Thesis (doctoral)--Københavns universitet, 1957. / Errata slip inserted. Includes bibliographical references (p. 221-[223]).

Thesis (doctoral)--Københavns universitet, 1957. / Errata slip inserted. Includes bibliographical references (p. 221-[223]).

Le symporteur Na+/I- (NIS) médie le captage de l'iode dans la glande thyroïde et cette propriété est exploitée depuis de nombreuses années en thérapeutique pour traiter les cancers différenciés de la thyroïde à l’iode radioactif 131 (Radiothérapie métabolique ou RAI). Cependant, 5 à 10% des patients deviennent réfractaires à la RAI, ce qui indique un mauvais pronostic. La réduction de l'expression NIS et son internalisation sont caractéristiques de ce processus. La mutation activatrice BRAFV600E est la plus fréquemment identifiée au sein des cancers différenciés de la thyroïde de type papillaires (CPT), qui est le type le plus répandu. Dans les thyrocytes de souris, BRAF muté induit la sécrétion de TGF qui active ensuite la voie Smad ce qui entraîne la répression du NIS. La NADPH oxydase 4 (NOX4), enzyme génératrice d’espèces réactives de l'oxygène (ROS), est un médiateur clé de la signalisation du TGFß dans de nombreux types cellulaires et sa surexpression a été détectée dans le cancer de la thyroïde. L'objectif de ce travail est d'évaluer si NOX4 est un médiateur de la répression NIS induite par BRAFV600E dans des lignées cellulaires thyroïdiennes. En utilisant une lignée cellulaire de thyroïde normal de rat (PC-BRAF), nous avons démontré que le TGF-β ou l'expression BRAFV600E promeut la diminution de l'ARNm NIS ainsi que celle du captage de l'iodure en revanche ils augmentent l’expression de l'ARNm NOX4. Le silençage de Nox4 par siRNA ou un traitement des cellules par SIS3, un inhibiteur de pSmad3, inhibe la répression du NIS médiée par BRAFV600E, indiquant l'implication de la voie Smad3 et de Nox4 dans cette répression. Dans la lignée tumorale BCPAP derivée d’un CPT humain et porteuse de la mutation BRAFV600E, nous avons également observé une augmentation de l'expression de l'ARNm NIS lorsque BRAFV600E ou NOX4 sont inhibés. Dans les cellules BCPAP, un traitement par H2O2 augmente l'expression de la protéine ADN méthyltransférase 1 (DNMT1) dans la fraction cellulaire enrichie en protéines liées à la chromatine. Un traitement par des antioxydants ou le silençage de NOX4 réduise ce recrutement. Le TGF augmente le niveaux de protéines DNMT1 dans la fraction cellulaire enrichie en chromatine, lequel qui est renversé par un traitement par un inhibiteur de NADPH oxydase : le Diphenyleneiodonium (DPI). La méthylation de l'ADN induite par le TGF et l'hypoacétylation de l'histone H3K9/K14, qui sont des marques de répression de la transcription, sont détectées au niveau du promoteur NIS. L’ensemble de ces données suggère que Nox4 est un acteur clé de la signalisation TGF-BRAFV600 et joue un rôle répressif sur l'expression du NIS, probablement par des mécanismes épigénétiques. Cette étude apporte des données fonctionnelles pour le développement de nouveaux outils thérapeutiques. / The co-transporter Na+/ I- (NIS) mediates iodide uptake in thyroid gland which is a key step in hormonal biosynthesis. Iodide accumulation by thyrocytes is the basis of radioiodine therapy (RAI) which is the standard post-surgery therapeutic approach to efficiently eliminate remaining cancer lesions and metastasis of differentiated thyroid cancer (DTC). However, 5-10% of DTC patients become RAI-refractory which is indicative of poor prognosis. Reduced NIS expression and NIS internalization are in this process. BRAFV600E mutation is the most common genetic event in papillary thyroid cancers (PTCs), the most prevalent type of DTC. In rat thyrocytes, BRAFV600E induces secretion of TGFβ that activates Smad pathway resulting in NIS downregulation and overexpression of TGFβ is associated with NIS repression in patients. NADPH oxidase NOX4, a professional reactive oxygen species (ROS) generating enzyme, is a key mediator of TGFβ signaling in many cell types and has been previously demonstrated to be overexpressed thyroid cancers. To better understand the molecular mechanisms involved in PTC loss of iodine avidity, the aim of this work is to evaluate whether NOX4 is a key player of BRAFV600E-mediated NIS repression in thyroid cell lines. Using a normal rat thyroid cell line (PC-BRAF) we demonstrated that TGF-β administration or expression of BRAFV600E resulted in reduced NIS mRNA, reduced iodine uptake and increased NOX4 mRNA expression. NOX4 silencing or treatment with SIS3 an inhibitor of Smad pathway partially inhibited NIS repression indicating the implication of both Smad pathway and NOX4. To confirm this results we used a human thyroid cancer cell lines that harbors BRAFV600E mutation (BCPAP and 8505c) and observed an increase in NIS expression followed by BRAFV600E or NOX4 downregulation. Exogenous H2O2 induced DNA methyl-transferase 1 (DNMT1) enrichment in tight-chromatin protein fraction which was decreased by antioxidants or NOX4 silencing in BCPAP cells. TGF increased DNMT1 protein levels in chromatin-enriched cell fraction which was reversed by NADPH oxidase inhibitor, Diphenyleneiodonium (DPI). TGF-mediated DNA methylation and histone H3K9/K14 hypoacetylation were detected in NIS promoter, which is a repressive transcriptional mark. The data obtained suggest that NOX4 is a mediator of BRAFV600-TGF signaling and has a repressive role over NIS expression probably through epigenetic mechanisms. These results should lead to a better understanding of NIS expression regulation in thyroid cancer, bringing functional data for the development of new therapeutic tools.

No description available.

International cybersecurity is arguably one of the most serious, complex and recent security-issues of our time. The connectivity between EU member states regarding cybersecurity due to the borderless nature of cyber, together with increasing threat-levels, has made the need for a common response widely acknowledged in the EU for several years. Even so, a common EU cybersecurity response involves problems such as reluctance of member states to share information, that cybersecurity management is linked to national security and therefore touches upon sovereignty, and different levels of cybersecurity development between member states. Despite this, the Network and Information Security Directive was adopted by the European Council in May 2016, involving EU-wide binding rules on cybersecurity. This thesis examines and explains, through a neo-functionalistic approach, how and why this development towards supranational management of cybersecurity in the EU has happened. The author finds that cybersecurity management seems to have institutionalized from a nascent phase during 2013, moving towards an ascendant phase during the end of 2013 and 2014, to end up between an ascendant and a mature phase during 2015 and 2016 – which makes the adoption of the NIS-directive logical. The neo-functionalistic explanation to the development of supranational cybersecurity management in the EU highlights the role of the Commission as a ‘policy entrepreneur’ and the publication of the EU cybersecurity strategy, accompanied by the proposal for the NISdirective in 2013. These regulatory outputs sparked further institutionalization by providing many opportunities and venues for member states to interact and build networks on cybersecurity issues, by initiatives with normative impact to foster an EU ‘cybersecurity community’, by the continuous strengthening of supranational cybersecurity actors such as ENISA, and by supranational cybersecurity cooperation platforms, such as the NIS-platform and the European Private Public Partnership on cybersecurity. Between 2013 and 2016, 21 EU Member States published national cybersecurity strategies, almost all referring clearly to their commitment to EU cybersecurity initiatives. This provides an indicator of a high level of legitimacy of supranational cybersecurity management. However, the thesis also finds that the strongest supporters of EU cybersecurity management are not the most powerful member states but rather the smaller ones. While not expressing a strong commitment to EU initiatives in cyber policy documents, the most powerful member states still agreed to the NIS-directive. This supports the neo-functionalist notion about the “stickiness” of an institutionalization-process, and the possibility that powerful states might have double paths, committing to EU regulation and institutionalization while still continuing their own way.

Active work to increase the efficiency of energy use is taking place in Sweden and throughout all of Europe. Electricity is an important part in our society’s energy system which means that the electrical grid operators and associated therewith has a central role in this work. Monitoring and controlling the electrical grids are managed from the distribution system operator’s DC, dispatch center. The aim of this report is to examine how the operations in a typical DC on the Swedish electricity distribution network will look like in five to ten years. The report focuses on DC’s that operate electrical grids at low- and medium voltage level. For a concrete way to determine how the DC will change over time the different operational processes that constitute the ope- ration of a DC were defined. Subsequently the changes that will affect the Swedish electrical grids within five to ten years were investigated and also in which way these changes will implicate the operational processes in a DC. The analysis shows that the DC’s will undergo a series of transformations in five to ten years. By integrating the various IT-systems in the dispatch center the main operation will be manageable from a single HMI, such as a DMS-system. This means that business processes such as monitoring, ope- rational order processing and error handling will be possible from a single system in the future. But the increasing communication between IT systems will also lead to increased demands for security because any intrusion in one of the systems could result in major damage.

Economic barriers remain an obstacle to ensuring that children in the United States are protected against vaccine-preventable diseases. Disparities persist despite programs in place to alleviate them, such as the Vaccines for Children program, which provides free vaccines for eligible children. Using data from the 2010 National Immunization Survey, this study addresses whether insurance status has an impact on immunization uptake by investigating associations between vaccine receipt and insurance type, VFC eligibility, and insurance continuity. Logistic regression was performed using possible important factors suggested in the literature. Among children in the national sample, results showed strong associations between up-to-date immunization status and insurance type, VFC eligibility, and insurance continuity, suggesting that additional steps must be taken to alleviate disparities in vaccine receipt. Regression analysis showed child’s age group, insurance continuity, and number of vaccine providers to be the strongest predictors of up-to-date status among children in the national sample.

Geographical Information Systems (GIS) are large systems that handles, stores and manipulates geographical data. This report is based on the fact that GIS-applications, in general, tend to be quite complex and contain large quantities of data as well as lots of functionality. Because of this, it is a challenge to design a good user-interface for such applications and the ones who suffer from this are the users. Thereby, the motivation for this report is formed, which is about proposing improvements to a user-interface of existing GIS-applications in order to increase the users satisfaction with it. The GIS-applications that are the focus of this report are the applications of the company Digpro. The question that attempts to be answered in this project is: "What can be done to improve the user-interface of existing GIS-applications from a general HCI-perspective and from the perspective of the users?". The method for doing this is to research for theory about HCI, and also through interactions with the users. These interactions are done by using Query Evaluation Techniques in the form of interviews and questionnaires. By using the result of these Query Evaluation Techniques combined with the theory gotten from the research, a number of improvement ideas have been developed and presented as mock-ups and concept sketches. These ideas have been evaluated using Heuristic Evaluation and a final prototype has been developed. In the end, the final prototype is the result of this project. The prototype includes all, but one, of the improvement ideas and shows the interaction between the ideas and the already existing user-interface. Further, since the prototype has been developed with a lot of regard for the users opinions in order to increase their satisfaction with the user-interface, the results are very much in line with the motivation for this master thesis.

No description available.

The purpose of this study is to investigate changes in municipalities that occur when the NIS and NIS 2 directives are introduced. The changes refer to internal and external changes that municipalities experience. Furthermore, an increased threat of cyber attacks as well as a lack of cyber security is the basis for conducting the survey. A research gap has been identified regarding municipalities' work with EU directives for cyber security, which the study intends to contribute to. The study's empirical data consists of six semi-structured interviews with various Swedish municipalities, where the result is the identified changes that the municipalities state. In a thematic analysis, the following themes are presented: IT focus, IT systems, competence development and cooperation, employment, clarity, conflict of interest, prerequisites for the NIS 2 directive and meaningfulness. The study uses Bolman and Deal's (2021) framework Four frame model, which forms the structure for the results and the analysis and strengthens the study by contributing with a comprehensive theory for possible changes. The study contributes with insight into the changes that municipalities may face upon the introduction of the NIS 2 directive, as well as what changes municipalities have experienced upon the introduction of the NIS directive. / Denna studie har till syfte att undersöka förändringar hos kommuner som uppstår vid införandet av NIS- och NIS 2-direktivet. Förändringarna avser interna och externa förändringar som kommuner upplever. Vidare ligger ett ökat hot om cyberattacker samt en bristande cybersäkerhet till grund för undersökningens genomförande. Ett forskningsgap har identifierats kring kommuners arbete med EU-direktiv för cybersäkerhet, vilket studien ämnar bidra till. Studiens empiri utgörs av sex stycken semistrukturerade intervjuer med olika svenska kummuner, där resultatet utgörs av de identifierade förändringar som kommunerna uppger. I en tematisk analys presenteras följande teman: IT-fokus, IT-system, kompetensutveckling och samarbete, anställning, tydlighet, intressekonflikter, förutsättningar för NIS 2-direktivet samt meningsfullhet. I studien tillämpas även Bolman och Deals (2021) ramverk Four frame model, vilken utgör strukturen för resultatet och analysen samt stärker studien genom att bidra med en heltäckande teori för möjliga förändringar. Studien ämnar bidra med insikt i de förändringar som kommuner kan ställas inför vid införandet av NIS 2-direktivet, samt vilka förändringar kommuner har upplevt vid införandet av NIS-direktivet.