In the presented research we propose to improve on historically accepted radiobiological models via Monte Carlo simulation of radiation tracks passing through a cell nucleus modeled with up-to-date subnuclear structures. This is performed by generating a radiation track database using the Monte Carlo code, Geant4-DNA, that simulates radiation interactions at the nanometer scale of DNA. These tracks are called upon from the database and intersected with a cell nucleus model that incorporates DNA-containing structures. This allows for a Monte Carlo simulation of how DNA double strand breaks are produced by radiation. The results can be used to correlate to many experimentally observed biological endpoints, e.g. chromosome aberrations as well as cell death.

Research in radiotherapy for cancer treatment focuses on finding methods that can improve the compromise between tumour cell inactivation versus damage to the surrounding healthy tissue. As new radiation modalities such as proton therapy become accessible for everyday clinical practice, a better understanding of the variation in biological response of the tumour and healthy tissues would improve treatment planning to achieve optimal outcome. The development of radiobiological models capable of accurate predictions of biological effectiveness is needed. Existing radiation quality descriptors such as absorbed dose and LET are insufficient to explain variation in biological effectiveness for different treatment modalities. The stochastic nature of ionizing radiation creates discrete patterns of energy deposition (ED) sites which can now be analysed through sophisticated computer simulations (e.g. Monte Carlo track structure codes). This opens the possibility to develop a nanometre characterization of radiation quality based on the spatial cluster patterns of ED. The aim of this thesis is to investigate the track structure (ED spatial pattern) properties of several radiation qualities at a micro- and nanometric scale while exploring their influence in biological response through correlations with published experimental data. This work uses track structure data simulated for a set of 15 different radiation qualities: 4 commonly used brachytherapy sources, 6 different proton energies, 4 different carbon ion energies, and 60Co photons used as reference radiation for quantification of biological effectiveness. At a micrometre level, the behaviour of the microdosimetric spread in energy deposition for target sizes of the order of cell nuclei was analysed. The degree of the influence it had in the biological response was found to be negligible for photon sources but for protons and carbon ions the impact increased with decreasing particle energy suggesting it may be a confounding factor in biological response. Finally, this thesis outlines a framework for modelling the relative biological effectiveness based on the frequency distribution of cluster order as a surrogate for the nanometre classification for the physical properties of radiation quality. The results indicate that this frequency is a valuable descriptor of ionizing radiation. The positive correlation across the different types of ionizing radiation encourages further development of the framework by incorporating the behavior of the microdosimetric spread and expanding tests to other experimental datasets.

Nos últimos anos, tem-se presenciado um contínuo aumento na demanda por transporte de carga ferroviário no Brasil, o que tem se refletido em maior volume de projetos para expansão ou revitalização da malha existente no país. Diante deste quadro atual, torna-se essencial que o profissional envolvido com a elaboração de projetos da via permanente tenha em mãos informações atualizadas a respeito da variedade de componentes da grade ferroviária existente no mercado, a fim de que os projetos atendam plenamente às necessidades do cliente. Assim sendo, o presente trabalho tem como principal objetivo pesquisar e analisar os tipos de componentes existentes no mercado usados na composição da grade ferroviária (trilhos, dormentes e fixações), com foco principal naqueles que podem ser aplicados às ferrovias de transporte de carga. Primeiramente, a partir de pesquisa em material bibliográfico nacional e internacional, serão descritos os principais aspectos técnicos que devem ser considerados no processo de avaliação destes componentes, tendo como base os parâmetros de projeto da via estabelecidos previamente de acordo com as exigências da operação de carga, tais como: carga por eixo, velocidade de operação, rampa máxima, etc. Em seguida, serão apresentados os tipos de trilhos, dormentes (madeira, concreto monobloco e bi-bloco, aço e plástico) e fixações (rígidas e elásticas) existentes atualmente no mercado e suas características de desempenho e condições de uso estabelecidas pelos respectivos fabricantes. Os dados obtidos nas duas etapas descritas anteriormente serão analisados e confrontados, de forma que seja possível explicitar as relações de interdependência que existem entre os diferentes tipos de componentes. Ao final do trabalho, será apresentado um modelo de fluxograma que reúne os dados de entrada para o projeto da ferrovia de transporte de carga, as diretrizes técnicas que devem ser atendidas em seu projeto e, por fim, os tipos de componentes da grade ferroviária que podem ser empregados de acordo com o caso estudado. Com isso, espera-se que o produto final gerado possa ser uma ferramenta útil na etapa de concepção de novos projetos ferroviários, visto que apresentará de maneira clara e objetiva um conjunto de informações bastante abrangente e atualizado a respeito dos critérios técnicos e das opções de componentes disponíveis no mercado, fornecendo uma orientação inicial consistente ao profissional envolvido sobre os materiais que podem ser aplicados à via em estudo. / Over the last years, a continuous increase on demand for railroad heavy haul transport has been witnessed in Brazil, reflecting in bigger volume of projects for expansion or improvement of the existing lines in the country. With this current situation, it becomes essential that the professional involved with the elaboration of projects of the permanent way should have information brought up to date regarding the variety of components of the existing railroad materials in the market, so that the projects take care of fully to the necessities of the customer. Thus being, the present work has as main objective to search and to analyze the types of existing components in the market used in the composition of the railroad superstructure (rails, ties and fastenings), with main focus in that which can be applied to the heavy haul railways. First, from research in national and international bibliographical material, the main aspects related to the performance that must be considered in the process of evaluation of these components will be describes, having as base the design parameters of the way established previously in accordance with the requirements of the load operation, such as: position for axle, speed of operation, maximum slope, and others. After that, the types of rails, ties (wood ties, monoblock and bi-block concrete ties, steel ties and plastic ties) and fastenings (rigid and elastic) currently available in the market and its characteristics of performance and conditions of use will be presented, according to the information provided by the its respective manufacturers. All the reports showed in the two previous described stages will be analyzed and compared, so that is possible to highlight the interdependence relations that exist between the different types of components. At the end of the work, a flowchart model which gathers the input data about the heavy haul railroad, the performance guidelines that should be followed and the types of components of the railroad superstructure that can be used in accordance to the studied case, will be presented. With that, it is expected that the produced flowchart could be a useful tool in the stage of design of a new railroad, once it will present in a clear and objective way an embracing and up-to-date set of information regarding the performance criteria and the options of components available in the market, supplying a consistent initial orientation to the designer about the materials that could be applied to the railway.

Radiotherapy aims to sterilize cancer cells through ionization induced damages to their DNA whilst trying to reduce dose burdens to healthy tissues. This can be achieved to a certain extent by optimizing the choice of radiation to treat the patient, i.e. the types of particles and their energy based on their specific interaction patterns. In particular, the formation of complex clusters of energy deposits (EDs) increases with the linear energy transferred for a given particle. These differences cause variation in the relative biological effectiveness (RBE). The complexity of ED clusters might be related to complex forms of DNA damage, which are more difficult to repair and therefore prone to inactivate the cells. Hence, mapping of the number and complexity of ED clusters for different radiation qualities could aid to infer a surrogate measure substituting physical dose and LET as main predictors for the RBE .   In this work the spatial patterns of EDs at the nanometre scale were characterized for various energies of proton, helium, lithium and carbon ions. A track structure Monte Carlo code, LIonTrack, was developed to accurately simulate the light ion tracks in liquid water. The methods to emulate EDs at clinical dose levels in cell nucleus-sized targets for both 60Co photons and light ions were established, and applied to liquid water targets. All EDs enclosed in such targets were analyzed with a specifically developed cluster algorithm where clustering was defined by a single parameter, the maximum distance between nearest neighbour EDs. When comparing measured RBE for different radiation qualities, there are cases for which RBE do not  increase with LET but instead increase with the frequencies of high order ED clusters. A test surrogate-measure based on ED cluster frequencies correlated to parameters of experimentally determined cell survival. The tools developed in this thesis can facilitate future exploration of semi-mechanistic modelling of the RBE.

The energy deposition characteristics of heavy ions vary substantially compared to those of photons. Many radiation biology studies have compared the damaging effects of different types of radiation to establish relative biological effectiveness among them. These studies are dependent on cell type, biological endpoint, radiation type, dose, and dose rate. The radiation field found in space is much more complicated than that simulated in most experiments, both from a point of dose-rate as well as the highly mixed field of radiative particles encompassing a broad spectrum of energies. To establish better estimates for radiation risks on long-term, deep space missions, the damaging ability of heavy ions requires further understanding. Track structure studies provide significant details about the spatial distribution of energy deposition events in and around the sensitive targets of a mammalian cell. The damage imparted by one heavy ion relative to another can be established by modeling the track structures of ions that make up the galactic cosmic ray (GCR) spectrum and emphasizing biologically relevant target geometries. This research was undertaken to provide a better understanding of the damaging ability of GCR at the cellular level. By comparing ions with equal stopping power values, the differences in track structure will illuminate variations in cell particle traversals and ionization density within cell nuclei. For a cellular target, increased particle traversals, along with increased ionization density, are key identifiers for increased damaging ability. Performing Monte Carlo simulations with the computer code, FLUKA, this research will provide cellular dosimetry data and detail the track structure of the ions. As shown in radiobiology studies, increased ionizations within a cell nucleus generally lead to increased DNA breaks and increased free radical production, resulting in increased carcinogenesis and cell death. The spatial distribution of dose surrounding ions tracks are compared for inter- and intracellular regions. A comparison can be made for many different ions based upon dose and particle fluence across those different regions to predict relative damaging ability. This information can be used to improve estimates for radiation quality and dose equivalent from the space radiation environment.

The purpose of this thesis is to present data pertinent to and propose conclusions regarding the coordination of radiobiologic effectiveness (RBE) and linear energy transfer (LET). RBE is a quantity relating the effectiveness of different radiations in causing cell death. LET is a measure of the rate of energy transferred to material by an ionizing particle. This relationship of these values varies for different particles. The reason for this is still inconclusive. The petitioner has made use of a toolkit for Geant4, known as Geant4-DNA, to perform track-structure analysis on a chromosome model. Geant4 is an object-oriented program for the "simulation of the passage of particles through matter" developed by CERN that makes use of Monte Carlo methods and is expanded by Geant4-DNA to handle low-energy electron physics as well as physic-chemical effects. The chromosome model, in this case, has been developed by the petitioner as a nucleus with a basic, uniform distribution of chromatin. Radiation damage to DNA, in the form of aberrations, lesions and strand breaks, can be coordinated to energy deposited or number of ionizations occurring in the target (in this case DNA or chromatin fiber). Certain threshold values have been established as indicate of different types of DNA damage. The ultimate goal of this work is to score these clusters of events against the threshold values to determine the severity of DNA damage. The final comparison of the results for different particles will provide for a better understanding of the RBE-LET relationships by improving the understanding of the underlying nanodosimetric qualities.

Nos últimos anos, tem-se presenciado um contínuo aumento na demanda por transporte de carga ferroviário no Brasil, o que tem se refletido em maior volume de projetos para expansão ou revitalização da malha existente no país. Diante deste quadro atual, torna-se essencial que o profissional envolvido com a elaboração de projetos da via permanente tenha em mãos informações atualizadas a respeito da variedade de componentes da grade ferroviária existente no mercado, a fim de que os projetos atendam plenamente às necessidades do cliente. Assim sendo, o presente trabalho tem como principal objetivo pesquisar e analisar os tipos de componentes existentes no mercado usados na composição da grade ferroviária (trilhos, dormentes e fixações), com foco principal naqueles que podem ser aplicados às ferrovias de transporte de carga. Primeiramente, a partir de pesquisa em material bibliográfico nacional e internacional, serão descritos os principais aspectos técnicos que devem ser considerados no processo de avaliação destes componentes, tendo como base os parâmetros de projeto da via estabelecidos previamente de acordo com as exigências da operação de carga, tais como: carga por eixo, velocidade de operação, rampa máxima, etc. Em seguida, serão apresentados os tipos de trilhos, dormentes (madeira, concreto monobloco e bi-bloco, aço e plástico) e fixações (rígidas e elásticas) existentes atualmente no mercado e suas características de desempenho e condições de uso estabelecidas pelos respectivos fabricantes. Os dados obtidos nas duas etapas descritas anteriormente serão analisados e confrontados, de forma que seja possível explicitar as relações de interdependência que existem entre os diferentes tipos de componentes. Ao final do trabalho, será apresentado um modelo de fluxograma que reúne os dados de entrada para o projeto da ferrovia de transporte de carga, as diretrizes técnicas que devem ser atendidas em seu projeto e, por fim, os tipos de componentes da grade ferroviária que podem ser empregados de acordo com o caso estudado. Com isso, espera-se que o produto final gerado possa ser uma ferramenta útil na etapa de concepção de novos projetos ferroviários, visto que apresentará de maneira clara e objetiva um conjunto de informações bastante abrangente e atualizado a respeito dos critérios técnicos e das opções de componentes disponíveis no mercado, fornecendo uma orientação inicial consistente ao profissional envolvido sobre os materiais que podem ser aplicados à via em estudo. / Over the last years, a continuous increase on demand for railroad heavy haul transport has been witnessed in Brazil, reflecting in bigger volume of projects for expansion or improvement of the existing lines in the country. With this current situation, it becomes essential that the professional involved with the elaboration of projects of the permanent way should have information brought up to date regarding the variety of components of the existing railroad materials in the market, so that the projects take care of fully to the necessities of the customer. Thus being, the present work has as main objective to search and to analyze the types of existing components in the market used in the composition of the railroad superstructure (rails, ties and fastenings), with main focus in that which can be applied to the heavy haul railways. First, from research in national and international bibliographical material, the main aspects related to the performance that must be considered in the process of evaluation of these components will be describes, having as base the design parameters of the way established previously in accordance with the requirements of the load operation, such as: position for axle, speed of operation, maximum slope, and others. After that, the types of rails, ties (wood ties, monoblock and bi-block concrete ties, steel ties and plastic ties) and fastenings (rigid and elastic) currently available in the market and its characteristics of performance and conditions of use will be presented, according to the information provided by the its respective manufacturers. All the reports showed in the two previous described stages will be analyzed and compared, so that is possible to highlight the interdependence relations that exist between the different types of components. At the end of the work, a flowchart model which gathers the input data about the heavy haul railroad, the performance guidelines that should be followed and the types of components of the railroad superstructure that can be used in accordance to the studied case, will be presented. With that, it is expected that the produced flowchart could be a useful tool in the stage of design of a new railroad, once it will present in a clear and objective way an embracing and up-to-date set of information regarding the performance criteria and the options of components available in the market, supplying a consistent initial orientation to the designer about the materials that could be applied to the railway.

The present state of modeling radio-induced effects at the cellular level neglects to account for the microscopic inhomogeneity of the nucleus from the non-aqueous contents by approximating the entire cellular nucleus as a homogenous medium of water. Charged particle track-structure calculations utilizing this principle of superposition are thereby neglecting to account for approximately 30% of the molecular variation within the nucleus. To truly understand what happens when biological matter is irradiated, charged particle track-structure calculations need detailed knowledge of the secondary electron cascade, resulting from interactions with not only the primary biological component – water – but also the non-aqueous contents, down to very low energies. This paper presents developments for a novel approach, which to our knowledge has never been done before, to reducing the homogenous water approximation. The purpose of our work is to develop of a completely self-consistent computational method for predicting molecule-specific ionization, excitation, and scattering cross sections in the very low energy regime that can be applied in a condensed history Monte Carlo track-structure code. The present methodology begins with the calculation of a solution to the many-body Schrödinger equation and proceeds to use Monte Carlo methods to calculate the perturbations in the internal electron field to determine the aforementioned processes. Results are computed for molecular water in the form of linear energy loss, secondary electron energies, and ionization-to-excitation ratios and compared against the low energy predictions of the GEANT4-DNA physics package of the Geant4 simulation toolkit.

Les rayonnements ionisants sont connus pour induire des dommages critiques au sein de la matière biologique et spécialement au sein de l’ADN. Parmi ces dommages, les cassures doubles brins de l’ADN (DSB) sont considérées comme les principales responsables des effets létaux des rayonnements. Comprendre et prédire comment ces cassures sont créées et réparées dans les noyaux cellulaires demeure un défi dans la recherche en radiobiologie. Ce travail s’inscrit dans ce contexte, dans la modélisation des cassures double brin de l’ADN (DSB) à partir des dépôts d’énergie créés par l’irradiation au niveau intracellulaire. Le détail topologique au niveau nanométrique des dépôts d’énergie nécessaire à ce travail est obtenu par modélisation Monte Carlo à l’aide du code Geant4 et, en particulier son extension Geant4-DNA pour des processus à très faible énergie. Les dommages étudiés étant ceux localisés dans l’ADN, le premier objectif de ce travail a été de réaliser une géométrie détaillée de celui-ci afin de l’implémenter dans les calculs Monte Carlo. Deux types de noyaux cellulaires, représentant un fibroblaste et un endothélium, ont été décrits afin d’évaluer l’influence de la densité d’ADN dans les résultats sur la topologie des dépôts pouvant donner lieux à des cassures de la molécule. Cette géométrie nous permet d’effectuer une première sélection des dépôts d’énergie pouvant contribuer aux cassures car situées sur la chaîne sucre-phosphate. Ces dépôts sont ensuite analysés à l’aide d’un algorithme de clustérisation de manière à les regrouper sous forme d’agrégats afin d’étudier leur localisation et complexité. Néanmoins, dans cette étude, seule les interactions physiques entre les rayonnements ionisants et la cible sont modélisées, il n’est donc pas possible d’obtenir un nombre absolu de cassures de brins car cette modélisation n’inclue pas l’étape de création et de transport des radicaux libres pouvant donner lieu à des dommages indirects. Ainsi, le but de ce travail était d’évaluer la dépendance relative des dommages radio-induits directs avec la densité d’ADN, la qualité du rayonnement, la morphologie du noyau ou encore la condensation de la chromatine. Les différentes modélisations réalisées ont permis de quantifier l’influence de ces différents paramètres dans le nombre et la complexité des dommages directs induits dans l’ADN, pouvant ensuite contribuer aux effets tardifs sur le devenir cellulaire. / Ionizing radiations are known to induce critical damages on biological matter and especially on DNA. Among these damages, DNA double strand breaks (DSB) are considered as key precursor of lethal effects of ionizing radiations. Understand and predict how DNA double and simple strand breaks are created by ionising radiation and repaired in cell nucleus is nowadays a major challenge in radiobiology research. This work presents the results on the simulation of the DNA double strand breaks produced from the energy deposited by the irradiation at the intracellular level. At the nanometric scale, the only method to accurately simulate the topological details of energy deposited on the biological matter is the use of Monte Carlo codes. In this work, we used the Geant4 Monte Carlo code and, in particular, the low energy electromagnetic package extensions, referred as Geant4-DNA processes.In order to evaluate DNA radio-induced damages, the first objective of this work consisted in implementing a detailed geometry of the DNA on the Monte Carlo simulations. Two types of cell nuclei, representing a fibroblast and an endothelium, were described in order to evaluate the influence of the DNA density on the topology of the energy deposits contributing to strand breaks. Indeed, the implemented geometry allows the selection of energy transfer points that can lead to strand breaks because they are located on the backbone. Then, these energy transfer points were analysed with a clustering algorithm in order to reveal groups of aggregates and to study their location and complexity.In this work, only the physical interactions of ionizing radiations are simulated. Thus, it is not possible to achieve an absolute number of strand breaks as the creation and transportation of radical species which could lead to indirect DNA damages is not included. Nevertheless, the aim of this work was to evaluate the relative dependence of direct DNA damages with the DNA density, radiation quality, cell nuclei morphology or also chromatin condensation. The results presented in this work have allowed the quantification of the influence of these different parameters in the number and complexity of directs DNA damages which can then contribute to the late effects on cell fate.

Este trabalho apresenta o estudo dos efeitos dinâmicos de duas pontes ferroviárias para trens de carga pesada e trens de alta velocidade considerando a interação veículo-estrutura. O estudo centrou-se principalmente no desenvolvimento de uma metodologia iterativa para a simulação do fenômeno de interação. Em seguida, a metodologia desenvolvida foi utilizada para analisar a ponte Suaçuí (Brasil) e a ponte Antuã (Portugal), e para realizar um estudo paramétrico para avaliar o comportamento não linear da interface via-estrutura de algumas tipologias de pontes ferroviárias. A fim de entender os princípios básicos que governam a resposta dinâmica do sistema veículo-estrutura, foi realizada uma revisão das formulações analíticas e os conceitos básicos de interação veículo-estrutura. A partir das formulações analíticas desenvolveu-se uma metodologia para a resolução de problemas dinâmicos de interação, aproveitando as ferramentas de modelagem do programa ABAQUS por meio do programa MATLAB. A validação do aplicativo foi realizada comparando as respostas de exemplos simples analisados com programas de referência. A principal vantagem desta metodologia é a flexibilidade na seleção dos métodos de resolução do problema dinâmico, permitindo inclusive a incorporação de não linearidades tanto no modelo do veículo quanto da ponte. Utilizando a capacidade de simulação do aplicativo para problemas não lineares foi realizado um estudo paramétrico para verificar os parâmetros que mais influenciam no comportamento não linear da interface via-estrutura e uma aplicação prática para avaliar o desempenho de algumas tipologias de pontes ferroviárias. Para a análise dinâmica da ponte Suaçuí e Antuã desenvolveram-se modelos numéricos tridimensionais de elementos finitos no programa ABAQUS. As propriedades dos materiais das pontes, assim como as propriedades dinâmicas dos veículos foram determinadas a partir de técnicas de calibração numéricas, experimentais e da literatura. A calibração dos modelos numéricos foi realizada utilizando metodologias iterativas baseadas em técnicas de otimização, tais como os algoritmos genéticos. Na falta de dados experimentais das irregularidades, estas foram geradas a partir de funções de densidade espectral de potência. A validação dos modelos numéricos da ponte envolveu a comparação dos resultados numéricos, obtidos da análise de interação, e os resultados experimentais, encontrados nos ensaios dinâmicos sob ação de tráfego. Os resultados da comparação mostraram que os modelos numéricos conseguem reproduzir com boa aproximação as respostas medidas experimentalmente. Finalmente, são realizadas simulações das pontes sob ação de tráfego para diferentes velocidades de circulação dos veículos, a fim de verificar a segurança estrutural da ponte e da via, além do conforto dos passageiros. / This research presents the study of the dynamic effects of two railway bridges for heavy axle load trains and high speed trains considering the vehicle-structure interaction. The study was mainly focused on the development of an iterative method for simulating the interaction phenomenon. The developed methodology was used to investigate the Suaçuí railway bridge (Brazil) and the Antuã railway bridge (Portugal), and to carry out a parametric study to evaluate the non-linear behavior of the trackstructure interface of some typologies of railway bridges. In order to understand the basic principles that govern the dynamic response of the vehicle-structure system, a review of the analytical formulations and the basics of the vehicle-structure interaction were performed. Based on the analytical formulations a methodology for solving dynamic interaction problems was developed, taking advantage of modeling tools of the ABAQUS software managed from MATLAB. The validation of the methodology was carried out by comparing responses of simple examples analyzed with reference programs. The main advantage of this methodology is the flexibility in the selection of the methods for solving the dynamic problem, even allowing the incorporation of nonlinearities in the vehicle and bridge model. Using the capability of the developed program for modeling nonlinear problems it was carried out a parametric study to determine the parameters that influence in the non-linear behavior of the track-structure interface and a practical application to evaluate the performance of some typologies of railway bridges. For dynamic analysis of the Suaçuí and Antuã railway bridge threedimensional numerical finite element models in ABAQUS program were developed. Material properties of the bridges, as well as the dynamic properties of the vehicles were determined through numerical and experimental calibration techniques and from the literature. The calibration of numerical models was performed using iterative methodologies based on optimization techniques, such as genetic algorithms. In absence of experimental data irregularities of the Suaçuí bridge, these were generated using spectral density functions. The validation of numerical models of the bridges involved the comparison of numerical results obtained from the interaction analysis with experimental results obtained from dynamic tests under traffic loads. The results of comparison showed that the numerical models were capable to reproduce with good accuracy the responses experimentally measured. Finally simulations of the bridges under traffic loads were performed for different vehicle speeds in order to evaluate the structural and track safety and passenger comfort.