Cette thèse s'inscrit dans le cadre de l'étude, à la fois théorique et numérique, de la diffraction d'une onde harmonique par la jonction entre deux guides d'ondes ouverts. Nous démontrons que ce problème est bien posé. Pour cela, nous utilisons des conditions de rayonnement modales, qui sont fondées sur la représentation de la solution dans un guide droit à l'aide des modes guidés (liés au spectre ponctuel de l'opérateur transverse) et des modes de radiation (liés au spectre continu de l'opérateur transverse). Cette représentation semble difficile à mettre en oeuvre dans une méthode numérique, à cause du continuum des modes de radiation. Comme alternative, nous utilisons des PMLs (Perfectly Matched Layers) pour borner le domaine de calcul dans les directions transverses, ce qui modifie singulièrement la nature de l'opérateur transverse : il perd son caractère autoadjoint et son spectre devient exclusivement discret. Parmi ses nouveaux modes, se trouvent désormais des modes à fuite, dont les propriétés sont étudiées. Nous expliquons en quoi la perte du caractère autoadjoint implique que le calcul des modes peut être délicat. Nous expliquons ensuite comment utiliser ces nouveaux modes (formant maintenant un ensemble discret) dans des méthodes numériques pour la jonction entre deux guides d'ondes ouverts (conditions aux limites transparentes fondées sur des opérateurs de Dirichlet-to-Neumann, méthode multimodale).

Ce travail porte sur l'étude d'une méthode d'éléments finis discontinus (ou méthode de type Galerkin Discontinu, DGTD) basée sur l'utilisation d'un maillage héxaédrique régulier, proposée pour la résolution des équations de Maxwell dans le domaine temporel, afin de l'adapter à la caractérisation de structures rayonnantes et de l'associer à des techniques de domaines fictifs.<br />On présente tout d'abord une méthode Galerkin Discontinu s'appuyant sur une formulation centrée pour approcher les flux numériques aux interfaces du maillage et sur un schéma en temps explicite de type saute-mouton. Ainsi, le schéma obtenu est non-diffusif, stable, peu dispersif, parfaitement adapté à l'utilisation de maillages localement raffinés de manière non-conforme. La méthode a été dotée de parois absorbantes performantes (modèle Unsplit-PML), permettant de prendre en compte facilement des objets à cheval entre le domaine de calcul et la couche absorbante. Nous avons ensuite utilisé la méthode pour effectuer des calculs d'impédances, de paramètres S et de T.O.S. sur des structures rayonnantes planaires. La comparaison entre la simulation et la mesure de ces structures montre le bon fonctionnement de la méthode.<br />Nous avons alors couplé une méthode de domaines fictifs avec la méthode DGTD afin de prendre en compte la présence d'objets métalliques à géométries complexes. La méthode des domaines fictifs utilise deux maillages de manière indépendante: un maillage cartésien, pour faire évoluer le champ électromagnétique dans l'espace libre, et un maillage surfacique qui permet de prendre en compte l'objet métallique. La convergence de la méthode (pour la méthode FDTD) est liée à une relation de compatibilité entre le maillage volumique et le maillage surfacique: le plus petit élément du maillage surfacique impose la taille des éléments du maillage volumique. Ainsi, pour des objets présentant de tout petits détails, cette condition n'est assurée que si le maillage volumique est de l'ordre du plus petit élément du maillage surfacique, ce qui peut devenir extrêmement contraignant sans le recours à des techniques de raffinement local, telle que celle rendue possible par la méthode Galerkin Discontinu et utilisée ici.

We are concerned with the high-fidelity subsurface imaging of the soil, which commonly arises in geotechnical site characterization and geophysical explorations. Specifically, we attempt to image the spatial distribution of the Lame parameters in semi-infinite, three-dimensional, arbitrarily heterogeneous formations, using surficial measurements of the soil's response to probing elastic waves. We use the complete waveforms of the medium's response to drive the inverse problem. Specifically, we use a partial-differential-equation (PDE)-constrained optimization approach, directly in the time-domain, to minimize the misfit between the observed response of the medium at select measurement locations, and a computed response corresponding to a trial distribution of the Lame parameters. We discuss strategies that lend algorithmic robustness to the proposed inversion schemes. To limit the computational domain to the size of interest, we employ perfectly-matched-layers (PMLs). The PML is a buffer zone that surrounds the domain of interest, and enforces the decay of outgoing waves. In order to resolve the forward problem, we present a hybrid finite element approach, where a displacement-stress formulation for the PML is coupled to a standard displacement-only formulation for the interior domain, thus leading to a computationally cost-efficient scheme. We discuss several time-integration schemes, including an explicit Runge-Kutta scheme, which is well-suited for large-scale problems on parallel computers. We report numerical results demonstrating stability and efficacy of the forward wave solver, and also provide examples attesting to the successful reconstruction of the two Lame parameters for both smooth and sharp profiles, using synthetic records. We also report the details of two field experiments, whose records we subsequently used to drive the developed inversion algorithms in order to characterize the sites where the field experiments took place. We contrast the full-waveform-based inverted site profile against a profile obtained using the Spectral-Analysis-of-Surface-Waves (SASW) method, in an attempt to compare our methodology against a widely used concurrent inversion approach. We also compare the inverted profiles, at select locations, with the results of independently performed, invasive, Cone Penetrometer Tests (CPTs). Overall, whether exercised by synthetic or by physical data, the full-waveform inversion method we discuss herein appears quite promising for the robust subsurface imaging of near-surface deposits in support of geotechnical site characterization investigations.

The c-Myc transcription factor is a key player in cell homeostasis, being commonly deregulated in human carcinogenesis. In this PhD thesis we have addressed the question how regulatory mechanisms restrain the oncogenic activity of c-Myc and its impact on cell differentiation. In the first half, we report that PML promotes destabilization of c-Myc protein and re-activation of c-Myc-repressed target genes. The consequent re-expression of the cell cycle inhibitor CDKN1A/p21 mediates differentiation of leukemic cells. In the second half of the thesis we identified a novel mechanism of gene regulation by c-Myc, which is mediated through its interaction with DNA-bound RARα. In undifferentiated cells, c-Myc/Max dimers cooperate with RARα in the repression of genes required for differentiation. Upon phosphorylation of c-Myc by the previously identified Pak2, the complex switches from a repressive to an activating function by releasing Max and recruiting transcriptional coactivators. These findings add a new and at least partially Max-independent mechanism for transcriptional regulation by c-Myc and also discover an unexpected function of c-Myc in inhibiting and promoting cellular differentiation. Taken together, our results describe two new mechanisms that counteract the oncogenic activity of c-Myc. Both PML and Pak2 can be considered as tumor suppressors since they modulate c-Myc function in a way that ultimately promotes differentiation of leukemic cells. This knowledge provides the basis for novel approaches to be exploited for the development of c-Myc-targeted therapies. / El factor de transcripció c-Myc juga un paper clau en l’homeòstasi cel·lular, essent freqüentment desregulat en la carcinogènesi humana. En aquesta tesi s’ha estudiat com diferents mecanismes reguladors poden frenar l’activitat oncogènica de c-Myc i el subsegüent impacte en la diferenciació cel·lular. A la primera meitat de la tesi, es demostra que PML promou la desestabilització de la proteïna c-Myc i, en conseqüència, la reactivació dels genes diana reprimits per c-Myc. Entre aquests gens diana es troba l’inhibidor del cicle cel·lular CDKN1A/p21, la reexpressió del qual provoca la diferenciació de cèl·lules leucèmiques induïda per PML. En la segona meitat, s’identifica un nou mecanisme de regulació transcripcional per part de c-Myc a través de la interacció amb RARα, el qual està unit a l’ADN. En cèl·lules indiferenciades, els dimers c-Myc/Max cooperen amb RARα en la repressió de gens essencials per a la diferenciació. Un cop c-Myc és fosforil·lat per la kinasa Pak2, el complex de c-Myc amb RARα esdevé activador mitjançant la pèrdua de Max i el reclutament de coactivadors transcripcionals. Aquest descobriment suposa un nou mecanisme mitjançant el qual c-Myc pot exercicir la regulació gènica almenys en part independentment de Max, i també revela una funció desconeguda de c-Myc en la inhibició i promoció de la diferenciació cel·lular. En conjunt, aquests resultats descriuen dos nous mecanismes que contrarestren l’activitat oncogènica de c-Myc. PML i Pak2 poden ser considerats supressors de tumors ja que modulen la funció de c-Myc per a promoure la diferenciació de les cèl·lules leucèmiques. Aquests descobriments poden utilitzar-se com a base pel desenvolupament de noves teràpies anti-tumorals que tinguin com a diana la proteïna c-Myc.

Made available in DSpace on 2014-06-12T18:05:18Z (GMT). No. of bitstreams: 2 arquivo6239_1.pdf: 3987684 bytes, checksum: 3de61823bef92babc3a0eebd8393e838 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2006 / O gene de fusão PML-RAR&#945; é o mais freqüente marcador molecular da Leucemia Aguda Promielocítica (LAP). Com o objetivo de comparar os métodos moleculares qualitativo e quantivo, avaliar os níveis de expressão do gene correlacionar com características biológicas foram de pacientes com LAP ao diagnostico e pós-consolidação. O RNA total foi extraído a partir de e o cDNA sintetizado por RT-PCR. O gene ABL foi utilizado como controle constitutivo e a análise quantitativa realizada por curva padrão. Ao diagnóstico houve concordância dos métodos na detecção do gene PML-RAR&#945; e o coeficiente normalizado de expressão foi 55,3. Após a consolidação do tratamento apenas um paciente apresentou a expressão do gene PML-RAR&#945; que foi detectado pela PCR quantitativa. Não foram encontradas diferenças significantes na análise de associação dos níveis de expressão do gene PML-RAR&#945; com carocteristicas biológicas. Os resultados permitiram estimar o nível de expressão do gene PML-RAR&#945; no grupo estudado e o estabelecimento de parâmetros para o seguimento de pacientes com LAP

La prédiction de la réduction passive du bruit nécessite l’utilisation de modèles d’impédance acoustique fiables. La proposition de tels modèles en présence d’écoulement est un problème qui reste ouvert. Les travaux réalisés dans cette thèse sont consacrés à la mise en place d’une méthode expérimentale et numérique permettant de tester la validité de modèles d’impédance acoustique de traitements SDOF en présence d’écoulement. Cette approche repose sur la comparaison de résultats expérimentaux issus d’un banc aéroacoustique, et de résultats numériques issus d’un modèle FEM-PML axisymétrique basé sur l’équation de Galbrun. Ainsi, dans la première partie de cette thèse, le modèle FEM-PML utilisé est présenté. Dans la seconde partie, des modèles d’impédance acoustique de SDOF tenant compte de l’écoulement sont exposés, ainsi que la méthode de validation de ces modèles et les résultats de ces validations. / Prediction of noise reduction requires reliable acoustic impedance models. The proposal of such models in the presence of a mean flow is a problem which remains open. This thesis is devoted to the development of an experimental and a numerical method to test the validity of SDOF treatments acoustic impedance models in the presence of mean flow. This approach is based on the comparison of experimental results from an aeroacoustical duct, and numerical results from a FEM-PML axisymmetric model based on Galbrun’s equation. Thus, in the first part of this thesis, the FEM-PML model is presented. In the second part, some acoustic impedance models are exposed, and the validation method and the results of these validations are presented.

Les cassures double-brin de l’ADN (CDB) sont des événements clés dans la réponse aux rayonnements ionisants qui, avec le profil génétique et épigénétique individuel, peuvent conditionner le devenir des tissus sains d’un individu exposé. À la suite des cassures de la molécule d’ADN et de la déstabilisation de la chromatine, une série de modifications post-traductionnelles des histones se produit, notamment la phosphorylation de la serine 139 de l'histone H2A.X (gamma-H2A.X), conduisant à la formation de foyers radio-induits. La réparation des CDB, et donc la disparition de ces foyers, a lieu dans les heures suivant l’exposition. Toutefois, une certaine proportion de ces foyers gamma-H2A.X persiste 24 heures après l’irradiation. La nature et le rôle de ces foyers persistants sont encore peu clairs. L’objectif de ce travail est d'explorer les caractéristiques de ces foyers persistants et leurs conséquences sur le devenir des cellules. Pour étudier la dynamique des foyers radio-induits, nous avons exposé des HUVEC synchronisées en phase G0/G1 à des doses de 1 et 5 Gy de rayons X. Les foyers radio-induits ont été étudiés à partir de 10 minutes et jusqu'à 7 jours après l'exposition par l’analyse de gamma-H2A.X et de l’association temporelle de la protéine 53BP1 et des CN-PML (corps nucléaires PML). L’impact des foyers persistants sur la prolifération cellulaire a également été exploré. Nous avons analysé en microscopie à fluorescence une moyenne de 4 000 cellules pour chaque condition à l'aide d'une analyse d’image permettant la détection automatique des noyaux et des foyers. L'analyse d'un grand nombre d‘évènements nous a permis de discriminer des sous-populations de cellules ou de foyers sur la base de différentes caractéristiques, telles que leur aire ou la phase du cycle cellulaire, et de mesurer leur représentativité dans l'ensemble de la population de cellules exposées. Ainsi, nous avons déterminé que les foyers gamma-H2A.X persistant ont une aire supérieure à 0,72 ± 0,11 µm² et qu’ils sont toujours colocalisés avec 53BP1. Plus de 70% des cellules exposées à 5 Gy ont au moins un foyer persistant 24 heures après l'exposition. De plus, ces foyers persistants sont observables au moins jusqu'à 7 jours après l’irradiation. Une association spatiale significative entre les CN-PML et les foyers gamma-H2A.X a été observée à partir de 10 minutes après l'exposition et 24 heures après l’exposition, environ 90% des foyers persistants sont associés à un CN-PML. De plus, la présence de foyers persistants ne bloque pas définitivement la prolifération des cellules. Cependant, la fréquence des foyers persistants est plus faible dans les cellules filles que dans les cellules irradiées, probablement en raison d'une certaine proportion de distribution asymétrique des foyers persistants entre les cellules filles. Nous avons également mesuré une corrélation positive entre la présence d'un foyer persistant et la probabilité de mauvaise ségrégation de l'ADN par l'observation de phénomènes de catastrophes mitotiques. Il semble donc que la structure formée après le passage d'un foyer persistant à travers les phases S et G2 soit susceptible d’empêcher la séparation correcte des chromatides sœurs du chromosome affecté. Nous suggérons donc que la nature des foyers persistants n’est pas la même avant et après la première division cellulaire due à une résolution anormale de l'anaphase. Ces assemblages chromosomiques atypiques résultants d’anaphases anormales pourraient être létaux pour la cellule ou entraîner un déséquilibre du dosage génique et une instabilité génomique accrue pouvant conduire à une mosaïque de phénotypes cellulaires. / The DNA double-stranded breaks (DSB) are key events in the cell response to ionizing radiation that may affect, with the individual genetic and epigenetic profile, the fate of healthy tissues of people exposed. Following initial breaks and chromatin destabilization, a set of post-translational modifications of histones occurs, including the phosphorylation of serine 139 of histone H2AX (gamma-H2A.X), which leads to the formation of ionizing radiation-induced foci (IRIF). DSB repair results in the disappearance of most IRIF within hours after exposure. However, a proportion of IRIF remains 24 hours upon irradiation. The nature and role of these persistent IRIF are still unclear. The goal of this work is to explore the characteristics of these persistent IRIF and their consequences on the cell behavior. To investigate the dynamic of IRIF in our model, we exposed G0/G1-phase synchronized HUVECs to 1 or 5 Gy of X-rays. IRIF were studied from 10 minutes up to 7 days after exposure by monitoring gamma-H2A.X foci, their temporal association with 53BP1 protein and PML NBs (Promyelocytic leukemia nuclear bodies), and their impact on cell proliferation. We analyzed a mean of 4 000 cells for each condition using an automated detection of nuclei and foci. The analysis of a large number of cells and foci allowed us to screen subpopulations of cells or foci through different characteristics, such as size, shape or cell cycle phase among others, and to weight their representativeness in the whole population of exposed cells. We identified that persistent gamma-H2A.X foci after irradiation had a size superior to 0.72 ± 0.11 µm² and always collocated with 53BP1. More than 70% of cells exposed to 5 Gy had at least one persistent IRIF 24 hours after exposure and we observed these persistent IRIF up to 7 days post irradiation. A significant spatial association between PML NBs and IRIF was observed from 10 minutes after exposure; at 24h post irradiation, around 90% of persistent IRIF were associated with PML NBs. Moreover we demonstrated that persistent IRIF did not block cell proliferation definitively. The frequency of IRIF was lower in daughter cells, probably due to a certain amount of asymmetric distribution of IRIF between them. We report a positive association between the presence of an IRIF and the likelihood of DNA missegregation by observation of mitotic catastrophes. Hence, the structure formed after the passage of a persistent IRIF across the S and G2 phases may impede the correct segregation of sister chromatids of the chromosome affected. Consequently, the nature of IRIF in the nucleus of daughter cells might differ before and after the first cell division due to an abnormal resolution of anaphase. The resulting atypical chromosomal assembly may be lethal or result in a gene dosage imbalance and possible enhanced genomic instability, and could lead to a patchwork of cell phenotypes.

This master thesis covers the dynamic soil structure interaction of soil-steel culverts applyinga methodology based on the frequency domain response. At the first stage of this masterthesis, field tests were performed on one bridge using controlled excitation. Then, themethodology followed uses previous research, the field tests, finite element models (FEM)and perfectly matched layer (PML) elements.Firstly, a 2D model of the analysed bridge, Hårestorp, was made to compare the frequencyresponse functions (FRF) with the ones obtained from the field tests. Simultaneously, a 3Dmodel of the bridge is created for the following purposes: compare it against the 2D modeland the field tests, and to implement a model updating procedure with the particle swarmalgorithm to calibrate the model parameters. Both models use PML elements, which areverified against previous solution from the literature. The verification concludes that thePML behave correctly except for extreme parameter values.In the course of this master thesis, relatively advanced computation techniques were requiredto ensure the computational feasibility of the problem with the resources available.To do that, a literature review of theoretical aspects of parallel computing was performed, aswell as the practical aspects in Comsol. Then, in collaboration with Comsol Support and thehelp given by PDC at KTH it was possible to reduce the computational time to a feasiblepoint of around two weeks for the model updating of the 3D model.The results are inconclusive, in terms of searching for a perfectly fitting model. Therefore,further research is required to adequately face the problem. Nevertheless, there are some accelerometerswhich show a considerable level of agreement. This thesis concludes to discardthe 2D models due to their incapability of facing the reality correctly, and establishes a modeloptimisation methodology using Comsol in connection with Matlab.

The main objective of this research is to model and analyse complex electromagnetic problems by means of a new hybridised computational technique combining the frequency domain Method of Moments (MoM), Finite-Difference Time-Domain (FDTD) method and a subgridded Finite-Difference Time-Domain (SGFDTD) method. This facilitates a significant advance in the ability to predict electromagnetic absorption in inhomogeneous, anisotropic and lossy dielectric materials irradiated by geometrically intricate sources. The Method of Moments modelling employed a two-dimensional electric surface patch integral formulation solved by independent linear basis function methods in the circumferential and axial directions of the antenna wires. A similar orthogonal basis function is used on the end surface and appropriate attachments with the wire surface are employed to satisfy the requirements of current continuity. The surface current distributions on structures which may include closely spaced parallel wires, such as dipoles, loops and helical antennas are computed. The results are found to be stable and showed good agreement with less comprehensive earlier work by others. The work also investigated the interaction between overhead high voltage transmission lines and underground utility pipelines using the FDTD technique for the whole structure, combined with a subgridding method at points of interest, particularly the pipeline. The induced fields above the pipeline are investigated and analysed. FDTD is based on the solution of Maxwell¿s equations in differential form. It is very useful for modelling complex, inhomogeneous structures. Problems arise when open-region geometries are modelled. However, the Perfectly Matched Layer (PML) concept has been employed to circumvent this difficulty. The establishment of edge elements has greatly improved the performance of this method and the computational burden due to huge numbers of time steps, in the order of tens of millions, has been eased to tens of thousands by employing quasi-static methods. This thesis also illustrates the principle of the equivalent surface boundary employed close to the antenna for MoM-FDTD-SGFDTD hybridisation. It depicts the advantage of using hybrid techniques due to their ability to analyse a system of multiple discrete regions by employing the principle of equivalent sources to excite the coupling surfaces. The method has been applied for modelling human body interaction with a short range RFID antenna to investigate and analyse the near field and far field radiation pattern for which the cumulative distribution function of antenna radiation efficiency is presented. The field distributions of the simulated structures show reasonable and stable results at 900 MHz. This method facilitates deeper investigation of the phenomena in the interaction between electromagnetic fields and human tissues. / Ministry of Higher Education Malaysia and Universiti Tun Hussein Onn Malaysia (UTHM)

台灣位處環太平洋地震帶，為全球地震風險潛勢較高的地區之一；因台灣高科技產業蓬勃發展，地震保險需求殷切，再加上開放保險費率自由化的政策及金控效應，趨使保險業間競爭白熱化，惡性價格競爭及保險經紀人的推波助瀾，保險公司的清償能力面臨重大考驗。 台灣在保險監理方面如同日本、美國採行風險基礎資本額（RBC）制度，惟國際間位處高度地震風險潛勢之國家大都另建立一套地震保險監理機制，以確保保險公司的巨災準備金足以支付回歸期地震所造成的損失，其中以美國加州及加拿大政府均採用地震保險PML申報制度作為地震保險監理之依據最值得台灣學習。 地震保險PML評估可採用CRESTA Zone平均損失幅度表計算或採用認許的地震風險評估電腦軟體推估獲得，實施的關鍵為主管機關應建立具有公信力的CRESTA Zone平均損失幅度表。本文特就二種評估方式的利弊做深入的比較分析，並藉由地震風險評估軟體的架構說明影響地震保險PML的因素與權重，作為保險公司落實地震風險管理之依據。 本研究參考Solvency II的三大支柱提出建立地震保險監理機制之結論與建議如下： 1.鼓勵建立保險公司的地震風險管理機制。 2.公佈CRESTA Zone平均損失幅度表，作為保險公司地震保險PML申報依據，以落實產物保險業之地震保險監理機制。 3.依據保險公司申報資料，提供保險主管機關實施差異化管理之依據。 4.主動揭露經營績效、強化保險市場紀律，建立公平合理的經營環境。 期待藉由建立適當的地震保險監理機制，減輕或消弭產物保險市場面臨自由化的惡性價格競爭與保險經營面的不合理現象，進而達到健全保險經營環境、促進保險業長期穩定發展，並確保社會大眾之保險權益的目標。 關鍵詞：地震保險監理機制、地震保險PML、巨災準備金、風險基礎資本額、地震風險評估軟體 / Located at the Pacific Rim earthquake zone, Taiwan has been recognized as one of the severe seismic hazard areas in the world. With the bloom of high tech industry in the past two decades, the demand of earthquake insurance has been considerably increasing. However, along with the liberalization of insurance market, the new business model of financial holdings and the expanding influence from international brokers, insurance companies’ solvency capacity has been significantly challenged. Taiwanese Government, same as Japan and U.S., adopts Risk-Based Capital (RBC) method in insurance supervision, while most countries with high earthquake potential have set up independent earthquake insurance supervision systems to ensure insurers’ earthquake reserves capable to compensate the huge earthquake losses. Among all the measures, the PML reporting system adopted by Canada and the State of California to regulate and trace insurance companies’ financial statuses could be an adequate paradigm for Taiwan. The PML estimation could be obtained either using computer models or following default mean damage ratio table. This research compares the strength and weakness between these two methods, and presents the importance of parameters and key points in earthquake insurance management. Based on the three pillars of Solvency II, the conclusions and recommendations of this paper are: (1)Encourage insurance companies to build up the earthquake risk management mechanism; (2)Establish the official default mean damage ratio table for PML reporting system; (3)Adopt differential supervision practice to different level insurance companies; (4)Promote the self-disclosure of key business information and enhance market discipline. Establishing a sound earthquake insurance supervision system would not only ease the immoderate low-price competition but the whole insurance environment could also be stabilized and improved. It will ultimately achieve the objective to insure society liability and benefit the public as well. Keywords: Earthquake Insurance, Earthquake Model, Catastrophic Risk Management, Insurance Supervision, Risk-Based Capital, CRESTA Zone, PML