Les Récepteurs Couplés aux Protéines-G forment la plus importante famille de protéines membranaires chez l’homme et sont impliqués dans de nombreux processus de signalisation cellulaire. Aussi, ils forment un vivier très important de cibles thérapeutiques, déjà identifiées ou potentielles. L’activation d’un RCPG est amorcée par la liaison d’un ligand dans sa partie extra-cellulaire, modifiant ainsi ses propriétés dynamiques intrinsèques. Ces changements structuraux vont alors se répercuter le long des domaines trans-membranaires et promouvoir la dissociation de la Protéine-G hétéro-trimérique, de l’autre côté de la membrane, propageant ainsi le signal au compartiment intra-cellulaire. Ce processus peut être modulé par la liaison de nombreux autres partenaires des RCPGs. Malgré de nombreuses données structurales existantes, ces mécanismes restent encore mal connus à l’échelle moléculaire. Ainsi, la dynamique moléculaire s’est révélée être un outil formidable pour mieux comprendre ces mécanismes. Toutefois, les échelles de taille et de temps requises pour discuter de la dynamique de ces systèmes membranaires limitent ces études aux laboratoires ayant accès à une très grande puissance de calcul. L’objectif des travaux présentés dans ce manuscrit a été de prédire et de mieux comprendre la dynamique d’interaction de différents récepteurs de cette famille avec leurs partenaires, en développant un protocole de dynamique moléculaire, peu coûteux en ressources de calcul, combinant le champ de forces gros-grains MARTINI à un protocole de dynamique moléculaire « Replica-Exchange ».Dans un premier temps, nous présentons la validation de notre protocole pour la prédiction de la liaison de peptides à leur récepteur avec l’étude des peptides Neurotensine, agoniste du Récepteur de la Neurotensine-1, et CVX15, antagoniste du Récepteur Chemokine C-X-C de type-4. Nous montrons également que notre protocole est capable de prédire la sélectivité de plusieurs peptides dérivés de la Neurotensine envers plusieurs récepteurs sauvages et mutés, ne présentant qu’un résidu de différence.Dans un second temps, nous nous sommes intéressés à la dynamique de formation d’un hétéro-dimère de RCPGs impliquant le Récepteur de la Ghréline et le récepteur de la Dopamine D2, couplés aux protéines Gq et Gi respectivement. Ce modèle validé au laboratoire par des mesures LRET montre une interface impliquant une forte complémentarité entre les protéines-G. En se basant sur notre modèle, nous avons conçu et synthétisé des peptides inhibiteurs de la formation de cet hétéro-dimère de protéines-G.Enfin, nous présentons d’autres exemples d’applications de notre protocole et comment il peut être utilisé de concert avec l’expérience avec : la prédiction de la liaison de toxines de serpents aux Récepteurs de la Vasopressine-1a et V2 ; la prédiction de la liaison des peptides Ghréline et Leap2 au Récepteur GHSR-1a et la prédiction de la sélectivité de couplage de différents récepteurs aux peptides C-terminaux de la sous-unité α des protéines-G. / G-Protein Coupled Receptors form the largest family of human membrane proteins and are involved in many cellular signaling processes. Thus, they constitute a pool of already identified or potential pharmacological targets. The activation of a GPCR starts with the binding of a ligand in its extra-cellular part, further modifying its intrinsic dynamical properties. These structural rearrangements are then transmitted along the transmembrane domains and promote the dissociation of the G-protein on the other side of the bilayer, thus propagating the signal into the intra-cellular compartment. This activation process can be modulated by the binding of many other partners of GPCRs. Despite many structural data now available, these mechanisms are still badly known at the molecular scale. In agreement, molecular dynamics simulations appear to be a method of choice to get a better description of these mechanisms. Nevertheless, the size and the time scales required for the simulation of these membrane systems limit such studies to laboratories having access to large computational facilities.The objective of this work was to predict and get a dynamical view of the interactions of several GPCRs with their partners, by developing an affordable molecular dynamics protocol that combines the coarse-grained MARTINI force field to Replica-Exchange MD simulations.In a first step, we validated our protocol by showing its ability to predict the dynamical binding of peptides to their receptors, through the study of Neurotensin, an agonist of the Neurotensin-1 receptor and CVX15, an antagonist of the CXCR4 chemokine receptor. We also show that the same protocol is able to predict the selectivity of several Neurotensin derived peptides against several wild-type/mutated receptors differing by a single residue.In a second step, we were concerned by the dynamical assembly of a GPCR heterodimer involving the Ghrelin and the Dopamine D2 receptors, respectively coupled to Gq and Gi proteins. Our model was validated by LRET measurements confirming a large protein:protein interface and a high complementarity between G-proteins. Based on this model, we designed and synthesized some peptides able to inhibit the assembly of this G-proteins heterodimer.Finally, we describe other applications of our protocol and how it can be employed and confronted to experiments to : predict the dynamical binding of toxins from snake’s venom to the Vasopressin-1a and Vasopressin-2 receptors ; predict the binding of the Ghrelin and Leap2 peptides to their GHSR-1a receptor and predict the coupling selectivity of several receptors to peptides mimicking the C-terminus of the α subunit of G-proteins.

Ultrafeinkörnige metallische Werkstoffe haben verstärkt wissenschaftliche Bedeutung erlangt. Um dieser neuartigen Werkstoffklasse über die grundlagenorientierte Forschung hinaus einen Einsatz in technischen Anwendungen zu ermöglichen, ist es notwendig, deren Verhalten unter verschiedenen einsatzrelevanten Belastungsbedingungen vorhersagen zu können. In der vorliegenden Arbeit wird das Schädigungsverhalten einer ultrafeinkörnigen Aluminiumlegierung in den Bereichen der hochzyklischen (HCF) und niedrigzyklischen (LCF) Ermüdung sowie des Rissfortschritts untersucht. Im Mittelpunkt steht dabei die Identifikation der mikrostrukturell wirksamen Mechanismen bei der Entstehung und Ausbreitung von Ermüdungsrissen. Es werden ein homogen ultrafeinkörniger und ein bimodaler Zustand sowie verschiedene duktilitätsoptimierte Zustände betrachtet und systematisch der Einfluss der Korngröße, der Korngrößenverteilung, der Ausscheidungscharakteristik sowie der Festigkeit und Duktilität auf das Ermüdungs- und Rissfortschrittsverhalten ermittelt. Die Untersuchungen zeigen, dass das Schädigungsverhalten der ultrafeinkörnigen Aluminiumlegierung insbesondere durch die Korngröße und Korngrößenverteilung sowie den Kohärenzgrad der festigkeitssteigernden Ausscheidungen beeinflusst wird.

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Achieving high computation efficiency, in terms of Cycles per Instruction (CPI), for high-performance computing kernels is an interesting and challenging research area. Dense Linear Algebra (DLA) computation is a representative high-performance computing ap- plication, which is used, for example, in LU and QR factorizations. Unfortunately, mod- ern off-the-shelf microprocessors fall significantly short of achieving theoretical lower bound in CPI for high performance computing applications. In this thesis, we perform an in-depth analysis of the available parallelisms and propose suitable algorithmic and architectural variation to significantly improve the computation efficiency. There are two standard approaches for improving the computation effficiency, first, to perform application-specific architecture customization and second, to do algorithmic tuning. In the same manner, we first perform a graph-based analysis of selected DLA kernels. From the various forms of parallelism, thus identified, we design a custom processing element for improving the CPI. The processing elements are used as building blocks for a commercially available Coarse-Grained Reconfigurable Architecture (CGRA). By per- forming detailed experiments on a synthesized CGRA implementation, we demonstrate that our proposed algorithmic and architectural variations are able to achieve lower CPI compared to off-the-shelf microprocessors. We also benchmark against state-of-the-art custom implementations to report higher energy-performance-area product. DLA computations are encountered in many engineering and scientific computing ap- plications ranging from Computational Fluid Dynamics (CFD) to Eigenvalue problem. Traditionally, these applications are written in highly tuned High Performance Comput- ing (HPC) software packages like Linear Algebra Package (LAPACK), and/or Scalable Linear Algebra Package (ScaLAPACK). The basic building block for these packages is Ba- sic Linear Algebra Subprograms (BLAS). Algorithms pertaining LAPACK/ScaLAPACK are written in-terms of BLAS to achieve high throughput. Despite extensive intellectual efforts in development and tuning of these packages, there still exists a scope for fur- ther tuning in this packages. In this thesis, we revisit most prominent and widely used compute bound algorithms like GMM for further exploitation of Instruction Level Parallelism (ILP). We further look into LU and QR factorizations for generalizations and exhibit higher ILP in these algorithms. We first accelerate sequential performance of the algorithms in BLAS and LAPACK and then focus on the parallel realization of these algorithms. Major contributions in the algorithmic tuning in this thesis are as follows: Algorithms: We present graph based analysis of General Matrix Multiplication (GMM) and discuss different types of parallelisms available in GMM We present analysis of Givens Rotation based QR factorization where we improve GR and derive Column-wise GR (CGR) that can annihilate multiple elements of a column of a matrix simultaneously. We show that the multiplications in CGR are lower than GR We generalize CGR further and derive Generalized GR (GGR) that can annihilate multiple elements of the columns of a matrix simultaneously. We show that the parallelism exhibited by GGR is much higher than GR and Householder Transform (HT) We extend generalizations to Square root Free GR (also knows as Fast Givens Rotation) and Square root and Division Free GR (SDFG) and derive Column-wise Fast Givens, and Column-wise SDFG . We also extend generalization for complex matrices and derive Complex Column-wise Givens Rotation Coarse-grained Recon gurable Architectures (CGRAs) have gained popularity in the last decade due to their power and area efficiency. Furthermore, CGRAs like REDEFINE also exhibit support for domain customizations. REDEFINE is an array of Tiles where each Tile consists of a Compute Element and a Router. The Routers are responsible for on-chip communication, while Compute Elements in the REDEFINE can be domain customized to accelerate the applications pertaining to the domain of interest. In this thesis, we consider REDEFINE base architecture as a starting point and we design Processing Element (PE) that can execute algorithms in BLAS and LAPACK efficiently. We perform several architectural enhancements in the PE to approach lower bound of the CPI. For parallel realization of BLAS and LAPACK, we attach this PE to the Router of REDEFINE. We achieve better area and power performance compared to the yesteryear customized architecture for DLA. Major contributions in architecture in this thesis are as follows: Architecture: We present design of a PE for acceleration of GMM which is a Level-3 BLAS operation We methodically enhance the PE with different features for improvement in the performance of GMM For efficient realization of Linear Algebra Package (LAPACK), we use PE that can efficiently execute GMM and show better performance For further acceleration of LU and QR factorizations in LAPACK, we identify macro operations encountered in LU and QR factorizations, and realize them on a reconfigurable data-path resulting in 25-30% lower run-time

Detailed information about the oceanic environment is essential for many applications in the field of marine geology, marine biology, coastal engineering, and marine operations. Especially, knowledge of the properties of the sediment body is often required. Acoustic remote sensing techniques have become highly attractive for classifying the sea bottom and for mapping the sediment properties, due to their high coverage capabilities and low costs compared to common sampling methods. In the last decades, a number of different acoustic devices and related techniques for analyzing their signals have evolved. Each sensor has its specific application due to limitations in the frequency range and resolution. In practice, often a single acoustic tool is chosen based on the current application, supported by other non-acoustic data where required. However, different acoustic remote sensing techniques can supplement each other, as shown in this thesis. Even more, a combination of complementary approaches can contribute to the proper understanding of sound propagation, which is essential when using sound for environmental classification purposes. This includes the knowledge of the relation between acoustics and sediment properties, the focus of this thesis. Providing a detailed three dimensional picture of the sea bottom sediments that allows for gaining maximum insight into this relation is aimed at.<p><p><p>Chapters 4 and 5 are adapted from published work, with permission:<p>DOI:10.1121/1.3569718 (link: http://asadl.org/jasa/resource/1/jasman/v129/i5/p2878_s1) and<p>DOI:10.1109/JOE.2010.2066711 (link: http://ieeexplore.ieee.org/xpl/articleDetails.jsp?tp=&arnumber=5618582&queryText%3Dsiemes)<p>In reference to IEEE copyrighted material which is used with permission in this thesis, the IEEE does not endorse any of the Université libre de Bruxelles' products or services.<p> / Doctorat en Sciences de l'ingénieur / info:eu-repo/semantics/nonPublished

The thesis is focused on the analysis of the theoretical part of the unbound mixtures, their implementation and compliance. Further deals with determining the extent frost susceptibility direct and indirect method in the Czech Republic and the Member States of the European Union. The practical part is focused on the performance of tests on selected samples of unbound mixtures for which was gradually increased the content of fine particles and that direct and indirect method of determining the rate of frost susceptibility and also the evaluation of direct methods of particular customized way, which does not impose the appropriate standard. At the conclusion of the work is carried out an evaluation of the samples and comparison of the different methods with each other.

Since their inception, building materials are constantly improving. New ways to explore and improve the material's properties are constantly investigated (especially to improve the mechanical and deformation characteristics of the materials). This thesis is focused on identifying and comparing values of the modulus of elasticity of fine-grained composites. These features are compared with respect to water cement ratio, ageing and compressive strength of the investigated materials. Afterwards, the values of the modulus of elasticity are studied in the relation to the tested materials.

Ultrafeinkörnige metallische Werkstoffe haben verstärkt wissenschaftliche Bedeutung erlangt. Um dieser neuartigen Werkstoffklasse über die grundlagenorientierte Forschung hinaus einen Einsatz in technischen Anwendungen zu ermöglichen, ist es notwendig, deren Verhalten unter verschiedenen einsatzrelevanten Belastungsbedingungen vorhersagen zu können. In der vorliegenden Arbeit wird das Schädigungsverhalten einer ultrafeinkörnigen Aluminiumlegierung in den Bereichen der hochzyklischen (HCF) und niedrigzyklischen (LCF) Ermüdung sowie des Rissfortschritts untersucht. Im Mittelpunkt steht dabei die Identifikation der mikrostrukturell wirksamen Mechanismen bei der Entstehung und Ausbreitung von Ermüdungsrissen. Es werden ein homogen ultrafeinkörniger und ein bimodaler Zustand sowie verschiedene duktilitätsoptimierte Zustände betrachtet und systematisch der Einfluss der Korngröße, der Korngrößenverteilung, der Ausscheidungscharakteristik sowie der Festigkeit und Duktilität auf das Ermüdungs- und Rissfortschrittsverhalten ermittelt. Die Untersuchungen zeigen, dass das Schädigungsverhalten der ultrafeinkörnigen Aluminiumlegierung insbesondere durch die Korngröße und Korngrößenverteilung sowie den Kohärenzgrad der festigkeitssteigernden Ausscheidungen beeinflusst wird.

In the first part of the thesis, the molecular structure and electronic properties of phospholipids at the single molecule level and also for a monolayer structure are investigated via ab initio calculations under different degrees of hydration. The focus of the study is on phosphatidylcholines, in particular dipalmitoylphosphatidylcholine (DPPC), which are the most abundant phospholipids in biological membranes. Upon hydration, the phospholipid shape into a sickle-like structure. The hydration dramatically alters the surface potential, dipole and quadrupole moments of the lipids, and probably guides the interactions of the lipids with other molecules and the communication between cells. The vibrational spectrum of DPPC and DPPC-water complexes are completely assigned and it is shown that water hydrating the lipid head groups enables efficient energy transfer across membrane leaflets on sub-picosecond time scales. Moreover, the vibrational modes and lifetimes of pure and hydrated DPPC lipids, at human body temperature, are estimated by performing ab initio molecular dynamics simulations. The vibrational modes of the water molecules close to the head group of DPPC are active in the frequency range between 0.5 - 55 THz, with a peak at 2.80 THz in the energy spectrum. The computed lifetimes for the high-frequency modes agree well with recent data measured at room temperature, where high-order phonon scattering is not negligible. The structure and auto-ionization of water at the water-phospholipid interface are investigated by ab initio molecular dynamics and ab initio Monte Carlo simulations using local density approximation and generalized gradient approximation for the exchange-correlation energy functional. Depending on the lipid head group, strongly enhanced ionization is observed, leading to dissociation of several water molecules into H+ and OH- per lipid. The results can shed light on the phenomena of the high proton conductivity along membranes that has been reported experimentally. In the second part of the thesis, Monte Carlo simulations of the lipid bilayer, on the basis of a coarse grained model, are performed to gain insight into the mechanical properties of planar lipid bilayers. By using a rescaling method, the Poisson's ratio is calculated for different phases. Additional information on the bending rigidity, determined from height fluctuations on the basis of the Helfrich Hamiltonian, allows for calculation of the Young's modulus for each phase. In addition, the free energy barrier for lipid flip-flop process in the fluid and gel phases are estimated. The main rate-limiting step to complete a flip-flop process is related to a free energy barrier that has to be crossed in order to reach the center of the bilayer. The free energy cost for performing a lipid flip-flop in the gel phase is found to be five times greater than in the fluid phase, demonstrating the rarity of such events in the gel phase. Moreover, an energy barrier is estimated for formation of transient water pores that often precedes lipid translocation events and accounts for the rate-limiting step of these pore-associated lipid translocation processes.

FCC組織を有する純金属と合金において強ひずみ加工法の1つである側方押出し加工（ECAP）法を用いて超微細結晶材を作製し，ECAPの各段階における力学特性と微細組織を調査した．微細組織形成過程におけるセル壁の形成から結晶粒界の形成に着目し，積層欠陥エネルギーと固溶原子による固溶強化の効果の観点から，強ひずみ加工における加工硬化ステージの推移と微細組織形成の関係を議論した. / 博士(工学) / Doctor of Philosophy in Engineering / 同志社大学 / Doshisha University