In this thesis is written a brief history of electric cars up to the present. Hybrid vehicles are described and particular attention is given to the description of electric vehicles. A method for accumulating electrical energy by electrochemical accumulators is provided. Finally, there are operation costs of electric cars.

Les expériences rares, qu’elles soient positives ou négatives, surprennent par leur avènement inopiné et brutal. Toutefois, le plus surprenant reste l’incapacité des organisations à en tirer des leçons appropriées. Les expériences rares challengent les approches traditionnelles de l’apprentissage organisationnel fondées sur la réplication et l’amélioration progressive. De plus, les expériences rares sont souvent complexes : elles sont composées d’une grande variété d’éléments qui interagissent de façon incertaine. De ce fait, elles sont marquées par un niveau élevé d’ambiguïté causale qui peut conduire à un apprentissage superstitieux. Dans ces conditions, la littérature souligne la nécessité de mettre en oeuvre un apprentissage délibéré fondé sur la codification des connaissances. Mais la codification est une arme à double tranchant, qui peut rigidifier l’organisation et la littérature reste assez silencieuse sur comment réaliser une « bonne codification ». Ce travail de thèse s’intéresse alors à la question suivante : comment développer et mettre en oeuvre une stratégie de codification appropriée pour faciliter un apprentissage organisationnel délibéré à partir d’une expérience rare et complexe ? Cette recherche menée au sein de l’Institut de Radioprotection et de Sûreté Nucléaire s’appuie sur étude de cas réaliste critique. Elle vise à étudier deux apprentissages délibérés mis en place au sein de l’institut pour apprendre de deux accidents nucléaires graves : l’accident Fukushima Daiichi et l’accident Three Mile Island. Les résultats obtenus identifient trois mécanismes générateurs clés du processus de codification, leurs modes d’activation et la façon dont ils se combinent. Ces mécanismes s’activent grâce à la fois au contexte environnemental et à l’apparition de structures dédiées à la codification, puis se combinent pour former différentes configurations qui supportent deux cycles distincts d’apprentissage. Ces deux cycles sont essentiels pour apprendre d’une expérience rare et complexe. / Rare experiences, whether they are positive or negative, surprise by their unexpected and brutal occurrence. However, more surprising is organizations’ incapability to draw lessons from such rare experiences. Indeed, these experiences challenge traditional approaches of organizational learning based on replication and incremental improvement. In addition, rare experiences are often complex: they are composed of a large variety of elements that interact in uncertain ways. As a result, rare experiences are characterized by a high level of causal ambiguity that can lead to superstitious learning. In these circumstances, the literature emphasizes the need to implement deliberate learning based on knowledge codification. However, codification is a double-edged sword, which can produce organizational rigidity. Besides, research remains quite silent on how to achieve a "well-performed codification”. This research addresses the following question: how to develop and implement an appropriate codification strategy to facilitate deliberate organizational learning from rare and complex experiences? This research is conducted in the Institute of Radioprotection and Nuclear Safety. It is based on a critical realist case study which aims to study two deliberate learning process implemented within the institute to learn from two serious nuclear accidents: Fukushima Daiichi accident and Three Mile Island accident. Our results identify three key generative mechanisms of the codification process, their activation modes and how they are combined. These mechanisms are activated by both the environmental context and the emergence of dedicated structures to codification. The combination of these mechanisms forms different configurations that support two distinct learning cycles which are essential for learning from a rare and complex experience.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

We report on some experiences with the general purpose Computer Algebra Systems (CAS) Axiom, Macsyma, Maple, Mathematica, MuPAD, and Reduce solving systems of polynomial equations and the way they present their solutions. This snapshot (taken in the spring 1996) of the current power of the different systems in a special area concentrates both on CPU-times and the quality of the output.

Neisseria meningitidis, a commensal β-proteobacterium residing exclusively in the human nasopharynx, is a leading cause of sepsis and epidemic meningitis worldwide. While comparative genome analysis was able to define hyperinvasive lineages that are responsible for most of the cases of invasive meningococcal disease (IMD), the genetic basis of their virulence remains unclear. Recent studies demonstrate that the type II C CRISPR/Cas system of meningococci is associated with carriage and less invasive lineages. CRISPR/Cas, an adaptive defence system against foreign DNA, was shown to be involved in gene regulation in Francisella novicida. This study shows that knockout strains of N. meningitidis lacking the Cas9 protein are impaired in the adhesion to human nasopharyngeal cells in a strain-dependant manner, which constitutes a central step in the pathogenesis of IMD. Consequently, this study indicates that the meningococcal CRISPR/Cas system fulfils functions beyond the defence of foreign DNA and is involved in the regulation of meningococcal virulence. / Neisseria meningitidis, ein ß-Proteobakterium, welches als Kommensale ausschließlich den humanen Nasopharynx besiedelt, ist ein weltweit führender Verursacher von Sepsis und epidemischer Meningitis. Auch wenn mittels vergleichender Genomanalysen hyperinvasive Stämme definiert werden konnten, welche für die meisten Fälle von invasiven Meningokokkenerkrankungen verantwortlich sind, bleibt die genetische Grundlage ihrer Virulenz ungeklärt. In vorangegangenen Studien konnte gezeigt werden, dass das Typ II-C CRISPR/Cas-System der Meningokokken assoziiert ist mit Trägerstämmen. CRISPR/Cas ist ein adaptives Verteidigungssystem der Bakterien gegen fremde DNA, das darüber hinaus Aufgaben in der Genregulation von Francisella novicida erfüllt. Diese Arbeit zeigt, dass knockout Stämme von N. meningitidis, denen das Cas9-Protein fehlt, in Abhängigkeit von ihrem genetischen Hintergrund die Fähigkeit verlieren an Zellen des menschlichen Nasopharynx zu adhärieren. Die Adhäsion an den Wirtszellen stellt einen zentralen Schritt in der Pathogenese der invasiven Meningokokkenerkrankungen dar. Die Ergebnisse dieser Arbeit deuten darauf hin, dass das CRISPR/Cas-System in Meningokokken neben seiner Funktion als bakterielles Immunsystem an der Regulation der bakteriellen Virulenz beteiligt sein könnte.

Die Rolle von Connexinen und Gap Junction-vermittelter Kommunikation in pluripotenten Stammzellen sowie der frühen Embryonalentwicklung sind bis heute nicht vollständig aufgeklärt. Mutationen in humanen Connexinen verursachen eine Vielzahl von Krankheiten. Connexin-defiziente iPS Zellen stellen eine gute Basis für die Erforschung der Rolle von Connexinen während der Embryonalentwicklung und bei der Krankheitsentstehung dar. Das Ziel der vorliegenden Arbeit war es, das CRISPR/Cas9-System in pluripotenten Stammzellen erfolgreich anzuwenden und ein Protokoll zur Erstellung verschiedener Cx43-Defektmutanten zu entwerfen. Nach der Etablierung der CRSIPR/Cas9-Methode in HEK293T-Zellen konnte in der vorliegenden Arbeit darüber hinaus erfolgreich eine Cx43-Defizienz in FSiPS-Zellen erzeugt werden. Weiterhin wurden mehrere Cx43-Mutanten geschaffen und initial auf Pluripotenzmarker und ihr Differenzierungspotential untersucht. Diese Arbeit bildet die Basis für weitere Untersuchungen des Cx43 in iPS-Zellklonen und davon abgeleiteten Zelltypen sowie artifiziellen 3D-Gewebekulturen. Darüber hinaus bildet sie die Grundlage für die Bildung weiterer Connexin-Defektmutanten sowie von iPS-Zellen mit krankheitsrelevanten Mutationen. / The roles of connexins and gap junction-mediated communication in pluripotent stem cells and early embryonic development have not been fully elucidated to date. Mutations in human connexins cause a variety of diseases. Connexin-deficient iPS cells provide a good basis for studying the role of connexins during embryonic development and in disease development. The aim of the present work was to successfully apply the CRISPR/Cas9 system in pluripotent stem cells and to design a protocol to generate different Cx43 defective mutants. Furthermore, after establishing the CRSIPR/Cas9 method in HEK293T cells, a Cx43 deficiency in FSiPS cells was successfully generated. Furthermore, several Cx43 mutants were created and initially screened for pluripotency markers and their differentiation potential. This work forms the basis for further studies of Cx43 in iPS cell clones and derived cell types as well as artificial 3D tissue cultures. Furthermore, it forms the basis for the generation of further connexin defect mutants as well as iPS cells with disease-relevant mutations.

The covid-19 pandemic has hit every part of life hard. From visiting the supermarket to halting world trade. One of the most obvious effects of the pandemic has been the political one. All across the world political parties have been competing for power during these unusual times.  This paper will analyze whether populistic parties around Europe have changed their views on the covid-19 pandemic restrictions. In order to analyze this a comparative idea analysis will be used in order to compare and analyze political parties views on this subject. In order to conduct this analysis the studie compare four different populistic parties around europé. These parties are as followed, AFD and Die Linke in germany, PVV in the Netherlands followed by Syriza in Greece. The study will be using material from the four different parties to conduct the analysis and compare the material. The analysis shows that only one out of four parties has had a change in their views on the pandemic restrictions. This study is an important contribution the field of populism. It will grant a unique opportunity to study such a unique time of our the world that the covid-19 pandemis really is.

The discovery and development of clustered, regularly interspaced, short palindromic repeats and CRISPR-associated proteins (CRISPR-Cas) systems have revolutionized targeted genomic medicine. In my thesis, we discuss our efforts to improve and optimize various CRISPR-Cas systems for therapeutic genome editing applications. In part one, we propose that aberrant splice site disruption could be a simple and efficient strategy for treating some mutations associated with β-thalassemia. Specifically, we show that disruption of common mutant alleles in the HBB gene by Cas9 and Cas12a results in restoration of normal β-globin splicing, functional expression of HBB, and improved quality of erythroid maturation in edited β-thalassemia patient CD34+ hematopoietic stem and progenitor cells. In part two, we demonstrate that optimization of the nuclear localization signal (NLS) sequence framework is an effective method to improve the mutagenesis frequencies of Cas12a nuclease. In particular, the 3xNLS-NLP-cMyc-cMyc framework improves genome editing in mammalian and primary cells, relative to previous Cas12a NLS frameworks. We show that our NLS optimization approach can be applied to various Cas12a orthologs resulting in high editing activity without sacrificing the high intrinsic specificity of Cas12a nucleases. Furthermore, we demonstrate that NLS-optimized enAspCas12a can efficiently disrupt the ATF4-binding motif at the +55 enhancer of BCL11A, which may serve as an alternative therapeutic strategy for β-hemoglobinopathies. In part three, we develop and characterize fusion enhanced base editor (feBE) systems, which are fusions of base editors to our Cas9-programmable DNA binding domain (pDBD) and Cas9-Cas9 platforms. We report that our feBEs are more active than previously described base editor platforms at canonical and noncanonical PAMs. Furthermore, we show that feBEs can selectively edit a therapeutically relevant target site, CCR5, with minimal editing at a highly homologous off-target site. Taken together, my thesis research aimed to engineer CRISPR-Cas tools to improve their efficiency and specificity for therapeutic genome editing applications.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21687号 / 医博第4493号 / 新制||医||1036(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 竹内 理, 教授 清水 章, 教授 遊佐 宏介 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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