Orientador: Marcelo Moraes Guzzo / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Fisica Gleb Wataghin / Made available in DSpace on 2018-08-07T11:07:30Z (GMT). No. of bitstreams: 1 MouraJunior_CelioAdregade_D.pdf: 3776986 bytes, checksum: 07c139c8c30b32426082bda432e718e0 (MD5) Previous issue date: 2006 / Resumo: Fazemos uma estimativa do número de Chuveiros Atmosféricos Extensos originados por neutrinos do tau em Detetores de Fluorescência como os do Observatório Pierre Auger. Consideramos modelos de produção de neutrinos do elétron e do múon de altíssimas energias em objetos extra galácticos e Defeitos Topológicos, assim como mudança de sabor na propagação dos neutrinos da fonte até a Terra. Para a seção de choque dos neutrinos utilizamos um modelo que extrapola os parâmetros do Modelo Padrão até energias da ordem de 1021 e V. Porém esses parâmetros foram comprovados até a ordem de 1012 e V. gerando incertezas nos números obtidos para altíssimas energias. Concluímos que, dependendo da relação entre fluxo e seção de choque, existe uma região restrita de energia dos neutrinos do tau que pode gerar eventos com chuveiros atmosféricos duplos detectáveis em Detetores de Fluorescência. A energia dos neutrinos do tau deve ser de aproximadamente 1018 e V e o número de eventos pode variar algumas ordens de magnitude em torno de um evento por ano, dependendo dos modelos propostos e das caracteristicas do detetor / Abstract: We calculate the possible number of Extensive Air Showers originated by tau neutrinos in Fluorescence Detectors like the ones of the Pierre Auger Observatory. We consider models of production of electron and muon neutrinos in extra galactic objects and Topological Defects, as well as the possibility of neutrino flavor change in the propagation of the neutrinos between the source and the Earth. The neutrino cross section was calculated by the extrapolation of the standard model parton distribution functions until energies of the order of 1021 e V. However, due to uncertainties in the extrapolation for energies higher than 1012 e V the results are not robust. We conclude that, depending on the relation between flux and cross section, there is a strict range of energy for the tau neutrinos to generate double extensive air showers detectable in Fluorescence Detectors. The tau neutrino energy must be approximately 1018 e V and the event rate can vary some orders of magnitude around one event per year , depending on the flux-cross section relation and detector characteristics / Doutorado / Física das Particulas Elementares e Campos / Doutor em Ciências

Orientador: Carola Dobrigkeit Chinellato / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Física Gleb Wataghin / Made available in DSpace on 2018-08-22T13:08:19Z (GMT). No. of bitstreams: 1 Castilho_CamileMendes_M.pdf: 4872331 bytes, checksum: 59af4c2607b071fd467957e83946bcf8 (MD5) Previous issue date: 2013 / Resumo: Duas questões importantes no estudo da física de raios cósmicos são quais são as fontes astrofísicas dessas partículas e como é o campo magnético por elas atravessado. O Observatório Pierre Auger, localizado na província de Mendoza, na Argentina, é um experimento que tem como objetivo estudar raios cósmicos de altas energias (superior a 1 EeV). Entre os objetivos do observatório, está buscar possíveis fontes desses raios cósmicos e estudar o campo magnético por eles atravessado. Considerando que partículas ultra-energéticas sofrem deflexões em campos magnéticos que são inversamente proporcionais _as suas energias, espera-se que aquelas provenientes de uma mesma fonte cheguem á Terra com suas direções alinhadas sobre a esfera celeste e com desvios angulares satisfazendo essa dependência com a energia. Um grupo de raios cósmicos com suas direções e energias satisfazendo essas características é chamado de multipleto. Nesta dissertação, foram analisados 2196 raios cósmicos com energias acima de 20 EeV, detectados pelo Observatório Pierre Auger entre 1o de janeiro de 2004 e 22 de novembro de 2012, a _m de realizar uma busca por multipletos. Para encontrar estes multipletos, foi utilizado o Método da _Arvore de Extensão Mínima. Este método é utilizado para separar o conjunto de raios cósmicos em subconjuntos. Uma vez encontrados esses subconjuntos, foi verificado se as direções dos raios cósmicos do subconjunto satisfazem a correlação esperada entre as suas direções e os inversos de suas energias. Para isso foi calculado o coeficiente de correlação e a dispersão angular nas coordenadas dos raios cósmicos de cada subconjunto em um plano tangente _a esfera celeste no ponto correspondente _a direção média. Se o coeficiente de correlação for superior a um valor mínimo e a dispersão angular for menor do que um valor máximo pré-estabelecidos, o multipleto em questão é considerado um multipleto correlacionado. Após identificarmos estes multipletos, foi possível encontrar as posições das possíveis fontes dos raios cósmicos que o compõem e obter informação sobre o poder de deflexão do campo magnético por eles atravessado nas direções das respectivas fontes. Para o período em questão foram encontrados três multipletos correlacionados com um número de eventos igual ou superior a doze. Para estes três multipletos foram procuradas posições de possíveis fontes. Realizando uma comparação entre as posições encontradas e um catalogo de objetos astrofísicos, foram encontrados objetos próximos ás direções das fontes encontradas / Abstract: Two important questions in the study of ultra-high-energy cosmic rays are related to the astrophysical sources of these particles and the characteristics of the magnetic field they have traversed in their way from the sources to Earth. The Pierre Auger Observatory was designed and built in Argentina in order to address these and other questions about ultra-high energy cosmic rays. Its design goals included being able to measure ultra-high energy cosmic rays (above 1 EeV) with unprecedented statistics. Considering that the trajectories of ultra-high energy particles are defected by the magnetic fields traversed and that the defection is inversely proportional to their energies, it can be expected that particles having different energies and coming from a single source will arrive at Earth with their directions aligned on the celestial sphere and with angular deviations satisfying that dependence with the energy. A group of cosmic rays with their directions and energies satisfying those characteristics is called a multiplet. In this work, we search for multiplets in a data sample of 2196 cosmic rays with energies above 20 EeV recorded by the Pierre Auger Observatory between 1st January 2004 and 22nd November 2012. We applied the method of the minimum spanning tree to separate the whole data set into subsets and then analyzed the subsets, checking whether the directions of the cosmic rays in each subset satisfy the expected correlation with the inverse of their energies. After identifying multiplets which satisfy the correlation, it is possible to find theposition of the sources of the cosmic rays and estimate the defection power of the magnetic field these particles must have traversed in the corresponding directions of the sources. In the period covered by our analysis we have found three multiplets with twelve or more events. For each multiplet we have found the direction of the possible source and the defection power of the magnetic field and looked for nearby astrophysical objects in a catalog / Mestrado / Física / Mestra em Física

Orientadores: José Augusto Chinellato, Márcio Aparecido Müller / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Física Gleb Wataghin / Made available in DSpace on 2018-08-19T10:08:45Z (GMT). No. of bitstreams: 1 Theodoro_VanessaMenezes_M.pdf: 42012954 bytes, checksum: 1cd4d5a5b5ebfd4b0836da1f0709faa6 (MD5) Previous issue date: 2011 / Resumo: O Observatório Pierre Auger foi construído para detectar raios cósmicos de altas energias. Um dos principais objetivos das pesquisas realizadas pelo Observatório Auger, é o estudo da composição de massa dos raios cósmicos primários. O conteúdo muônico dos chuveiros atmosféricos extensos, produzidos a partir das interações dessas partículas primárias no alto da atmosfera, é um dos parâmetros mais sensíveis para o estudo da composição de massa. Ao nível do solo, as partículas detectadas com os 1600 tanques Cherenkov, que constituem o detector de superfície do Observatório, são essencialmente uma mistura de fótons, elétrons e pósitrons, que formam a componente eletromagnética; e os múons da componente muônica dos chuveiros extensos. A contribuição relativa dessas componentes depende do estágio de desenvolvimento do chuveiro e da distância radial ao eixo do mesmo. Nas regiões mais afastadas do eixo do chuveiro, num determinado estagio de seu desenvolvimento, um chuveiro iniciado por um núcleo de ferro, pode sob as mesmas condições que um chuveiro com primário de próton, induzir até 40% mais múons. Um dos métodos possíveis para estimar a contribuição muônica é o uso da estrutura temporal do sinal Cherenkov no detector de superfície. Esses sinais digitalizados em FADCs, mostram que múons induzem picos de sinais acima de um contínuo eletromagnético formado de pequenos picos. De forma que essa estrutura de sinal característica das componentes dependem da distância radial ao eixo do chuveiro. Esse trabalho tem como objetivo contribuir para a identificação e discriminação das componentes muônicas e eletromagnética dos chuveiros, a partir de um desenvolvimento matemático sobre o método de análise ¿Muon Jump¿. O método de jumps é baseado nas estruturais temporais dos sinais das componentes registrados pelos tanques Cherenkov do Observatório Auger e digitalizados em unidades FADCs. Usando essa característica estrutura temporal dos sinais, poderemos estimar o sinal de cada componente, definindo filtros de separação nas distribuições temporais dos sinais das frentes dos chuveiros e nas distribuições das derivadas desses sinais. Partindo dos diferentes sinais depositados por múons e partículas eletromagnéticas nos tanques Cherenkov, fizemos um estudo de contaminação desse sinal muônico pela componente eletromagnética, de forma individual e em frentes de chuveiros atmosféricos. Com isso, definimos o conceito de um filtro a ser aplicado nas distribuições de sinais, que nos permitisse separar de forma eficiente os sinais produzidos pelas partículas / Abstract: The Pierre Auger Observatory was built to detect high-energy cosmic rays. Studies of the mass composition of the highest energy cosmic rays is a major focus of research developed by the Pierre Auger Observatory. The muon content of the extensive air showers produced from the interactions of these primary particles with the atmosphere, is one of the most sensitive parameters to the mass composition. At the ground level, the detected particles by the Surface Detector of the Auger Observatory consists of 1660 water-Cherenkov detectors, are essentially a mixture of photons, electrons and positrons, the electromagnetic component, and muons, the muonic component. The relative contribution of these components depends on the stage developmental stage and on the radial distance of the showers. Far enough from the shower axis at a given development stage, a shower initiated by a iron primary may induce up to 40% more muons than a proton primary under the same conditions. The time structure of the Cherenkov signal profile in the surface detectors of particles reaching ground is used to estimate the muonic contribution. The Cherenkov signals are digitized as FADCs traces, and show that muons induce peaks signal above a continuous electromagnetic formed of small peaks. So this characteristic structure of the muonic and eletromagnetic peaks depend on the radial distance from the shower axis. The goals of my work is to contribute to the identification and discrimination of the eletromagnetic and muonic components, from a mathematical model to apply filters in the signal distributions of the particles. This method is based on the Jump method. Using the detailed time structure of signs, we can estimate the sign of each component, defining a set of separation filters to make an efficient selection of the muonic signal. The different signals deposited by muons and electromagnetic particles in Cherenkov tanks, allowed us to study the electromagnetic contamination in individual muonic signals and in the showers fronts / Mestrado / Física / Mestra em Física

Orientador: Carola Dobrigkeit Chinellato / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Física Gleb Wataghin / Made available in DSpace on 2018-08-19T15:55:43Z (GMT). No. of bitstreams: 1 Selmi-Dei_DanielPakk_D.pdf: 9650136 bytes, checksum: a6af22f88f369a8903480bc20071c354 (MD5) Previous issue date: 2012 / Resumo: Esta tese apresenta um estudo das deflexões nas trajetórias de raios cósmicos com energia ultra-alta (> 1018 eV) devido à sua propagação pelo campo magnético da Via Láctea. Partindo de dados coletados no Observatório Pierre Auger, localizado na Argentina, a técnica do backtracking foi aplicada sob diversas hipóteses relativas à carga elétrica do núcleo primário. Uma situação histórica é feita desde a época da descoberta da radiação cósmica até as últimas técnicas de detecção desenvolvidas por Pierre Auger, descobridor dos chuveiros atmosféricos extensos. A natureza das cascatas é descrita para o entendimento de como direções de chegada e energias são inferidas através dos experimentos de hoje. Alguns detalhes do espectro do uxo de raios cósmicos nas energias mais altas são expostos. As metodologias relativas aos telescópios de uorescência e ao arranjo de superfície, empregados no Observatório Auger, são introduzidas. É estabelecida uma relação entre ambas as técnicas de detecção e alguns resultados importantes, obtidos nos últimos anos pela Colaboração Auger, são apresentados. É feita uma descrição da dinâmica de campos magnéticos em plasmas astrofísicos e de dados observacionais da rotação de Faraday para embasar a escolha dos modelos de campo magnético galácticos. A magnetohidrodinâmica também é usada para explicar por que é interessante considerar certos objetos aceleradores candidatos a fontes de raios cósmicos. A distribuição de matéria na Via Láctea é então caracterizada em relação aos dados de evolução estelar e passa a ser assumida a hipótese de que a nucleossíntese elementar ocorre de modo semelhante em outras galáxias. Em seguida, são definidos os modelos utilizados para a descrição dos campos magnéticos nas regiões do bojo, disco e halo da galáxia. A superposição de um modelo da componente irregular também é considerada. A técnica do backtracking de antipartículas (e, equivalentemente, o forwardtracking de partículas) é descrita segundo um novo método numérico de passos adaptativos introduzido neste trabalho. Algumas ferramentas de análise são propostas a partir dos dados de reconstrução das trajetórias. Em última análise, é demonstrado que esse método desenvolvido concorda com o método numérico de Runge e Kutta de quarta ordem. Os resultados apresentados nesta tese levam à conclusão de que se os modelos presentes descrevem aproximadamente o campo magnético de larga escala da Via Láctea, então raios cósmicos com energia ultra-alta são signicantemente de etidos durante a propagação. Para um evento real detectado no Observatório Auger, a escolha da composição química compatível com núcleos produzidos nas reações de nucleossíntese estelar permitiu indicar regiões da Via Láctea que podem abrigar objetos astrofísicos candidatos a fonte. Assumindo que um magnetar galáctico ativo conhecido radie partículas com E > 1019 eV, foi possível prever excessos do uxo bem localizados em certas direções do céu. Já a depleção desse uxo na direção do Aglomerado de Virgem pode ser explicada através da imposição de limites na composição química da radiação cósmica com incidência normal ao plano galáctico. Por último, sob a hipótese de que AGNs sejam as fontes dos núcleos atômicos ultra-energéticos observados, uma relação entre composição química e energia da partícula primária é derivada / Abstract: This thesis presents a study of the deflections of ultra-high energy (> 1018 eV) cosmic rays caused by its propagation through the large scale magnetic field of the Milky Way. From data collected by the Pierre Auger Observatory, in Argentina, the backtracking technique was applied under several hypotheses relative to the electric charge of the primary nucleus. A historical review is given since the discovery of the cosmic radiation until the last detection techniques developed by Pierre Auger, who was the discoverer of extensive air showers. The nature of the cascades is described for an understanding about how the arrival directions and energies are inferred from experiments performed today. Some details regarding the spectrum of the cosmic ray flux at the highest energies are exposed. The methodologies relative to the fluorescence telescopes and the surface array, employed at the Auger Observatory, are introduced. A relation is established between both techniques of detection and some important results obtained in the last years by the Auger Collaboration are presented. A description of the magnetic field dynamics in astrophysical plasmas and the observational data of Faraday rotation serve as a basis for the choice of galactic magnetic field models. Magnetohydrodynamics is also used to explain why it is interesting to consider certain objects as candidates for the source and acceleration of cosmic rays. The Milky Way is then characterized in respect to stellar evolution data and the hypotheses that the nucleosynthesis of the elements occurs in a similar way in other galaxies is assumed. Finally, models to describe the magnetic fields in the bulge, disk and halo regions are defined. The superposition of a model for the irregular component is also considered. The backtracking technique of antiparticles (and equivalently, the forwardtracking of particles) is described according to a new numerical adaptive stepsize method introduced in this work. Some analysis tools are proposed based on data from the reconstructed trajectories. Lastly, it is shown that the method developed here agrees with the fourth-order Runge-Kutta numerical method. The results presented is this thesis lead to the conclusion that if the present models describe approximately the large scale magnetic field of the Milky Way, then ultra-high energy cosmic rays are significantly de ected during propagation. For a real event detected at the Auger Observatory, the choice for a chemical composition compatible with the nuclei produced in stellar nucleosynthesis reactions allowed to pinpoint regions inside the MilkyWay that can house astrophysical objects as candidate sources. Assuming that a known active galactic magnetar radiates particles with E >1019 eV, it was possible to predict well localized ux excesses in certain directions of the sky. The depletion of that flux in the direction of the Virgo Cluster can be explained by the imposition of limits on the chemical composition of cosmic radiation with incidence normal to the galactic plane. In the last place, under the hypothesis that AGN are sources of the observed ultra-high energy atomic nuclei, a relation between chemical composition and particle energy is derived / Doutorado / Física / Doutor em Ciências

Orientadores: Ernesto Kemp, Anderson Campos Fauth / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Física Gleb Wataghin / Made available in DSpace on 2018-08-20T22:56:12Z (GMT). No. of bitstreams: 1 Daniel_Bruno_M.pdf: 8374007 bytes, checksum: 352eb3cb6108ee55f40579c9db6d47a4 (MD5) Previous issue date: 2012 / Resumo: O Observatório Pierre Auger foi desenvolvido com o objetivo de estudar os raios cósmicos de energia ultra-alta (maior que 10¹8 eV ), cujo fluxo é extremamente baixo. Sua configuração híbrida consiste em 1600 detectores de radiação Cherenkov, produzida pela passagem de partículas dos chuveiros atmosféricos na água, e 4 estações com telescópios de fluorescência, que detectam a emissão de luz que ocorre após a excitação das moléculas de nitrogênio da atmosfera. O observatório cobre uma área de cerca de 3000 km² . Neste trabalho será feita uma descrição detalhada dos detectores de superfície e de seu procedimento de reconstrução de eventos, no qual são determinadas a energia e direção de chegada do raio cósmico primário. Serão mostrados alguns resultados da caracterização e teste do tanque Cherenkov de Campinas e análises realizadas sobre o procedimento de reconstrução, nas quais são estudadas as consequências da exclusão de uma estação e o impacto da utilização de tanques irregulares, com fotomultiplicadoras de ganho alterado ou desligadas. Os resultados destes estudos mostram que os procedimentos de calibração e seleção de eventos atualmente utilizados no Observatório Pierre Auger são eficientes, garantindo a qualidade dos dados, mas que algumas modificações poderiam trazer um aumento na taxa de detecção, e também que a configuração mencionada em algumas propostas de expansão do observatório, com apenas uma fotomultiplicadora por tanque, pode reduzir a confiabilidade dos eventos / Abstract: The Pierre Auger Observatory was designed to study the ultra-high energy (> 10¹8 eV ) cosmic rays, whose flux is extremely low. Its hybrid configuration consists on 1600 detectors of Cherenkov radiation, produced by the passage of particles from the air showers by water, and 4 fluorescence telescope stations, to detect light emitted after the excitation of nitrogen molecules of the atmosphere. The observatory covers an area of 3000 km² . This work will give a detailed description of the surface detectors and its event reconstruction procedure, where the energy and arrival direction of the primary cosmic ray is determined. Some results of the characterization and test of the Cherenkov tank of Campinas will be showed, and also some analysis about the reconstruction, with studies of the consequences of the exclusion of a station and the impact of the use of irregular tanks, with photomultiplier\\\'s operating in low gain or turned of. This studies show that the calibration and event selection procedures used at the Pierre Auger Observatory are efficient, providing high quality for the data taken, but some modifications could bring an increase of the detection rate. It is also shown that the configuration for the tanks mentioned in some proposals of expansion of the observatory, with a single photomultiplier by tank, could reduce the con#ability of the events / Mestrado / Física / Mestre em Física

Orientador: Carola Dobrigkeit Chinellato / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Fisica Gleb Wataghin / Made available in DSpace on 2018-08-04T03:39:35Z (GMT). No. of bitstreams: 1 Selmi-Dei_DanielPakk_M.pdf: 2342914 bytes, checksum: 162b44347e391de172fb12130f4bad2a (MD5) Previous issue date: 2005 / Resumo: Esta dissertação cobre a análise dos primeiros eventos detectados simultaneamente pelos tanques de superfície e telescópios de fluorescência durante a fase de prototipagem do Observatório Pierre Auger, na Argentina, entre dezembro de 2001 e abril de 2002. Há muitos anos diversos experimentos espalhados pelo mundo, dedicados à detecção de raios cósmicos, vêm coletando e montando uma estatística bem estabelecida do fluxo, direção de chegada, energia e composição química até 1019 eV através do constante desenvolvimento de novas técnicas. Ficou comprovado, porém, que radiação cósmica acima de 1020 eV existe, uma contradição com previsões teóricas que imediatamente abriu um leque de questões, variando desde qual origem extragalática poderiam ter, até o modo como se propagam pelo espaço. A riqueza e detalhamento que o estudo dessas partículas envolve são sintetizados em três partes neste trabalho. O primeiro capítulo aborda a radiação desde suas mais prováveis fontes geradoras e mecanismos de aceleração, os efeitos a que está sujeita durante a propagação pelo espaço e, por fim, o conjunto de processos desencadeados a partir da chegada no topo da atmosfera terrestre até o nível do solo -o chamado chuveiro atmosférico extenso. Com essa motivação inicial, a segunda parte abrange a totalidade do que será o Projeto Auger em sua fase final: um observatório que emprega as duas técnicas mais bem sucedidas já utilizadas em outros experimentos de menor porte, juntamente com a física, a matemática e o embasamento computacional da análise e reconstrução das propriedades que caracterizam uma partícula primária. No último capítulo é colocado em prática tudo o que foi discutido no anterior , com algumas restrições existentes na época em questão. A mais evidente é o funcionamento do observatório como um protótipo, quando foram operadas apenas parte de um olho (conjunto de telescópios de fluorescência) e do arranjo de solo. Outra são os códigos disponibilizados para análise pela colaboração, em constante desenvolvimento em paralelo com simulações. Uma análise completa da reconstrução geométrica e energética de todos os eventos registrados é apresentada e depois confrontada com resultados de outros membros da colaboração, dando um panorama geral do que se propõe o projeto no futuro, quais seus principais aspectos a serem melhorados e que ferramentas de análise ainda devem ser desenvolvidas / Abstract: This dissertation covers the analysis of the first events detected simultaneously by water tanks and fluorescence telescopes during the prototype phase of the Pierre Auger Observatory, between December 2001 and April 2002. For years several experiments over the world dedicated to the detection of cosmic rays collected and built a well established statistics for the flux, arrival direction, energy and chemical composition up to 1019 eV with the constant development of new techniques. It is a fact, though, that cosmic radiation over 1020 eV exists, a contradiction to previous theoretical results that immediately raises questions like which extragalactic origin they could have or how they propagate through space. The richness and level of detail involved in the study of such particles are synthesized in three parts in this work. The first chapter approaches cosmic radiation from its most likely sources and acceleration mechanisms, the effects to which it is subjected during propagation through space and, at last, the set of processes caused by the arrival at the top of the Earth's atmosphere to the ground level -the so-called extensive air shower . After this initial motivation, the second part covers the totality of what is to be the Auger Project in its final phase: an observatory that employs the two most successful techniques ever used in other smaller-scale experiments, along with the physics, mathematics and computational basis of the analysis and reconstruction of the properties that characterize a primary particle. Everything discussed previously is put into practice in the last chapter, with some of the restrictions at the time. The most evident is the operation of the observatory as a prototype, when only parts of one eye (set of fluorescence telescopes) and surface array were available. Another one are the codes available to analysis by the collaboration, in constant development in parallel with simulations. A complete analysis of the geometry and energy reconstruction of all events registered is presented and cross-checked with results from other collaboration members, giving a general view of the project's proposal for the future, its main aspects to be improved and which analysis tools are still to be developed. / Mestrado / Física / Mestre em Física

L’efficacité d’une radioimmunothérapie (RIT) peut impliquer la coexistence des effets ciblés et des effets dit « non ciblés ». Les effets ciblés regroupent les effets biologiques observés dans les cellules ou tissus traversés par les particules ionisantes alors que les effets non-ciblés (ou bystander) sont observés dans des cellules qui n’ont pas été irradiées mais qui sont au proche voisinage des cellules exposées. Nous avons au cours de cette étude évalué in vitro et in vivo, la contribution des effets ciblés et non ciblés dans l’efficacité obtenue lors de la RIT alpha (212Pb, 213Bi) et de la RIT Auger (125I). Les effets ciblés ont été mesurés in vitro sur les cellules irradiées (cellules donneuses) alors que les effets bystander sont mesurés sur les cellules non irradiées (cellules receveuses) par une méthode de transfert de milieu. Elle consiste, à traiter les cellules receveuses dans un milieu de culture pré-incubé pendant 2h avec les cellules donneuses. Nos résultats montrent que la contribution des effets ciblés est nettement plus importante qu’en RIT alpha qu’Auger. En RIT alpha, on observe que les lésions de l’ADN (foci 53BP1et γ-H2AX) pourraient être différenciées en lésions complexes (sites multilésés = observation de gros foci) ou simples lésions (petit foci). Par contre en RIT Auger, ce sont les effets non ciblés qui prédominent sur les effets ciblés. L’utilisation d’inhibiteurs pharmacologiques des ROS montre l’implication du stress oxydatif dans ces effets non ciblés observés en RIT alpha et Auger. Ces effets non ciblés ont été observés également in vivo sur des souris athymiques porteuses de carcinoses péritonéales de petites tailles ; démontrant ainsi leur contribution dans l’efficacité thérapeutique finale observée après la RIT alpha et Auger. L’ensemble de ces résultats indiquent que même si des lésions de l’ADN sont produites après irradiation, que les effets non ciblés pourraient aussi contribuer à l’efficacité thérapeutique finale observée avec les anticorps couplés aux émetteurs de particules alpha ou d’électrons Auger. Ces résultats sont particulièrement intéressants pour la thérapie ciblée car les vecteurs utilisés n’ont pas souvent accès à l’ensemble des cellules constituant la tumeur. / We investigated in vitro and in vivo the relative contribution of targeted and non-targeted effects in the therapeutic efficacy against tumors of antibodies radiolabeled with alpha particle (212Pb, 213Bi) or Auger electron (125I) emitters. Targeted effects occurs in cells directly crossed by ionising particles while non-targeted effects are measured in cells neighbouring irradiated cells. Targeted effects were measured in vitro in cells exposed to antibodies radiolabeled with alpha or Auger emitters (donor cells) while non-targeted effects were investigated in recipient cells. Recipient cells consisted of cells not exposed to radiolabeled-mAbs, but grown in medium previously incubated for 2h with donor cells. We showed that the relative contribution of targeted effects versus non-targeted effects was higher during alpha RIT than Auger RIT. Alpha particles produced 53BP1 and gamma-H2AX foci in donor cells that could be differentiated in large, medium and small foci, while only small foci were observed in recipient cells. We assumed that large foci would correspond to locally multiply damage sites in DNA. Conversely, Auger RIT led predominantly to non-targeted effects compared with targeted effects. Use of radical scavengers showed that oxidative stress was involved in non-targeted effects. In vivo, we showed in athymic nude mice bearing tumor xenograft that non-targeted effects were also involved and participated to therapeutic efficacy of radiolabeled antibodies. These results indicate that although producing single DNA lesion, non-targeted effects can contribute to the therapeutic efficacy of mAbs radiolabeled with alpha particle or Auger electron emitters. These findings are particularly relevant for targeted therapy in which vectors cannot gain access to every tumor cell.

L'identification des sources de rayons cosmiques d'ultra-haute énergie (au-delà de 10^18 eV) constituerait une avancée majeure aussi bien dans le domaine de l'astrophysique que dans celui de la physique des particules. La difficulté principale dans la recherche de telles sources réside dans la perte de l'information directionnelle des rayons cosmiques les moins énergétiques. En effet, leur direction est sujette à des déviations d'amplitude inversement proportionnelle à leur énergie à cause des champs magnétiques qu'il traversent lors de leur propagation jusqu'à la Terre. D'autre part, pour des énergies supérieures à 4x10^(19)eV, l'interaction des rayons cosmiques avec le fond diffus cosmologique limite l'horizon de leurs sources à l'Univers proche (200 Mpc ou moins). Cette thèse a été effectuée au sein de l’observatoire Pierre Auger, le plus grand détecteur de rayons cosmiques de haute énergie. Elle est dédiée à l'étude, la sélection, la reconstruction, ainsi qu'à l'analyse des évènements de plus haute énergie. D'autre part, les particules de plus bas numéro atomique sont plus susceptibles de garder leur direction mais la composition des rayons cosmiques est inconnue à de telles énergies. Une méthode de sélection des événements les plus similaires aux protons a été élaborée et développée dans cette thèse pour étudier la possibilité de leur utilisation pour une "astronomie protons" / Identifying the sources of the ultra-high energy cosmic rays (UHECRs, above 10^{18} eV), the most energetic particles known in the universe, would be an important leap forward for both the astrophysics and particle physics knowledge. However, developing a cosmic-ray astronomy is arduous because magnetic fields, that permeate our Galaxy and the extra-Galactic space, deflect cosmic rays that may lose the directional information on their sources. This problem can be reduced by studying the highest energy end of the cosmic ray spectrum. Indeed, magnetic field deflections are inversely proportional to the cosmic ray energy. Moreover, above 4x10^{19} eV, cosmic rays interact with cosmic photon backgrounds, losing energy. This means that the sources of the highest energy cosmic rays observed on Earth can be located only in the nearby universe (200 Mpc or less). The largest detector ever built for detecting cosmic rays at such high energies is the Pierre Auger Observatory, in Argentina. It combines a 3000 km^2 surface array of water Cherenkov detectors with fluorescence telescopes to measure extensive air showers initiated by the UHECRs. This thesis was developed inside the Auger Collaboration and was devoted to study the highest energy events observed by Auger, starting from the selection and reconstruction up to the analysis of their distribution in the sky. Moreover, since the composition at these energies is unknown, we developed a method to select proton-like events, since high Z cosmic rays are too much deflected by magnetic fields to be used for cosmic-ray astronomy.

Hintergrund: Die Entwicklung von Therapieprinzipien zur Behandlung von Krebserkrankungen hat eine anhaltende, sehr hohe wissenschaftliche Relevanz. Ziel dabei ist es, möglichst selektiv nur das erkrankte Gewebe zu schädigen. Besonders relevant ist dabei die Adressierung von für das Zellüberleben wichtigen Strukturen, wie etwa der DNA. Erreicht werden kann dies zum Beispiel durch eine Sensitivierung der DNA gegenüber energiereicher Strahlung. Ein vielversprechender Ansatz ist dabei die Generierung von Auger-Elektronen, welche auf subzellulärer Reichweite eine hohe Energie abgeben (hoher Linearer Energietransfer) und zu DNA-Strangbrüchen führen können. Dass durch unmittelbar an die DNA gekoppelte Auger-Emitter eine besonders effektive DNA-Schädigung zu erreichen ist, wurde zum Beispiel für 111Indium, 123Iod, 125Iod als auch für 99mTechnetium gezeigt. Es konnte sowohl in Untersuchungen an Zellen, als auch an Plasmid-DNA eine erfolgreiche Anregung nicht-radioaktiver Substanzen zur Auger-Emission durch ionisierende Strahlung, wie auch durch UV-Bestrahlung erreicht werden. Bekannt ist diese Sensitivierung gegenüber energiereicher Strahlung für in die DNA integrierte halogenierte DNA-Basen, wie zum Beispiel Iododeoxyuridin, mit Iod markierte DNA-Farbstoffen, wie etwa Iodo-Hoechst, als auch für DNA-gebundenes Platin. Ein bereits Iod enthaltender DNA-Farbstoff ist der Fluoreszenzfarbstoff Propidiumiodid (PI), welcher in die DNA interkaliert. Ob über die Markierung von DNA mit PI eine Sensitivierung gegenüber energiereicher Strahlung durch die Anregung des Iods zur Auger-Emission erreicht werden kann, wird in dieser Arbeit untersucht. Material und Methode: In den Versuchen wurde das Plasmid pUC 19 (2686 Basenpaare) mit unterschiedlichen Strahlenqualitäten (Röntgenstrahlung, niederenergetische Elektronenbestrahlung durch 99mTechnetium, hochenergetische Elektronenbestrahlung durch 188Rhenium, Partikelbestrahlung durch 223Radium, UV-Bestrahlung (254 nm und 366 nm) und Bestrahlung mit visuellem Licht (530-575 nm)) und Modulatoren (Wasserstoffperoxid H2O2, Zinndichlorid SnCl2, Dimethylsulfoxid DMSO) mit und ohne PI behandelt. Die Entstehung von DNA-Einzel-und Doppelstrangbrüchen führt zu einer Veränderung der Plasmidkonformation von einer superspiralisierten (supercoiled SC) zu entspannteren Formen (Einzelstrangbruch ESB-> open circle OC, Doppelstrangbruch DSB-> linearisiert L). Diese verschiedenen Plasmidkonformationen haben unterschiedliche Laufeigenschaften in der Gelelektrophorese und wurden so aufgetrennt. Nach einer Gelfärbung mit dem Fluoreszenzfarbstoff Ethidiumbromid (EtBr) erfolgte die quantitative Auswertung der Fluoreszenzintensität der unterschiedlichen Plasmidkonformations-Banden. Ergebnisse: Als grundsätzliche Voraussetzung für die nachfolgenden Versuche wurde zunächst die konzentrationsabhängige Markierung der DNA mit PI nachgewiesen, welche zu einer proportionalen Zunahme der Fluoreszenzintensität führt. Die Markierung ist stabil über die Zeit und verursacht keine DNA-Strangbrüche, jedoch eine Konformationsänderung der DNA. Eine Interaktion zwischen PI und der nachfolgenden Gelfärbung mit EtBr besteht nicht. Untersuchungen zur Chemotoxizität der Modulatoren ergaben für H2O2 keine relevante DNA-Strangbruchinduktion und für SnCl2 einen starken DNA-schädigenden Effekt mit einer konzentrationsabhängigen Induktion von ESB und DSB, welche durch den Radikalfänger DMSO verhinderbar waren, also über Radikale vermittelt wurden. Die Kombination aus H2O2 und SnCl2 führt zu einer Verstärkung der DNA-Schädigung. Für die ionisierende Strahlung konnte für alle Strahlenqualitäten eine dosisabhängige DNA-Schädigung mit Entstehung von ESB und bei höheren Dosen von DSB gezeigt werden, welche weitestgehend durch DMSO verhinderbar, also radikalvermittelt, waren. Die PI-Markierung der DNA führte in Kombination mit ionisierender Strahlung zu keiner Verstärkung der DNA-Schädigung. Es ließ sich sogar eher ein diskret protektiver Effekt durch PI bei hohen Dosen nachweisen. Da bekannt ist, dass für die Anregung eine Energie grade größer als die Energie der K-Schalen-Elektronen des Iods besonders effektiv ist, wurde vergleichend die Röntgenbestrahlung mit unterschiedlichen Beschleunigungspannungen (32 kV und 200 kV) untersucht. Jedoch führte auch hier die PI-Markierung nicht zu der erwarteten stärkeren DNA-Schädigung bei 200 kV. Die Untersuchung zur UV-Bestrahlung ergab für die Wellenlänge 254 nm einen DNA-toxischen Effekt. Durch die PI-Markierung ließ sich eine geringe Zunahme der ESB, jedoch keine DSB verzeichnen, so dass eine Auger-Emission unwahrscheinlich erscheint. Es scheint aber zu einer direkten Wechselwirkung mit der DNA zu kommen, da die Schädigung durch DMSO nicht vollständig verhinderbar ist. Für die Wellenlänge 366 nm wurde eine DNA-Toxizität, sowohl ohne, als auch mit PI-Markierung ausgeschlossen. Eine Kombination mit H2O2 führte zu einer massiven DNA-Destruktion mit Entstehung von ESB und DSB, welche durch Zugabe von DMSO suffizient verhindert werden konnten. Eine Bestrahlung mit visuellem Licht (530 - 575 nm) verursachte keine DNA-Schädigung. Durch die Markierung mit PI ließ sich eine konzentrationsabhängige DNA-Schädigung mit Entstehung von ESB erreichen. Es konnten jedoch keine DSB detektiert werden, so dass eine Auger-Emission unwahrscheinlich ist. DMSO kann die Schädigung nur partiell verhindern, so dass ein anderer direkter Effekt anzunehmen ist, am wahrscheinlichsten durch die optimale Anregung zur Fluoreszenz im Bereich des Absorptionsmaximums des PI. Schlussfolgerung: Es ließ sich für alle untersuchten Strahlenqualitäten, sowohl ionisierende Strahlung als auch Lichtbestrahlung, kein Effekt im Sinne einer Anregung zur Auger-Emission und der damit einhergehenden zu erwartenden Entstehung von DSB durch die Markierung mit PI unter den gegebenen Versuchsbedingungen nachweisen. Jedoch ließen sich Wechselwirkung bei der Bestrahlung mit Licht verzeichnen, so dass das grundlegende Prinzip einer Sensitivierung gegenüber energiereicher Strahlung für die Entwicklung von Therapiekonzepten weiterhin im Fokus steht.:1 Einleitung 1 2 Material und Methoden 3 2.1 Material 3 2.1.1 DNA 3 2.1.2 Chemikalien 4 2.1.3 Radionuklide und Bestrahlungssysteme 6 2.2 Methoden 10 2.2.1 Experimentelles Design 10 2.2.2 Charakterisierung der Plasmidkonformationen 12 2.2.3 Dosimetrie 13 2.2.4 Statistische Auswertung 14 3 Ergebnisse 15 3.1 Standardisierung der Messergebnisse und Quantifizierung 15 3.2 Einfluss physikalischer und chemischer Parameter auf die Plasmid-DNA 15 3.2.1 Festlegung Inkubationstemperatur und pH-Wert 15 3.2.2 Einfluss von DMSO auf die Plasmid-DNA 16 3.2.3 Einfluss von PI auf die Plasmid-DNA 16 3.2.3.1 Einfluss von DMSO auf Konformationsänderung durch PI 21 3.2.4 Einfluss von H2O2 auf die Plasmid-DNA und Wirkung von DMSO 23 3.2.5 Einfluss von H2O2 und PI auf die Plasmid-DNA 24 3.2.6 Einfluss von SnCl2 im TechneScan PYP-Kit auf die Plasmid-DNA 26 3.2.6.1 Einfluss von DMSO auf die Schädigung durch SnCl2 27 3.2.6.2 Einfluss von H2O2 auf die Schädigung durch SnCl2 29 3.2.6.3 Einfluss von DMSO auf die Schädigung durch SnCl2 und H2O2 30 3.3 Dosiswirkungsbeziehungen nach Exposition mit unterschiedlichen Strahlenqualitäten 31 3.3.1 Bestrahlung mit externer Röntgenstrahlung 31 3.3.1.1 Schädigung durch Röntgenbestrahlung und Einfluss von DMSO 31 3.3.1.2 Einfluss von PI auf Schädigung durch Röntgenbestrahlung mit Röhrenspannung von 200 kV und 32 kV 33 3.3.2 Bestrahlung mit 99mTc 36 3.3.2.1 Bestrahlung mit 99mTc und Einfluss von PI 36 3.3.3 Bestrahlung mit 188Re 40 3.3.3.1 Bestrahlung mit 188Re und Einfluss von PI 40 3.3.4 Bestrahlung mit 223Ra 42 3.3.4.1 Bestrahlung mit 223Ra und Einfluss von PI 43 3.3.5 Bestrahlung mit UV-Licht (254 nm) und Einfluss von PI 46 3.3.5.1 Einfluss von DMSO auf die Schädigung durch UV-Bestrahlung mit 254 nm 47 3.3.6 Bestrahlung mit UV-Licht (366 nm) und Einfluss von PI 48 3.3.6.1 Einfluss von H2O2 auf die Bestrahlung mit UV-Licht (366 nm) 49 3.3.6.2 Einfluss von DMSO auf die Schädigung durch H2O2 und UV-Bestrahlung (366 nm) 51 3.3.7 Bestrahlung mit VIS (530-575 nm) und Einfluss von PI 52 3.3.7.1 Einfluss von DMSO auf die Schädigung durch PI und VIS-Bestrahlung 54 4 Diskussion 56 4.1 Experimentelles Designe 58 4.1.1 DNA-Markierung mit PI 58 4.1.2 DNA-Markierung mit EtBr 59 4.2 Untersuchungen zur Chemotoxizität 60 4.2.1 Wechselwirkung zwischen H2O2 und Plasmid-DNA 60 4.2.2 Wechselwirkung zwischen SnCl2 und Plasmid DNA 60 4.2.2.1 Wechselwirkung zwischen H2O2 und SnCl2 61 4.3 Untersuchungen zu ionisierender Strahlung 62 4.3.1 DNA-Schädigung durch ionisierende Strahlung 62 4.3.2 Wechselwirkung zwischen ionisierender Strahlung und PI 63 4.4 Untersuchungen zur Bestrahlung mit Licht 66 4.4.1 Bestrahlung mit UV-Licht (254 nm) 66 4.4.2 Bestrahlung mit UV-Licht (366 nm) 67 4.4.2.1 Wechselwirkung zwischen H2O2 und UV-Licht (366 nm) 67 4.4.3 Bestrahlung mit visuellem Licht (VIS 530 - 575 nm) 68 4.4.4 Grenzen der Methode und Fehlerbetrachtung 69 4.5 Ausblick 70 5 Zusammenfassung 72 6 Summary 75 7 Literaturverzeichnis 77 8 Anhang 84 8.1 Abbildungsverzeichnis 84 8.2 Tabellenverzeichnis 92 8.3 Tabellen mit Daten zu den Abbildungen 96 8.3.1 Einfluss von PI auf die Plasmidkonformation 96 8.3.2 Einfluss von DMSO auf die Konformationsänderung durch PI 99 8.3.3 Einfluss von H2O2 auf die Plasmid-DNA und Wirkung von DMSO 100 8.3.4 Einfluss von H2O2 und PI auf die Plasmid-DNA 101 8.3.5 Einfluss von SnCl2 im TechneScan PYP-Kit auf die Plasmid-DNA 102 8.3.6 Einfluss von DMSO auf die Schädigung durch SnCl2 102 8.3.7 Einfluss von H2O2 auf die Schädigung durch SnCl2 103 8.3.8 Einfluss von DMSO auf die Schädigung durch H2O2 und SnCl2 104 8.3.9 Schädigung durch Röntgenbestrahlung und Einfluss von DMSO 104 8.3.10 Einfluss von PI auf Schädigung durch Röntgenbestrahlung mit Röhrenspannung von 200 kV und 32 kV 105 8.3.11 Bestrahlung mit 99mTc und Einfluss von PI 106 8.3.12 Bestrahlung mit 188Re und Einfluss von PI 107 8.3.13 Bestrahlung mit 223Ra und Einfluss von PI 108 8.3.14 Bestrahlung mit UV-Licht (254 nm) und Einfluss von PI 109 8.3.15 Einfluss von DMSO auf die Schädigung durch UV-Bestrahlung mit 254 nm 110 8.3.16 Bestrahlung mit UV-Licht (366 nm) und Einfluss von PI 110 8.3.17 Einfluss von H2O2 auf die Bestrahlung mit UV-Licht (366 nm) 110 8.3.18 Einfluss von DMSO auf die Schädigung durch H2O2 und UV- Bestrahlung (366 nm) 111 8.3.19 Bestrahlung mit VIS (530-575 nm) und Einfluss von PI 112 8.3.20 Einfluss von DMSO auf die Schädigung durch PI und VIS-Bestrahlung 113 8.3.21 Vergleich Strahlenqualitäten 114 9 Erklärung zur Eröffnung des Promotionsverfahrens 116 10 Erklärung zur Einhaltung gesetzlicher Vorgaben 117 11 Danksagung 118 / Introduction and aim of the study: The development of therapeutic principles for the treatment of cancer has a lasting, very high scientific relevance. The aim is to damage the diseased tissue only. The addressing of structures that are important for cell survival, such as the DNA, is particularly relevant. This can for example be achieved, by sensitizing the DNA to energized radiation. A promising approach is the generation of Auger electrons, which release high energy (high linear energy transfer) at sub-cellular range and can lead to DNA strand breaks. It has been shown that the direct coupling of Auger emitters to the DNA like indium-111, iodine-123, iodine-125 and technetium-99m cause particularly effective DNA damage. In investigations on cells as well as on plasmid DNA a successful excitation of non-radioactive substances for the emission of Auger electrons by ionizing radiation as well as UV-radiation was achieved. This sensitivity to energized radiation is known for halogenated DNA bases integrated into the DNA, such as iododeoxyuridine, iodine-labelled DNA dyes such as iodo-Hoechst and DNA-linked platinum. A DNA dye that already contains iodine is the fluorescent dye propidium iodide (PI) which intercalates into the DNA. This paper examines whether the labeling of DNA with PI can be used to achieve a sensitivity to energized radiation by excitation the iodine to Auger-emission. Materials and methods: In the experiments, the plasmid pUC 19 (2686 base pairs) was treated with different radiation qualities (X-ray radiation, low-energy electron irradiation by technetium-99m, high-energy electron irradiation by rhenium-188, particle-irradiation by radium-223, UV-irradiation (254 nm and 366 nm) and irradiation with visual light (530-575 nm)) and modulators (hydrogen peroxide H2O2, tin dichloride SnCl2, dimethyl sulfoxide DMSO) both with and without PI. The formation of DNA single- and double-strand breaks leads to alteration in plasmid conformation from superspiralized (supercoiled SC) to more relaxed forms (single strand break SSB-> open circle OC, double strand break DSB-> linear L). These different plasmid conformations have different running properties in gel electrophoresis and were separated this way. After gel staining with the fluorescent dye ethidium bromide (EtBr) the fluorescence intensity of the different plasmid conformational bands was evaluated quantitatively. Results: As a basic prerequisite for the subsequent experiments, the concentration-dependent labelling of the DNA with PI was demonstrated first, which leads to a proportional increase in fluorescence intensity. The labelling is stable over time and does not cause DNA strand breaks, but a conformational alteration of the DNA. There is no interaction between PI and the subsequent gel staining with EtBr. Investigations on the chemotoxicity of the modulators showed no relevant DNA strand breakage induction for H2O2 and a strong DNA-damaging effect for SnCl2 with a concentration-dependent induction of SSB and DSB, which was prevented by the radical scavanger DMSO, i. e. radical induced. The combination of H2O2 and SnCl2 leads to an increase of the DNA damage. For ionizing radiation, dose-dependent DNA damage with the formation of SSB and at higher doses of DSB, which was largely prevented by DMSO, i. e. radical induced, could be shown for all radiation qualities. The PI labeling of the DNA in combination with ionizing radiation did not lead to any amplification of the DNA damage. In fact, a discrete protective effect of PI at high doses could be demonstrated. Because it is known that the excitation with energy just greater than the energy of the K-shell electrons of iodine is particularly effective, the X-ray irradiation with different accelerating voltages (32 kV and 200 kV) was compared. However, the PI-labelling did not lead to the expected stronger DNA damage at 200 kV. The investigation of UV irradiation showed a DNA-toxic effect for the wavelength 254 nm. Due to the PI-labelling, a slight increase in SSB but no DSB were recorded, so that an Auger emission appears unlikely. However, it seems that there is a direct interaction with the DNA, because the damage is not completely preventable by DMSO. For the wavelength 366 nm a DNA toxicity was excluded, both without and with PI-marking. A combination with H2O2 led to a massive DNA destruction with the formation of SSB and DSB, which could be prevented sufficiently by the addition of DMSO. Irradiation with visual light (530-575 nm) did not cause DNA damage. By labelling with PI, concentration-dependent DNA damage with the formation of SSB could be achieved. However, no DSB could be detected, so that an Auger emission is unlikely. DMSO can only partially prevent the damage, so that another direct effect can be assumed, most likely through optimal excitation of the fluorescence around the absorption maximum of PI. Conclusion: For all investigated radiation qualities, i. e. ionizing radiation as well as light irradiation, no effect could be proven in the sense of an excitation to Auger emission and the associated expected development of DSB by labelling with PI under the given test conditions. However, interactions could be observed for the irradiation with light, so that the basic principle of sensitization to energized radiation for the development of therapy concepts remain of interest.:1 Einleitung 1 2 Material und Methoden 3 2.1 Material 3 2.1.1 DNA 3 2.1.2 Chemikalien 4 2.1.3 Radionuklide und Bestrahlungssysteme 6 2.2 Methoden 10 2.2.1 Experimentelles Design 10 2.2.2 Charakterisierung der Plasmidkonformationen 12 2.2.3 Dosimetrie 13 2.2.4 Statistische Auswertung 14 3 Ergebnisse 15 3.1 Standardisierung der Messergebnisse und Quantifizierung 15 3.2 Einfluss physikalischer und chemischer Parameter auf die Plasmid-DNA 15 3.2.1 Festlegung Inkubationstemperatur und pH-Wert 15 3.2.2 Einfluss von DMSO auf die Plasmid-DNA 16 3.2.3 Einfluss von PI auf die Plasmid-DNA 16 3.2.3.1 Einfluss von DMSO auf Konformationsänderung durch PI 21 3.2.4 Einfluss von H2O2 auf die Plasmid-DNA und Wirkung von DMSO 23 3.2.5 Einfluss von H2O2 und PI auf die Plasmid-DNA 24 3.2.6 Einfluss von SnCl2 im TechneScan PYP-Kit auf die Plasmid-DNA 26 3.2.6.1 Einfluss von DMSO auf die Schädigung durch SnCl2 27 3.2.6.2 Einfluss von H2O2 auf die Schädigung durch SnCl2 29 3.2.6.3 Einfluss von DMSO auf die Schädigung durch SnCl2 und H2O2 30 3.3 Dosiswirkungsbeziehungen nach Exposition mit unterschiedlichen Strahlenqualitäten 31 3.3.1 Bestrahlung mit externer Röntgenstrahlung 31 3.3.1.1 Schädigung durch Röntgenbestrahlung und Einfluss von DMSO 31 3.3.1.2 Einfluss von PI auf Schädigung durch Röntgenbestrahlung mit Röhrenspannung von 200 kV und 32 kV 33 3.3.2 Bestrahlung mit 99mTc 36 3.3.2.1 Bestrahlung mit 99mTc und Einfluss von PI 36 3.3.3 Bestrahlung mit 188Re 40 3.3.3.1 Bestrahlung mit 188Re und Einfluss von PI 40 3.3.4 Bestrahlung mit 223Ra 42 3.3.4.1 Bestrahlung mit 223Ra und Einfluss von PI 43 3.3.5 Bestrahlung mit UV-Licht (254 nm) und Einfluss von PI 46 3.3.5.1 Einfluss von DMSO auf die Schädigung durch UV-Bestrahlung mit 254 nm 47 3.3.6 Bestrahlung mit UV-Licht (366 nm) und Einfluss von PI 48 3.3.6.1 Einfluss von H2O2 auf die Bestrahlung mit UV-Licht (366 nm) 49 3.3.6.2 Einfluss von DMSO auf die Schädigung durch H2O2 und UV-Bestrahlung (366 nm) 51 3.3.7 Bestrahlung mit VIS (530-575 nm) und Einfluss von PI 52 3.3.7.1 Einfluss von DMSO auf die Schädigung durch PI und VIS-Bestrahlung 54 4 Diskussion 56 4.1 Experimentelles Designe 58 4.1.1 DNA-Markierung mit PI 58 4.1.2 DNA-Markierung mit EtBr 59 4.2 Untersuchungen zur Chemotoxizität 60 4.2.1 Wechselwirkung zwischen H2O2 und Plasmid-DNA 60 4.2.2 Wechselwirkung zwischen SnCl2 und Plasmid DNA 60 4.2.2.1 Wechselwirkung zwischen H2O2 und SnCl2 61 4.3 Untersuchungen zu ionisierender Strahlung 62 4.3.1 DNA-Schädigung durch ionisierende Strahlung 62 4.3.2 Wechselwirkung zwischen ionisierender Strahlung und PI 63 4.4 Untersuchungen zur Bestrahlung mit Licht 66 4.4.1 Bestrahlung mit UV-Licht (254 nm) 66 4.4.2 Bestrahlung mit UV-Licht (366 nm) 67 4.4.2.1 Wechselwirkung zwischen H2O2 und UV-Licht (366 nm) 67 4.4.3 Bestrahlung mit visuellem Licht (VIS 530 - 575 nm) 68 4.4.4 Grenzen der Methode und Fehlerbetrachtung 69 4.5 Ausblick 70 5 Zusammenfassung 72 6 Summary 75 7 Literaturverzeichnis 77 8 Anhang 84 8.1 Abbildungsverzeichnis 84 8.2 Tabellenverzeichnis 92 8.3 Tabellen mit Daten zu den Abbildungen 96 8.3.1 Einfluss von PI auf die Plasmidkonformation 96 8.3.2 Einfluss von DMSO auf die Konformationsänderung durch PI 99 8.3.3 Einfluss von H2O2 auf die Plasmid-DNA und Wirkung von DMSO 100 8.3.4 Einfluss von H2O2 und PI auf die Plasmid-DNA 101 8.3.5 Einfluss von SnCl2 im TechneScan PYP-Kit auf die Plasmid-DNA 102 8.3.6 Einfluss von DMSO auf die Schädigung durch SnCl2 102 8.3.7 Einfluss von H2O2 auf die Schädigung durch SnCl2 103 8.3.8 Einfluss von DMSO auf die Schädigung durch H2O2 und SnCl2 104 8.3.9 Schädigung durch Röntgenbestrahlung und Einfluss von DMSO 104 8.3.10 Einfluss von PI auf Schädigung durch Röntgenbestrahlung mit Röhrenspannung von 200 kV und 32 kV 105 8.3.11 Bestrahlung mit 99mTc und Einfluss von PI 106 8.3.12 Bestrahlung mit 188Re und Einfluss von PI 107 8.3.13 Bestrahlung mit 223Ra und Einfluss von PI 108 8.3.14 Bestrahlung mit UV-Licht (254 nm) und Einfluss von PI 109 8.3.15 Einfluss von DMSO auf die Schädigung durch UV-Bestrahlung mit 254 nm 110 8.3.16 Bestrahlung mit UV-Licht (366 nm) und Einfluss von PI 110 8.3.17 Einfluss von H2O2 auf die Bestrahlung mit UV-Licht (366 nm) 110 8.3.18 Einfluss von DMSO auf die Schädigung durch H2O2 und UV- Bestrahlung (366 nm) 111 8.3.19 Bestrahlung mit VIS (530-575 nm) und Einfluss von PI 112 8.3.20 Einfluss von DMSO auf die Schädigung durch PI und VIS-Bestrahlung 113 8.3.21 Vergleich Strahlenqualitäten 114 9 Erklärung zur Eröffnung des Promotionsverfahrens 116 10 Erklärung zur Einhaltung gesetzlicher Vorgaben 117 11 Danksagung 118

Os detectores de superfície do observatório Pierre Auger são tanques repletos de água e completamente escuros com sensores fotomultiplicadores instalados na parte interna. Quando as partículas carregadas de chuveiros atmosféricos atravessam a água com velocidade acima a da luz nesse meio, geram radiação ultravioleta devido ao efeito Cherenkov. Os sensores fotomultiplicadores desses detectores medem e convertem essa radiação em sinais elétricos que são enviados para a central de dados, registrando assim um evento. Alguns eventos apresentam comportamento incomum, caracterizado por apresentar mais de uma estrutura na série temporal, coincidentes em pelo menos dois detectores de superfície distantes. Esse trabalho se dedicou a investigar sobre as características e origens desses eventos. Devido ao grande número de dados registrados pelo Observatório Pierre Auger, foi preciso desenvolver uma ferramenta computacional para reconhecer e selecionar aqueles eventos que apresentam as estruturas desejadas de forma automática. Após, esse filtro, tentamos determinar um padrão buscando semelhanças ou tendências em variáveis dos chuveiros, como a energia e a direção de chegada. Em segunda análise olhamos para os eventos híbridos, chuveiros observados pelos detectores de superfície e pelos telescópios de fluorescência simultaneamente, de modo a analisar o desenvolvimento longitudinal do chuveiro. Na sequência, foram realizado algumas simulações de chuveiros para alguns dos eventos selecionados com o algoritmo desenvolvido. Esses eventos foram então reconstituídos, simulando uma detecção pelo observatório, com o intuito de determinar se a origem desse sinal anômalo está relacionada a uma resposta dos detectores. O último passo, foi analisar a razão entre a proporção de eventos selecionados e o número total de eventos observados em função da energia da partícula primária, o que revelou uma relação entre essas duas grandezas. / The surface detectors of Pierre Auger observatory are water filled tanks and completely dark with photomultiplier sensors installed indoors. When charged particles of air showers cross the water with velocities above that of light in this medium, ultraviolet radiation is generated due to the Cherenkov effect. The photomultiplier sensors of these detectors measure and convert this radiation into electrical signals that are sent to the data center, thus recording an event. Some events have unusual behavior, characterized by having more than one structure in its time series, coincident in at least two distant surface detectors. This work was dedicated to investigate the characteristics and origins of these events. Due to the large amount of data recorded by the Pierre Auger Observatory it was necessary to develop a computational tool to automatically recognize and select those events that present the desired structure type. After applying this filter, we tried to determine a pattern by looking for similarities or trends in air-shower variables, such as energy and direction of arrival. In a second analysis, we looked at the hybrid events, air showers observed by the surface detectors and the fluorescence telescopes simultaneously, in order to analyze the longitudinal development of air shower. In the sequence, we performed some simulations of air showers for some events selected with the developed algorithm. These events were then reconstituted, simulating a detection by the observatory for the purpose of determinin if the origin of this anomalous signal is related to a response of the detectors. The last step was to analyze the ratio between the proportion of selected events and the total number of events observed as a function of the energy of the primary particle, which revealed a relation between these two quantities.