency and voltage. To expand on the grid interface converters application concept, a medium voltage power converter in 22 kV DC and 13.8 kV AC is designed utilizing novel techniques and the latest technologies in semiconductors, 10 kV SiC MOSFETs. The benefits of this design are a small form factor, high efficiency, immunity to electromagnetic interference and power quality. This work presents a failure mode analysis of the power converter aforementioned, the analysis examined the fault dynamics and an evaluation of the protections schemes at the converter level. The failure analysis revealed the need of a protection scheme extremely imbalanced cell voltages and failure propagation. Hence, a protection module based on TVS (Transient Voltage Suppression) diodes was successfully designed and tested. Due to the high voltages present in this equipment, an FEA (Finite Element Analyses) simulation is performed to verify and control the electric field (E-field) intensity within the protection module itself and in the converter assembly. Experimental results are provided for insulation design integrity (partial discharge test), for the efficacy of the protection module against the fault, and for the impact of the protection module on the operation performance.