Inversion of analytic characteristic functions and infinite convolutions of exponential and Laplace densities

This paper shows that certain quotients of entire functions are characteristic functions. Under some conditions, we provide expressions for the densities of such characteristic functions which turn out to be generalized Dirichlet series which in turn can be expressed as an infinite linear combination of exponential or Laplace densities. We apply these results to several examples.

On the stability of the optimal value and the optimal set in optimization problems

The paper develops a stability theory for the optimal value and the optimal set mapping of optimization problems posed in a Banach space. The problems considered in this paper have an arbitrary number of inequality constraints involving lower semicontinuous (not necessarily convex) functions and one closed abstract constraint set. The considered perturbations lead to problems of the same type as the nominal one (with the same space of variables and the same number of constraints), where the abstract constraint set can also be perturbed. The spaces of functions involved in the problems (objective and constraints) are equipped with the metric of the uniform convergence on the bounded sets, meanwhile in the space of closed sets we consider, coherently, the Attouch-Wets topology. The paper examines, in a unified way, the lower and upper semicontinuity of the optimal value function, and the closedness, lower and upper semicontinuity (in the sense of Berge) of the optimal set mapping. This paper can be seen as a second part of the stability theory presented in [17], where we studied the stability of the feasible set mapping (completed here with the analysis of the Lipschitz-like property).

On the presence of hepatic stellate cells in portal spaces

Previous studies in mice with hypervitaminosis A have demonstrated that fat-storing cells (hepatic stellate cells-HSCs) participate in schistosomal granuloma fibrogenesis. The origin of such cells in portal areas, away from the Disse spaces, was herein investigated. HSCs were identified in frozen sections of the liver by means of Sudan III staining. They appeared as red-stained cells disposed along the sinusoids of normal mice, but were never found within portal spaces. However, in the chronically inflamed portal spaces of Capillaria hepatica-infected mice, Sudan III-positive cells were frequently present among leukocytes and fibroblast-like cells. Thus, there are no resident HSCs in portal spaces, but their presence there in chronic inflammatory processes indicates that they are able to migrate from peri-sinusoidal areas in order to reach the portal areas.

Dissecting TCR-MHC/peptide complex interactions with A2/peptide multimers incorporating tumor antigen peptide variants: crucial role of interaction kinetics on functional outcomes.

Soluble peptide/MHC-class-I (pMHC) multimers have recently emerged as unique reagents for the study of specific interactions between the pMHC complex and the TCR. Here, we assessed the relative binding efficiency of a panel of multimers incorporating single-alanine-substituted variants of the tumor-antigen-derived peptide MAGE-A10(254-262) to specific CTL clones displaying different functional avidity. For each individual clone, the efficiency of binding of multimers incorporating MAGE-A10 peptide variants was, in most cases, in good although not linear correlation with the avidity of recognition of the corresponding variant. In addition, we observed two types of discrepancies between efficiency of recognition and multimer binding. First, for some peptide variants, efficient multimer binding was detected in the absence of measurable effector functions. Some of these peptide variants displayed antagonist activity. Second, when comparing different clones we found clear discrepancies between the dose of peptide required to obtain half-maximal lysis in CTL assays and the binding efficiency of the corresponding multimers. These discrepancies, however, were resolved when the differential stability of the TCR/pMHC complexes was determined. For individual clones, decreased recognition correlated with increased TCR/pMHC off-rate. TCR/pMHC complexes formed by antagonist ligands displayed off-rates faster than those of TCR/pMHC complexes formed with weak agonists. In addition, when comparing different clones, the efficiency of multimer staining correlated better with relative multimer off-rates than with half-maximal lysis values. Altogether, the data presented here reconcile and extend our previous results on the impact of the kinetics of interaction of TCR with pMHC complexes on multimer binding and underline the crucial role of TCR/pMHC off-rates for the functional outcome of such interactions.

Theory for correlation functions of processes driven by external colored noise

We study steady-state correlation functions of nonlinear stochastic processes driven by external colored noise. We present a methodology that provides explicit expressions of correlation functions approximating simultaneously short- and long-time regimes. The non-Markov nature is reduced to an effective Markovian formulation, and the nonlinearities are treated systematically by means of double expansions in high and low frequencies. We also derive some exact expressions for the coefficients of these expansions for arbitrary noise by means of a generalization of projection-operator techniques.

Bayes linear spaces

Linear spaces consisting of σ-finite probability measures and infinite measures (improper priors and likelihood functions) are defined. The commutative group operation, called perturbation, is the updating given by Bayes theorem; the inverse operation is the Radon-Nikodym derivative. Bayes spaces of measures are sets of classes of proportional measures. In this framework, basic notions of mathematical statistics get a simple algebraic interpretation. For example, exponential families appear as affine subspaces with their sufficient statistics as a basis. Bayesian statistics, in particular some well-known properties of conjugated priors and likelihood functions, are revisited and slightly extended

New insights into cellular prion protein (PrPc) functions: the 'ying and yang' of a relevant protein.

The conversion of cellular prion protein (PrPc), a GPI-anchored protein, into a protease-K-resistant and infective form (generally termed PrPsc) is mainly responsible for Transmissible Spongiform Encephalopathies (TSEs), characterized by neuronal degeneration and progressive loss of basic brain functions. Although PrPc is expressed by a wide range of tissues throughout the body, the complete repertoire of its functions has not been fully determined. Recent studies have confirmed its participation in basic physiological processes such as cell proliferation and the regulation of cellular homeostasis. Other studies indicate that PrPc interacts with several molecules to activate signaling cascades with a high number of cellular effects. To determine PrPc functions, transgenic mouse models have been generated in the last decade. In particular, mice lacking specific domains of the PrPc protein have revealed the contribution of these domains to neurodegenerative processes. A dual role of PrPc has been shown, since most authors report protective roles for this protein while others describe pro-apoptotic functions. In this review, we summarize new findings on PrPc functions, especially those related to neural degeneration and cell signaling.

Better-quasi-order : ideals and spaces

This thesis deals with combinatorics, order theory and descriptive set theory. The first contribution is to the theory of well-quasi-orders (wqo) and better-quasi-orders (bqo). The main result is the proof of a conjecture made by Maurice Pouzet in 1978 his thèse d'état which states that any wqo whose ideal completion remainder is bqo is actually bqo. Our proof relies on new results with both a combinatorial and a topological flavour concerning maps from a front into a compact metric space. The second contribution is of a more applied nature and deals with topological spaces. We define a quasi-order on the subsets of every second countable To topological space in a way that generalises the Wadge quasi-order on the Baire space, while extending its nice properties to virtually all these topological spaces. The Wadge quasi-order of reducibility by continuous functions is wqo on Borei subsets of the Baire space, this quasi-order is however far less satisfactory for other important topological spaces such as the real line, as Hertling, Ikegami and Schlicht notably observed. Some authors have therefore studied reducibility with respect to some classes of discontinuous functions to remedy this situation. We propose instead to keep continuity but to weaken the notion of function to that of relation. Using the notion of admissible representation studied in Type-2 theory of effectivity, we define the quasi-order of reducibility by relatively continuous relations. We show that this quasi-order both refines the classical hierarchies of complexity and is wqo on the Borei subsets of virtually every second countable To space - including every (quasi-)Polish space. -- Cette thèse se situe dans les domaines de la combinatoire, de la théorie des ordres et de la théorie descriptive. La première contribution concerne la théorie des bons quasi-ordres (wqo) et des meilleurs quasi-ordres (bqo). Le résultat principal est la preuve d'une conjecture, énoncée par Pouzet en 1978 dans sa thèse d'état, qui établit que tout wqo dont l'ensemble des idéaux non principaux ordonnés par inclusion forme un bqo est alors lui-même un bqo. La preuve repose sur de nouveaux résultats, qui allient la combinatoire et la topologie, au sujet des fonctions d'un front vers un espace métrique compact. La seconde contribution de cette thèse traite de la complexité topologique dans le cadre des espaces To à base dénombrable. Dans le cas de l'espace de Baire, le quasi-ordre de Wadge est un wqo sur les sous-ensembles Boréliens qui a suscité énormément d'intérêt. Cependant cette relation de réduction par fonctions continues s'avère bien moins satisfaisante pour d'autres espaces d'importance tels que la droite réelle, comme l'ont fait notamment remarquer Hertling, Schlicht et Ikegami. Nous proposons de conserver la continuité et d'affaiblir la notion de fonction pour celle de relation. Pour ce faire, nous utilisons la notion de représentation admissible étudiée en « Type-2 theory of effectivity » initiée par Weihrauch. Nous introduisons alors le quasi-ordre de réduction par relations relativement continues et montrons que celui-ci à la fois raffine les hiérarchies classiques de complexité topologique et forme un wqo sur les sous-ensembles Boréliens de chaque espace quasi-Polonais.

New insights into cellular prion protein (PrPc) functions: the 'ying and yang' of a relevant protein.

The conversion of cellular prion protein (PrPc), a GPI-anchored protein, into a protease-K-resistant and infective form (generally termed PrPsc) is mainly responsible for Transmissible Spongiform Encephalopathies (TSEs), characterized by neuronal degeneration and progressive loss of basic brain functions. Although PrPc is expressed by a wide range of tissues throughout the body, the complete repertoire of its functions has not been fully determined. Recent studies have confirmed its participation in basic physiological processes such as cell proliferation and the regulation of cellular homeostasis. Other studies indicate that PrPc interacts with several molecules to activate signaling cascades with a high number of cellular effects. To determine PrPc functions, transgenic mouse models have been generated in the last decade. In particular, mice lacking specific domains of the PrPc protein have revealed the contribution of these domains to neurodegenerative processes. A dual role of PrPc has been shown, since most authors report protective roles for this protein while others describe pro-apoptotic functions. In this review, we summarize new findings on PrPc functions, especially those related to neural degeneration and cell signaling.

Quasiconformal mappings and inequalities involving special functions

This PhD thesis in Mathematics belongs to the field of Geometric Function Theory. The thesis consists of four original papers. The topic studied deals with quasiconformal mappings and their distortion theory in Euclidean n-dimensional spaces. This theory has its roots in the pioneering papers of F. W. Gehring and J. Väisälä published in the early 1960’s and it has been studied by many mathematicians thereafter. In the first paper we refine the known bounds for the so-called Mori constant and also estimate the distortion in the hyperbolic metric. The second paper deals with radial functions which are simple examples of quasiconformal mappings. These radial functions lead us to the study of the so-called p-angular distance which has been studied recently e.g. by L. Maligranda and S. Dragomir. In the third paper we study a class of functions of a real variable studied by P. Lindqvist in an influential paper. This leads one to study parametrized analogues of classical trigonometric and hyperbolic functions which for the parameter value p = 2 coincide with the classical functions. Gaussian hypergeometric functions have an important role in the study of these special functions. Several new inequalities and identities involving p-analogues of these functions are also given. In the fourth paper we study the generalized complete elliptic integrals, modular functions and some related functions. We find the upper and lower bounds of these functions, and those bounds are given in a simple form. This theory has a long history which goes back two centuries and includes names such as A. M. Legendre, C. Jacobi, C. F. Gauss. Modular functions also occur in the study of quasiconformal mappings. Conformal invariants, such as the modulus of a curve family, are often applied in quasiconformal mapping theory. The invariants can be sometimes expressed in terms of special conformal mappings. This fact explains why special functions often occur in this theory.

Training executive functions in the laboratory and in real life : cognitive consequences of computer-based exercises and bilingualism

The question of the trainability of executive functions and the impact of such training on related cognitive skills has stirred considerable research interest. Despite a number of studies investigating this, the question has not yet been solved. The general aim of this thesis was to investigate two very different types of training of executive functions: laboratory-based computerized training (Studies I-III) and realworld training through bilingualism (Studies IV-V). Bilingualism as a kind of training of executive functions is based on the idea that managing two languages requires executive resources, and previous studies have suggested a bilingual advantage in executive functions. Three executive functions were studied in the present thesis: updating of working memory (WM) contents, inhibition of irrelevant information, and shifting between tasks and mental sets. Studies I-III investigated the effects of computer-based training of WM updating (Study I), inhibition (Study II), and set shifting (Study III) in healthy young adults. All studies showed increased performance on the trained task. More importantly, improvement on an untrained task tapping the trained executive function (near transfer) was seen in Study I and II. None of the three studies showed improvement on untrained tasks tapping some other cognitive function (far transfer) as a result of training. Study I also used PET to investigate the effects of WM updating training on a neurotransmitter closely linked to WM, namely dopamine. The PET results revealed increased striatal dopamine release during WM updating performance as a result of training. Study IV investigated the ability to inhibit task-irrelevant stimuli in bilinguals and monolinguals by using a dichotic listening task. The results showed that the bilinguals exceeded the monolinguals in inhibiting task-irrelevant information. Study V introduced a new, complementary research approach to study the bilingual executive advantage and its underlying mechanisms. To circumvent the methodological problems related to natural groups design, this approach focuses only on bilinguals and examines whether individual differences in bilingual behavior correlate with executive task performances. Using measures that tap the three above-entioned executive functions, the results suggested that more frequent language switching was associated with better set shifting skills, and earlier acquisition of the second language was related to better inhibition skills. In conclusion, the present behavioral results showed that computer-based training of executive functions can improve performance on the trained task and on closely related tasks, but does not yield a more general improvement of cognitive skills. Moreover, the functional neuroimaging results reveal that WM training modulates striatal dopaminergic function, speaking for training-induced neural plasticity in this important neurotransmitter system. With regard to bilingualism, the results provide further support to the idea that bilingualism can enhance executive functions. In addition, the new complementary research approach proposed here provides some clues as to which aspects of everyday bilingual behavior may be related to the advantage in executive functions in bilingual individuals.

Optimization of trial wave functions for use in quantum Monte Carlo with application to LiH

Methods for both partial and full optimization of wavefunction parameters are explored, and these are applied to the LiH molecule. A partial optimization can be easily performed with little difficulty. But to perform a full optimization we must avoid a wrong minimum, and deal with linear-dependency, time step-dependency and ensemble-dependency problems. Five basis sets are examined. The optimized wavefunction with a 3-function set gives a variational energy of -7.998 + 0.005 a.u., which is comparable to that (-7.990 + 0.003) 1 of Reynold's unoptimized \fin ( a double-~ set of eight functions). The optimized wavefunction with a double~ plus 3dz2 set gives ari energy of -8.052 + 0.003 a.u., which is comparable with the fixed-node energy (-8.059 + 0.004)1 of the \fin. The optimized double-~ function itself gives an energy of -8.049 + 0.002 a.u. Each number above was obtained on a Bourrghs 7900 mainframe computer with 14 -15 hrs CPU time.

Individual differences in risk-taking and associated characteristics : a test of specificity in executive functions /

Multiple measures have been devised by clinicians and theorists from many different backgrounds for the purpose of assessing the influence of the frontal lobes on behaviour. Some utilize self-report measures to investigate behavioural characteristics such as risktaking, sensation seeking, impulsivity, and sensitivity to reward and punishment in an attempt to understand complex human decision making. Others rely more on neuroimaging and electrophysiological investigation involving experimental tasks thought to demonstrate executive functions in action, while other researchers prefer to study clinical populations with selective damage. Neuropsychological models of frontal lobe functioning have led to a greater appreciation of the dissociations among various aspects of prefrontal cortex function. This thesis involves (1) an examination of various psychometric and experimental indices of executive functions for coherence as one would predict on the basis of highly developed neurophysiological models of prefrontal function, particularly those aspects of executive function that involve predominantly cognitive abilities versus processes characterized by affect regulation; and (2) investigation of the relations between risk-taking, attentional abilties and their associated characteristics using a neurophysiological model of prefrontal functions addressed in (1). Late adolescence is a stage in which the prefrontal cortices undergo intensive structural and functional maturational changes; this period also involves increases in levels of risky and sensation driven behaviours, as well as a hypersensitivity to reward and a reduction in inhibition. Consequently, late adolescence spears to represent an ideal developmental period in which to examine these decision-making behaviours due to the maximum variability of behavioural characteristics of interest. Participants were 45 male undergraduate 18- to 19-year olds, who completed a battery of measures that included self-report, experimental and behavioural measures designed to assess particular aspects of prefrontal and executive functioning. As predicted, factor analysis supported the grouping of executive process by type (either primarily cognitive or affective), conforming to the orbitofrontal versus dorsolateral typology; risk-taking and associated characteristics were associated more with the orbitofrontal than the dorsolateral factor, whereas attentional and planning abilities tended to correlate more strongly with the dorsolateral factor. Results are discussed in light of future assessment, investigation and understanding of complex human decision-making and executive functions. Implications, applications and suggestions for future research are also proposed.

Role of the protein tyrosine phosphatase DEP-1 in Src activation and the mediation of biological cell functions of endothelial and breast cancer cells

L’implication des protéines tyrosines phosphatases (PTPs) dans la régulation de la signalisation et la médiation des fonctions cellulaires a été bien établie dans les dernières années. Cependant, les mécanismes moléculaires par lesquels les PTPs régulent les processus fondamentaux tels que l’angiogenèse demeurent méconnus. Il a été rapporté que l’expression de la PTP DEP-1 (Density-enhanced phosphatase 1) augmente avec la densité cellulaire et corrèle avec la déphosphorylation du récepteur VEGFR2. Cette déphosphorylation contribue à l’inhibition de contact dans les cellules endothéliales à confluence et diminue l’activité du VEGFR2 en déphosphorylant spécifiquement ses résidus catalytiques Y1054/1059. De plus, la plupart des voies de signalisation en aval du VEGFR2 sont diminuées sauf la voie Src-Gab1-AKT. DEP-1 déphosphoryle la Y529 de Src et contribue à la promotion de la survie dans les cellules endothéliales. L’objectif de cette thèse est de mieux définir le rôle de DEP-1 dans la régulation de l’activité de Src et les réponses biologiques dans les cellules endothéliales. Nous avons identifié les résidus Y1311 et Y1320 dans la queue C-terminale de DEP-1 comme sites majeurs de phosphorylation en réponse au VEGF. La phosphorylation de ces résidus est requise pour l’activation de Src et médie le remodelage des jonctions cellules-cellules dépendantes de Src. Ce remodelage induit la perméabilité, l’invasion et la formation de capillaires en réponse au VEGF. Nos résultats démontrent que la phosphorylation de DEP-1 sur résidu tyrosine est requise pour diriger la spécificité de DEP-1 vers son substrat Src. Les travaux révèlent pour la première fois un rôle positif de DEP-1 sur l’induction du programme angiogénique des cellules endothéliales. En plus de la phosphorylation sur tyrosine, DEP-1 est constitutivement phosphorylé sur la thréonine 1318 situé à proximité de la Y1320 en C-terminal. Cette localisation de la T1318 suggère que ce résidu pourrait être impliqué dans la régulation de la Y1320. En effet, nous avons observé que la T1318 de DEP-1 est phosphorylée potentiellement par CK2, et que cette phosphorylation régule la phosphorylation de DEP-1 sur tyrosine et sa capacité de lier et d’activer Src. En accord avec ces résultats, nos travaux révèlent que la surexpression du mutant DEP-1 T1318A diminue le remodelage des jonctions cellules-cellules et par conséquent la perméabilité. Nos résultats suggèrent donc que la T1318 de DEP-1 constitue un nouveau mécanisme de contrôle de la phosphorylation sur tyrosine et que ceci résulte en l’activation de Src et l’induction des fonctions biologiques des cellules endothéliales en réponse au VEGF. Suite à ces travaux dans les cellules endothéliales qui démontrent un rôle positif de DEP-1 dans la médiation des réponses angiogéniques, nous avons voulu approfondir nos connaissances sur l’implication potentielle de DEP-1 dans les cellules cancéreuses où l’activité de Src est requise pour la progression tumorale. Malgré le rôle connu de DEP-1 comme suppresseur tumoral dans différents types de cancer, nous avons émis l’hypothèse que DEP-1 pourrait promouvoir les fonctions biologiques dépendantes de Src telles que la migration et l’invasion dans les cellules cancéreuses. Ainsi, nous avons observé que l’expression de DEP-1 est plus élevée dans les lignées basales de cancer du sein qui sont plus invasives comparativement aux lignées luminales peu invasives. Dans les lignées basales, DEP-1 active Src, médie la motilité cellulaire dépendante de Src et régule la localisation des protéines impliquées dans l’organisation du cytosquelette. L’analyse d’un micro-étalage de tissu a révélé que l’expression de DEP-1 est associée avec une réduction tendencielle de survie des patients. Nos résultats proposent donc, un rôle de promoteur tumoral pour DEP-1 dans la progression du cancer du sein. Les travaux présentés dans cette thèse démontrent pour la première fois que DEP-1 peut agir comme promoteur des réponses angiogéniques et du phénotype pro-invasif des lignées basales du cancer du sein probablement du à sa capacité d’activer Src. Nos résultats suggèrent ainsi que l’expression de DEP-1 pourrait contribuer à la progression tumorale et la formation de métastases. Ces découvertes laissent donc entrevoir que DEP-1 représente une nouvelle cible thérapeutique potentielle pour contrer l’angiogenèse et le développement du cancer.

Searching for novel gene functions in yeast : identification of thousands of novel molecular interactions by protein-fragment complementation assay followed by automated gene function prediction and high-throughput lipidomics

La compréhension de processus biologiques complexes requiert des approches expérimentales et informatiques sophistiquées. Les récents progrès dans le domaine des stratégies génomiques fonctionnelles mettent dorénavant à notre disposition de puissants outils de collecte de données sur l’interconnectivité des gènes, des protéines et des petites molécules, dans le but d’étudier les principes organisationnels de leurs réseaux cellulaires. L’intégration de ces connaissances au sein d’un cadre de référence en biologie systémique permettrait la prédiction de nouvelles fonctions de gènes qui demeurent non caractérisées à ce jour. Afin de réaliser de telles prédictions à l’échelle génomique chez la levure Saccharomyces cerevisiae, nous avons développé une stratégie innovatrice qui combine le criblage interactomique à haut débit des interactions protéines-protéines, la prédiction de la fonction des gènes in silico ainsi que la validation de ces prédictions avec la lipidomique à haut débit. D’abord, nous avons exécuté un dépistage à grande échelle des interactions protéines-protéines à l’aide de la complémentation de fragments protéiques. Cette méthode a permis de déceler des interactions in vivo entre les protéines exprimées par leurs promoteurs naturels. De plus, aucun biais lié aux interactions des membranes n’a pu être mis en évidence avec cette méthode, comparativement aux autres techniques existantes qui décèlent les interactions protéines-protéines. Conséquemment, nous avons découvert plusieurs nouvelles interactions et nous avons augmenté la couverture d’un interactome d’homéostasie lipidique dont la compréhension demeure encore incomplète à ce jour. Par la suite, nous avons appliqué un algorithme d’apprentissage afin d’identifier huit gènes non caractérisés ayant un rôle potentiel dans le métabolisme des lipides. Finalement, nous avons étudié si ces gènes et un groupe de régulateurs transcriptionnels distincts, non préalablement impliqués avec les lipides, avaient un rôle dans l’homéostasie des lipides. Dans ce but, nous avons analysé les lipidomes des délétions mutantes de gènes sélectionnés. Afin d’examiner une grande quantité de souches, nous avons développé une plateforme à haut débit pour le criblage lipidomique à contenu élevé des bibliothèques de levures mutantes. Cette plateforme consiste en la spectrométrie de masse à haute resolution Orbitrap et en un cadre de traitement des données dédié et supportant le phénotypage des lipides de centaines de mutations de Saccharomyces cerevisiae. Les méthodes expérimentales en lipidomiques ont confirmé les prédictions fonctionnelles en démontrant certaines différences au sein des phénotypes métaboliques lipidiques des délétions mutantes ayant une absence des gènes YBR141C et YJR015W, connus pour leur implication dans le métabolisme des lipides. Une altération du phénotype lipidique a également été observé pour une délétion mutante du facteur de transcription KAR4 qui n’avait pas été auparavant lié au métabolisme lipidique. Tous ces résultats démontrent qu’un processus qui intègre l’acquisition de nouvelles interactions moléculaires, la prédiction informatique des fonctions des gènes et une plateforme lipidomique innovatrice à haut débit , constitue un ajout important aux méthodologies existantes en biologie systémique. Les développements en méthodologies génomiques fonctionnelles et en technologies lipidomiques fournissent donc de nouveaux moyens pour étudier les réseaux biologiques des eucaryotes supérieurs, incluant les mammifères. Par conséquent, le stratégie présenté ici détient un potentiel d’application au sein d’organismes plus complexes.