Dissertations / Theses: 'Real analytic function' – Grafiati (2024)

Abstract:

Les fonctions analytiques généralisées sont définies par des séries convergentes de monômes à coeficients réels et exposants réels positifs. Nous étudions l'extension de la géométrie analytique réelle associée à ces algèbres de fonctions. Nous introduisons pour cela la notion de variété analytique réelle généralisée. Il s'agit de variétés topologiques à bord munies de la structure du faisceau des fonctions analytiques réelles généralisées. Notre résultat principal est un théorème de monomialisation locale de ces fonctions.

Abstract:

In this paper we examine continuous functions which on the surface seem to defy well-known mathematical principles. Before describing these functions, we introduce the Baire Category theorem and the Cantor set, which are critical in describing some of the functions and counterexamples. We then describe generic continuous functions, which are nowhere differentiable and monotone on no interval, and we include an example of such a function. We then construct a more conceptually challenging function, one which is everywhere differentiable but monotone on no interval. We also examine the Cantor function, a nonconstant continuous function with a zero derivative almost everywhere. The final section deals with products of derivatives.

Abstract:

Orientadores: Sergio Antonio Tozoni, Alexander Kushpel
Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Matematica, Estatistica e Computação Cientifica
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Resumo: O objetivo da dissertação e desenvolver um texto em português sobre Análise Harmônica na esfera d-dimensional real e aplicar os resultados deste texto no estudo de um teorema de multiplicadores. Nos dois primeiros capítulos e realizado um estudo sobre funções harmônicas em um domínio do espaço euclidiano Rd+1, harmônicos esféricos, representações de SO(d+1), harmônicos zonais, polinômios ultraesféricos e sobre o operador de Laplace Beltrami para a esfera. Finalmente, no terceiro capítulo é estudado um teorema de multiplicadores recente, o qual fornece condições suficientes para que um operador multiplicador seja limitado de Lp(Sd) em Lq(Sd), para quaisquer p e q, 1=p, q=8. Como aplicação deste teorema são obtidas estimativas superiores para n-larguras de Kolmogorov de classes de Sobolev nos espaços Lq(Sd), 1=p, q= 8, g > 0
Abstract: The purpose of this work is to develop a text in Portuguese about Harmonic Analysis on the d-dimensional real sphere Sd and to apply the results of the text to study a multiplier theorem. In the first two chapters it is made a study about harmonic functions in a domain of the euclidian space Rd+1, spherics harmonics, representations of SO(d+1), zonal harmonics, ultraspherics polynomials and about the Laplace Beltrami operator on the sphere. Finally, in the third chapter it is studied a recent multiplier theorem which gives sufficient conditions for a multiplier operator be bounded from Lp(Sd) to Lq(Sd), for 1=p, q=8. As application of this theorem are obtained upper bounds for n-widths of Kolmogorov type of Sobolev classes in the spaces Lq(Sd), 1=p, q= 8, g > 0
Mestrado
Matematica
Mestre em Matemática

Abstract:

The paper begins with a short survey of monotone functions. The functions of bounded variation are introduced and some basic properties of these functions are given. Finally the jump function of a function of bounded variation is defined.

Abstract:

This thesis covers the analysis of sparse and irregular fuel consumption data of long

distance haulage articulate trucks. It is shown that this kind of data is hard to analyse with multivariate as well as with functional methods. To be able to analyse the data, Principal Components Analysis through Conditional Expectation (PACE) is used, which enables the use of observations from many trucks to compensate for the sparsity of observations in order to get continuous results. The principal component scores generated by PACE, can then be used to get rough estimates of the trajectories for single trucks as well as to detect outliers. The data centric approach of PACE is very useful to enable functional analysis of sparse and irregular data. Functional analysis is desirable for this data to sidestep feature extraction and enabling a more natural view on the data.

Abstract:

This thesis concerns the classes of analytic functions on bounded, n-connected domains known as the Smirnov classes Ep, where p > 0. Functions in these classes satisfy a certain growth condition and have a relationship to the more well known classes of functions known as the Hardy classes Hp. In this thesis I will show how the geometry of a given domain will determine the existence of non-constant analytic functions in Smirnov classes that possess real boundary values. This is a phenomenon that does not occur among functions in the Hardy classes.The preliminary and background information is given in Chapters 1 and 3 while the main results of this thesis are presented in Chapters 2 and 4. In Chapter 2, I will consider the case of the simply connected domain and the boundary characteristics that allow non-constant analytic functions with real boundary values in certain Smirnov classes. Chapter 4 explores the case of an n-connected domain and the sufficient conditions for which the aforementioned functions exist. In Chapter 5, I will discuss how my results for simply connected domains extend Neuwirth-Newman's Theorem and finish with an open problem for n-connected domains.

Abstract:

One topic of this thesis are products of two Eisenstein series. First we investigate the subspaces of modular forms of level N that are generated by such products. We show that of the weight k is greater than 2, for many levels, one can obtain the whole of M[subspace]k(N) from Eisenstein series and products of two Eisenstein series. We also provide a result in the case k=2 and treat some spaces of modular forms of non-trivial nebentypus. We then analyse the L-functions of products of Eisenstein series. We reinterpret a method by Rogers-Zudilin and use it in two applications, the first concerning critical L-values of a product of two Eisenstein series, and the second special values of derivatives of L-functions. The last part of this thesis deals with the theory of Eichler-cohom*ology for arbitrary real weights, which was first developed by Knopp in 1974. We establish a new approach to Knopp's theory using techniques from the spectal theory of automorphic forms, reprove Knopp's main theorems, and also providea vector-valued version of the theory.

Abstract:

This thesis is about using appropriate tools in functional analysis arid classical analysis to tackle the problem of existence and uniqueness of nonlinear partial differential equations. There being no unified strategy to deal with these equations, one approaches each equation with an appropriate method, depending on the characteristics of the equation.The correct setting of the problem in appropriate function spaces is the first important part on the road to the solution. Here, we choose the setting of Sobolev spaces. The second essential part is to choose the correct tool for each equation.In the first part of this thesis (Chapters 3 and 4) we consider a variety of nonlinear hyperbolic partial differential equations with mixed boundary and initial conditions. The methods of compactness and monotonicity are used to prove existence and uniqueness of the solution (Chapter 3). Finding a priori estimates is the main task in this analysis. For some types of nonlinearity, these estimates cannot be easily obtained, arid so these two methods cannot be applied directly. In this case, we first linearise the equation, using linear recurrence (Chapter 4).In the second part of the thesis (Chapter 5), by using an appropriate tool in functional analysis (the Sobolev Imbedding Theorem), we are able to improve previous results on a posteriori error estimates for the finite element method of lines applied to nonlinear parabolic equations. These estimates are crucial in the design of adaptive algorithms for the method, and previous analysis relies on, what we show to be, unnecessary assumptions which limit the application of the algorithms. Our analysis does not require these assumptions.In the last part of the thesis (Chapter 6), staying with the theme of choosing the most suitable tools, we show that using classical analysis in a proper way is in some cases sufficient to obtain considerable results. We study in this chapter nonexistence of positive solutions to Laplace's equation with nonlinear Neumann boundary condition. This problem arises when one wants to study the blow-up at finite time of the solution of the corresponding parabolic problem, which models the heating of a substance by radiation. We generalise known results which were obtained by using more abstract methods.

Abstract:

The PhD thesis considers four topics in dynamical systems and is based on one paper and three manuscripts. In Paper I we apply methods of interval analysis in order to compute the rigorous enclosure of rotation number. The described algorithm is supplemented with a method of proving the existence of periodic points which is used to check rationality of the rotation number. In Manuscript II we provide a numerical algorithm for computing critical points of the multiplier map for the quadratic family (i.e., points where the derivative of the multiplier with respect to the complex parameter vanishes). Manuscript III concerns continued fractions of quadratic irrationals. We show that the generating function corresponding to the sequence of denominators of the best rational approximants of a quadratic irrational is a rational function with integer coefficients. As a corollary we can compute the Lévy constant of any quadratic irrational explicitly in terms of its partial quotients. Finally, in Manuscript IV we develop a method for finding rigorous enclosures of all odd periodic solutions of the stationary Kuramoto-Sivashinsky equation. The problem is reduced to a bounded, finite-dimensional constraint satisfaction problem whose solution gives the desired information about the original problem. Developed approach allows us to exclude the regions in L2, where no solution can exist.

Abstract:

Modern systems produce a great amount of information and cues from which human operators must take action. On one hand, these complex systems can place a high demand on an operator's cognitive load, potentially overwhelming them and causing poor performance. On the other hand, some systems utilize extensive automation to accommodate their complexity; this can cause an operator to become complacent and inattentive, which again leads to deteriorated performance (Wilson, Russell, 2003a; Wilson, Russell, 2003b). An ideal human-machine interface would be one that optimizes the functional state of the operator, preventing overload while not permitting complacency, thus resulting in improved system performance.An operator's functional state (OFS) is the momentary ability of an operator to meet task demands with their cognitive resources. A high OFS indicates that an operator is vigilant and aware, with ample cognitive resources to achieve satisfactory performance. A low OFS, however, indicates a non-optimal cognitive load, either too much or too little, resulting in sub-par system performance (Wilson, Russell, 1999).With the ability to measure and detect changes in OFS in real-time, a closed-loop system between the operator and machine could optimize OFS through the dynamic allocation of tasks. For instance, if the system detects the operator is in cognitive overload, it can automate certain tasks allowing them to better focus on salient information. Conversely, if the system detects under-vigilance, it can allocate tasks back to the manual control of the operator. In essence, this system operates to "dynamically match task demands to [an] operator's momentary cognitive state", thereby achieving optimal OFS (Wilson, Russell, 2007).This concept is termed adaptive aiding and has been the subject of much research, with recent emphasis on accurately assessing OFS in real-time. OFS is commonly measured indirectly, like using overt performance metrics on tasks; if performance is declining, a low OFS is assumed. Another indirect measure is the subjective estimate of mental workload, where an operator narrates his/her perceived functional state while performing tasks (Wilson, Russell, 2007). Unfortunately, indirect measures of OFS are often infeasible in operational settings; performance metrics are difficult to construct for highly-automated complex systems, and subjective workload estimates are often inaccurate and intrusive (Wilson, Russell, 2007; Prinzel et al., 2000; Smith et al., 2001).OFS can be more directly measured via psychophysiological signals such as electroencephalogram (EEG) and electrooculography (EOG). Current research has demonstrated these signals' ability to respond to changing cognitive load and to measure OFS (Wilson, Fisher, 1991; Wilson, Fisher, 1995; Gevins et al., 1997; Gevins et al., 1998; Byrne, Parasuraman, 1996). Moreover, psychophysiological signals are continuously available and can be obtained in a non-intrusive manner, pre-requisite for their use in operational environments.The objective of this study is to advance schemes which detect change in OFS by monitoring psychophysiological signals in real-time. Reviews on similar methods can be found in, e.g., Wilson and Russell (2003a) and Wilson and Russell (2007). Many of these methods employ pattern recognition to classify mental workload into one of several discrete categories. For instance, given an experiment with easy, medium and hard tasks, and assuming the tasks induce varying degrees of mental workload on a subject, these methods classify which task is being performed for each epoch of psychophysiological data. The most common classifiers are artificial neural networks (ANN) and multivariate statistical techniques such as stepwise discriminant analysis (SWDA). ANNs have proved especially effective at classifying OFS as they account for the non-linear and higher order relationships often present in EEG/EOG data; they routinely achieve classification accuracy greater than 80%.However, the discrete output of these classification schemes is not conducive to real-time change detection. They accurately classify OFS, but they do not indicate when OFS has changed; the change points remain ambiguous and left to subjective interpretation. Thus, the present study introduces several online algorithms which objectively determine change in OFS via real-time psychophysiological signals.The following chapters describe the dataset evaluated, discuss the statistical properties of psychophysiological signals, and detail various algorithms which utilize these signals to detect real-time changes in OFS. The results of the algorithms are presented along with a discussion. Finally, the study is concluded with a comparison of each method and recommendations for future application.

Abstract:

Orientador: Sergio Antonio Tozoni
Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Matematica, Estatistica e Computação Cientifica
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Resumo: O objetivo da dissertação é realizar um estudo dos espaços de Besov sobre a esfera unitária d-dimensional real Sd. No primeiro capítulo são estudados espaços de interpolação utilizando dois métodos de interpolação real. Em particular são estudados os Teoremas de Equivalência e de Reiteração para os J-método e K-método. No segundo capítulo é realizado um estudo rápido sobre análise harmônica na esfera Sd, incluindo um estudo sobre harmônicos esféricos, harmônicos zonais, somas de Cesàro e sobreum teorema de multiplicadores. O terceiro e último capítulo é o mais importante e nele são aplicados os resultados dos capítulos anteriores. São introduzidos os espaços de Besov, decompondo uma função suave definida sobre a esfera d-dimensional, em uma série de harmônicos esféricos e usando uma seqüência de polinômios zonais que podem ser vistos como uma generalização natural dospolinômios de Vallée Poussin definidos sobre o círculo unitário. O principal resultado estudado diz que todo espaço de Besov pode ser obtido como espaço de interpolação de dois espaços de Sobolev
Abstract: The purpose of this work is to make a study about Besov¿s spaces on the unit d-dimensional real sphere Sd. In the first chapter are studied spaces of interpolation using two real interpolation methods. In particular, are studied The Equivalence Theorem and The Reiteration Theorem for the J-method and the K-method. In the second chapter it is made a short study about harmonic analysis on the sphere Sd, including a study about spherics harmonics, zonal harmonics, Cesàro sums and about a multiplier theorem.The third and last chapter is the most important of this work. In this chapter are applied the results of the others chapters. Are introduced the Besov spaces, decomposing a smooth function defined on the d-dimensional sphere, in a series of harmonics spherics and using a sequence o zonal polynomials which can be seen as a natural generalization of the Vallée Poussin polynomials defined on the unit circle. The main result studied says that every Besov¿s space can be got as a interpolation space of two Sobolev¿s spaces
Mestrado
Mestre em Matemática

Abstract:

The aim of this thesis was to investigate the cellular role of the mouse RBBP6 gene using the interference RNA (RNAi) gene targeting technology and also to understand the relevance of two promoters for the RBBP6 gene.

Abstract:

In this thesis, we present a MAC-layer packet scheduling algorithm, called Best-effort Packet Scheduling Algorithm(BPA), for real-time switched Ethernet networks. BPA considers a message model where application messages have trans-node timeliness requirements that are specified using Jensen's benefit functions. The algorithm seeks to maximize aggregate message benefit by allowing message packets to inherit benefit functions of their parent messages and scheduling packets to maximize aggregate packet-level benefit. Since the packet scheduling problem is NP-hard, BPA heuristically computes schedules with a worst-case cost of O(n^2), faster than the O(n^3) cost of the best known Chen and Muhlethaler's Algorithm(CMA) for the same problem. Our simulation studies show that BPA performs the same or significantly better than CMA.We also construct a real-time switched Ethernet by prototyping an Ethernet switch using a Personal Computer(PC) and implementing BPA in the network protocol stack of the Linux kernel for packet scheduling. Our actual performance measurements of BPA using the network implementation reveal the effectiveness of the algorithm.Finally, we derive timeliness feasibility conditions of real-time switched Ethernet systems that use the BPA algorithm. The feasibility conditions allow real-time distributed systems to be constructed using BPA, with guaranteed soft timeliness.
Master of Science

Abstract:

Elevated blood pressure (BP) and reduced glomerular filtration rate (GFR) are risk factors for cardiovascular disease. BP and GFR are influenced by heritable factors. Only small proportion of this heritability has been explained so far. This project aimed to identify genetic loci contributing to population variation in BP or GFR through application of candidate gene and large scale genotyping approaches. The candidate gene approach utilised tagging single nucleotide polymorphisms (SNP) in genes of the urotensin-II (U-II) pathway in a sample of white European subjects (3 family collections and 5 unrelated subject studies – altogether 10,748 subjects). This was followed by gene expression studies in 2 collections of human kidneys and phylogenetic analysis of the system to examine its evolutionary conservation from fish to human. The large scale genotyping project utilised data from 50K IBC genotyping array in a cohort of families (520 pedigrees) from general population of UK. None of the 28 SNPs in U-II pathway genes was associated with BP or GFR. Gene expression levels of UTS2 and UTS2R were strongly correlated (r=0.83, p<0.0001) but renal expression was not associated with human hypertension. The phylogenetic analysis showed that strong purifying selection acting on this system in lower vertebrates was lost in primates. The large scale genotyping approach showed strong signal of association in the 5,10-methylenetetrahydrofolate reductase (NAD(P)H) gene (MTHFR) locus with clinic diastolic BP. Each minor copy (G) of rs17037388 was associated with 2.03mmHg reduction in clinic diastolic BP (p=3.01x10[superscript -06]). Gene candidate and large scale genotyping approaches performed in parallel provide useful information about genetic architecture of complex traits. The data from genetic association in candidate U-II system genes did not provide evidence on its association with BP or GFR. Large scale genotyping experiment led to identification of genuine association signal with clinic diastolic BP.

Abstract:

Cette thèse traite du choix optimal des investissem*nts à la lumière de la théorie des options réelles et de la prise en compte des différents modes de production. Nous proposons dans un premier temps plusieurs extensions du modèle d'investissem*nt irréversible de Pindyck (1988): introduction de processus plus complexes pour décrire l'évolution de la valeur de marché et de fonctions de production très générales pour décrire l'activité de la firme ; prise en compte de l'aversion au risque dans un cadre d'optimisation dynamique. Dans un second temps, nous montrons comment les options d'échange de Margrabe (1978) permettent de résoudre certains problèmes de choix d'investissem*nt. Nous en proposons diverses extensions et illustrations
Cette thèse traite du choix optimal des investissem*nts à la lumière de la théorie des options réelles et de la prise en compte des différents modes de production. Nous proposons dans un premier temps plusieurs extensions du modèle d'investissem*nt irréversible de Pindyck (1988): introduction de processus plus complexes pour décrire l'évolution de la valeur de marché et de fonctions de production très générales pour décrire l'activité de la firme ; prise en compte de l'aversion au risque dans un cadre d'optimisation dynamique. Dans un second temps, nous montrons comment les options d'échange de Margrabe (1978) permettent de résoudre certains problèmes de choix d'investissem*nt. Nous en proposons diverses extensions et illustrations

Abstract:

Functional magnetic resonance imaging (fMRI) is a prime example of multi-disciplinary research. Without the beautiful physics of MRI, there wouldnot be any images to look at in the first place. To obtain images of goodquality, it is necessary to fully understand the concepts of the frequencydomain. The analysis of fMRI data requires understanding of signal pro-cessing, statistics and knowledge about the anatomy and function of thehuman brain. The resulting brain activity maps are used by physicians,neurologists, psychologists and behaviourists, in order to plan surgery andto increase their understanding of how the brain works. This thesis presents methods for real-time fMRI and non-parametric fMRIanalysis. Real-time fMRI places high demands on the signal processing,as all the calculations have to be made in real-time in complex situations.Real-time fMRI can, for example, be used for interactive brain mapping.Another possibility is to change the stimulus that is given to the subject, inreal-time, such that the brain and the computer can work together to solvea given task, yielding a brain computer interface (BCI). Non-parametricfMRI analysis, for example, concerns the problem of calculating signifi-cance thresholds and p-values for test statistics without a parametric nulldistribution. Two BCIs are presented in this thesis. In the first BCI, the subject wasable to balance a virtual inverted pendulum by thinking of activating theleft or right hand or resting. In the second BCI, the subject in the MRscanner was able to communicate with a person outside the MR scanner,through a virtual keyboard. A graphics processing unit (GPU) implementation of a random permuta-tion test for single subject fMRI analysis is also presented. The randompermutation test is used to calculate significance thresholds and p-values forfMRI analysis by canonical correlation analysis (CCA), and to investigatethe correctness of standard parametric approaches. The random permuta-tion test was verified by using 10 000 noise datasets and 1484 resting statefMRI datasets. The random permutation test is also used for a non-localCCA approach to fMRI analysis.

Abstract:

[ES] Uno de los aspectos más apasionantes de la transcripción es la plasticidad transcriptómica y proteómica mediada por los procesos de regulación post-transcripcional (PTR). Los mecanismos PTR como el splicing alternativo (AS) y la poliadenilación alternativa (APA) han emergido como procesos estrechamente regulados que juegan un papel clave en la generación de la complejidad transcriptómica y están asociados con la coordinación de la diferenciación celular o el desarrollo de tejidos. Sin embargo nuestro conocimiento sobre cómo estos mecanismos regulan las propiedades de los productos resultantes para definir el fenotipo es aún muy reducido. La cantidad de variantes existentes y el amplio rango de posibles consecuencias funcionales, hacen su validación funcional una tarea impracticable si se realiza caso por caso. Además, la falta de herramientas para la evaluación funcional orientada a isoformas ha provocado que gran parte del trabajo computacional haya empleado pipelines ad-hoc aplicadas a sistemas biológicos específicos o simplemente hayan confiado en análisis de enriquecimiento GO, los cuales no son informativos del impacto en las propiedades de las isoformas que hay detrás de la regulación PTR.De hecho, a pesar de las más de sesenta mil publicaciones relativas al AS, muy pocas isoformas se han asociado con propiedades específicas, mientras que el número de nuevas variantes AS/APA con function desconocida crece exponencialmente debido a las técnicas de secuenciación de segunda generación (NGS). Además, y debido a limitaciones técnicas de las NGS para reconstruir la estructura de los transcritos, las tecnologías de secuenciación de tercera generación (TGS) están definiendo una nueva era en la que, por primera vez, es posible conocer la secuencia de elementos estructurales y funcionales en los mRNAs.En esta tesis se han abordado tres propósitos principales para poder avanzar en el estudio funcional de las isoformas. En primer lugar, con las TGS siendo cada vez más utilizadas, la evaluación de la calidad de los transcriptomas \textit{de novo} es esencial para asegurar la fiabilidad de la diversidad transcriptómica encontrada. La falta de análisis de calidad orientados a secuencias largas ha motivado el desarrollo de SQANTI, una pipeline automatizado para la exhaustiva evaluación de TGS transcriptomas. En segundo lugar, la información a nivel de gen de la mayoría de bases de datos funcionales sigue siendo el principal escollo para el estudio de la variabilidad entre isoformas, especialmente en el caso de las isoformas nuevas, en las que las bases de datos estáticas impiden su caracterización. Así, hemos diseñado IsoAnnot, que construye una base de datos de anotaciones funcionales con resolución a nivel de isoformas integrando información diseminada por múltiples bases de datos y métodos de predicción. Finalmente, la indisponibilidad de métodos para estudiar el impacto funcional de la regulación de isoformas, nos ha motivado a desarrollar tappAS, una herramienta dinámica, flexible y diseñada para facilitar el abordaje de este tipo de estudios. Por lo tanto, durante esta tesis hemos desarrollado una infraestructura que resuelve los retos principales del análisis funcional de isoformas, proporcionando un conjunto de nuevos métodos y herramientas que ofrecen una oportunidad única para explorar cómo el fenotipo se especifica post-transcripcionalmente, mediante la alteración de las propiedades funcionales de las isoformas expresadas. La aplicación de nuestro análisis a un doble sistema de diferenciación neuronal en ratón definió el efecto de la regulación de isoformas entre la diferenciación de motoneuronas y oligodendrocitos para múltiples elementos funcionales. Entre ellos, hemos descubierto regiones transmembrana que son diferencialmente incluidas en las isoformas expresadas entre ambos tipos celulares y cuya regulación podría estar contribuyendo al control de
[CAT] Un dels aspectes més emocionants de la biologia del transcriptoma és l'adaptabilitat contextual de transcriptomes i proteomes eucariotes mitjançant la regulació post-transcripcional (PTR). Els mecanismes PTR, com el splicing alternatiu (AS) i la poliadenilació alternativa (APA), s'han convertit en processos molt regulats que juguen un paper clau en la generació de la complexitat del transcriptoma i en la coordinació de la diferenciació cel·lular o del desenvolupament de teixits. No obstant això, el nostre coneixement de com aquests mecanismes imprimeixen característiques funcionals diferents al conjunt resultant d'isoformes per definir el fenotip observat és encara escàs. El nombre de variants de PTR i les seues conseqüències potencialment funcionals fa que la validació funcional sigui una tasca poc pràctica si es fa cas per cas. A més, la manca d'enfocaments funcionals orientats a isoformes ha fet que gran part del treballs computacionals per esbrinar qüestions funcionals a nivell de transcriptoma siguen estratègies computacionals ad hoc aplicades a sistemes biològics específics o bé basats en un simple anàlisi d'enriquiment GO, que no aporten informació sobre l'impacte de la PTR sobre les propietats de les isoformes. Així, malgrat les més de 60.000 publicacions existents sobre AS, poques de les isoformes existents s'han associat a propietats específiques, mentre que el nombre de noves variants AS/APA amb funcions desconegudes i fins i tot inexplorades augmenta de manera exponencial gràcies a la seqüenciació de nova generació (NGS). A causa de les limitacions tècniques del NGS per reconstruir l'estructura dels transcrits, la seqüenciació d'alt rendiment de transcrits de longitud completa mitjançant tecnologies de tercera generació (TGS) obre una nova era en la transcriptòmica, ja que millora la definició dels models genètics i, per primera vegada, permet associar amb precisió esdeveniments funcionals dins de la molècula d'ARN. Aquesta tesi aborda tres grans reptes per a progressar en l'estudi de la funció de les isoformes. En primer lloc, amb l'aparició i la popularitat creixent del TGS, la definició precisa i la caracterització completa dels transcriptomes de novo són essencials per garantir la qualitat de qualsevol conclusió sobre la diversitat del transcriptoma. La manca d'anàlisis de qualitat orientats a lectures llargues va motivar el desenvolupament de SQANTI (https://bitbucket.org/ ConesaLab / sqanti), una estratègia computacional automatitzada per a la caracterització estructural i l'avaluació de la qualitat dels transcriptomes de longitud completa. En segon lloc, els recursos funcionals existents centrats en el gen suposen una gran limitació per a l'estudi extensiu de la variabilitat funcional de les isoformes, especialment en les noves isoformes, que no es poden caracteritzar per bases de dades estàtiques. Per tant, vam dissenyar IsoAnnot, que construeix dinàmicament una base de dades amb anotacions funcionals a nivell d'isoforma, que utilitza com a informació d'entrada les seqüències dels transcrits i integra informació de diverses bases de dades i mètodes de predicció. Finalment, com no hi havia cap mètode per interrogar l'impacte funcional del PTR, vam desenvolupar nous enfocaments i eines fàcils d'utilitzar, com ara tappAS (http://tappas.org/), dissenyada per facilitar als investigadors els estudis funcionals de transcriptoma complet i de regulació d'isoformes en contexts específics. Per tant, aquesta tesi descriu el desenvolupament d'un marc d'anàlisi que aborda els reptes fonamentals de l'anàlisi funcional d'isoformes. Aplicada a un sistema de diferenciació neuronal murina, vam descobrir regions transmembrana específiques d'isoformes, la modulació de les quals per PTR podria contribuir a controlar la dinàmica mitocondrial específica del tipus cel·lular durant la determinació del destí neuronal.
[EN] One of the most exciting aspects of transcriptome biology is the contextual adaptability of eukaryotic transcriptomes and proteomes by post-transcriptional regulation (PTR). PTR mechanisms such as alternative splicing (AS) and alternative polyadenylation (APA) have emerged as tightly regulated processes playing a key role in generating transcriptome complexity and coordinating cell differentiation or tissue development. However, how these mechanisms imprint distinct functional characteristics on the resulting set of isoforms to define the observed phenotype remains poorly understood. The number of PTR variants and their resulting range of potentially functional consequences makes their functional validation an impractical task if done on a case-by-case basis. Besides, the lack of isoform-oriented functional profiling approaches has made that much of the computational work done to elucidate transcriptome-wide functional questions has either involved ad hoc computational pipelines applied to specific biological systems or has relied on simple GO-enrichment analysis that are not informative about the PTR impact on isoform properties. Thus, even though more than 60,000 publications on AS, a few number of existing isoforms have been associated with specific properties while the number of novel AS/APA variants with unknown and even unexplored functions is exponentially increasing thanks to the use of next-generation sequencing (NGS). Due to the technical limitations of NGS to reconstruct the transcript structure, high-throughput sequencing of full-length transcripts using third-generation technologies (TGS) is opening up a new transcriptomics era that enhances the definition of gene models and, for the first time, enables to precisely associate functional events within the RNA molecule.This thesis addresses three major challenges to the progression of the study of isoform function. First, with the emergence and increasing popularity of TGS, the accurate definition and comprehensive characterisation of de novo transcriptomes is essential to ensure the quality of any conclusions on transcriptome diversity drawn from these data. The lack of long-read oriented quality aware analysis motivated the development of SQANTI \url{(https://bitbucket.org/ConesaLab/sqanti)}, an automated pipeline for the structural characterization and quality assessment of full-length transcriptomes. Secondly, the gene-centric nature of functional resources remained the major limitation to the extended study of functional isoform variability, especially for novel isoforms, which cannot be characterised by static databases. Thus, we designed IsoAnnot, which dynamically constructs an isoform-resolved rich database of functional annotations by using as input transcript sequences and integrating information disseminated across several databases and prediction methods. Finally, because no methods to interrogate the functional impact of PTR were available, we developed novel approaches and user-friendly tools such as tappAS \url{(http://tappas.org/)}, designed to facilitate researchers the transcriptome-wide functional study of context-specific isoform regulation.Thereby, this thesis describes the development of an analysis framework that tackles the fundamental challenges of the isoform functional analysis by providing a set of novel methods and tools that offer an unique opportunity to explore how the phenotype is specified by altering the functional characteristics of expressed isoforms. Applied to a murine neural differentiation system, our pipeline profiled the effect of isoform regulation on the inclusion of several functional elements within transcripts between motor-neuron and oligodendrocyte differentiation systems and specifically, we discovered isoform-specific transmembrane regions whose modulation by PTR might contribute to control cell type-specific mitochondrial dynamics during neural fate determination.
This work was funded by the following grants: From 2014 to 2018. FPU: Training programme for Academic Staff. Spanish Ministry of Education, FPU2013/02348. From 2016 to 2019. NOVELSEQ: Novel methods for new challenges in the analysis of high-throughput sequencing data. MINECO, BIO2015-1658-R. From 2014 to 2017. DEANN: Developing a European American NGS Network. EU Marie Curie IRSES, GA-612583.
Fuente Lorente, LDL. (2019). Development of a bioinformatics approach for the functional analysis of alternative splicing [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/124974
TESIS

Abstract:

TFE-fusion renal cell carcinomas (TFE-fusion RCCs) are caused by chromosomal translocations that lead to the overexpression of the TFE3 and TFEB genes (Kauffman et aI, 2014). The mechanisms causing kidney tumour development starting from TFE3/TFEB gene overexpression, remain largely uncharacterized and effective targeted therapies are yet to be identified, hence the need to model these diseases in an experimental animal system (Kauffman et al, 2014). Here we show that kidney-specific TFEB overexpression, in both constitutive and inducible conditional transgenic mouse lines, resulted in a phenotype characterized by renal clear cells, multi-layered basem*nt membranes, severe cystic pathology, and ultimately papillary carcinomas with hepatic metastases. These features closely recapitulate the phenotype observed in both TFEB- and TFE3-mediated human kidney tumors. Analysis of kidney samples from these mice revealed both transcriptional induction of genes belonging to the WNT pathway and enhanced WNT βcatenin signalling. The use of specific WNT signalling inhibitors normalized the proliferation rate of primary kidney cells derived from transgenic mice and significantly rescued the disease phenotype in the mouse model. These data shed new light on the mechanisms underlying TFE-fusion RCCs and suggest a possible therapeutic strategy based on the inhibition of the WNT pathway.

Abstract:

Sistemas de tempo-real embarcados distribuídos se caracterizam pela complexidade e especificidade de seus projetos. Tanto a complexidade quanto a especificidade apresentam forte influência dos diversos requisitos ligados às restrições advindas das três características que distinguem tais sistemas, i.e. presença de fortes restrições temporais, restrições de sistemas embarcados e distribuição de processamento. Estes requisitos, chamados de requisitos não-funcionais, afetam diversas partes do sistema de maneira não uniforme, tornando-se por esta razão difícil o seu gerenciamento. Metodologias orientadas a objetos não apresentam mecanismos específicos para tratar tais requisitos, o que implica na aplicação de um significativo esforço ao se realizar o reuso ou a manutenção de componentes afetados por requisitos de natureza nãofuncional. Novas tecnologias têm surgido com o objetivo de contornar este problema, notadamente a orientação a aspectos. Este paradigma propõe a separação no tratamento dos requisitos não-funcionais contribuindo com a modularização do sistema. Esta dissertação propõe a aplicação de orientação a aspectos para a especificação de sistemas tempo-real embarcados distribuídos. Para isto realizou-se a adaptação de uma metodologia de desenvolvimento de sistemas orientada a aspectos, a FRIDA (From RequIrements to Design using Aspects), contextualizando-a para o domínio de interesse. A utilização desta metodologia provê suporte ao mapeamento de requisitos em elementos de projeto de modo a promover a rastreabilidade entre as fases de análise e projeto. Na fase de projeto é proposta a utilização de aspectos em conjunto com elementos do perfil RT-UML para o tratamento dos requisitos identificados e especificados na fase de análise.
Distributed real-time embedded systems generally have complex and very specific projects. Those characteristics are influenced by several requirements that have relation with constraints about the time, embedded and distribution restrictions. Those requirements, called non-functional requirements, can affect the whole system in a nonuniform way, what makes it difficult to handle with this kind of requirement. Objectoriented methodologies do not present specific mechanisms to handle those requirements, what imply in a significant effort to perform reuse and maintainability tasks in those components affected by non-functional requirements. New technologies are emerging to fulfill this gap, noteworthy the aspect orientation. This paradigm proposes the separation in handling functional and non-functional requirements, giving a contribution to the system modularity. This dissertation proposes the use of aspect orientation to specify distributed realtime embedded systems. To support this proposal, it was performed an adaptation of an aspect-oriented method called FRIDA (From RequIrements to Design using Aspects). The use of this method supports the mapping of requirements in design model elements, in order to promote traceability between analysis and design phases. The presented approach proposes the use of RT-UML together with aspect oriented elements in design phase aiming to improve the handling of those requirements specified in the analysis phase.

Abstract:

In dieser Arbeit werden Algorithmen für die Berechnung elektronischer Korrelations- undAnregungsenergien mittels der Coupled-Cluster Methode auf adaptiven Gittern entwickeltund implementiert. Die jeweiligen Funktionen und Operatoren werden adaptiv durchMultiskalenanalyse dargestellt, was eine Basissatz unabängige Beschreibung mit kontrollierternumerischer Genauigkeit ermöglicht. Gleichungen für die Coupled-Cluster Methodewerden in einem verallgemeinerten Rahmen, unabhängig von virtuellen Orbitalenund globalen Basissätzen, neu formuliert. Hierzu werden die amplitudengewichtetenAnregungen in virtuelle Orbitale ersetzt durch Anregungen in n-Elektronenfunktionen,welche durch Gleichungen im n-Elektronen Ortsraum bestimmt sind. Die erhaltenenGleichungen können, analog zur Basissatz abh¨angigen Form, mit leicht angepasster Interpretationdiagrammatisch dargestellt werden. Aufgrund des singulären Coulomb Potentialswerden die Arbeitsgleichungen mit einem explizit korrelierten Ansatz regularisiert.Coupled-Cluster singles mit genäherten doubles (CC2) und ähnliche Modelle werden,für geschlossenschalige Systeme und in regularisierter Form, in die MADNESS Bibliothek(eine allgemeine Bibliothek zur Darstellung von Funktionen und Operatoren mittelsMultiskalenanalyse) implementiert. Mit der vorgestellten Methode können elektronischeCC2 Paarkorrelationsenergien und Anregungsenergien mit bestimmter numerischerGenauigkeit unabhängig von globalen Basissätzen berechnet werden, was anhand vonkleinen Molekülen verifiziert wird
In this work algorithms for the computation of electronic correlation and excitation energieswith the Coupled-Cluster method on adaptive grids are developed and implemented.The corresponding functions and operators are adaptively represented with multiresolutionanalysis allowing a basis-set independent description with controlled numericalaccuracy. Equations for the coupled-cluster model are reformulated in a generalizedframework independent of virtual orbitals and global basis-sets. For this, the amplitudeweighted excitations into virtuals are replaced by excitations into n-electron functionswhich are determined by projected equations in the n-electron position space. The resultingequations can be represented diagrammatically analogous to basis-set dependentapproaches with slightly adjusted rules of interpretation. Due to the singular Coulombpotential, the working equations are regularized with an explicitly correlated ansatz.Coupled-cluster singles with approximate doubles (CC2) and similar models are implementedfor closed-shell systems and in regularized form into the MADNESS library(a general library for the representation of functions and operators with multiresolutionanalysis). With the presented approach electronic CC2 pair-correlation energiesand excitation energies can be computed with definite numerical accuracy and withoutdependence on global basis sets, which is verified on small molecules.

Abstract:

Hereditary leiomyomatosis and renal cell cancer (HLRCC) and hereditary paragangliomatosis (HPGL) are familial cancer syndromes, caused by germline mutations in genes encoding the Tricarboxylic Acid Cycle (TCAC) enzymes fumarate hydratase (FH) and succinate dehydrogenase (SDH) respectively. Both FH and SDH function as tumour-suppressor genes and the conditions are inherited as autosomal dominant traits. Germline FH mutations predispose individuals to develop benign smooth muscle tumours of the skin and uterus (leiomyomas) and renal carcinoma, whilst individuals with mutations in SDHB, -C, and -D develop paragangliomas and phaeochromocytomas. In order to study the genetic and functional consequences of FH and SDH mutations, and to elucidate mechanisms of tumourigenesis, which are poorly understood, I have undertaken a comprehensive analysis of tumours from both HPGL and HLRCC patients, using gene and protein expression analysis, metabolomic profiling and cytogenetic analysis of HPGL tumours. Tumours from both syndromes over- express hypoxia-inducible factor-alpha (HIFla), the central signalling protein in hypoxia, and HIFIa-target genes including vascular endothelial growth factor (VEGF) and Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3). HLRCC and HPGL tumours accumulate the TCAC intermediates succinate and fumarate which have been shown to up-regulate HIFla in vitro by inhibiting the prolyl hydroxylases (PHD) that target HIFlct for proteosomal degradation. Therefore, 'pseudo-hypoxia' - the constitutive expression of HIFla in normoxic conditions - is likely to contribute largely to the tumourigenesis of HLRCC and HPGL and is most likely to occur as a direct result of accumulation of TCAC intermediates and PHD inhibition. To further investigate the tumourigenesis of HLRCC, I have successfully created a conditional Fhl (the mouse hom*ologue of human FH) mouse knockout which causes hypertrophy when targeted to smooth muscle. I aim to create further temporal and tissue specific knockouts of Fhl, and if these mice develop tumours provide a model of HLRCC for the testing of anti-cancer drugs and therapies.

Abstract:

The molecular consequences of read-through transcription in Saccharomyces cerevisiae genes transcribed by RNA Polymerases I and II (Pol I and Pol II) are investigated in the two results sections of this thesis (Part I and Part II). In these studies, nascent and steady state RNA analyses are employed to evaluate transcriptional termination. Part I focuses on the impact that co-expressed Pol II transcribed genes can have on each other when placed in a convergent orientation. Transcriptional interference (TI), previously shown to occur between tandemly arranged genes, inhibits initiation of transcription on a downstream gene. These studies demonstrate that TI can also occur with S.cerevisiae Pol II genes arranged convergently. When the GAL10 and GAL7 genes are rearranged in a convergent orientation, transcriptional initiation occurs at full levels. However as soon as the two transcripts begin to overlap, elongation is restricted resulting in a severe reduction in steady state mRNA accumulation. This effect is only observed in the cis arrangement arguing against RNAi effects acting on the potential generation of antisense transcripts. These data reinforce the necessity to separate adjacent Pol II transcription units by efficient termination signals. Part II describes experiments that define the nascent termination site of Pol I transcribed rRNA genes. Furthermore, transcription run-on (TRO) analysis was performed on yeast strains in which specific factors involved in the Pol I transcription and RNA processing had been deleted. In particular, S.cerevisiae strains lacking the RPA12p subunit of Pol I have a severe defect in transcriptional termination at the nascent level indicating a direct role for this subunit in termination. Additionally, a yeast strain lacking Rnt1p, a protein involved in early rRNA processing, shows an altered transcriptional termination profile suggesting a link between processing and termination efficiency. In contrast to TI in Pol II, read-through transcription in Pol I may not significantly reduce rRNA gene synthesis.

Abstract:

Optimised allocation of system architectures is a well researched area as it can greatly reduce the developmental cost of systems and increase performance and reliability in their respective applications.In conjunction with the recent shift from federated to integrated architectures in automotive, and the increasing complexity of computer systems, both in terms of software and hardware, the applications of design space exploration and optimised allocation of system architectures are of great interest.This thesis proposes a method to derive architectures and their allocations for systems with real-time constraints.The method implements integer linear programming to solve for an optimised allocation of system architectures according to a set of linear constraints while taking resource requirements, communication dependencies, and manual design choices into account.Additionally, this thesis describes and evaluates an industrial use case using the method wherein the timing characteristics of a system were evaluated, and, the method applied to simultaneously derive a system architecture, and, an optimised allocation of the system architecture.This thesis presents evidence and validations that suggest the viability of the method and its use case in an industrial setting.The work in this thesis sets precedence for future research and development, as well as future applications of the method in both industry and academia.

Abstract:

L’objectif général de cette thèse a été d’approfondir la compréhension actuelle des bases génétiques et de la pathophysiologie de leucémies B agressives, à savoir deux sous-types de leucémie lymphoïde chronique (LLC) et la leucémie prolymphocytaire B (LPLB). La LLC, qui est la forme de leucémie adulte la plus fréquente en Occident, est caractérisée par une accumulation de lymphocytes B monoclonaux (CD20+, CD5+ and CD23+) dans le sang périphérique, la moelle osseuse ainsi que les organes lymphoïdes secondaires. La LLC est une maladie très hétérogène, où un large panel d’altérations génétiques mènent à des résultats cliniques variables. Le gain du bras court du chromosome 2 (gain 2p) est une anomalie chromosomique récurrente dans la LLC et d’autres cancers. Notre groupe avait décrit l’association du gain 2p avec la résistance aux traitements et des facteurs de mauvais pronostic comme l’IGHV non-muté et la délétion 11q. Des analyses cytogénétiques et moléculaires nous ont notamment permis d’identifier une région minimale de gain incluant entre autres les gènes XPO1 et REL. Dans la partie principale de ma thèse, l’analyse fonctionnelle du rôle de REL, par trois stratégies complémentaires d’inhibition pharmacologique, d’inactivation du gène et d’activation transcriptionelle, a permis l’identification de REL comme un acteur central de la survie cellulaire dans la LLC. De plus, j’ai développé plusieurs modèles cellulaires de LLC permettant la surexpression de n’importe quel gène, seul ou en combinaison, pour approfondir les études sur REL et XPO1, et identifier de potentielles coopérations oncogéniques menant au phénotype des LLC avec gain 2p. Enfin, nous avons analysé la hiérarchie et l’évolution clonale des anomalies chromosomiques dans les LLC avec gain 2p. La LLC avec délétion 17p est associée avec une absence de réponse aux traitements standards et donc avec la pire issue clinique possible. Nous avons montré que la délétion 17p et le gain 8q24 ont un impact synergique sur le résultat clinique, et que les patients ayant cette LLC « double-hit » ont un pronostic particulièrement défavorable. La LPLB est un lymphome agressif, habituellement résistant aux chimio-immunothérapies standard, et défini par la présence de prolymphocytes dans le sang périphérique excédant 55% des cellules lymphoïdes. Nous décrivons les aspects cytogénétiques et moléculaires d’une large cohorte de 34 cas de LPLB, ainsi que leurs réponses aux nouveaux inhibiteurs spécifiques in vitro. In fine, notre travail a permis une meilleure compréhension de la LLC et de la LPLB, et d’ouvrir la voie au développement de nouvelles stratégies thérapeutiques
The overall aim of this thesis consisted of expanding the current understanding of the genetic basis and physiopathology of aggressive B-cell leukemias, namely in chronic lymphocytic leukemia (CLL) subtypes and in B-cell prolymphocytic leukemia (B-PLL). CLL, the most common form of adult leukemia in the West, is characterized by an accumulation of monoclonal B cells (CD20+, CD5+ and CD23+) in the peripheral blood, bone marrow, and secondary lymphoid organs. CLL is a highly heterogeneous disease, with a large panel of genetic alterations leading to variable clinical outcomes. Gain of the short arm of chromosome 2 (2p gain) is a frequent chromosomal abnormality in CLL and in other malignancies. Our group has reported that 2p gain was associated with drug refractoriness and poor prognosis factors such as unmutated IGHV and 11q deletion. Using cytogenetic and molecular analyses, we have notably identified a minimal region of gain which encompasses among others XPO1 and REL. In my main thesis project, functional analysis of the role of REL, using three complementary strategies of pharmacological inhibition, gene knockout and transcriptional activation, led to its identification as a key player driving cell survival in CLL. Moreover, I developed several CLL cellular models that allow the overexpression of any gene, alone or in combination, in order to further investigate the roles of REL and XPO1 in CLL and identify potential oncogenic cooperation driving phenotypic features of 2p gain CLL. Finally, we have analyzed the hierarchy and the clonal evolution of the chromosomal abnormalities in 2p gain CLL. CLL with 17p deletion, del(17p), is associated with a lack of response to standard treatment and thus the worst clinical outcome. Our findings showed that del(17p) and 8q24 gain have a synergistic impact on outcome, therefore patients with this “double-hit” CLL have a particularly poor prognosis. B-PLL is an aggressive leukemia, usually resistant to standard chemo-immuno therapy, defined by the presence of prolymphocytes in peripheral blood exceeding 55% of lymphoid cells. We described the cytogenetic and molecular features of a large cohort of 34 B-PLL cases, as well as their in vitro response to novel targeted drugs. Altogether, this work enabled a better understanding of CLL and B-PLL, as well as paving the way for the development of novel therapeutic strategies

Abstract:

High speed facilities are considered the backbone of any successful transportation system; Interstates, freeways, and expressways carry the majority of daily trips on the transportation network. Although these types of roads are relatively considered the safest among other types of roads, they still experience many crashes, many of which are severe, which not only affect human lives but also can have tremendous economical and social impacts. These facts signify the necessity of enhancing the safety of these high speed facilities to ensure better and efficient operation. Safety problems could be assessed through several approaches that can help in mitigating the crash risk on long and short term basis. Therefore, the main focus of the research in this dissertation is to provide a framework of risk assessment to promote safety and enhance mobility on freeways and expressways. Multi-level Safety Performance Functions (SPFs) were developed at the aggregate level using historical crash data and the corresponding exposure and risk factors to identify and rank sites with promise (hot-spots). Additionally, SPFs were developed at the disaggregate level utilizing real-time weather data collected from meteorological stations located at the freeway section as well as traffic flow parameters collected from different detection systems such as Automatic Vehicle Identification (AVI) and Remote Traffic Microwave Sensors (RTMS). These disaggregate SPFs can identify real-time risks due to turbulent traffic conditions and their interactions with other risk factors. In this study, two main datasets were obtained from two different regions. Those datasets comprise historical crash data, roadway geometrical characteristics, aggregate weather and traffic parameters as well as real-time weather and traffic data. At the aggregate level, Bayesian hierarchical models with spatial and random effects were compared to Poisson models to examine the safety effects of roadway geometrics on crash occurrence along freeway sections that feature mountainous terrain and adverse weather. At the disaggregate level; a main framework of a proactive safety management system using traffic data collected from AVI and RTMS, real-time weather and geometrical characteristics was provided. Different statistical techniques were implemented. These techniques ranged from classical frequentist classification approaches to explain the relationship between an event (crash) occurring at a given time and a set of risk factors in real time to other more advanced models. Bayesian statistics with updating approach to update beliefs about the behavior of the parameter with prior knowledge in order to achieve more reliable estimation was implemented. Also a relatively recent and promising Machine Learning technique (Stochastic Gradient Boosting) was utilized to calibrate several models utilizing different datasets collected from mixed detection systems as well as real-time meteorological stations. The results from this study suggest that both levels of analyses are important, the aggregate level helps in providing good understanding of different safety problems, and developing policies and countermeasures to reduce the number of crashes in total. At the disaggregate level, real-time safety functions help toward more proactive traffic management system that will not only enhance the performance of the high speed facilities and the whole traffic network but also provide safer mobility for people and goods. In general, the proposed multi-level analyses are useful in providing roadway authorities with detailed information on where countermeasures must be implemented and when resources should be devoted. The study also proves that traffic data collected from different detection systems could be a useful asset that should be utilized appropriately not only to alleviate traffic congestion but also to mitigate increased safety risks. The overall proposed framework can maximize the benefit of the existing archived data for freeway authorities as well as for road users.
ID: 031988164; System requirements: World Wide Web browser and PDF reader.; Mode of access: World Wide Web.; Thesis (Ph.D.)--University of Central Florida, 2012.; Includes bibliographical references.
Ph.D.
Doctorate
Civil, Environmental, and Construction Engineering
Engineering and Computer Science
Civil Engineering

Abstract:

La sécurité et le confort dans une tâche de conduite automobile sont des facteurs clés qui intéressent plusieurs acteurs (constructeurs, urbanistes, départements de transport), en particulier dans le contexte actuel d’urbanisation croissante. Il devient dès lors crucial d'évaluer l'état affectif du conducteur lors de la conduite, en particulier son niveau de stress qui influe sur sa prise de décision et donc sur ses performances de conduite. Dans cette thèse, nous nous concentrons sur l'étude des changements de niveau de stress ressenti durant une expérience de conduite réelle qui alterne ville, autoroute et repos. Les méthodes classiques sont basées sur des descripteurs proposés par des experts, appliquées sur des signaux physiologiques. Ces signaux sont prétraités, les descripteurs ad-hoc sont extraits et sont fusionnés par la suite pour reconnaître le niveau de stress. Dans ce travail, nous avons adapté une méthode de sélection de variables fonctionnelles, basée sur les forêts aléatoires, avec élimination récursive des descripteurs (RF-RFE). En effet, les biosignaux, considérés comme variables fonctionnelles, sont tout d’abord projetés sur une base d’ondelettes. L’algorithme RF-RFE est ensuite utilisé pour sélectionner les groupes d’ondelettes, correspondant aux variables fonctionnelles, selon un score d’endurance. Le choix final de ces variables est basé sur ce score proposé afin de quantifier la capacité d’une variable à être sélectionnée et dans les premiers rangs. Dans une première étape, nous avons analysé la fréquence cardiaque (HR), électromyogramme (EMG), fréquence respiratoire (BR) et activité électrodermale (EDA), issus de 10 expériences de conduite menées à Boston, de la base de données du MIT, drivedb. Dans une seconde étape, nous avons conduit 13 expériences in-vivo similaires, en alternant conduite dans la ville et sur autoroute dans la région de Grand Tunis. La base de données résultante, AffectiveROAD contient -comme dans drivedb- les biosignaux tels que le HR, BR, EDA mais aussi la posture. Le prototype de plateforme de réseau de capteurs développé, a permis de collecter des données environnementales à l’intérieur du véhicule (température, humidité, pression, niveau sonore et GPS) qui sont également inclues dans AffectiveROAD. Une métrique subjective de stress, basée sur l’annotation d’un observateur et validée a posteriori par le conducteur au vu des enregistrements vidéo acquis lors de l’expérience de conduite, complète cette base de données. Nous définissons ici la notion de stress par ce qui résume excitation, attention, charge mentale, perception de complexité de l'environnement par le conducteur. La sélection de variables fonctionnelles dans le cas de drivedb a révélé que l'EDA mesurée au pied est l'indicateur le plus révélateur du niveau de stress du conducteur, suivi de la fréquence respiratoire. La méthode RF-RFE associée à des descripteurs non experts, conduit à des performances comparables à celles obtenues par la méthode basée sur les descripteurs sélectionnés par les experts. En analysant les données d’AffectiveROAD, la posture et l’EDA mesurée sur le poignet droit du conducteur ont émergé comme les variables les plus pertinentes. Une analyse plus approfondie de l'EDA a par la suite été menée car ce signal a été retenu, pour les deux bases de données, parmi les variables fonctionnelles sélectionnées pour la reconnaissance du niveau de stress. Ceci est cohérent avec diverses études sur la physiologie humaine qui voient l’EDA comme un indicateur clé des émotions. Nous avons ainsi exploré le caractère fractal de ce biosignal à travers une analyse d'auto-similarité et une estimation de l'exposant de Hurst basée sur les ondelettes. L'analyse montre un comportement d’auto-similarité des enregistrements de l'EDA pour les deux bases de données, sur une large gamme d’échelles. Ceci en fait un indicateur potentiel temps réel du stress du conducteur durant une expérience de conduite réelle
The safety and comfort in a driving task are key factors of interest to several actors (vehicle manufacturers, urban space designers, and transportation service providers), especially in a context of an increasing urbanization. It is thus crucial to assess the driver’s affective state while driving, in particular his state of stress which impacts the decision making and thus driving task performance. In this thesis, we focus on the study of stress level changes, during real-world driving, experienced in city versus highway areas. Classical methods are based on features selected by experts, applied to physiological signals. These signals are preprocessed using specific tools for each signal, then ad-hoc features are extracted and finally a data fusion for stress-level recognition is performed. In this work, we adapted a functional variable selection method, based on Random Forests Recursive Feature Elimination (RF-RFE). In fact, the biosignals considered as functional variables, are first decomposed using wavelet basis. The RF-RFE algorithms are then used to select groups of wavelets coefficients, corresponding to the functional variables, according to an endurance score. The final choice of the selected variables relies on this proposed score that allows to quantify the ability of a variable to be selected and this, in first ranges. At a first stage, we analyzed physiological signals such as: Heart Rate (HR), Electromyogram (EMG), Breathing Rate (BR), and the Electrodermal Activity (EDA), related to 10 driving experiments, extracted from the open database of MIT: drivedb, carried out in Boston area. At a second stage, we have designed and conducted similar city and highway driving experiments in the greater Tunis area. The resulting database, AffectiveROAD, includes, as in drivedb, biosignals as HR, BR and EDA and additional measurement of the driver posture. The developed prototype of the sensors network platform allowed also to gather data characterizing the vehicle internal environment (temperature, humidity, pressure, sound level, and geographical coordinates) which are included in AffectiveROAD database. A subjective stress metric, based on driver video-based validation of the observer’s annotation, is included in AffectiveROAD database. We define here the term stress as the human affective state, including affect arousal, attention, mental workload, and the driver’s perception of the environment complexity. The functional variable selection, applied to drivedb, revealed that the EDA captured on foot followed by the BR, are relevant in the driver’s stress level classification. The RF-RFE method along with non-expert based features offered comparable performances to those obtained by the classical method. When analyzing the AffectiveROAD data, the posture and the EDA captured on the driver’s right wrist emerged as the most enduring variables. For both databases, the placement of the EDA sensor came out as an important consideration in the stress level assessment. A deeper analysis of the EDA was carried out since its emergence as a key indicator in stress level recognition, for the two databases. This is consistent with various human physiology studies reporting that the EDA is a key indicator of emotions. For that, we investigated the fractal properties of this biosignal using a self-similarity analysis of EDA measurements based on Hurst exponent (H) estimated using wavelet-based method. Such study shows that EDA recordings exhibits self-similar behavior for large scales, for the both databases. This proposes that it can be considered as a potential real-time indicator of stress in real-world driving experience

Abstract:

Introdução: Estudos recentes mostram que pacientes com lesão renal aguda apresentam maior mortalidade em longo prazo e evoluem mais para doença renal crônica do que pacientes com controles sem lesão renal aguda. Os fatores associados à pior evolução desses pacientes são controversos e suas causas de óbito desconhecidas. Objetivos: Avaliar a sobrevida e as causas de óbito após a alta hospitalar de pacientes com lesão renal aguda. Analisar a recuperação da função renal na alta hospitalar e a sua evolução em longo prazo. Métodos: Estudo retrospectivo de pacientes internados em 2005 e 2006 com lesão renal aguda e que tiveram lata hospitalar livres de diálise. Foram analisadas as suas características clínicas e laboratoriais, e verificadas a mortandade e a evolução da função renal até 31 de maio de 2008. As causas de óbito foram pesquisadas no \"Programa de Aprimoramento das Informações de Mortalidade\" da cidade de São Paulo e comparadas com a população geral da mesma faixa etária. A curva de sobrevida dos pacientes com lesão renal aguda foi comparada com a da população de São Paulo. A evolução da filtração glomerular durante o primeiro ano após a alta hospitalar foi avaliada considerando-se os valores da creatina sérica encontradas em medidas ambulatoriais. Resultados: Foram incluídos 507 pacientes que foram seguidos por um tempo mediano de 21 meses. Ao final do estudo 38% haviam morrido. As principais causas de óbito foram doenças do aparelho circulatório e neoplasias, achado semelhante ao da população de São Paulo. A causa de óbito se relacionou com a presença de comorbidades existentes antes da lesão renal aguda. A sobrevida dos pacientes foi pior do que a da população de São Paulo e os fatores associados à sua pior sobrevida foram a presença de hepatopatia, índice de Khan de alto risco, internação em serviço clínico e novo episódio de lesão renal aguda na mesma internação. Na alta hospitalar, 50% dos pacientes apresentavam recuperação completa da função renal, 36% recuperação parcial e 14% não tinham recuperado a função renal. Os fatores associados com a recuperação completa da função renal foram: menor gravidade na lesão renal aguda, presença de provável doença renal crônica e necessidade de ventilação mecânica. O estudo da evolução da função renal se restringiu a 278 pacientes. Estes mostraram dois tipos de comportamento: aqueles com recuperação completa da função renal apresentavam, na alta hospitalar, um filtração glomerular maior do que a referência, e estes valores foram se aproximando ao longo do primeiro ano após a alta. Já aqueles com recuperação parcial e os que não recuperaram a função renal evoluíram com melhora da filtração glomerular durante o primeiro ano, porém sem atingir os valores de referência. Conclusões: Os pacientes que apresentam lesão renal aguda mantêm uma alta mortalidade após a alta hospitalar que está relacionada à presença de comorbidades anteriores à internação. Somente metade dos pacientes apresenta recuperação completa da função renal na alta hospitalar, e a recuperação está associada à menor gravidade da lesão renal aguda. A ausência de informação sobre a função renal após a alta hospitalar ocorreu em 25% dos pacientes. No primeiro ano após a alta hospitalar a filtração glomerular tende a se aproximar dos valores de referência, porém sem atingi-los.
Introduction: Recent studies show that the patients who suffered an acute kidney injury episode have increased long-term mortality and develop more chronic kidney disease than those without acute kidney injury. Factors associated with this poor outcome are controversial, and causes of death of these patients are unknown. Objectives: To evaluate survival and causes of death after hospital discharge of patients with acute kidney injury. To analyze the recovery of renal function at hospital discharge its long-term outcome. Methods: A retrospective study of patients hospitalized in 2005 and 2006 with acute kidney injury who were discharged free of dialysis. We analyzed their clinical and laboratorial features, and checked the mortality and evolution of their renal function until May, 2008. Causes of death were investigated in the \"Programa de Aprimoramento das Informações de Mortalidade\" of São Paulo City and compared with general population of similar age. The survival curve of patients who suffered an acute kidney injury episode was compared with the survival curve of São Paulo population. The evolution of glomerular filtration rate during the first year after hospital discharge was assessed by considering the values of serum creatinine measurements found in outpatients. Results: We included 507 patients who were followed for a median of 21 months. At the end of the study 38% of them had died. The main causes of death were circulatory diseases and neoplasms; a finding similar to São Paulo population. The causes of death were related to the presence of comorbidities before the acute kidney injury. The survival curve of these patients was worse than those of São Paulo population; the factors associated with poor survival were presence of chronic liver failure, Khan index of high risk, admission in medical ward and a new episode of acute kidney injury during the same hospitalization. At hospital discharge, 50% of patients had complete renal recovery, 36% partial renal recovery and 14% had not recovered renal function. The factors associated with complete recovery of renal function were less severe acute kidney injury, presence of presumed chronic kidney disease and need for mechanical ventilation. The study of the evolution of renal function was restricted to 278 patients. These patients showed two types of evolution: those with complete renal recovery were discharged with a glomerular filtration rate greater than the reference, and these values were approached during the first year after discharge. Patients with partial renal recovery and those who did recover renal function at hospital discharge had an improvement in glomerular filtration rate during the first year, without reaching the reference value. Conclusion: Patients with acute kidney injury remain a high mortality after hospital discharge which is related to the presence of comorbidities before hospitalization. Only half of patients had complete renal recovery at hospital discharge, and recovery is associated with reduced severity of acute kidney injury. The lack of information on renal function after discharge occurred in 25% of the included patients. During the first year after hospital discharge the glomerular filtration rate tends to approach to reference values but without reach them.

Abstract:

Familial renal cell carcinoma (RCC) only accounts for 3% of all RCC, yet the study of these inherited forms has provided important insights into the more common sporadic RCC. Somatic VHL inactivation is found in 70% of sporadic clear cell RCC (ccRCC) though is rarely found in other forms of RCC including papillary and chromophobe types. VHL-independent RCC tumourigenesis is poorly understood and current research involves identifying novel RCC candidate genes to further understand the mechanisms involved. In this study a constitutional balanced translocation, t(5;19)(p15.3;q12), associated with familial RCC was characterised using an oligonuleotide CGH array followed by genomic sequencing and the previously uncharacterised gene, UBE2QL1, was found to be disrupted by the 5p15.3 breakpoint. UBE2QL1 expression was down-regulated in 78.6% of sporadic RCC and UBE2QL1 promoter region hypermethylation and gene deletions were detected in 20.3% and 17.3% of sporadic RCC, respectively. Re-expression of UBE2QL1 in deficient RCC cell lines suppressed anchorage independent growth and colony formation. UBE2QL1 shows hom*ology to the E2 class of ubiquitin conjugating enzymes and was shown to possess an active-site cysteine (C88) that is monoubiquitinated in vivo. In addition, UBE2QL1 co-immunoprecipitation and co-localisation studies demonstrated a protein interaction with FBXW7 (an F box protein for the SCF E3 ubiquitin ligase) and was shown to facilitate the degradation of the known FBXW7 substrates, cyclin E1 and mTOR. These findings demonstrate that UBE2QL1 functions as a novel renal tumour suppressor gene and ubiquitin conjugating enzyme.

Abstract:

Nous nous intéressons à l'étude des singularités réelles à l'aide d'arguments provenant de l'intégration motivique. Une telle démarche a été initiée par S. Koike et A. Parusiński puis poursuivie par G. Fichou. Afin de donner une classification des singularités réelles, T.-C. Kuo a défini la notion d'équivalence blow-analytique. Il s'agit d'une relation d'équivalence pour les germes analytiques réels n'admettant pas de module continu pour les singularités isolées. Cette notion est étroitement liée à la notion d'applications analytiques par arcs définie par K. Kurdyka. Il est donc naturel d'adapter des arguments provenant de l'intégration motivique pour l'étude de l'équivalence blow-analytique. La difficulté réside désormais dans le fait de trouver des méthodes permettant de montrer que deux germes sont équivalents et de construire des invariants permettant de distinguer deux germes qui ne sont pas dans la même classe. Nous travaillons avec une variante plus algébrique de cette notion, l'équivalence blow-Nash introduite par G. Fichou. La première partie de la thèse consiste en un théorème d'inversion donnant des conditions pour que l'inverse d'un homéomorphisme blow-Nash soit encore blow-Nash. L'intérêt d'un tel énoncé est que de telles applications apparaissent dans la définition de l'équivalence blow-Nash. La seconde partie est consacrée à l'étude d'une nouvelle fonction zêta motivique. Il s'agit d'associer à un germe analytique une série formelle. Cette fonction zêta motivique généralise les fonctions zêta de Koike-Parusiński et de Fichou et admet une formule de convolution. Il s'agit d'un invariant pour l'équivalence blow-Nash
The main purpose of this thesis is to study real singularities using arguments from motivic integration as initiated by S. Koike and A. Parusiński and then continued by G. Fichou. In order to classify real singularities, T.-C. Kuo introduced the blow-analytic equivalence which is an equivalence relation on real analytic germs without moduli for isolated singularities. This notion is closely related to the notion of arc-analytic maps introduced by K. Kurdyka, thus it is natural to adapt arguments from motivic integration to the study of the relation. The difficulty lies in finding efficient ways to prove that two germs are equivalent and in constructing invariants that distinguish germs which are not in the same class. We focus on the blow-Nash equivalence, a more algebraic notion which was introduced by G. Fichou. The first part of this thesis consists in an inverse theorem for blow-Nash maps. Under certain assumptions, this ensures that the inverse of a homeomorphism which is blow-Nash is also blow-Nash. Such maps are involved in the definition of the blow-Nash equivalence. In the second part, we associate a power series to an analytic germ, called the zeta function of the germ. This construction generalizes the zeta functions of Koike-Parusiński and Fichou. Furthermore, it admits a convolution formula while being an invariant for the blow-Nash equivalence

Abstract:

Les mutations hétérozygotes du gène codant pour le facteur de transcription HNF1B sont à l'origine d'un syndrome multisystémique complexe connu sous le nom de « Renal Cysts and Diabetes » (RCAD). Un modèle de souris généré dans notre laboratoire s'est avéré reproduire plusieurs caractéristiques de la maladie humaine. Nous avons réalisé un séquençage ARNm-microARN à différents stades de développement (E14,5 ; E15,5 ; E17,5) de ce modèle. Nous avons montré que les gènes les plus dérégulés étaient impliqués dans les processus métaboliques de transport, de lipides et d’acides organiques et étaient exprimés dans les tubules proximaux et, dans une moindre mesure, dans l’anse de Henlé et les canaux collecteurs. Nous avons sélectionné quatre microARN (miR-802, 194-2, 192 et -30a), régulés à la baisse et potentiellement contrôlés par HNF1B. Des expériences de transactivation de gène rapporteur dans des cellules HEK-293 ont montré que HNF1B était capable de transactiver la transcription de ces microARN via des sites de liaison présents dans les séquences régulatrices de ces gènes. En utilisant des microARN MIMICS nous avons par la suite montré que mir-802, mir-194-2 et mir-192 étaient capables d'inhiber l’expression d’un gène rapporteur contenant la région 3'UTR de HNF1B. L'analyse d'échantillons d'urine de 22 patients RCAD et de 22 contrôles sains a permis d'identifier 146 peptides excrétés de manière différentielle et associés au syndrome. En utilisant ces résultats dans un modèle mathématique, classificateur prédit efficacement le syndrome RCAD avec une sensibilité de 91.7% et une spécificité de 91.1% sur une large population de patients
Heterozygous mutations in the gene encoding the transcription factor HNF1B are the cause of a complex multisystem syndrome known as Renal Cysts And Diabetes (RCAD). A mouse model generated in our laboratory was shown to reproduce several features of the human disease. We performed high-throughput mRNA-microRNA sequencing at different developmental stages (E14.5, E15.5, E17.5). We showed that the most down-regulated genes were involved in transport, lipid and organic acid metabolic processes and expressed in proximal tubules and to a lesser extent in the loop of Henle and collecting ducts. We then selected four microRNAs (mir-802, 194-2, 192 and -30a), which were down-regulated and potentially controlled by HNF1B. Luciferase assays in HEK-293 cells showed that HNF1B was able to specifically transactivate in a dose response mode these microRNAs through binding HNF1B-binding sites in their regulatory promoter/enhancer upstream sequences. We subsequently showed by luciferase assays using miRNA MIMICS that mir-802, mir-194-2 and mir-192 were able to inhibit luciferase vectors containing the 3’UTR of Hnf1b. Analysis of urine samples from 22 RCAD patients and 22 healthy controls led to the identification of 146 peptides differentially excreted and associated with RCAD including a similarity regarding collagen and uromodulin fragments with the RCAD mouse model. Combining the peptides into a mathematical model we used independent cohorts of patients to validate the prediction of the RCAD syndrome. Our classifier efficiently predicted RCAD syndrome with 91.7% sensitivity and 91.1% specificity on a wide population

Abstract:

The natural environments of organisms present a multitude of biotic and abiotic challenges that require both short-term ecological and long-term evolutionary responses. Though most environmental response studies have focused on effects at the ecosystem, community and organismal levels, the ultimate controls of these responses are located in the genome of the organism. Soil nematodes are highly responsive to, and display a wide variety of responses to changing environmental conditions, making them ideal models for the study of organismal interactions with their environment. In an attempt to examine responses to environmental stress (desiccation and freezing), genomic level analyses of gene expression during anhydrobiosis of the Antarctic nematode Plectus murrayi was undertaken. An EST library representative of the desiccation induced transcripts was established and the transcripts differentially expressed during desiccation stress were identified. The expressed genome of P. murrayi showed that desiccation survival in nematodes involves differential expression of a suite of genes from diverse functional areas, and constitutive expression of a number of stress related genes. My study also revealed that exposure to slow desiccation and freezing plays an important role in the transcription of stress related genes, improves desiccation and freezing survival of nematodes. Deterioration of traits essential for biological control has been recognized in diverse biological control agents including insect pathogenic nematodes. I studied the genetic mechanisms behind such deterioration using expression profiling. My results showed that trait deterioration of insect pathogenic nematode induces substantial overall changes in the nematode transcriptome and exhibits a general pattern of metabolic shift causing massive changes in metabolic and other processes. Finally, through field observations and molecular laboratory experiments the validity of the growth rate hypothesis in natural populations of Antarctic nematodes was tested. My results indicated that elemental stoichiometry influences evolutionary adaptations in gene expression and genome evolution. My study, in addition to providing immediate insight into the mechanisms by which multicellular animals respond to their environment, is transformative in its potential to inform other fundamental ecological and evolutionary questions, such as the evolution of life-history patterns and the relationship between community structure and ecological function in ecosystems.

Abstract:

Les travaux réalisés dans le cadre de cette thèse ont pour objectif de proposer un langage de description temporelle pour des systèmes temps-réel et d’établir les conditions de leur ordonnançabilité sous l’algorithme Earliest Deadline First (EDF). Les langages de description temporelle permettent de spécifier le comportement temporel d’une application indépendamment de son comportement fonctionnel. Le programmeur déclare dans ces langages à quels instants précis doivent être déclenchées et terminées les activités du système. Cette gestion du temps, précise et explicite, apporte au système son caractère déterministe. Le langage proposé, Extended Timing Definition Language (E-TDL), étend des langages dirigés par le temps existants, en particulier Giotto et TDL, en introduisant un nouveau modèle de tâche donné par quatre paramètres : phase, pire temps d’exécution, temps d’exécution logique TEL (intervalle de temps séparant le lancement de la tâche et sa terminaison) et période. L’introduction de ce nouveau modèle de tâche nécessite de revisiter en particulier le problème de l’ordonnançabilité des tâches pour EDF. Cette thèse propose et développe une analyse basée sur la fonction de demande pour des ensembles de tâches décrites en E-TDL et s’exécutant en contexte monoprocesseur. Une condition nécessaire et suffisante est obtenue au travers d’une analyse précise des intervalles séparant les activations de tâches au sein de différents modules s’exécutant indépendamment et pouvant changer de mode à des instants prédéfinis. Une borne de la longueur des intervalles sur lesquels doit s’opérer la vérification est déterminée. Un outil mettant en œuvre cette analyse a été développé
The goal of this research is to define a time-triggered language for modeling real-time systems and to provide the conditions for their schedulability under Earliest Deadline First (EDF). Time-triggered languages separate the functional part of applications from their timing definition. These languages permit to model the real-time system temporal behavior by assigning system activities to particular time instants. We propose a new time-triggered framework, Extended Timing Definition Language (E-TDL), that enhances the basic task model used in Giotto and TDL while keeping compositional and modular structure brought by the latter. An E-TDL task is characterized by: an offset, a worst case execution time, a Logical Execution Time (a time interval between task release and its termination) and a period. The schedulability analysis of the system based on this new task model should be, in particular for EDF, investigated. We develop, on the concept of the processor demand criterion, conditions for the feasibility of an E-TDL system running on a single CPU under EDF. A necessary and sufficient condition is obtained by considering the global schedules that are made up of execution traces occurring at the same time in distinct modules that are able to switch their modes at predefined instants. We estimate a maximal length of the interval on which the schedulability condition must be checked. A tool suite performing the schedulability analysis of the E-TDL systems is developed

Abstract:

This thesis consists of two papers on the spectral geometry of locally symmetric spaces of Riemannian and Lorentzian signature. Both works are concerned with the idea of relating analysis on such spaces to structures on their boundaries.

The first paper is motivated by a conjecture of Patterson on the Selberg zeta function of Kleinian groups. We consider geometrically finite hyperbolic cylinders with non-compact Riemann surfaces of finite area as cross sections. For these cylinders, we present a detailed investigation of the Bunke-Olbrich extension operator under the assumption that the cross section of the cylinder has one cusp. We establish the meromorphic continuation of the extension of Eisenstein series and incomplete theta series through the limit set. Furthermore, we derive explicit formulas for the residues of the extension operator in terms of boundary values of automorphic eigenfunctions.

The motivation for the second paper comes from conformal geometry in Lorentzian signature. We prove the existence and uniqueness of a sequence of differential intertwining operators for spherical principal series representations, which are realized on boundaries of anti de Sitter spaces. Algebraically, these operators correspond to hom*omorphisms of generalized Verma modules. We relate these families to the asymptotics of eigenfunctions on anti de Sitter spaces.

Abstract:

O objetivo principal deste trabalho é o estudo da regularidade anallítica global de certos operadores diferenciais definidos no toro. Uma ferramenta fundamental utilizada neste estudo são as séries parciais de Fourier, que nos permitem caracterizar tanto as distribuições periódicas quanto as funções anallíticas reais periódicas através do comportamento assintótico de seus coeficientes parciais de Fourier. Neste sentido, apresentamos também um estudo detalhado das relações destes objetos com seus coeficientes parciais de Fourier
The main goal of this work is to study global analytic regularity properties of certain differential operators acting in the torus. A main tool that will be used to achieve our goals are the partial Fourier series, which allow us to characterize objects such as periodic distributions or periodic real analytic functions in terms of the growth of their partial Fourier coefficients

Abstract:

Complicações renais e urológicas incluindo nefrolitíase, cristalúria, cólica renal e lombalgia, são eventos adversos bem conhecidos do indinavir (IDV), um inibidor de protease (IP) largamente utilizado no tratamento de pacientes infectados com o vírus da imunodeficiência humana (HIV). Prévios estudos em ratos demonstraram que o IDV, um potente IP capaz de provocar uma sustentada supressão da carga viral do HIV, induz vasoconstricção renal, diminui a filtração glomerular (RFG) e reduz a excreção urinária de nitrito (NO2-), sugerindo que a vasoconstricção causada pelo IDV deve ser mediada pelo óxido nítrico (NO). Os objetivos deste estudo foram investigar a ocorrência de insuficiência renal (clearance de creatinina < 80ml/min) em pacientes com infecção pelo HIV tratados com terapia anti-retroviral altamente potente incluindo o inibidor de protease IDV, e mensurar a excreção urinária de nitrato (NO3-) nestes pacientes, comparando-os com outro grupo de pacientes tratados com efavirenz (EFV), um inibidor de transcriptase reversa não-análogo de nucleosídeo (NNRTI). No período compreendido entre março de 2000 e outubro de 2003, estudamos 36 pacientes infectados pelo HIV que estavam em terapia com IDV na dose de 800 mg de 8/8 horas por pelo menos 12 meses. Os pacientes foram avaliados para uma variedade de parâmetros clínicos e laboratoriais: idade, peso, tempo de infecção, tempo de uso de IDV, uso de sulfametoxazol-trimetoprim (SMX-TMP) ou sulfadiazina, exames bioquímicos (colesterol total, triglicérides, magnésio, sódio, potássio e creatinina), exame do sedimento urinário, clearance de creatinina, osmolaridade urinária, volume urinário de 24 h, fração de excreção de sódio (FENa), fração de excreção de potássio (FEK) e fração de excreção de água (FEH2O). NO3 urinário foi mensurado em 18 pacientes recebendo terapia anti-retroviral com IDV e 8 pacientes recebendo terapia com EFV. Leucocitúria ocorreu em 78.8% dos pacientes tratados com IDV. Clearance de creatinina diminuído foi observado em 21 pacientes e foi associado com menor peso e uso de derivados de sulfa. Nestes pacientes com diminuição da função renal, também detectamos menor osmolaridade urinária e uma FEH2O mais alta. A excreção urinária de NO3- foi significativamente menor nos pacientes tratados com IDV (908 ± 181) quando comparados aos pacientes do grupo EFV (2247 ± 648, p<0.01). Nossos resultados mostram que insuficiência renal ocorreu em 58% dos pacientes tratados com IDV e foi associada com menor peso corpóreo e uso de derivados de sulfa. A menor excreção urinária de NO3- e as alterações na osmolaridade e FEH2O sugerem que o IDV diminui a produção de óxido nítrico e causa dano tubular, respectivamente. Sugerimos então que os pacientes em uso de IDV sejam monitorados routineiramente para função renal através do clearance de creatinina.
Renal and urological complications including nephrolithiasis, crystalluria, renal colic and flank pain are significant side effects of the HIV protease inhibitor indinavir (IDV), and IDV has been widely used in the treatment of human immunodeficiency virus (HIV) infection. Previous studies in rats demonstrated that IDV, a potent protease inhibitor that causes profound and sustained supression of HIV replication, also induces renal vasoconstriction, decreases glomerular filtration rate (GFR) and reduces urinary excretion of nitrite (NO2-), suggesting that IDV-vasoconstriction may be mediated by nitric oxide (NO). The objectives of this study were to investigate the occurrence of renal failure (creatinine clearance <80ml/min) in human HIV patients treated with highy active antiretroviral therapy (HAART), including IDV, and to measure urinary excretion of nitrate (NO3-) in those patients, comparing it with that of another group of patients treated with the non-nucleoside reverse-transcriptase inhibitor efavirenz (EFV). From March 2000 through October 2003, we evaluated 36 patients infected with HIV who was receiving IDV 800 mg q8h for at least 12 months. The patients were assessed for a variety of clinical and laboratory parameters including age, body weight, duration of infection, time of IDV treatment, trimethoprim/sulfamethoxazole (TMP/SMX) or sulfadiazine use, biochemistry (total cholesterol, triglycerides, magnesium, sodium, potassium and creatinine), urinalysis, creatinine clearance, urine osmolality, 24-hour urine volume, fractional excretion of sodium (FENa), potassium (FEK) and water (FEH2O). Urinary NO3 was measured in 18 IDV-treated patients and compared with that of 8 EFV-treated patients. Leukocyturia occurred in 78.8% of the IDV-treated patients. Reduced creatinine clearance was observed in 21 patients and was associated with lower body weight and sulfa-derivated use. In these renal failure patients, we also detected a lower osmolality and a higher FEH2O. Excretion of NO3- was significantly lower in IDV-treated patients (908 ± 181) than in EFV-treated patients (2247 ± 648, p<0.01). Our data show that renal failure occurred in 58% of IDV-treated patients and was associated with lower body weight and sulfa administration. The lower NO3- excretion suggests that this drug decreases nitric oxide production, and the alterations in osmolality and FEH2O indicate that it also causes tubular damage. Based on our findings, we suggest that the renal function of patients under IDV treatment should be closely monitored with creatinine clearance.

Abstract:

Abstract of thesis submitted in partial fulfilment of the requirements for the Degree of Master of Commerce and Management Dynamics of macroeconomic variables in Fiji : a cointegrated VAR analysis By Shiu Raj Singh The objective of this study is to examine how macroeconomic variables of Fiji inter-relate with aggregate demand and co-determine one another using a vector autoregression (VAR) approach. This study did not use a prior theoretical framework but instead used economic justification for selection of variables. It was found that fiscal policy, which is generally used as a stabilisation tool, did not have a positive effect on real Gross Domestic Product (GDP) growth in the short term. Effects on GDP growth were positive over the long term but not statistically significant. Furthermore, expansionary fiscal policy caused inflationary pressures. Fiji has a fixed exchange rate regime, therefore, it was expected that the focus of monetary policy would be the maintenance of foreign reserves. It was, however, found that monetary expansion in the short term resulted in positive effects on real GDP growth and resulted in inflation. The long term effects of monetary policy on real GDP growth were negative, which are explained by the fixed exchange rate regime, endogenous determination of money supply by the central bank, an unsophisticated financial market and, perhaps, an incomplete transmission of the policy. Both merchandise trade and visitor arrivals growth were found to positively contribute to short term and long term economic growth. Political instability was found not to have significant direct effects on real GDP growth but caused a significant decline in visitor arrivals which then negatively affected economic growth in the short term.

Abstract:

Trotz Fortschritte in den letzten Dekaden ist das Langzeitüberleben von Nierentransplantaten unzureichend. Die Personalisierung der Behandlung kann dabei zu erheblichen Verbesserungen führen. Vor diesem Hintergrund wurde eine Kohorte von 587 Patienten im ersten Jahr nach der Transplantation untersucht und ein breites Spektrum von Markern zur langfristigen Prognose etabliert. In dieser Dissertation beschreibe ich in vier Manuskripten und zwei Kapiteln meine Arbeit zur personalisierten Transplantationsmedizin. Der klinische Verlauf von Patienten nach Nierentransplantation wurde untersucht. Die wichtigen Komplikationen standen im Vordergrund: Virusreaktivierungen – insbesondere die BK- und Cytomegalieviren – und akute Abstoßung. Folgende Analysen wurden durchgeführt: (i) Systematische Analyse der Assoziationen zwischen Virusreaktivierungen und deren Einfluss auf das Transplantationsergebnis; (ii) Bewertung der Auswirkungen antiviraler Behandlungsstrategien auf die Transplantationsergebnisse; (iii) Entwicklung eines Tools zur Prätransplantations-Risikoeinschätzung der Abstoßung und (iv) Erstellung eines mathematischen Modells für die personalisierte Charakterisierung der Immunantwort gegen das BK-Virus. Zusammengenommen haben die vier Studien das Potenzial, (i) die Patientenversorgung zu verbessern, (ii) die Überwachung von Virusreaktivierungen zu optimieren, (iii) Präventionsstrategien gegen virale Reaktivierungen zu stratifizieren, (iv) die Behandlung der Patienten an das individuelle Risiko akuter Abstoßung anzupassen, und (v) zur Personalisierung der Immuntherapie beizutragen. Die Studien zeigen, wie das große Datenvolumen einer klinischen Studie zur Weiterentwicklung der personalisierten Medizin unter Einsatz effektiver Strategien für Datenmanagement, Analyse und Interpretation genutzt werden kann. Es ist zu erwarten, dass diese Ergebnisse die klinische Praxis beeinflussen und so das langfristige Überleben und die Lebensqualität der Patienten verbessern.
In spite of the developments in the last decades, long-term graft survival rates in kidney transplantation are still poor: Personalization of treatment can thereby lead to a drastic improvement in long-term outcomes. With this goal, a cohort of 587 patients was characterized for a wide range of markers during the first post-transplantation year to assess their long-term prognosis. Here, I describe along four manuscripts and two chapters my work on personalized medicine for renal transplantation.In detail, we have studied the clinical evolution of patients with emphasis on two most relevant complications: viral reactivations – particularly those of BK virus and cytomegalovirus – and acute rejection. We have analysed in depth these phenomena by (i) exhaustively analysing the associations between different viral reactivations and their influence on transplantation outcome, (ii) evaluating the effects of antiviral treatment strategies on viral reactivation and other transplantation outcomes with emphasis on sex-associated differences, (iii) developing a tool for the pre-transplantation risk assessment of acute cellular rejection, and (iv) creating a mathematical model for the personalized characterization of the immune response against the BK virus under immunosuppression. Taken together, these studies have the potential of improving patient care, optimizing monitoring of viral reactivations, stratifying antiviral prevention strategies, tailoring immunosuppression and monitoring to the individual risk of acute rejection, and contributing to personalization of immunotherapy. They demonstrate how the large volume of data obtained within a clinical study can be employed to further the development of personalized medicine, employing effective data management, analysis and interpretation strategies. We expect these results to eventually inform clinical practice, thereby improving long-term survival and quality of life after kidney transplantation.

Abstract:

The purpose of this bachelor thesis is to investigate how an ideal job applicant is described when searching real estate janitors and real estate managers in job advertising using a Swedish linguistic perspective. This is achieved by looking at how the model reader is constructed i.e. if the ways to describe the two occupational groups differ, if the descriptions tend to include or exclude groups of applicants, and if and how a relationship is created between the employer and the recipient and if so what kind of relationship. The material consists of ten job advertisem*nts where the employer is looking for real estate janitors and ten job advertisem*nts where the employer is looking for real estate managers. The choice of method for the study is systemic functional grammar, critical discourse analysis and gender coding. Theoretically I also start from the systemic functional grammar and the critical discourse analysis, though with an emancipatory approach. The descriptions of the dream candidates that is created in the ads differ between the two occupations. Real estate janitor is a job which requires more practical skills, while the job as a manager requires more theoretical skills. The ideal real estate janitor has equal numbers of masculine and feminine qualities. The dream candidate is self-propelled, service-oriented and is able to plan the working day in an efficient way. Since the employer seems to have a dominant attitude towards the janitor their relationship tends to not be very close. The ideal dream candidate created for real estate managers is also very self-sufficient, but he or she also has a strong internal drive and likes to run projects in combination with a strong sense of responsibility. The ideal real estate manager has a little more feminine than masculine qualities. The relationship between the employer and the ideal real estate manager is more symmetrical than the relationship that is constructed with the ideal real estate manager.

Abstract:

This thesis is composed of three chapters that propose some novel approaches on tail risk for financial market and forecasting in finance and macroeconomics. The first part of this dissertation focuses on financial market correlations and introduces a simple measure of tail correlation, TailCoR, while the second contribution addresses the issue of identification of non- normal structural shocks in Vector Autoregression which is common on finance. The third part belongs to the vast literature on predictions of economic growth; the problem is tackled using a Bayesian Dynamic Factor model to predict Norwegian GDP.Chapter I: TailCoRThe first chapter introduces a simple measure of tail correlation, TailCoR, which disentangles linear and non linear correlation. The aim is to capture all features of financial market co- movement when extreme events (i.e. financial crises) occur. Indeed, tail correlations may arise because asset prices are either linearly correlated (i.e. the Pearson correlations are different from zero) or non-linearly correlated, meaning that asset prices are dependent at the tail of the distribution.Since it is based on quantiles, TailCoR has three main advantages: i) it is not based on asymptotic arguments, ii) it is very general as it applies with no specific distributional assumption, and iii) it is simple to use. We show that TailCoR also disentangles easily between linear and non-linear correlations. The measure has been successfully tested on simulated data. Several extensions, useful for practitioners, are presented like downside and upside tail correlations.In our empirical analysis, we apply this measure to eight major US banks for the period 2003-2012. For comparison purposes, we compute the upper and lower exceedance correlations and the parametric and non-parametric tail dependence coefficients. On the overall sample, results show that both the linear and non-linear contributions are relevant. The results suggest that co-movement increases during the financial crisis because of both the linear and non- linear correlations. Furthermore, the increase of TailCoR at the end of 2012 is mostly driven by the non-linearity, reflecting the risks of tail events and their spillovers associated with the European sovereign debt crisis. Chapter II: On the identification of non-normal shocks in structural VARThe second chapter deals with the structural interpretation of the VAR using the statistical properties of the innovation terms. In general, financial markets are characterized by non- normal shocks. Under non-Gaussianity, we introduce a methodology based on the reduction of tail dependency to identify the non-normal structural shocks.Borrowing from statistics, the methodology can be summarized in two main steps: i) decor- relate the estimated residuals and ii) the uncorrelated residuals are rotated in order to get a vector of independent shocks using a tail dependency matrix. We do not label the shocks a priori, but post-estimate on the basis of economic judgement.Furthermore, we show how our approach allows to identify all the shocks using a Monte Carlo study. In some cases, the method can turn out to be more significant when the amount of tail events are relevant. Therefore, the frequency of the series and the degree of non-normality are relevant to achieve accurate identification.Finally, we apply our method to two different VAR, all estimated on US data: i) a monthly trivariate model which studies the effects of oil market shocks, and finally ii) a VAR that focuses on the interaction between monetary policy and the stock market. In the first case, we validate the results obtained in the economic literature. In the second case, we cannot confirm the validity of an identification scheme based on combination of short and long run restrictions which is used in part of the empirical literature.Chapter III :Nowcasting NorwayThe third chapter consists in predictions of Norwegian Mainland GDP. Policy institutions have to decide to set their policies without knowledge of the current economic conditions. We estimate a Bayesian dynamic factor model (BDFM) on a panel of macroeconomic variables (all followed by market operators) from 1990 until 2011.First, the BDFM is an extension to the Bayesian framework of the dynamic factor model (DFM). The difference is that, compared with a DFM, there is more dynamics in the BDFM introduced in order to accommodate the dynamic heterogeneity of different variables. How- ever, in order to introduce more dynamics, the BDFM requires to estimate a large number of parameters, which can easily lead to volatile predictions due to estimation uncertainty. This is why the model is estimated with Bayesian methods, which, by shrinking the factor model toward a simple naive prior model, are able to limit estimation uncertainty.The second aspect is the use of a small dataset. A common feature of the literature on DFM is the use of large datasets. However, there is a literature that has shown how, for the purpose of forecasting, DFMs can be estimated on a small number of appropriately selected variables.Finally, through a pseudo real-time exercise, we show that the BDFM performs well both in terms of point forecast, and in terms of density forecasts. Results indicate that our model outperforms standard univariate benchmark models, that it performs as well as the Bloomberg Survey, and that it outperforms the predictions published by the Norges Bank in its monetary policy report.
Doctorat en Sciences économiques et de gestion
info:eu-repo/semantics/nonPublished

Abstract:

Obwohl der Wildtyp des Hepatitis-B-Virus (HBV) nicht zytopathogen und die Pathogenese der Hepatitis B generell immunvermittelt ist, können in immunsupprimierten Nierentransplantatempfängern mit chronischer Hepatitis B schwere Leberschäden bis hin zu Leberzirrhose und Leberversagen entstehen. Die Entwicklung von Leberzirrhose in den Nierentransplantierten ist assoziiert mit der Akkumulation und Persistenz von komplexen HBV-Varianten mit Mutationen im Core-Promotor / X-Gen, Deletionen im Core (C)-Gen und teilweise zusätzlichen Deletionen im präS-Bereich. Dies lässt eine Rolle der Varianten in der speziellen Pathogenese bei Immunsupprimierten vermuten. In der vorliegenden Arbeit wurden funktionelle Analysen der komplexen Varianten im Vergleich zu Referenz-Wildtypgenomen und Wildtyp-ähnlichen Genomen der Patienten aus der frühen Infektionsphase durchgeführt, um Hinweise auf den potentiellen Beitrag der Varianten zur Pathogenese zu erlangen. Die Analysen erfolgten durch transiente Transfektion der humanen Hepatomazelllinie HuH7 mit repräsentativen HBV-Gesamtgenomen, die aus 2 Patienten während des Krankheitsverlaufs von einer asymptomatischen Infektion hin zur Leberzirrhose isoliert und kloniert worden waren. Trotz einiger Unterschiede im Detail wiesen die komplexen Varianten einen gemeinsamen, drastisch vom Wildtyp abweichenden Phänotyp auf. Dieser war gekennzeichnet durch eine veränderte Transkription mit reduzierten präC- und Oberflächen-mRNAs und verstärkter Expression der prägenomischen RNA, eine starke Reduktion des häufigsten Spleißprodukts der prägenomischen RNA, SP1, eine extrem reduzierte oder fehlende Expression und/oder Sekretion aller Oberflächenproteine und des HBeAg, ein verändertes intrazelluläres Verteilungsmuster des schwach exprimierten Core-Proteins und teilweise der Oberflächenproteine sowie eine erhöhte Replikation und Anreicherung gegenüber Wildtyp-HBV aufgrund einer verstärkten reversen Transkription der prägenomischen RNA. Dieser Phänotyp basierte zum Teil auf den Mutationen in Core-Promotor und C-Gen, wurde jedoch deutlich durch zusätzliche Mutationen in den übrigen Genomabschnitten beeinflusst. Die vielfältigen Veränderungen der Varianten unterstützen ihren vermuteten Beitrag zur Pathogenese.
Although wild-type hepatitis B virus is not cytopathogenic and the pathogenesis of hepatitis B is generally immune mediated, also immuno-suppressed patients, such as renal transplant recipients, with chronic hepatitis B may develop liver cirrhosis and end-stage liver disease. In renal transplant recipients, the development of liver cirrhosis is associated with the accumulation and persistence of complex HBV variants with mutations in core promoter / X gene, deletions in core (C) gene and sometimes additional deletions in the preS region. This suggests a role of these variants in the special pathogenesis in immuno-suppressed patients. In the present work, the complex variants were functionally analyzed in comparison to reference wild-type genomes and wild-type-like HBV genomes from the early asymptomatic phase of infection. For the analyses, representative cloned full-length HBV genomes isolated from 2 patients before and during liver cirrhosis were transiently transfected into the human hepatoma cell line HuH7. In spite of some variations, the complex variants showed a common phenotype, which was drastically altered compared to wild-type. It was characterized by reduced preC and surface mRNAs and increased expression of pregenomic RNA, by a strong reduction of the major spliced pregenomic RNA, SP1, by a partial or complete defect in expression and/or secretion of surface proteins and HBeAg, by an aberrant intracellular localization of the weakly expressed core protein and in some cases of the surface proteins, and by an enhanced replication and enrichment over wild-type HBV due to an enhanced reverse transcription of variant pregenomic RNA. The phenotypic alterations were often based on the mutations in core promoter and C gene but were considerably influenced by the additional mutations in other genomic regions. The multiple functional changes of the variants support their assumed contribution to pathogenesis.

Abstract:

FIP=Factory Instrumentation Protocol. On réalise un circuit intégré de communication pour le réseau FIP, projet national de communication entre automates réflexes, capteurs et actionneurs. Le circuit intégré est spécifié pour permettre soit la connexion de capteurs simples, soit la connexion de capteurs intelligents ou des automates de réseau. La conception de ce circuit intégré «à la demande» résulte d'une méthodologie originale. Cette méthodologie est orientée vers la conception de circuits VLSI de communication à partir d'une bibliothèque d'opérateurs flexibles, d'une part pour réduire le temps de conception, d'autre part pour donner la possibilité aux ingénieurs non spécialistes en conception de concevoir eux-mêmes leur circuit

Abstract:

Dans cette thèse sont montrés des développements de l'approximation de la phase aléatoire (RPA) dans le contexte de théories à séparation de portée. On présente des travaux sur le formalisme de la RPA en général, et en particulier sur le formalisme "matrice diélectrique" qui est exploré de manière systématique. On montre un résumé d'un travail sur les équations RPA dans le contexte d'orbitales localisées, notamment des développements des orbitales virtuelles localisées que sont les "orbitales oscillantes projetées" (POO). Un programme a été écrit pour calculer des fonctions telles que le trou de d'échange, la fonction de réponse, etc... sur des grilles de l'espace réel (grilles parallélépipédiques ou de type "DFT"). On montre certaines de ces visualisations. Dans l'espace réel, on expose une adaptation de l'approximation du dénominateur effectif (EED), développée originellement dans l'espace réciproque en physique du solide. Également, les gradients analytiques des énergies de corrélation RPA dans le contexte de la séparation de portée sont dérivés. Le formalisme développé ici à l'aide d'un lagrangien permet une dérivation tout-en-un des termes courte- et longue-portée qui émergent dans les expressions du gradient, et qui montrent un parallèle intéressant. Des applications sont montrées, telles que des optimisations de géométries aux niveaux RSH-dRPA-I et RSH-SOSEX d'un ensemble de 16 petites molécules, ou encore le calcul et la visualisation des densités corrélées au niveau RSH-dRPA-I
In this thesis are shown developments in the random phase approximation (RPA) in the context of range-separated theories. We present advances in the formalism of the RPA in general, and particularly in the "dielectric matrix" formulation of RPA, which is explored in details. We show a summary of a work on the RPA equations with localized orbitals, especially developments of the virtual localized orbitals that are the "projected oscillatory orbitals" (POO). A program has been written to calculate functions such as the exchange hole, the response function, etc... on real space grid (parallelepipedic or of the "DFT" type) ; some of those visualizations are shown here. In the real space, we offer an adaptation of the effective energy denominator approximation (EED), originally developed in the reciprocal space in solid physics. The analytical gradients of the RPA correlation energies in the context of range separation has been derived. The formalism developed here with a Lagrangian allows an all-in-one derivation of the short- and long-range terms that emerge in the expressions of the gradient. These terms show interesting parallels. Geometry optimizations at the RSH-dRPA-I and RSH-SOSEX levels on a set of 16 molecules are shown, as well as calculations and visualizations of correlated densities at the RSH-dRPA-I level