Ce travail s’insère dans le cadre de l’expérience NEMO cherchant à mettre en évidence une radioactivité extrêmement rare : la double désintégration bêta sans émission de neutrino et par suite d’obtenir des informations sur la nature Dirac-Majorana et sur la masse du neutrino. La particularité de cette expérience actuellement en fin de prise de données au Laboratoire Souterrain de Modane est l’extrême rareté du signal recherché (T1/2 > 1024 ans, quelques événements par an). Il s’ensuit donc des conditions très contraignantes sur toutes les composantes du bruit de fond, et parmi celles-ci sur les niveaux de radon et de thoron. Après quelques rappels sur les propriétés du radon et du thoron et leur influence sur les données de l’expérience NEMO, ce travail de thèse a porté sur la détection de ces gaz radioactifs par la technique de collection électrostatique des descendants sur la surface d’une diode silicium et la détection des alpha émis. Nous avons montré que les rendements de détection sont fortement influencés par les conditions expérimentales et que le niveau de radon pouvait être contrôlé actuellement au niveau du mBq/m3. Une série des mesures de spectrométrie gamma nous a permis de comprendre l’origine du bruit de fond du détecteur de radon, et ainsi d’envisager dans l’avenir un gain en sensibilité en augmentant le volume de détection et en effectuant une sélection très poussée des matériaux non radioactifs. Par contre, pour le thoron, qui n’avait jamais été étudié jusqu’à présent, les efficacités de détection sont très faibles à cause des périodes courtes mises en jeu. Un monitorage continu du thoron dans le gaz de NEMO est donc exclu, ce qui souligne l’importance pour l’expérience NEMO que le dispositif expérimental puisse contrôler son propre bruit de fond. / This work is part of the NEMO (Neutrino Ettore Majorana Observatory) experiment that is looking for an extremely rare radioactivity: the double beta decay without neutrino emission. Such process could prove the Majorana nature of the neutrino and could give an estimation of its absolute mass. The particularity of this experiment, currently running in the Modane underground laboratory (LSM), is the extreme weak signal (for T1/2 ~ 1024 years, a few events per year). It requires therefore very stringent conditions on all components of the background among which the level of radon and thoron activity. After a reminding of the general properties of radon and thoron as well as their influence on the NEMO data, this thesis focuses on the detection of these radioactive gases using the technique of electrostatic collection. The radon and/or the thoron daughters are collected by an electrostatic field on the surface of a silicon diode, where their characteristic alphas are detected. We have shown that the detection efficiencies are strongly influenced by the experimental conditions and that sensitivity around 1 mBq/m3 can be achieved for the radon in a gas. A series of measures through low background gamma spectrometer allowed us to understand the origin of the radon background, and thus showing that better sensitivity could be obtained by increasing the detection volume and by carrying out a strict selection of non-radioactive materials. For the thoron gas, which had never been studied before, the detection efficiencies have been found very low as a consequence of the short periods involved. Therefore, a continuous monitoring of the level of thoron in the NEMO gas is excluded, which underlines the importance for the NEMO experimental device to be able to control its own background. / Nghiên cứu này nằm trong khuôn khổ thí nghiệm NEMO, hiện đang trong những bước lấy số liệu cuối cùng tại phòng thí nghiệm ngầm Modane, nhằm ghi nhận phân rã bêta kép không kèm theo phát xạ neutrino, để từ đó chứng minh bản chất Majorana của hạt neutrino và cho phép ước lượng khối lượng tuyệt đối của hạt này. Phân rã này, nếu thật sự tồn tại, là loại phân rã cực hiếm (T1/2 > 1024 năm, tương đương với vài tín hiệu ghi nhận được mỗi năm). Vì thế, nó đòi hỏi những điều kiện rất gắt gao đối với mọi thành phần cấu thành nên phông nền bức xạ, trong đó bao gồm hoạt độ của radon và thoron. Sau khi nhắc lại những tính chất cơ bản của radon và thoron, cũng như ảnh hưởng của chúng tới số liệu của NEMO, bản luận văn tập trung vào việc đo hoạt độ của hai khí phóng xạ này bằng cách thu nhận các hạt nhân con của chúng thông qua trường tĩnh điện, tiếp đó ghi nhận các hạt alpha phát ra tại bề mặt một đi-ốt silic. Nghiên cứu này đã chỉ ra rằng hiệu suất đo phụ thuộc vào nhiều điều kiện thực nghiệm, và thiết bị này cho phép chúng tôi kiểm soát khí radon ở mức mBq/m3. Một lọat các phép đo với phổ kế gamma đã giúp chúng tôi hiểu được căn nguyên phông nền bức xạ của thiết bị, và từ đó dự kiến có thể cải thiện độ nhạy của thiết bị bằng cách tăng thể tích đo và chọn lọc các loại vật liệu có độ phóng xạ thấp. Tuy nhiên, với khí thoron, vốn vẫn chưa được nghiên cứu kỹ cho tới hiện nay, hiệu suất đo được là rất nhỏ do chu kỳ bán rã quá ngắn của các hạt nhân liên quan. Vì vậy, việc theo dõi thoron trong khí ga của NEMO đã bị loại trừ, đồng nghĩa với việc khẳng định tầm quan trọng của việc kiểm soát phông nền bức xạ thoron của chính thiết bị ghi nhận bêta kép trong thí nghiệm NEMO.

La série de détecteurs NEMO est conçue pour la recherche de la double désintégration β sans émission de neutrino qui prouverait que le neutrino est une particule de Majorana (i.e. identique à son antiparticule) et massif. Après avoir présenté l’état des lieux en physique des neutrinos et les détecteurs NEMO 3 et SuperNEMO, cette thèse s’articule en deux parties indépendantes. La première concerne l’étude du bruit de fond provenant des neutrons pour optimiser le blindage destiné au premier module de SuperNEMO. La conclusion de cette étude montre que l’ajout de plaques de polyéthylène boré par rapport au blindage de NEMO 3 (de part et d’autre du blindage en fer) permet d’obtenir un bruit de fond négligeable provenant des neutrons, dans la fenêtre en énergie du canal deux électrons où la double désintégration β sans émission de neutrino du sélénium-82 est attendue, en cinq ans de prise de données de ce premier module. La seconde partie, via l’analyse des données du détecteur NEMO 3, permet une indication de la désintégration double β standard du néodyme-150 vers l’état excité 0+1 du samarium-150. La feuille de néodyme qui est placée dans le détecteur est analysée en détail pour obtenir cette indication à 3, 7σ avec une demi-vie mesurée de : T1/2 (150 Nd0+ →0+1 ) = [7, 12 ± 1, 28 (stat.) ± 0, 91 (syst.)] × 10E19 ans / The NEMO detector series is designed to search for the neutrinoless double β decay, which would prove that the neutrino is a Majorana particle (i.e. identical to its own antiparticle) and has a nonzero mass. After an introduction to neutrino physics and a description of both the NEMO 3 and SuperNEMO detectors, this thesis is articulated in two independent parts.The first provides an investigation of the neutron background in order to optimize the shielding for the first SuperNEMO module. The outcome of the study recommends the addition of borated polyethylene to the NEMO 3 shielding (on both sides of the iron shielding) to obtain a negligible background, coming from neutrons in the energy window of the two-electron channel where the neutrinoless double β decay of selenium-82 is expected, for the duration of five years for which data will be taken with this first module. In the second part, the neodymium foil located in the NEMO 3 detector is deeply analyzed to obtain an indication of the standard double β decay of neodymium-150 to the 0+1 excited state of samarium-150. The measured half-life, with a significance of 3.7σ, is: T1/2 (150 Nd 0+ →0+1 ) = [7.12 ± 1.28 (stat.) ± 0.91 (syst.)] × 10E19 years

Chaque individu est exposé quotidiennement à des agents infectieux comme les bactéries, les champignons, les virus et les parasites sans pour autant développer une maladie. Cependant, certains vont développer des infections graves et récurrentes, causées par des microbes dont certains ont un faible pouvoir pathogène pour l’homme. Ceci suggère, qu’il existe entre les individus sensibles et résistants une variabilité au niveau du système immunitaire. Deux types de déficits immunitaires primitifs (DIP) de transmission mendélienne ont été décrits. Les DIP dit « classiques » sont monogéniques et prédisposent majoritairement à une susceptibilité infectieuse à large spectre d’agents pathogènes (un gène, plusieurs infections). Les seconds DIP sont également monogéniques mais sont responsables d’une susceptibilité infectieuse réduite à un groupe de pathogènes (un gène, un seul type d’infection). Chez de nombreux, patients, le défaut génétique responsable de DIP n’est pas identifié. Dans ce contexte, l’objectif de recherche de mon doctorat a été de caractériser deux DIP responsables d’une susceptibilité aux infections bactériennes. J’ai tout d’abord mis en évidence un nouveau mécanisme physiopathologique de la protéine NEMO, régulateur de la voie NF-κB, responsable d’un DIP associé à une dysplasie ectodermale anhidrotique (EDA). Ce mécanisme pathologique est caractérisé par une expression et une structure protéique conservées mais confère sélectivement un défaut de liaison de NEMO à l’ubiquitine, interaction essentielle dans l’activation de la voie NF-κB. Ceci démontre qu’une expression et une structure protéique normales n'excluent en rien un rôle pathologique de mutations dans le gène NEMO, dans un EDA-DIP. Dans un deuxième temps, j’ai mis en évidence un nouveau DIP affectant la voie de l’explosion oxydative spécifiquement dans les polymorphonucléaires et qui confère une susceptibilité sélective aux infections bactériennes de type pyogènes. Le patient étudié est né de parents consanguins et a présenté des infections récurrentes des voies respiratoires supérieures ainsi qu’une cellulite à Staphylococcus epidermidis. Par une approche génétique associant analyse de liaison et séquençage de l'exome, une mutation homozygote rare a été identifiée dans le gène codant NRAMP1. Cette mutation co-ségrège avec la maladie selon un mode de transmission autosomique récessif et altère spécifiquement l’expression de la protéine dans les granulocytes. Ce premier déficit en NRAMP1 décrit chez l’homme, compromet à la fois la voie de l’explosion oxydative et le contrôle de l’infection in vitro par Staphylococcus aureus dans les granulocytes. Cette étude implique NRAMP1 dans l'immunité contre les bactéries pyogènes via son rôle dans la production des espèces réactives de l’oxygène dans les granulocytes. Ce travail ouvre la voie vers un meilleur diagnostique et conseil génétique pour les patients souffrant de PID. / Human populations are exposed to infectious agents such as bacteria, fungi, viruses and parasites on a daily basis without developing any disease. However, a minority of individuals will suffer from infections to some microbes that are usually non-pathogenic to man, or will undergo severe and/or recurrent diseases usually easily treatable for others. This means that there is variability among individuals regarding their immune system, underlined by genetics between susceptible and resistant individuals. Two types of primary immuno deficiencies with a Mendelian mode of inheritance have been described. The first known as the classical primary immunodeficiency and is monogenic and predisposes in general to infections with a broad spectrum of infectious agents (one gene, multiple infections). The second type is also monogenic but predisposes generally to infections limited to a particular group of pathogens (one gene, one type of infection). The aim of my doctoral research was to characterize two new immunodeficiencies. First I highlighted a new physiopathological mechanism of the NEMO protein, a regulator of NF-κB pathway. This defect is characterized by normal protein expression and folding, but a specific defect of NEMO’s ubiquitin binding, which is an essential mechanism for the activation and regulation of the NF-κB pathway. This demonstrates that normal expression and structure of the protein do not exclude a pathological role of NEMO mutations in EDA-ID. I also described a new immune deficiency affecting the respiratory burst pathway in granulocytes which specifically confers a selective susceptibility to pyogenic bacterial infections. We studied a patient who was born from consanguineous parents, and who suffered from recurrent infections of the upper respiratory tract and cellulitis to S. epidermidis. By a genetic approach involving linkage analysis and exome sequencing, I identified a rare homozygous mutation (V484M) in the gene encoding for the NRAMP1 protein that co segregates with the disease with an autosomal recessive transmission. Specifically, this mutation impairs NRAMP1 protein expression in granulocytes, while expression remains normal in other phagocytic cells. NRAMP1 deficiency impairs both the respiratory burst and control of in vitro infection by S. aureus in granulocytes. Therefore, we identified the first NRAMP1 human deficiency. The mutation selectively affects granulocytes and is clinically responsible for pyogenic infections. This study helps to delineate the role of NRAMP1 in immunity against pyogenic bacteria through its involvement in reactive oxygen species production in granulocytes.

Cette thèse présente une solution pour améliorer la mobilité des réseaux, dans le cadre de communications véhiculaires ainsi que pour la distribution de contenu. Les solutions actuelles pour les communications véhiculaires (c'est-à-dire lorsqu'un réseau est mobile) reposent sur la mise en place de tunnels, permettant également d'utiliser simultanément les différentes interfaces disponibles sur le véhicule (multi-homing). Même avec des tunnels, ces solutions ne sont pas en mesure d'équilibrer le trafic sur les interfaces réseau disponibles, elles ne parviennent pas à tirer partie du multi-homing. De plus, certaines des solutions existantes pour la mobilité de réseau cachent la mobilité aux hôtes connectés au routeur mobile. De fait, cela empêche les hôtes de participer aux décisions relatives au multi-homing, telles que le choix de l'interface réseau à utiliser, ce qui est pourtant utile pour réaliser du routage à moindre coût. Dans cette thèse, nous proposons de combiner un protocole de mobilité réseau (tel que NEMO) avec le protocole de TCP-multivoies (MPTCP), ce qui permet aux nœuds hôtes de participer à la mobilité et au multi-homing. Cette nouvelle combinaison améliore significativement le routage et l'encapsulation de paquets causée par les tunnels. En outre, cela augmente le débit, la tolérance de panne, le temps d'aller-retour et réduit le délai de transmission. La deuxième contribution de ce travail propose une solution de continuité de session pour la distribution de contenu dans les réseaux 5G. Dans le réseau 5G, les équipements d'accès IP seront au plus proche des nœuds terminaux afin d'améliorer l'expérience utilisateur et de réduire la charge de trafic dans le réseau central. Le fait est qu'à un instant donné un terminal ne peut être raccordé qu'à une seule passerelle (SGW/PGW) à la fois. Et comme la passerelle change lors de la mobilité, les sessions en cours seront rompues, impactant les applications temps réelle, le streaming vidéo, les jeux, etc. Pour cela, la thèse présente une solution de continuité de session avec l'aide de TCP-multivoie en bénéficiant du fait que les serveurs de contenu sont stationnaires. / This thesis presents a solution for boosting network mobility in the context of vehicular communications and content distribution in fixed network. Existing solutions for vehicular communications (i.e., network mobility), relies on tunneling in order to use multiple available interfaces on a vehicle. Even with tunnels, these solutions are unable to balance the traffic over available network interfaces thus do not reach the goal to provide optimum multi-homing benefits. Moreover, some of the existing solutions for network mobility, hide the mobility from the hosts connected to the mobile router. This in result inhibits the host nodes from participating in multi-homing related decisions such as interface selection which can be helpful in performing least cost routing. In this thesis, we propose to combine network mobility protocol with MPTCP which enables the host nodes to participate in mobility and multi-homing. This novel combination significantly improves routing and tunneling packet overhead. Moreover it increases throughput, fault tolerance, round-trip time and reduces transmission delay. The second contribution of this work is providing a solution for session continuity in context of content distribution in 5G networks. In 5G network, the IP edges will be closer to the host nodes in order to improve the user experience and reduce traffic load in the core network. The fact that a host can only be connected to a single gateway (SGW/PGW) at a time, would break the ongoing sessions for real time applications like video streaming or gaming during an occurrence of mobility event requiring gateway relocation. The thesis presents the solution for session continuity with the help of multipath TCP by benefiting from the fact that the content servers are stationary.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23378号 / 医博第4747号 / 新制||医||1052(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 武藤 学, 教授 上杉 志成, 教授 篠原 隆司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Tax Crimes Abstract The diploma thesis deals with tax crimes. The aim is to create a systematic overview and evaluation of the current criminal law of tax crimes in the legal order of the Czech Republic. The initial chapter focuses on the general definition of terms, including developmental stages of tax crimes, which mentions the reintroduction of criminality in the preparation of tax evasion, charge and similar mandatory payments in the Criminal Code in specific cases. The next chapter is devoted to a historical evolution into the development of tax crime legislation. The third chapter analyzes the legislative framework of the criminal law regulation of tax crimes in the Czech legal system. As part of the analysis of the crime tax fraud is explained how carousel fraud abusing the tax system within the EU works, as it is one of the most exploited tax evasions in the field of value added tax. This chapter also pays attention to the principle of nemo tenetur ipsum accusare in connection with taxation of income that originated from criminal activities. The next chapter deals with the prevention of tax evasion, with an emphasis on reverse-charge, which is based on the principle that the obligation to declare value added tax is transferred from the provider to its recipient. I follow up with the criminal...

Scaffold proteins facilitate many aspects of intracellular signaling. These proteins can regulate two or more proteins in the same pathway, or coordinate signaling from multiple pathways. Scaffold proteins are therefore key control points for the flux of signaling and play essential roles in biological systems. There are four possible mechanisms by which scaffold proteins achieve activation and propagate signaling: 1) rigid protein binding between two or more proteins to co-localize binding partners, 2) ligand-induced activation such as may result from a conformational change, 3) disorder-to-order transition where the scaffold protein folds as a result of a protein-protein interaction, and 4) dynamic processes such as phosphorylation. The scaffold protein NF-κB essential modulator (NEMO) functions via ligand-induced activation and serves as the key control point for canonical NF-κB signaling. The work described in this thesis investigates the role of a previously uncharacterized domain within NEMO that is required for function, which we term the Intervening Domain (IVD). Bioinformatic analysis reveals a high level of sequence conservation across species within this domain. Conformational changes following ligand binding are observed for NEMO and these changes require conserved sequences in the IVD. Additionally, a functional IVD is shown to increase the binding affinity of NEMO for IKKβ, enhance the thermal stability of NEMO, and is required to propagate NF-κB signaling in cells. A fluorescence-based assay is also developed to characterize the formation of a complex composed of NEMO, a zinc ion, and IκBα. A separate fluorescence-based assay is developed to measure IKK activity and is used to determine that NEMO alone or in the presence of linear tetraubiquitin does not enhance the rate of IKKβ phosphorylation of an IκBα-derived peptide. Furthermore, a number of organic small molecules and macrocycles are screened against the NEMO-IKKβ interaction. One small molecule was validated as an inhibitor and its biophysical properties and inhibition kinetics are described in this thesis. These analyses represent the first characterization of a highly conserved domain required for the function of the key control point in NF-κB signaling. The IVD domain of NEMO could be targeted for development of an allosteric effector for therapeutic discovery.

Users (or software agents) are served by multiple networked terminal devices, each of which may in turn have multiple network interfaces. This multi-homing at both ???user??? and ???device??? level presents new opportunities for mobility handling. Mobility may be handled by switching ongoing application data streams between devices, by utilising intermediary adaptation or connectivity enhancement services, or both. However this requires middleware support that is not provided by current systems. This thesis presents a set of integrated solutions to enable this kind of mobility handling, based on concept of Personal Networks (PN). Personal Networks (PN) consist of dynamic conglomerations of terminal and service devices tasked to facilitate the delivery of information to and from a single focal point, which may be a human user or software agent. This concept creates the potential to view mobility handling as a path selection problem, since there may be multiple valid terminal device and service proxy configurations that can successfully carry a given communication session from one PN to another PN. Depending on context, it may be necessary to switch between paths. To this end, this thesis proposes and evaluates a set of inter-dependent mechanisms to facilitate the discovery and use of different candidate end-to-end paths. The proposal comprises mechanisms for secure inter-device mobility using delegated cryptographic identifiers, autonomous service proxy selection and composition, and distributed resolution of cryptographic identifiers to lower layer addresses.

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Users (or software agents) are served by multiple networked terminal devices, each of which may in turn have multiple network interfaces. This multi-homing at both ???user??? and ???device??? level presents new opportunities for mobility handling. Mobility may be handled by switching ongoing application data streams between devices, by utilising intermediary adaptation or connectivity enhancement services, or both. However this requires middleware support that is not provided by current systems. This thesis presents a set of integrated solutions to enable this kind of mobility handling, based on concept of Personal Networks (PN). Personal Networks (PN) consist of dynamic conglomerations of terminal and service devices tasked to facilitate the delivery of information to and from a single focal point, which may be a human user or software agent. This concept creates the potential to view mobility handling as a path selection problem, since there may be multiple valid terminal device and service proxy configurations that can successfully carry a given communication session from one PN to another PN. Depending on context, it may be necessary to switch between paths. To this end, this thesis proposes and evaluates a set of inter-dependent mechanisms to facilitate the discovery and use of different candidate end-to-end paths. The proposal comprises mechanisms for secure inter-device mobility using delegated cryptographic identifiers, autonomous service proxy selection and composition, and distributed resolution of cryptographic identifiers to lower layer addresses.