ATRX is a chromatin remodeling protein associated with X-linked Alpha-Thalassemia Mental Retardation syndrome and cancers that use the Alternative Lengthening of Telomere pathway. In the absence of ATRX there is a DNA damage response associated with telomeres and the expression of certain genes are perturbed. Recent findings (Law et al, 2010 Cell) have shown that ATRX is preferentially enriched at GC-rich tandem repeats in the genome. The mechanism for this localisation is unknown but may be related to the potential for these GC-rich tandem repeats to adopt non-B form DNA structures; ATRX has been shown to bind such structures (G4) in vitro. This study aims to understand the specific factors of the repeats that signal ATRX targeting. To address the research questions, an experimental system was developed, in which known targets, the ψζ VNTR and telomere repeats, were inserted into an inducible ectopic gene in the 293T-Rex cell line by site-directed recombination. ATRX was found to be enriched at the ectopic repeats compared to an endogenous negative control suggesting that it is recruited by the repeats independent of its original context. Furthermore, ATRX enrichment increased upon transcription of the ectopic gene, and this was dependent on the orientation of the repeat with the non-template strand being G-rich. Interestingly, when the repeat was transcribed, the distribution of ATRX across the repeats was asymmetrical with most ATRX binding downstream of the repeat. Moreover, there was a direct correlation between the repeat size and level of ATRX bound: the longer the repeat the higher the increase in ATRX enrichment. To determine the signal for ATRX binding, assays were performed to look for features which reflected the distribution of ATRX including H3K9me3, RNA polII, G4, R loops and DNA supercoiling. R loops look to be a strong candidate for the signaling of ATRX binding.

In these diploma thesis magnetically ordered materials are studied with the prospect of their application in spintronics. Specifically, we investigated metallic alloy FeRh, which undergoes a magnetic phase transition from antife- romagnetic phase to feromagnetic one around 100◦ C. This phenomenon can be readily used in memory devices. Laser spectroscopy is used as a nondestructive method without need of any electrical contacts. Magnetic properties of FeRh are studied by magnetooptical effects including quadratic magnetic linear dichroism. The measured polarization rotations are of the order of miliradians, therefore, the detection is realized by an optical bridge. At first, we concentrated on discrimina- ting of various magnetooptical effects from each other. The second part is focused on the phase transition induced by different means. Firstly, by heating the whole sample, secondly by illuminating the sample locally by continuous laser.

La surexpression de pompes d’efflux par les cellules cancéreuses permet l’élimination d’agents cytotoxiques, induisant alors une résistance à la chimiothérapie. Trois transporteurs ABC sont principalement impliqués dans cette résistance : ABCB1 (aussi appelé P-gp), ABCC1 (ou MRP1) et ABCG2 (ou BCRP, MXR, ABCP). Du fait de leur implication dans le phénotype de « MultiDrug Resistance », il est essentiel de mieux comprendre le fonctionnement de ces transporteurs. Une étude par mutagenèse dirigée a montré que les boucles intracellulaires, ICL0 et ICL1 sont impliquées dans le transport des substrats. Deux résidus sont particulièrement intéressants : W379 qui agirait comme un filtre des substrats ; et H457 qui participerait à la reconnaissance ou à la fixation des substrats. Par ailleurs, il est important de moduler cette chimiorésistance. Dans ce contexte nous avons développé une nouvelle classe d’inhibiteurs d’ABCB1 et ABCG2 non compétitifs basés sur un motif dipeptidique. Les composés les plus efficaces, CT1347 pour ABCB1 et CT1364 pour ABCG2, s’avèrent, d’une part peu ou pas cytotoxiques à fortes concentrations, abolissent d’autre part la résistance induite par ABCB1 ou ABCG2 et se comportent comme des inhibiteurs non compétitifs du Hoechst 33342 et de la daunorubicine. De plus, CT1364 inhibe l’activité ATPasique d’ABCG2 et induit une diminution rapide de l’expression de la protéine. Enfin, les 1ers tests in vivo de ce composé montrent que l’association avec l’irinotécan ralentit la croissance des xénogreffes de petite taille chez des souris / Resistance to chemotherapy is partly due to efflux pumps expressed in the plasma membrane which prevent the accumulation of anticancer drugs in the tumour cells. Three human ATP-binding Cassette (ABC) transporters are particularly involved in this phenotype: P-gp/ABCB1, MRP1/ABCC1, and the last discovered BCRP/ABCG2. Because of their involvement in chemoresistance, it is critical to understand the mechanism by which those ABC transporters recognize and transport drugs. The mutagenesis study of the intracellular loops, ICL0 and 1 shows that these loops are involved in this mechanism. Two amino acids were particularly remarkable: W379 which act as a substrate filter and H457 which can be involved in substrate recognition and binding. In order to restore the cancer cell sensitivity to chemotherapeutic drugs, we have developed a new class of peptide inhibitors, specific to one transporter. A structure-activity relationship study has been performed and made it possible to develop a second generation of molecules. The most efficient compound inhibiting ABCB1 (CT1347) or ABCG2 (CT1364) have none or limitated cytotoxic effects. These compounds restore the activity of chemotherapeutic drugs and act as non competitive inhibitors. Moreover, CT1364 inhibits the ATP hydrolysis activity and lead to a rapid reduction of ABCG2 expression. Initial in vivo tests that have been carried out with CT1364 associated with irinotecan allow to observe a growth reduction of small mice xenografts

Apresenta-se a evolução dos sitemas de comunicação, com ênfase especial nos sistemas com tecnologia óptica. Discute-se a necessidade contínua do aumento de capacidade de tais sistemas de comunicação, e a consequente repercussão sobre os futuros sistemas ópticos. Em vista da necessidade do aumento de capacidade dos futuros sistemas de comunicação óptica, apresentam-se em seguida duas propostas recentes da literatura, sendo uma referente à realização de um gerador de pulsos ópticos estreitos, e a outra referente à implementação de um extrator de relógio realizado com técnicas ópticas. Apresenta-se um breve resumo da teoria das malhas de sincronismo de fase, ou PLLs, mostrando como as duas propostas discutidas realizam funções típicas desses sistemas. Ressalta-se a necessidade dos PLLs de sistemas ópticos possuirem ganhos de malha (parâmetro K) elevados. Após a caracterização dos requisitos necessários para PLLs de futuros sistemas ópticos, e após um resumo de alguns conceitos necessários da teoria de redes e filtros elétricos, apresentam-se dois tipos de projeto de filtros para aqueles PLLs. As duas formas de projeto tem como objetivo viabilizar o uso de filtros de tipo e ordem arbitrários. Um tipo de projeto visa a realização da função de transferência do PLL com a curva de resposta igual à de um filtro escolhido. O outro tipo de projeto parte da realização do filtro de loop do PLL com as características de um tipo de filtro escolhido, e define métodos para ajustar a função de transferência resultante para esse PLL. Apresentam-se algoritmos para o cálculo de parâmetros importantes nos dois procedimentos. Após a discussão dos dois pontos de vista de projeto, apresentam-se exemplos de realização de PLLs de acordo com as técnicas apresentadas. Para cada exemplo, mostram-se as curvas de resposta em frequência tanto do PLL como do correspondente filtro de loop, bem como o lugar das raízes e a resposta de captura do PLL obtido. O processo de captura foi estudado por simulações que procuram reproduzir o mais fielmente possível as condições reais de implementação, sem entretanto considerar efeitos de ruído. Finalmente, mencionam-se brevemente possíveis linhas de pesquisa futuras, sendo o foco principal o uso de filtros com pólos e zeros finitos. / The evolution of communication systems is discussed, with emphasis on optical technology. Special consideration is given to the continuous need for increasing the capacity of such systems, and the impact over future optical communication. In view of the great demands imposed over the capacity of future optical systems, an overview is presented of two recent proposals found in the literature, one of such proposals being the implementation of a generator of short optical pulses, and the other being a clock extractor device realized through the use of optical techniques. A brief review is made of phase-locked loop (or PLL) theory, to show how the discussed proposals could be used to realize tipical functions found in these systems. The very high loop gains (the so-called parameter K) that must be used in PLLs of optical communication systems are emphasized. After discussion of the necessary characteristics for PLLs of future optical systems, and also after a review of some concepts of the theory of electrical networks and filters, two design procedures for filters to be used in such PLLs are presented. Both designs have the goal of allowing the use of loop filters with any type and order. The first type of design has the objective to realize a PLL transfer function that has a frequency response identical to the response of a chosen type of filter. The other design starts with a chosen type of filter for a PLL loop filter, arriving to an suitable PLL transfer function. Some algorithms for determination of important design parameters are also presented. After the discussion of the two types of design, some examples of PLLs obtained by such methods are presented. For each example, frequency response curves are presented for the PLL and the respective loop filter, as well as the root locus and the capture response for the PLL so obtained. The capture process was studied through the use of simulations with parameters intended to approximate real implementation conditions, although noise effects are not considered. Finally, some possible research lines are discussed, whose main focus is on filters with finite poles and zeros.

Neste trabalho, são estudados os problemas de sincronismo de fase nas redes mestre-escravo de via única (OWMS), nas topologias Estrela Simples, Cadeia Simples e mista, através da Teoria Qualitativa de Equações Diferenciais, com ênfase no Teorema da Variedade Central. Através da Teoria das Bifurcações, analisa-se o comportamento dinâmico das malhas de sincronismo de fase (PLL) de segunda ordem que compõem cada rede, frente às variações nos seus parâmetros constitutivos. São utilizadas duas funções de excitação muito comuns na prática: o degrau e a rampa de fase, aplicadas pelo nó mestre. Em cada caso, discute-se a existência e a estabilidade do estado síncrono. A existência de pontos de equilíbrio não-hiperbólicos, não permite uma aproximação linear, e nesses casos é aplicado o Teorema da Variedade Central. Através dessa rigorosa técnica de simplificação de sistemas dinâmicos é possível fazer uma aproximação homeomórfica em torno desses pontos, preservando a orientação no espaço de fases. Desse modo, é possível determinar, localmente, suas estabilidades. / This work presents stability analysis of the syncronous state for three types of one-way master-slave time distribution network topologies: single star, single chain and both of them, mixed. Using bifurcation theory, the dynamical behavior of second-order phase-locked loops employed to extract the syncronous state in each node is analyzed in function of the constitutive parameters. Two usual inputs, the step and the ramp phase pertubations, are supposed to appear in the master node and, in each case, the existence and stability of the syncronous state are studied. For parameter combinations resulting in non hyperbolic synchronous states, the linear approximation does not provide any information, even about the local behaviour of the system. In this case, the center manifold theorem permits the construction of an equivalent vector field representing the asymptotic behaviour of the original system in the neighborhood of these points. Thus, the local stability can be determined.

Integrabilität hat sich als ein wichtiges Konzept erwiesen, um die Grenzen einer störungstheoretischen Beschreibung zu überwinden und ein tiefer gehendes Verständnis von speziellen vierdimensionalen Quantenfeldtheorien zu erlangen. Die der Integrabilität zugrunde liegende algebraische Struktur ist der Yangian, welchen man als eine unendlichdimensionale Erweiterung einer Lie-Algebra auffassen kann. In der vorliegenden Arbeit untersuchen wir die Yang’sche Symmetrie von super Wilson Schleifen und Fischnetz Feynman Graphen. Im ersten Teil dieser Arbeit diskutieren wir Maldacena–Wilson Schleifen in N=4 SYM Theorie. Unter Ausnutzung der nicht-chiralen Superraumbeschreibung des N=4 SYM Modells konstruieren wir den supersymmetrisch vervollständigten Schleifenoperator, welcher dual ist zu einer durch den vollen AdS5xS5 Superstring beschriebenen Minimalfläche. Wir zeigen, dass dieser Schleifenoperator sowohl globale superkonforme als auch lokale kappa Symmetrie besitzt, wobei wir letztere zur 1/2 BPS Eigenschaft der bosonischen Maldacena–Wilson Schleife in Beziehung setzen. Weiterhin berechnen wir den Einschleifenerwartungswert des Operators und beweisen dessen Endlichkeit. Anschließend beschäftigen wir uns detailliert mit der Yang’schen Symmetrie von glatten super Maldacena–Wilson Schleifen. Wir untersuchen anhand einer generischen Eichtheorie die verschiedenen Möglichkeiten, die Yang’schen Generatoren zu realisieren und begründen unsere Wahl einer Darstellung in Form von eichkovarianten Operatoreinsetzungen. Unter Verwendung dieser Darstellung beweisen wir nachfolgend die Yang’sche Invarianz des vollen Einschleifenerwartungswertes der super Maldacena– Wilson Schleife. Im zweiten Teil dieser Arbeit beschäftigen wir uns mit Fischnetz Feynman Graphen, welche aus viervalenten Vertizes bestehen, die durch skalare Propagatoren miteinander verbunden sind. Wir zeigen, dass diese Diagramme zu allen Schleifenordnungen eine konforme Yang’sche Symmetrie aufweisen und konstruieren explizit die Yang’schen Generatoren, die diese Diagramme vernichten. Für Vielschleifendiagramme gelingt uns Letzteres durch eine Umformulierung der Symmetrie in Form von Eigenwertgleichungen inhomogener Monodromiematrizen, aus deren Entwicklung sich die Generatoren ablesen lassen. Die Yang’sche Symmetrie impliziert, dass Fischnetz Integrale partielle Differenzialgleichungen erfüllen, deren Form wir anhand des Boxintegrals illustrieren. / Quantum integrability has turned out to be an important concept in overcoming the limitations of perturbation theory and reaching a more profound understanding of particular four-dimensional quantum field theories. The algebraic structure that underlies integrability in field and string theory is the Yangian, which can be understood as an infinite-dimensional extension of a Lie algebra. Here, we investigate the Yangian symmetry of super Maldacena–Wilson loops and fishnet Feynman graphs. In the first part of this thesis, we discuss Maldacena–Wilson loops in N=4 SYM theory. Utilizing the non-chiral superspace formulation of the N=4 SYM model, we construct the full supersymmetric completion of this operator, which is the natural object dual to a minimal surface described by the full AdS5xS5 superstring. We show that the super loop operator enjoys global superconformal as well as local kappa symmetry, the latter being related to the 1/2 BPS property of the bosonic Maldacena–Wilson loop. Using a convenient type of transversal gauge, we establish the operators one-loop expectation value and prove it to be finite. We then perform a detailed study of the Yangian symmetries of smooth super Maldacena–Wilson loops. Focusing on a generic gauge theory setup, we analyze in detail the different options for representing the Yangian generators and argue for a representation in terms of gauge-covariant operator insertions. Subsequently, we utilize this approach to prove the Yangian invariance of the full one-loop expectation value. The second part of this thesis is devoted to the study of four-dimensional fishnet Feynman graphs, which are built from four-valent vertices that are joined by scalar propagators. We show that these diagrams feature a conformal all-loop Yangian symmetry, which we phase in terms of generators annihilating these graphs as well as in terms of inhomogeneous monodromy eigenvalue relations. The Yangian symmetry results in novel differential equations for this family of largely unsolved Feynman integrals and we shall study their form by considering the box integral as an example.

Apresenta-se a evolução dos sitemas de comunicação, com ênfase especial nos sistemas com tecnologia óptica. Discute-se a necessidade contínua do aumento de capacidade de tais sistemas de comunicação, e a consequente repercussão sobre os futuros sistemas ópticos. Em vista da necessidade do aumento de capacidade dos futuros sistemas de comunicação óptica, apresentam-se em seguida duas propostas recentes da literatura, sendo uma referente à realização de um gerador de pulsos ópticos estreitos, e a outra referente à implementação de um extrator de relógio realizado com técnicas ópticas. Apresenta-se um breve resumo da teoria das malhas de sincronismo de fase, ou PLLs, mostrando como as duas propostas discutidas realizam funções típicas desses sistemas. Ressalta-se a necessidade dos PLLs de sistemas ópticos possuirem ganhos de malha (parâmetro K) elevados. Após a caracterização dos requisitos necessários para PLLs de futuros sistemas ópticos, e após um resumo de alguns conceitos necessários da teoria de redes e filtros elétricos, apresentam-se dois tipos de projeto de filtros para aqueles PLLs. As duas formas de projeto tem como objetivo viabilizar o uso de filtros de tipo e ordem arbitrários. Um tipo de projeto visa a realização da função de transferência do PLL com a curva de resposta igual à de um filtro escolhido. O outro tipo de projeto parte da realização do filtro de loop do PLL com as características de um tipo de filtro escolhido, e define métodos para ajustar a função de transferência resultante para esse PLL. Apresentam-se algoritmos para o cálculo de parâmetros importantes nos dois procedimentos. Após a discussão dos dois pontos de vista de projeto, apresentam-se exemplos de realização de PLLs de acordo com as técnicas apresentadas. Para cada exemplo, mostram-se as curvas de resposta em frequência tanto do PLL como do correspondente filtro de loop, bem como o lugar das raízes e a resposta de captura do PLL obtido. O processo de captura foi estudado por simulações que procuram reproduzir o mais fielmente possível as condições reais de implementação, sem entretanto considerar efeitos de ruído. Finalmente, mencionam-se brevemente possíveis linhas de pesquisa futuras, sendo o foco principal o uso de filtros com pólos e zeros finitos. / The evolution of communication systems is discussed, with emphasis on optical technology. Special consideration is given to the continuous need for increasing the capacity of such systems, and the impact over future optical communication. In view of the great demands imposed over the capacity of future optical systems, an overview is presented of two recent proposals found in the literature, one of such proposals being the implementation of a generator of short optical pulses, and the other being a clock extractor device realized through the use of optical techniques. A brief review is made of phase-locked loop (or PLL) theory, to show how the discussed proposals could be used to realize tipical functions found in these systems. The very high loop gains (the so-called parameter K) that must be used in PLLs of optical communication systems are emphasized. After discussion of the necessary characteristics for PLLs of future optical systems, and also after a review of some concepts of the theory of electrical networks and filters, two design procedures for filters to be used in such PLLs are presented. Both designs have the goal of allowing the use of loop filters with any type and order. The first type of design has the objective to realize a PLL transfer function that has a frequency response identical to the response of a chosen type of filter. The other design starts with a chosen type of filter for a PLL loop filter, arriving to an suitable PLL transfer function. Some algorithms for determination of important design parameters are also presented. After the discussion of the two types of design, some examples of PLLs obtained by such methods are presented. For each example, frequency response curves are presented for the PLL and the respective loop filter, as well as the root locus and the capture response for the PLL so obtained. The capture process was studied through the use of simulations with parameters intended to approximate real implementation conditions, although noise effects are not considered. Finally, some possible research lines are discussed, whose main focus is on filters with finite poles and zeros.

Inicialmente, apresentam-se características de dispositivos eletrônicos conhecidos como PLLs (phase-locked loops). PLLs são amplamente empregados para se extrair sinais de tempo em canais de comunicação e em aplicações nas quais se deseja controle automático de freqüência. O objeto principal é estudar PLLs analógicos descritos por uma equação diferencial ordinária de terceira ordem. Assim, deduzem-se condições de estabilidade assintótica e identifica-se um regime de caos conservativo, que ocorre sob certas combinações de valores de parâmetros. Três métodos de controle não-linear/caótico são então apresentados e aplicados. Os métodos são os seguintes: o Método de Pyragas via realimentação de variável de estado; o Método de Pyragas com atraso temporal na realimentação; e o Método de Sinha, o qual efetua o controle perturbando um parâmetro do sistema. Simulações numéricas são levadas a cabo a fim de ilustrar o comportamento dinâmico do sistema quando sujeito à ação desses métodos. Este trabalho termina com um estudo de uma rede formada por uma cadeia de PLLs. Condições para soluções síncronas, periódicas e caóticas (dissipativas e conservativas) são deduzidas para tal rede. / Firstly, features of electronic devices known as PLLs (Phase-Locked Loops) are presented. PLLs are widely employed to extract time signals in communication channels and in applications where automatic control of frequency is desired. The main goal is to study analog PLLs described by a third-order nonlinear ordinary differential equation. Thus, conditions for asymptotic stability are derived and a regime of conservative chaos occurring under certain combinations of parameter values is identified. Then, three methods of control of nonlinear/ chaotic dynamics are presented and applied. The methods are the following: the Pyragas method via feedback of state variable; the Pyragas method with time delay in the feedback; and the Sinhas method, which performs the control by disturbing a parameter of the system. Numerical simulations are accomplished in order to illustrate the dynamical behavior of the system when subjected to the action of these methods. This work ends with a study of a single-chain PLL network. Conditions for synchronous, periodic and chaotic (dissipative and conservative) solutions are derived for such a network.

ATP-Binding-Cassette (ABC) transporters are primary active pumps that typically couple the binding and hydrolysis of ATP to the translocation of compounds across cellular membranes. Some, like ABCB1, ABCC1 and ABCC3, are polyspecific and can efflux clinically important drugs which may contribute to their therapeutic failure. In this study I have investigated (1) the mechanism of ABC transporter function, (2) studied the potential for regulation by ubiquitin ligases (both using ABCB1 as a model), and (3) tested the involvement of ABCC1 and ABCC3 in autocrine signalling in cancer. (1) In 1966, Jardetzky et. al [1] proposed that membrane pumps function by exposing their ligand-binding pocket alternately on different sides of the membrane. For ABC transporters, this coupling of the aspect and affinity of the ligand-binding cavities of the two transmembrane domains (TMDs) to the ATP catalytic cycle of the two nucleotide-binding domains (NBDs) is fundamental to the transport mechanism but is poorly understood at the molecular level. Structure data suggest signals are transduced through intracellular loops of the TMDs which slot into grooves on the top surface of the NBDs. At the base of these grooves is the Q-loop. By analysing the function of Q-loop mutants in combination with ligand binding cavity mutants I have discovered that the Q-loops are crucial to the transport cycle and that they are required to couple ligand binding to conformational changes at the NBDs necessary to drive the transporter into an inward closed state. 4 (2) ABCB1 is known to be a key component of chemical barrier separating the circulation from the cerebrospinal fluid. It has also been reported to transport β-amyloid across the lumenal membrane and into the circulation. Loss of ABCB1 from the barrier with age has therefore been suggested to play a role in Alzheimer’s Disease. The ubiquitin ligase Nedd4-1 has been implicated in the post-translational regulation of ABCB1 abundance in cells. Here, I report that ABCB1 can be ubiquitinated by Nedd4-1 in vitro and identify the residues modified (by mass spectrometry). (3) Lysophosphatidylinositol (LPI) is an autocrine metabolite produced by cancer cells that binds to the G-protein coupled transmembrane receptor GPR55 on the surface of cells. Stimulation of GPR55 activates a signalling cascade that induces proliferation and metastases of the cancer cells. How LPI is released from the cells was not known. In this study I show that ABCC1 and ABCC3, which are known to be expressed in ovarian and pancreatic cancers, can transport LPI into inside-out vesicles suggesting a new role for these “drug resistance” transporters in cancer biology.

Ce travail de thèse a pour objet de contribuer à la compréhension de la déformation des assemblages combustibles REP équipés de composants en alliages de zirconium (Zy-4 ou M5). En particulier, nous nous sommes intéressés à l’accélération de croissance, corrélée à l’apparition d’un type de défaut d’irradiation : les boucles à composante <c>. Des irradiations aux particules chargées nous ont permis de reproduire ces évolutions microstructurales et d’étudier leur représentativité. La morphologie du dommage primaire n’a ainsi que peu d’impact sur la microstructure de boucles <c> tandis que le taux de création de dommage (tout comme la température) semble jouer un rôle majeur. Par ailleurs, la dose seuil pour la nucléation des boucles <c> apparaît étroitement liée à la cinétique de croissance des amas lacunaires et des germes de boucles. Cette cinétique peut être influencée par le taux de création de dommage, les éléments d’alliages, mais également la contrainte ou la présence d’hydrogène (introduit dans le matériau lors de l’oxydation en réacteur). Ce travail a ainsi exploré de manière approfondie l’effet d’une contrainte appliquée dans les domaines d’élasticité et de plasticité ainsi que l’impact de l’hydrogène absorbé sur la nucléation et la croissance des boucles <c>. Conformément au mécanisme SIPA proposé dans la littérature, nous avons observé un effet de la contrainte sur les boucles <c>. Par ailleurs, cette étude met en évidence que l’hydrogène en solution et / ou sous forme d’hydrures influence significativement la nucléation et la croissance des boucles <c>. / The aim of this PhD work is to have a better understanding of axial elongation of the PWR fuel assemblies manufactured in zirconium alloys (Zy-4 or M5). More specifically, we focused on the growth acceleration of these assemblies, clearly correlated to the nucleation of specific irradiation defects: the c-loops. Irradiations by charged particles were performed in order to reproduce the microstructure evolution and to study its representativeness. Thus, primary damage morphology has no impact on the c-loop microstructures where as the damage creation rate (like the temperature) seems to play a major role. Moreover, the nucleation dose for c-loops appears clearly correlated to the nuclei and vacancy clusters growth kinetics. This kinetics could be influenced by the damage creation rate, the alloying elements, but also by an applied stress or the hydrogen content (which can be introduced during oxidation in reactor). Thus, this work has explored the effect of an applied stress (in the elasticity or plasticity domain) and the impact of the hydrogen pick-up on the nucleation and growth of c-loops. In accordance with the SIPA mechanism described in the literature, we observed an effect of the applied stress on the c-loop microstructures. Moreover, this study clearly shows an impact of hydrogen in solid solution and as precipitated hydrides on the nucleation and growth of c-loops.