Motivated by the classic works of Charles M. Stein, we focus on developing risk-estimation frameworks for denoising problems in both one-and two-dimensions. We assume a standard additive noise model, and formulate the denoising problem as one of estimating the underlying clean signal from noisy measurements by minimizing a risk corresponding to a chosen loss function. Our goal is to incorporate perceptually-motivated loss functions wherever applicable, as in the case of speech enhancement, with the squared error loss being considered for the other scenarios. Since the true risks are observed to depend on the unknown parameter of interest, we circumvent the roadblock by deriving finite-sample un-biased estimators of the corresponding risks based on Stein’s lemma. We establish the link with the multivariate parameter estimation problem addressed by Stein and our denoising problem, and derive estimators of the oracle risks. In all cases, optimum values of the parameters characterizing the denoising algorithm are determined by minimizing the Stein’s unbiased risk estimator (SURE). The key contribution of this thesis is the development of a risk-estimation approach for choosing the two critical parameters affecting the quality of nonparametric regression, namely, the order and bandwidth/smoothing parameters. This is a classic problem in statistics, and certain algorithms relying on derivation of suitable finite-sample risk estimators for minimization have been reported in the literature (note that all these works consider the mean squared error (MSE) objective). We show that a SURE-based formalism is well-suited to the regression parameter selection problem, and that the optimum solution guarantees near-minimum MSE (MMSE) performance. We develop algorithms for both glob-ally and locally choosing the two parameters, the latter referred to as spatially-adaptive regression. We observe that the parameters are so chosen as to tradeoff the squared bias and variance quantities that constitute the MSE. We also indicate the advantages accruing out of incorporating a regularization term in the cost function in addition to the data error term. In the more general case of kernel regression, which uses a weighted least-squares (LS) optimization, we consider the applications of image restoration from very few random measurements, in addition to denoising of uniformly sampled data. We show that local polynomial regression (LPR) becomes a special case of kernel regression, and extend our results for LPR on uniform data to non-uniformly sampled data also. The denoising algorithms are compared with other standard, performant methods available in the literature both in terms of estimation error and computational complexity. A major perspective provided in this thesis is that the problem of optimum parameter choice in nonparametric regression can be viewed as the selection of optimum parameters of a linear, shift-invariant filter. This interpretation is provided by deriving motivation out of the hallmark paper of Savitzky and Golay and Schafer’s recent article in IEEE Signal Processing Magazine. It is worth noting that Savitzky and Golay had shown in their original Analytical Chemistry journal article, that LS fitting of a fixed-order polynomial over a neighborhood of fixed size is equivalent to convolution with an impulse response that is fixed and can be pre-computed. They had provided tables of impulse response coefficients for computing the smoothed function and smoothed derivatives for different orders and neighborhood sizes, the resulting filters being referred to as Savitzky-Golay (S-G) filters. Thus, we provide the new perspective that the regression parameter choice is equivalent to optimizing for the filter impulse response length/3dB bandwidth, which are inversely related. We observe that the MMSE solution is such that the S-G filter chosen is of longer impulse response length (equivalently smaller cutoff frequency) at relatively flat portions of the noisy signal so as to smooth noise, and vice versa at locally fast-varying portions of the signal so as to capture the signal patterns. Also, we provide a generalized S-G filtering viewpoint in the case of kernel regression. Building on the S-G filtering perspective, we turn to the problem of dynamic feature computation in speech recognition. We observe that the methodology employed for computing dynamic features from the trajectories of static features is in fact derivative S-G filtering. With this perspective, we note that the filter coefficients can be pre-computed, and that the whole problem of delta feature computation becomes efficient. Indeed, we observe an advantage by a factor of 104 on making use of S-G filtering over actual LS polynomial fitting and evaluation. Thereafter, we study the properties of first-and second-order derivative S-G filters of certain orders and lengths experimentally. The derivative filters are bandpass due to the combined effects of LPR and derivative computation, which are lowpass and highpass operations, respectively. The first-and second-order S-G derivative filters are also observed to exhibit an approximately constant-Q property. We perform a TIMIT phoneme recognition experiment comparing the recognition accuracies obtained using S-G filters and the conventional approach followed in HTK, where Furui’s regression formula is made use of. The recognition accuracies for both cases are almost identical, with S-G filters of certain bandwidths and orders registering a marginal improvement. The accuracies are also observed to improve with longer filter lengths, for a particular order. In terms of computation latency, we note that S-G filtering achieves delta and delta-delta feature computation in parallel by linear filtering, whereas they need to be obtained sequentially in case of the standard regression formulas used in the literature. Finally, we turn to the problem of speech enhancement where we are interested in de-noising using perceptually-motivated loss functions such as Itakura-Saito (IS). We propose to perform enhancement in the discrete cosine transform domain using risk-minimization. The cost functions considered are non-quadratic, and derivation of the unbiased estimator of the risk corresponding to the IS distortion is achieved using an approximate Taylor-series analysis under high signal-to-noise ratio assumption. The exposition is general since we focus on an additive noise model with the noise density assumed to fall within the exponential class of density functions, which comprises most of the common densities. The denoising function is assumed to be pointwise linear (modified James-Stein (MJS) estimator), and parallels between Wiener filtering and the optimum MJS estimator are discussed.

Motivated by the classic works of Charles M. Stein, we focus on developing risk-estimation frameworks for denoising problems in both one-and two-dimensions. We assume a standard additive noise model, and formulate the denoising problem as one of estimating the underlying clean signal from noisy measurements by minimizing a risk corresponding to a chosen loss function. Our goal is to incorporate perceptually-motivated loss functions wherever applicable, as in the case of speech enhancement, with the squared error loss being considered for the other scenarios. Since the true risks are observed to depend on the unknown parameter of interest, we circumvent the roadblock by deriving finite-sample un-biased estimators of the corresponding risks based on Stein’s lemma. We establish the link with the multivariate parameter estimation problem addressed by Stein and our denoising problem, and derive estimators of the oracle risks. In all cases, optimum values of the parameters characterizing the denoising algorithm are determined by minimizing the Stein’s unbiased risk estimator (SURE). The key contribution of this thesis is the development of a risk-estimation approach for choosing the two critical parameters affecting the quality of nonparametric regression, namely, the order and bandwidth/smoothing parameters. This is a classic problem in statistics, and certain algorithms relying on derivation of suitable finite-sample risk estimators for minimization have been reported in the literature (note that all these works consider the mean squared error (MSE) objective). We show that a SURE-based formalism is well-suited to the regression parameter selection problem, and that the optimum solution guarantees near-minimum MSE (MMSE) performance. We develop algorithms for both glob-ally and locally choosing the two parameters, the latter referred to as spatially-adaptive regression. We observe that the parameters are so chosen as to tradeoff the squared bias and variance quantities that constitute the MSE. We also indicate the advantages accruing out of incorporating a regularization term in the cost function in addition to the data error term. In the more general case of kernel regression, which uses a weighted least-squares (LS) optimization, we consider the applications of image restoration from very few random measurements, in addition to denoising of uniformly sampled data. We show that local polynomial regression (LPR) becomes a special case of kernel regression, and extend our results for LPR on uniform data to non-uniformly sampled data also. The denoising algorithms are compared with other standard, performant methods available in the literature both in terms of estimation error and computational complexity. A major perspective provided in this thesis is that the problem of optimum parameter choice in nonparametric regression can be viewed as the selection of optimum parameters of a linear, shift-invariant filter. This interpretation is provided by deriving motivation out of the hallmark paper of Savitzky and Golay and Schafer’s recent article in IEEE Signal Processing Magazine. It is worth noting that Savitzky and Golay had shown in their original Analytical Chemistry journal article, that LS fitting of a fixed-order polynomial over a neighborhood of fixed size is equivalent to convolution with an impulse response that is fixed and can be pre-computed. They had provided tables of impulse response coefficients for computing the smoothed function and smoothed derivatives for different orders and neighborhood sizes, the resulting filters being referred to as Savitzky-Golay (S-G) filters. Thus, we provide the new perspective that the regression parameter choice is equivalent to optimizing for the filter impulse response length/3dB bandwidth, which are inversely related. We observe that the MMSE solution is such that the S-G filter chosen is of longer impulse response length (equivalently smaller cutoff frequency) at relatively flat portions of the noisy signal so as to smooth noise, and vice versa at locally fast-varying portions of the signal so as to capture the signal patterns. Also, we provide a generalized S-G filtering viewpoint in the case of kernel regression. Building on the S-G filtering perspective, we turn to the problem of dynamic feature computation in speech recognition. We observe that the methodology employed for computing dynamic features from the trajectories of static features is in fact derivative S-G filtering. With this perspective, we note that the filter coefficients can be pre-computed, and that the whole problem of delta feature computation becomes efficient. Indeed, we observe an advantage by a factor of 104 on making use of S-G filtering over actual LS polynomial fitting and evaluation. Thereafter, we study the properties of first-and second-order derivative S-G filters of certain orders and lengths experimentally. The derivative filters are bandpass due to the combined effects of LPR and derivative computation, which are lowpass and highpass operations, respectively. The first-and second-order S-G derivative filters are also observed to exhibit an approximately constant-Q property. We perform a TIMIT phoneme recognition experiment comparing the recognition accuracies obtained using S-G filters and the conventional approach followed in HTK, where Furui’s regression formula is made use of. The recognition accuracies for both cases are almost identical, with S-G filters of certain bandwidths and orders registering a marginal improvement. The accuracies are also observed to improve with longer filter lengths, for a particular order. In terms of computation latency, we note that S-G filtering achieves delta and delta-delta feature computation in parallel by linear filtering, whereas they need to be obtained sequentially in case of the standard regression formulas used in the literature. Finally, we turn to the problem of speech enhancement where we are interested in de-noising using perceptually-motivated loss functions such as Itakura-Saito (IS). We propose to perform enhancement in the discrete cosine transform domain using risk-minimization. The cost functions considered are non-quadratic, and derivation of the unbiased estimator of the risk corresponding to the IS distortion is achieved using an approximate Taylor-series analysis under high signal-to-noise ratio assumption. The exposition is general since we focus on an additive noise model with the noise density assumed to fall within the exponential class of density functions, which comprises most of the common densities. The denoising function is assumed to be pointwise linear (modified James-Stein (MJS) estimator), and parallels between Wiener filtering and the optimum MJS estimator are discussed.

Le sujet de cette thèse concerne l’étude de dynamiques induites par des impulsions lasers femtosecondes intenses. La première dynamique étudiée porte sur l’alignement de la molécule de CO2, pure ou en mélange avec l’argon ou l’hélium, en phase gazeuse dense (jusqu’à 20 bar), ce régime n’ayant jamais été étudié expérimentalement auparavant. L’alignement moléculaire, quand il est induit par une impulsion laser femtoseconde et intense, présente deux contributions qui apparaissent après passage de l’impulsion : un alignement permanent et un alignement transitoire. L’influence des collisions se manifeste alors par des transferts de population entre états rotationnels qui ont pour conséquence de faire décroître ces deux contributions. Le temps de décroissance de l’alignement permanent est seulement lié aux collisions inélastiques tandis que le temps de décroissance de l’alignement transitoire est lié à la fois aux collisions inélastiques et élastiques. Nous montrons alors que la détermination expérimentale de la contribution des collisions élastiques, expérimentalement difficile d’accès, est possible à partir de l’analyse des traces d’alignement moléculaire. Cette analyse se base sur la modélisation des taux de transfert entre états liés aux collisions inélastiques par des lois semi-empiriques du type ECS-(E)P. La contribution élastique des collisions déterminée est en bon accord avec des valeurs calculées selon un modèle classique. La deuxième dynamique étudiée est la dépendance en éclairement de l’effet Kerr électronique. Nous poursuivons alors les travaux menés par Loriot et al. en 2009 qui ont montré que l’indice Kerr électronique saturait avant de s’annuler puis de présenter une contribution négative lorsqu’on augmente l’éclairement (inversion du signe pour quelques dizaines de térawatts par centimètre carré). Nous avons alors étendu cette étude en observant à une longueur d’onde de 400 nm (800 nm dans l’étude originale) cette inversion du signe de l’indice Kerr dans l’air. / This thesis is devoted to the study of dynamics induced by intense femtoseconds lasers pulses. The first studied dynamics deals with molecular alignment of CO2-X mixtures (X=CO2, Ar, N2), in dense gases (up to 20 bar). Up to now, this regime has never been studied experimentally. In the field-free regime (after laser/matter interaction), molecular alignment exhibits two components : a permanent alignment and a transient one. The influence of collisions appears through population transfers between rotational states, which leads to a decrease of these two contributions. Permanent alignment relaxation time is only tied to inelastics collisions whereas transient alignment relaxation time is tied to both inelastics and elastics ones. We show that the determination of the elastic collisions contribution (for which the experimental determination is uneasy), is then possible thanks to the analysis of molecular alignment measurements. This analysis is based on the modelling of inelastics rotational state-to-state transfer rates by ECS-(E)P semi-empirical laws. The elastic contribution of collisions is experimentally determined and happened to be in a good agreement with classically calculated ones. The second studied dynamics is the intensity dependence of the electronic Kerr effect. We pursue the works led by Loriot and al. in 2009 which showed that electronic Kerr index saturated, before nullifying and then presenting a negative contribution when the intensity increases (inversion of the sign for some tens of terawatts by square centimeter). We complete the previous study by performing similar measurements in air at 400 nm (800 nm in the original study).

Les traitements pharmacologiques symptomatiques de la maladie d’Alzheimer (MA) actuellement commercialisés ont un effet modeste sur le fonctionnement cognitif. De plus, le développement clinique de nouveaux composés plus efficaces est freiné par l’absence de critères prédictifs pour juger précocement de leur efficacité clinique.Dans ce contexte, l’électroencéphalographie (EEG) pourrait constituer un bio-marqueur suffisamment sensible pour identifier précocement (Phase I) le potentiel thérapeutique d’une nouvelle molécule sur le fonctionnement cognitif. De plus, la difficulté pour détecter des améliorations subtiles dans les performances cognitives en Phase I (i.e. chez des sujets sains) pourrait être palliée par le développement de paradigmes expérimentaux, tels que la privation de sommeil (PS), visant à induire des déficits cognitifs réversibles chez le sujet sain.Ainsi, l’EEG et l’EEG couplée à la privation de sommeil (PS) seraient des stratégies innovantes et pertinentes pour juger et prédire l’efficacité clinique d’une molécule en Phase I.Dans ce travail, nous tentons de juger de la pertinence de telles stratégies en identifiant, chez des sujets sains, des marqueurs EEG du fonctionnement cognitif liés soit (1) à la prise d’un médicament ayant un effet sur la cognition, (2) soit à l’induction d’un déclin cognitif réversible, (3) soit à l’effet concomitant des deux paramètres. Pour y parvenir, deux études ont été réalisées.Dans une première étude, l’effet du donepezil sur l’activité électrique corticale a été étudié chez 30 volontaires adultes, jeunes et sains. Ces volontaires ont été traités par donepezil (5 mg/jour per os) (vs. placebo) pendant 15 jours suivant une procédure en double aveugle, randomisée et en cross-over. _x000D_A la fin de la période de traitement, un EEG (58 voies) a été réalisé au cours de deux tâches attentionnelles (auditive et visuelle). Les potentiels évoqués cognitifs (PEC), la cohérence de phase inter-essais (ITC) et la perturbation spectrale liée à l’événement (ERSP) ont ensuite été calculés.Dans une deuxième étude, l’effet d’une PS a été étudié chez 36 volontaires adultes, jeunes et sains. De plus, l’effet d’un médicament ayant un effet bien connu sur la cognition (en particulier sur la vigilance), le modafinil, a également été étudié sur cette PS.Suite à une PS de 24 h, les participants se sont vus administrés une dose de modafinil (200 mg en prise unique) (vs. placebo) suivant une procédure en double aveugle, randomisée et en cross-over. Un EEG (25 voies) a été réalisé au cours d’une tâche attentionnelle auditive (identique à celle de l’étude I) avant et après la PS. Les PEC, l’ITC et l’ERSP ont ensuite été calculés.Grâce à ces deux études, nous avons identifié, à l’échelle de groupe, des marqueurs EEG de la cognition liés soit à l’induction d’un déclin cognitif (induit par une PS), soit à l’intervention pharmacologique ciblant le système cholinergique (donepezil) ou différents neurotransmetteurs (modafinil). L’ensemble de ces marqueurs porterait sur la modulation de l’activité corticale au sein du réseau fronto-pariétal ventral, connu pour régir les processus attentionnels et exécutifs. Nous avons également confirmé que ce réseau serait sous-tendu par des activités oscillatoires δ/θ et α. L’efficience cognitive serait le reflet de l’intégrité de ce réseau.Nous avons conclu que l’EEG est un outil suffisamment sensible pour détecter des changements subtils dans les processus neurocognitifs de participants adultes, jeunes et sains suivant l’administration d’un traitement de la MA et de manière plus générale suivant l’administration d’un médicament ayant un effet sur la cognition lorsqu’un déclin cognitif est provoqué (PS).Sous réserve de réplication des résultats et d’analyses complémentaires, l’EEG ainsi que l’EEG couplée à la PS pourraient constituer des outils additionnels à l’évaluation cognitive pour prédire l’efficacité de nouveaux candidat médicaments de la MA. / Symptomatic pharmacological treatments currently marketed for Alzheimer’s disease (AD) have a modest effect on cognitive functioning. In addition, the clinical development of new and more effective compounds is hampered by the lack of predictive criteria to judge their early clinical efficacy.In this context, electroencephalography (EEG) could be a sufficiently sensitive biomarker to identify in an early stage (i.e. Phase I) the therapeutic potential of a new molecule on cognitive functioning. In addition, the difficulty to detect subtle improvements in cognitive performance in Phase I (i.e. in healthy subjects) could be overcome by the development of experimental paradigms such as sleep deprivation (SD), to induce cognitive deficits, still reversible in healthy subjects.EEG and EEG coupled with sleep deprivation (SD) would be innovative and relevant strategies to determine and predict the clinical effectiveness of a molecule in Phase I.In this work, we try to determine the relevance of such strategies by identifying, in healthy subjects, EEG markers of cognitive functioning related to (1) either the taking of a cognitive drug, (2) or the induction of a reversible cognitive decline, (3) or concomitant effects of the two parameters. In order to do that, two studies were performed.In a first study, the effect of donepezil on cortical electrical activity was studied in 30 young, healthy adult volunteers. These volunteers were treated with donepezil (5 mg/day orally) (vs. placebo) for 15 days following a double-blind, randomized, cross-over trial.At the end of the treatment period, an EEG (58 electrodes) was performed during two attentional tasks (auditory and visual). Event-related potentials (ERP), the inter-trial coherence (ITC) and the event-related spectral perturbation (ERSP) were then calculated.In a second study, the effect of SD was studied in 36 young, healthy adult volunteers. In addition, the effect of a cognitive drug (involving high alertness), the modafinil was also studied on this SD._x000D_Following a SD of 24 h, the participants were administered a dose of modafinil (200 mg in a single dose) (vs. placebo) in a double-blind, randomized, cross-over trial. An EEG (25 electrodes) was performed in a hearing attentional task (identical to that of Study 1) before and after the PS. The ERP, ITC and ERSP were then calculated.Through these two studies, we have found, at the group level, cognitive EEG markers related either to the induction of cognitive decline (SD) or pharmacological intervention targeting cholinergic system (donepezil) or several neurotransmitters (modafinil). All these markers would concern the modulation of cortical activity in the ventral frontoparietal network, known to regulate attentional and executive processes. We also confirmed that the network is underlying by δ/θ and α oscillatory activities. The cognitive efficiency would reflect the integrity of the network.We conclude that EEG is a sufficiently sensitive tool to detect subtle changes in neurocognitive processes of young, healthy adult volunteers, following the administration of a treatment of AD and more generally following the administration of a drug having an effect on cognition when cognitive decline is caused (SD).EEG and EEG coupled with SD could constitute additional tools to the current cognitive assessment for predicting the efficacy of new drug candidates for AD before initiation Phases II/III clinical trials. However, the present works needs to be replicated so that the EEG markers described here can be validated so as to be used in drug trials.

Introduction Numerous preventive programmes have emerged, and need to be investigated to determine their effects on the normal population. Earlier studies have shown a decrease in depressive symptoms, positive effects on children’s disruptive behaviour problems, and an improvement in parental competence. About a fifth of the parents in previous studies had problem-oriented (targeted) reasons for enrolment, whereas the rest of the parents had general (universal) reasons. The results of those studies suggest that the programmes are cost effective in terms of Quality-Adjusted Life Years. Aim Four sub-studies were performed, and their aims were to investigate the effect of parental training programmes (PTPs) in a naturalistic setting on parents’ mental health in the general population, to investigate how PTPs affect parents’ sense of parental competence, to investigate how PTPs affect parental stress and analyse the parents open questions about the PTPs, and to investigate the feasibility and to measure the effect on depression, anxiety, and social problems of two preventive school programmes for pupils in grade 7. Method In a longitudinal quantitative study in a real-world setting, 279 parents from the general population in northern Sweden participated in five PTPs. A comparison group of 702 parents without intervention was included. Simultaneously, a community sample of 59 pupils in grade 7 participated in two preventive school programmes. Both studies were conducted from 2010 to 2013. Parents were assigned to professionally supported interventions that included 5-10 two-hour sessions. Respondents filled in a web-based questionnaire with the General Health Questionnaire (GHQ), the Parents Sense of Competence (PSOC) for parents who had children aged 0-17 years, and the Swedish Parenthood Stress Questionnaire (SPSQ) for parents who had children aged 0-10 years. The intervention groups’ results were compared to comparison group of 702 parents from northern Sweden that had not participated in any parental training programme. In the school study, one of the preventive programmes was an ongoing programme called “Life-Skills”, and the other was an implemented Canadian programme called “Choosing Healthy Actions and Thoughts” (CHAT). The pupils completed a test battery including the Sense of Coherence (SOC), the Children’s Depression Inventory (CDI), and the Youth Self-Report (YSR) instruments. Follow up of the parental programme study was done six months after the post-intervention measure, and follow up of the school study was at one year. Results The improvements in GHQ were statistically significant for the mean of the 279 parents in the intervention group compared to the mean of a comparison group of the 702 parents who did not receive any intervention. This suggests that evidence-based PTPs enhance parental well-being even for parents without problems. The intervention group showed a statistically significant improvement in parental competence compared to the comparison group over time. The intervention itself had a significant effect on parental satisfaction, but the efficacy effect was not sustained when taking into account potential confounders. In the SPSQ, the intervention group was smaller due to the fact that the instrument was not validated for children over the age of 10 and one of the parental training groups was only for parents of teenagers. A reduction of stress in the sub-scale of health problems was detected, but no other subscale showed the intervention to have a significant effect when controlling for confounding variables. In the school study, both programmes had good feasibility according to the stake- holders and had several positive mental health outcomes over time. Compared to Life-Skills, CHAT had more significant positive effects on reducing anxious/depressive symptoms and girls experienced significant positive effects on reduced anxious/depressive behaviour, while boys reduced their aggressive behaviours. Conclusions Earlier studies indicate that PTPs enhance perceived parental competence among referred parents. The present study shows that PTPs applied in the general population might also enhance perceived parental benefits such as improved health and satisfaction, suggesting that PTPs can be an important preventive strategy to enhance parenthood. The results suggest that parents who feel a need to increase their parenting competence might participate in PTPs based on lower scores than the comparison control group both before and after the intervention. The school-based programme shows that schools may be a suitable arena for preventive programmes because there was a significant short-term improvement in depression symptoms. Further studies need to explore how parents’ participation in PTPs affects children’s mental health in the general population in quantitative longitudinal studies in real-word settings. There is also a need for bigger studies and RCTs on school preventions and on how children’s health develops naturally in the population.

La théorie de la responsabilité civile, en termes de la reconstruction rationnelle du droit constitue une connaissance nouvelle et importante de ce régime. L’analyse économique en reconstruit les règles et les institutions à partir de la norme de l’efficience. La théorie morale de la justice corrective interprète la responsabilité civile à travers l’égalité entre les parties. Mais, aucune de ces deux interprétations ne parvenue à expliquer la responsabilité civile. L’analyse économique, en traitant les règles de la responsabilité comme un moyen visant à maximiser la richesse, a modifié leur sens original. La justice corrective réduit la responsabilité civile au régime d’allocation équitable des coûts d’accident. La reconstruction de la responsabilité civile, afin de la comprendre, requiert de s’engager dans une approche philosophique qui trouve la rationalité dans la réalité. Dans cette optique, la responsabilité civile, contrairement à l’analyse économique ou à la justice corrective, est constituée à partir les droits et les principes indéniables, non les normes hypothétiques. La faute, en termes de droit de la volonté subjective, tout est redéfinie selon la pratique sociale sur l’attribution des résultats de nos actes, ce qui permet de croire que la responsabilité civile est toujours morale, même lorsque elle s’impose à partir d’une évaluation objective et extérieure. / Tort theory in terms of rational reconstruction of the law has constituted a new and important knowledge of the tort liability. Economic analysis has reconstructed the rules and institutions by the value of efficiency. Moral theory of corrective justice has interpreted liability through equality between the parties. But neither of these interpretations could come to explain liability. The economic analysis by treating the liability rules as a mean of wealth maximization has changed their original meaning. Corrective justice reduced tort liability to the regime fair allocation of accident costs. The reconstruction in order to understand civil liability requires engaging in a philosophical approach in which reality is the source of rationality. In this context, liability, unlike the economic analysis or corrective justice, is formed from undeniable rights and principles, not hypothetical norms. The negligence in terms of right of the subjective will is redefined by social practice on the attribution results of our actions, which suggests that civil liability is still moral idea, even when it is imposed from an objective and external assessment.

On considère généralement que la fonction d’onde macroscopique décrivant un condensat de paires de fermions possède une phase parfaitement définie et immuable. En réalité, il n’existe que des systèmes de taille finie, préparés à température non nulle ; le condensat possède alors un temps de cohérence fini, même lorsque le système est isolé. Cet effet fondamental, crucial pour les applications qui exploitent la cohérence macroscopique, restait très peu étudié.Dans cette thèse, nous relions le temps de cohérence à la dynamique de phase du condensat, et nous montrons par une approche microscopique que la dérivée temporelle de l’opérateur phase ˆθ0 est proportionnelle à un opérateur potentiel chimique qui inclut les deux branches d’excitations du gaz : celle, fermionique, de brisure des paires et celle, bosonique, de mise en mouvement de leur centre de masse. Pour une réalisation donnée de l’énergie E et du nombre de particules N, la phase évolue aux temps longs comme −2μmc(E,N)t/~ où μmc(E,N) est le potentiel chimique microcanonique ; les fluctuations de E et de N d’une réalisation à l’autre conduisent alors à un brouillage balistique de la phase, et à une décroissance gaussienne de la fonction de cohérence temporelle avec un temps caractéristique ∝ N1/2. En l’absence de telles fluctuations, la décroissance est au contraire exponentielle avec un temps de cohérence qui diverge linéairement en N à cause du mouvement diffusif de ˆθ0 dans l’environnement des modes excités. Nous donnons une expression explicite de ce temps caractéristique à bassetempérature dans le cas d’une branche d’excitation bosonique convexe lorsque les phonons interagissent via les processus 2 ↔ 1 de Beliaev-Landau. Enfin, nous proposons des méthodes permettant de mesurer avec un gaz d’atomes froids chaque contribution au temps de cohérence / It is generally assumed that a condensate of paired fermions at equilibrium is characterized by a macroscopic wavefunction with a well-defined, immutable phase. In reality, all systems have a finite size and are prepared at non-zero temperature ; the condensate has then a finite coherence time, even when the system is isolated. This fundamental effect, crucial for applicationsusing macroscopic coherence, was scarcely studied. Here, we link the coherence time to the condensate phase dynamics, and show using a microscopic theory that the time derivative of the condensate phase operator ˆθ0 is proportional to a chemical potential operator which includes both the fermionic pair-breaking and the bosonic pair-motion excitation branches.For a given realization of the number of particle N and of the energy E, the phase evolves at long times as −2μmc(E,N)t/~ where μmc(E,N) is the microcanonical chemical potential ; fluctuations of N and E from one realization to the other then lead to a ballistic spreading of the phase and to a Gaussian decay of the temporal coherence function with a characteristictime ∝ N1/2. On the contrary, in the absence of energy and number fluctuations, the decay of the temporal coherence function is exponential with a characteristic time scaling as N due to the diffusive motion of ˆθ0 in the environnement created by the excited modes. We give an explict expression of this characteristic time at low temperature in the case where the bosonicbranch is convex and the phonons undergo 2 ↔ 1 Beliaev-Landau process. Finally, we propose methods to measure each contribution to the coherence time using ultracold atoms.

This thesis titled, “Nature of Local Interactions at cisPro-Aro Peptide Sequences in Proteins: Evidences for van der Waals type Interactions. Design and Synthesis of Novel Covalent Surrogates for the Peptide Hydrogen Bond”, describes two important studies. The first is to gain a thorough understanding of the nature of interactions that govern cisPro stability at Pro-Aro sequences, which described in the first four chapters. The final chapter describes the synthesis of novel 4-carbon covalent surrogates for the peptide H-bonding interaction. Chapter 1: Local Interactions Governing cisPro Stability: Refining the Model Peptides Chapter 1 Section A: Understanding the role of inter-side chain CH•••Aro interaction in cis-trans isomerization at Pro-Aro and Aro-Pro Sequences. This chapter is divided into two sections. In the first section an exhaustive overview of earlier investigations into the nature of local interactions at Xaa-cisPro-Aro and Aro-cisPro-Xaa peptide sequences, by various groups, are discussed. Most studies have found evidence for the close assemblage between side chains of residues flanking cisPro motifs, when at least one of them is an aromatic group. An electronic C-H•••π nature has been proposed for these assemblies and they are proposed to influence the cisPro stability. We highlight those features in these studies that indicate that these interactions are not always electronically tunable, are insensitive to presence of strong chaotropes in the solvent and occur at protein sequences lacking Pro or cisPro; all of which contradict the electronic C-H•••π model for these inter-side chain assemblages and their perceived influence on cisPro stability. Chapter 1 Section B: Investigation of the Nature of H Xaa•••Aro interaction at Xaa-Pro-Pro-Phe-sequences In Section B, we design and synthesize Pro-Aro containing short peptide models to investigate the nature of local C-H•••Aro interactions in them. We synthesize a series of homologous Pro-Pro-Aro containing peptides (modeled based on earlier studies) and investigate the relative populations of its four Xaa-Pro rotamers using extensive 1D and 2D NMR techniques including TOCSY, HSQC and ROESY. We find several drawbacks that make this a relatively deficient model. Firstly, their relative populations of the rotamers (the most important data for current investigation) cannot be determined with high fidelity as they are dependent on the solvent polarity, solute concentration and chemical shift degeneracy of crucial NMR signals for the rotamers. Importantly, the populations of a few rotamers are influenced by strong 13-membered ring backbone H-bonds. Notably, some of the cisPro rotamers do not even contain the inter-side chain assembly, whose nature is under investigation. Design of novel models – unconstrained by H-bonds We design the Acyl-Pro-Pro-Aro-OMe peptides that lack the possibility of forming the 13-membered ring H-bonded structures. Thorough 1D and 2D NMR analyses of these models reveal that strong Type VI β-turn type 10-membered ring H-bonds are formed in the rotamers of these models – hence precluding their applications for current study. Interestingly, the relative rotamer populations are strongly influenced by solvent polarity and are entirely different from those of the corresponding C-terminal amide models. We further discover that the Pro-Pro-Aro motif is not essential to express the inter-side chain interactions – Ala-Pro-Aro are sufficient. Formation of the 10-membered H-bonding interactions, however, are not precluded. Chapter 2: Design and Synthesis of Acyl-Pro-Phe-OMe: Novel models to investigate the role of HαXaa•••Aro interactions on Xaa-cisPro-Aro stability. Chapter 2 Section A: Design, Synthesis and Conformational Analysis of Ibu-Pro-Phe-OMe Chapter 2 is divided into two sections. In Section A, we replace the amino acid at the N-terminal of the putative Pro residue with simple isosteric isobutyryl group, the resulting minimalist dipeptide model shows the exclusive influence of desired inter-side chain interactions in the cisPro rotamer. Solvent polarity and temperature coefficient studies reveal that absence of any intramolecular H-bonding or Oπ* interactions in it. 1D and 2D NMR analyses clearly indicate the close proximity between the side chains of Ibu and Phe exclusively in the cisPro rotamer. The Kc/t value decreases upon mutation of Phe to Ala. All these features favor the Ibu-Pro-Phe-OMe as an ideal minimalistic model for investigating the nature of Ibu•••Ph assemblages in the cisPro rotamer. Chapter 2 Section B: Investigation of CH•••Aro /Alp•••Alp interactions in Ibu-cisPro-Xaa-OMe In Section B, the 1D and 2D NMR analyses of the complete set of the aliphatic and aromatic analogues Ibu-Pro-Xaa-OMe were investigated. DMSO-d6 was found to be the best solvent for mimicking both the folded and the unfolded local environments of these short peptide sequences. The HαIbu•••Aro assemblage is observed in Aro analogues, but cannot be electronically tuned. The aliphatic analogues also surprisingly contain the HαIbu•••Alp interactions! The Kc/t values (cisPro %) increase in the aliphatic analogues too, where the aliphatic side chain is long. Increase in cisPro stability is not due to ring current effects or intramolecular H-bonds or Oπ* interactions. It seems to be due to van der Waals type interactions between the involved side chains, either of which need not be aromatic in nature. Chapter 3: Nature of Inter-Side Chain Interactions at Acyl-cisPro-Aro Sequences: Evidence for van der Waals Interactions Chapter 3 Section A: Investigation of nature of inter-side chain interactions in R-CO-cisPro-Phe-OMe Chapter 3 has two sections. Section A describes the systematic design and synthesis of Acyl-Pro-Phe-OMe homologues where first the steric bulk and hence the surface area of the aliphatic side chain of the acyl group is varied. Interaction of the phenyl ring of Phe seems to occur with the Cα-Cβ σ-bond of the acyl group. Branching at either Cα or Cβ seems to destabilize the cisPro rotamer. Aliphatic•••Aromatic interactions overwhelm the cisPro rotamer population to be greater than that of transPro. In the analogues where the acidity of the acyl Cα-H bond is increased, the Kc/t does not increase correspondingly. The Δδ(trans-cis) ppm shifts of HαAcyl protons are dependent exclusively on its acidity rather than on the Kc/t values. In carbamyl-Pro, which entirely lack the HαAcyl proton, the Kc/t values are significantly high and improve as the aliphatic surface on the alkoxy group increases. Introduction of benzyloxy carbamyl group at Pro renders almost the same Kc/t values as that of ethyloxy carbamate. All these data contradict the C-H•••π interaction model and strongly support a van der Waals type interaction between the Acyl (preceding cisPro) group’s Xα-Yβ σ-bond and the Aro or Alp side chains (succeeding cisPro). Chapter 3 Section B: Evidence for the Van der Waals nature of Inter Side Chain (Acyl•••S.C.Aro/Alp) interactions- Determination of Interactions energies In Section B, a thorough investigation of both aliphatic•••aliphatic and aliphatic•••aromatic interactions on the background of homologous Acyl-Pro-Aro/Alp-OMe peptide models is undertaken. These models uniquely allow the delineation of contribution of the van der Waals interactions and the ring current effects to the cis/trans isomerization in these peptides. We see that the energy of the van der Waals component of these aliphatic•••aliphatic and aliphatic…aromatic interactions increase linearly with increase in Kc/t, in both DMSO-d6 and D2O. On other hand, energy from the ring current effects largely remains invariant. The Acyl•••Aro/Alp interactions are not hydrophobic and are facilitated by conformational effects. Chapter 4: Crystallographic evidence for van der Waals interaction-mediated stabilization of cisPro conformers Chapter 4 Section A: Systematic crystallization and crystal structure analyses of homologous Xaa-cisPro-Alp and Xaa-cisPro-Aro rotamers: Evidence for van der Waals interactions Chapter 4 has two sections, both of which present crystallographic evidence for the van der Waals nature of the Xaa•••Aro interactions at Xaa-cisPro-Aro sequences. Section A describes the unique crystal structures of five of the Acyl-Pro-Alp-OMe analogues that have been synthesized in the current study. All of them remarkably crystallize with two features: 1) the Acyl-Pro peptide bond adopts the cisPro rotamer in all; and 2) the aliphatic side chains of the acyl group and the Alp side chain are involved in van der Waals type interactions. The cisPro rotamers of even the bulkiest motifs, namely Ibu-Pro-Val-OMe, Piv-Pro-Ile-OMe and Piv-Pro-Leu-OMe crystallize, stabilized by van der Waals packing between aliphatic groups of the acyl and the Leu/Ile/Val side chains. Where the side chains are not long enough to make sub-van der Waals contacts with each other, their acyl C′-Cα σ-bond rotations are restricted due to Oσ* interactions involving the charge on the acyl carbonyl O. Where this occurs, the short space between the acyl and Alp side chains are filled in by aliphatic groups from neighbouring molecules at sub van der Waals distances. The Pro, Alp and χ1(Alp) dihedral angles are restricted to narrow range of values, irrespective of the length of Alp side chain, indicating that this backbone conformation is a conformational minimum when i+3i backbone H-bond is removed, with Pro at the i+1st position. This is further substantiated in Piv-Pro-Gly-OMe, which crystallizes in trans-Pro form, but still adopts similar backbone dihedral angles in spite of lacking any Alp side chain for interactions with the acyl group. Three of the Acyl-Pro-Aro-OMe models also crystallize in cisPro rotamer forms – both exhibit van der Waals type contacts between the Acyl group and backbone of Phe, rather than the aromatic ring of Phe. The phenyl ring of Phe may or may not form intramolecular Ph•••Pro inter-side chain contacts – which is not a pre-requisite for cisPro stabilization. No C-H••• interactions are observed anywhere in these peptides – van der Waals type contacts alone predominate in all cases. There are no abnormal distortions in bond angles or lengths even in the most sterically hindered cases, signifying that the conformations of these cisPro rotamers involving aliphatic•••aliphatic type contacts are natural minima. Chapter 4 Section B: Mining the PDB for Statistical Evidence of van der Waals interactions Section B of chapter 4 describes the data mining and statistical analyses of Xaa-cisPro-Phe, Xaa-cisPro-Val and Xaa-cisProLeu sequences in the PDB. The PEARL program was used to mine the PDB data. The overall frequency of 5.3% for appearance of cisPro among all Xaa-Pro peptide bonds, improves when Xaa is Phe or Tyr. However, several anomalies highlight the need for refining the analyses set to only those sequences where the side chains of Xaa and Aro/Alp face each other. In this refined set, clearly, inter side chain Xaa•••Alp/Aro contacts take precedence over even Aro•••Pro interactions at Aro-cisPro sequences (where Xaa is Aro). The Phe and the Leu side chains induce similar conformational effects on the preceding Xaa-Pro backbone. So does Val. Strong aliphatic•••aliphatic inter side chain contacts at van der Waals distances are observed to flank cisPro in several proteins. Substitution at the Cα of Xaa governs the proximity of the approaching side chain of Alp / Aro residue. The Cα-H of Xaa steers away from the Aro side chain at Xaa-Pro-Phe sequences, as the Aro group gets closer to it – implying the absence of ordered C-H••• contacts between them. There is consistent parallel alignment between Cα-Cβ -bond of Xaa and the C -C bond of the approaching side chain of Alp or Aro group – clearly highlighting the presence of van der Waals type interactions between them. All these evidences clearly point towards the van der Waals nature of local interactions at cisPro-Aro/Alp peptide sequences. Chapter 5: A novel 4-carbon covalent surrogate model for peptide H-Bond Chapter 5 describes the design and synthesis of novel 4-carbon covalent surrogates for the peptide H-bond (HBS). These surrogates would allow the unique constraining of two peptide strands in their extended conformations. The covalent HBS contain four orthogonal functional groups for independent extension at all of the four ends – similar to an endogenous inter-strand peptide H-bond. The synthesis of the surrogate is achieved by directly using natural chiral amino acid derivatives, beginning from amino alcohols obtained from reduction of desired amino acids. Suitably N-protected alcohols undergo oxidation to aldehyde followed by Grignard addition of allyl magnesium bromide, TBDMS protection of the homoallylic alcohol and reductive ozonolysis of the olefin to get a primary alcohol which is subject to Fukuyama-Mitsunobu reaction with desire protected peptide. The residue preferences that produce strongest inter-strand H-bonds were explored. The designed 4-carbon covalent HBS was incorporated using this methodology in a Gramicidin-S analogue, its first structural mimic containing only a single turn motif. This HBS model will have wide applications for constraining peptides in a number of secondary structures.

Eléments essentiels du contrat, les clauses contractuelles méritent d’être étudiées afin de faciliter leur utilisation par les praticiens et leur appréhension par le juge.Délaissant toute visée exhaustive, ce travail n’a pas pour objet de répertorier ni de dénombrer matière par matière, à la manière d’un catalogue, les innombrables clauses foisonnant dans l’ensemble des branches du droit privé. Un tel projet ne livrerait que des enseignements parcellaires et descriptifs. Une réflexion générale sur les clauses prises comme instrument juridique ne présuppose pas de se livrer à un examen systématique de l’ensemble de leurs applications particulières, mais au contraire de mettre l’accent sur certains de leurs effets,jugés les plus remarquables.Une typologie des principales clauses devait tout d’abord être établie grâce à une approche fonctionnelle de leurs manifestations contractuelles. En effet, la volonté des parties d’organiser leur contrat tend généralement vers quatre grandes finalités : aménager l’exécution du contrat, gérer les risques encourus, éviter l’appréciation judiciaire et prévoir la fin du contrat et ses éventuelles sanctions. L’établissement d’une classification basée sur leur fonction permettait en outre de ne pas délaisser ni les clauses naissant au gré des besoins économiques ni les clauses considérées comme autonomes. Ce projet conduisait nécessairement à rechercher les modalités d’exécution des clauses d’une même catégorie permettant ainsi de proposer un régime juridique propre à chacune de ces catégories.Prolongeant l’analyse de leur fonction, il convenait alors dans une seconde partie d’étudier les liens existants entre les clauses et le contrat. Les clauses sont au service du contrat dont elles aménagent les obligations, prolongent les effets et précisent les sanctions.Or, parallèlement aux deux niveaux de dispositions que représentent la théorie générale du contrat et le droit des contrats spéciaux, il devait être démontré qu’une théorie générale des clauses contractuelles ne saurait constituer un troisième niveau de règles applicables au contrat. Néanmoins, une vision générale de l’influence de leurs effets, sur et en dehors du contrat, a permis d’établir des conditions de validité et des règles communes applicables à toutes les clauses. / Contractual clauses are key elements of a contract and should be studied more closely in order to facilitate their use by practioners and to enhance understanding by the judge.This work does not claim to be exhaustive. Its purpose is not to to identify, enumerate or catalogue the numerous clauses that abound in all branches of private law. Such a project would only yield a fragmented, descriptive insight. A general reflection on clauses as legal instruments does not necessitate a detailed examination of all applications but only that their most notable effects be highlighted.Firstly, a typology of the most important clauses had to be drawn up based on a functional approach regarding their contractual applications. The parties to a contract generally have in view four main goals: organising the execution of the contract, managing the risks, avoiding legal pitfalls, and foreseeing the end of the contract and any potential sanctions. The establishment of a classification based on function ensured that clauses arising from economic necessity as well as clauses considered to be independent would not beneglected. Hence, this project comprises research on the details of implementation of clauses in the same category, leading to the setting out of a legal regime appropriate to each category. Secondly, the aim of analysing the clauses’ functions led to studying the links between clauses and contracts. Clauses basically serve to organise the terms of the contract, extend its effects and establish sanctions. However, in parallel to the two levels – the general theory of contracts and special contracts law – it had to be demonstrated that a general theory of contractual clauses did not constitute a third level of rules applicable to contracts. Nevertheless, an overall view of the influence of their effects, both in terms of and beyond the contract, has allowed for the establishment of a general regime presenting the conditions of validity and common rules applicable to all clauses.

Le pouce opposable de la main joue un rôle essentiel dans le comportement humain, permettant une prise bien plus précise que celle des singes avec les pouces opposables. Comment le cerveau contrôle t-il les mains aussi précisément? Dans le cadre de cette thèse, nous avons étudié comment différentes régions du cerveau dédiées au contrôle moteur, en particulier le cortex moteur (M1) et l’aire motrice supplémentaire (AMS), contribuent à une pince pouce-index précise. Les résultats de nos études révèlent que des neurones dans l’AMS, en complément de ceux dans M1, communiquent directement avec les motoneurones de la moelle épinière contrôlant les muscles de la main. De plus, SMA communique aussi efficacement que M1 avec les muscles de la main, alors que chez le singe, celle avec M1 est plus efficace. Cette différence fonctionnelle dans la voie AMS-muscles entre le singe et l’Homme pourrait expliquer la plus grande capacité de ce dernier à contrôler finement la force produite par les doigts. / The human hand's opposable thumb plays a large role in human behavior, allowing for a grip far more precise than that of monkeys with opposable thumbs. However, it isn't well understood how the brain controls the hands in such a precise way. In these studies, we investigate how different parts of the brain dedicated to motor tasks, in particular the motor cortex (M1) and the supplementary motor area (SMA), contribute to a precise thumb-index finger grip. Our experiments suggest that some neurons in the SMA, in addition to those well-described in M1, may connect directly to the motoneurons in the spinal cord controlling the hand muscles. Moreover, we found that SMA communicates with the hand muscles as efficiently as M1, while in monkeys, SMA communicates less efficiently than M1. This functional difference in the SMA-muscles pathway between monkey and human may account for the higher capacity of the latter to precisely control the force produced by digits.