Comparative analysis of the transcriptome across distant species.

The transcriptome is the readout of the genome. Identifying common features in it across distant species can reveal fundamental principles. To this end, the ENCODE and modENCODE consortia have generated large amounts of matched RNA-sequencing data for human, worm and fly. Uniform processing and comprehensive annotation of these data allow comparison across metazoan phyla, extending beyond earlier within-phylum transcriptome comparisons and revealing ancient, conserved features. Specifically, we discover co-expression modules shared across animals, many of which are enriched in developmental genes. Moreover, we use expression patterns to align the stages in worm and fly development and find a novel pairing between worm embryo and fly pupae, in addition to the embryo-to-embryo and larvae-to-larvae pairings. Furthermore, we find that the extent of non-canonical, non-coding transcription is similar in each organism, per base pair. Finally, we find in all three organisms that the gene-expression levels, both coding and non-coding, can be quantitatively predicted from chromatin features at the promoter using a 'universal model' based on a single set of organism-independent parameters.

Arvonmääritysmallin kehittäminen sijoittajan näkökulmasta: Case F-secure

Työn tavoitteena on kehittää Microsoft Excel -taulukkolaskentaohjelmaan pohjautuva arvonmääritysmalli. Mallin avulla osaketutkimusta tekevät analyytikot ja sijoittajat voivat määrittää osakkeen fundamenttiarvon. Malli kehitetään erityisesti piensijoittajien työkaluksi. Työn toisena tavoitteena on soveltaa kehitettyä arvonmääritysmallia case-yrityksenä toimivan F-Securen arvonmäärityksessä ja selvittää mallin avulla onko F-Securen osake pörssissä fundamentteihin nähden oikein hinnoiteltu. Työn teoriaosassa esitellään arvonmäärityksen käyttökohteet ja historia, arvonmääritysprosessin vaiheet (strateginen analyysi, tilinpäätösanalyysi, tulevaisuuden ennakointi, yrityksen arvon laskeminen), pääoman kustannuksen määrittäminen ja sijoittajan eri arvonmääritysmenetelmät, joita ovat diskontattuun kassavirtaan perustuvassa arvonmäärityksessä käytettävät mallit sekä suhteellisen arvonmäärityksentunnusluvut. Empiirinen osa käsittää arvonmääritysmallin kehittämisen ja rakenteen kuvauksen sekä F-Securen arvonmääritysprosessin. Vaikka F-Securen tulevaisuus näyttää varsin valoisalta, osake on hinnoiteltu markkinoilla tällä hetkellä(23.02.2006) korkeammalle kuin näihin odotuksiin nähden olisi järkevää. Eri menetelmät antavat osakkeelle arvoja 2,25 euron ja 2,97 euron väliltä. Kehitetty Excel -malli määrittää F-Securen osakkeen tavoitehinnaksi eri menetelmien mediaanina 2,29 euroa. Tutkimuksen tuloksena F-Securen osaketta voidaan pitää yliarvostettuna, sillä sen hinta pörssissä on 3,05 euroa.

Organisaation asiakkuusosaamisen hallinta

Tutkielmassa tutkittiin organisaation asiakkuusosaamista suomalaisessa erikoistavarakaupassa. Tutkielman tärkeimpänä tavoitteena oli selvittää,mitä asiakkuusosaamisen hallinta on? Tutkimuksen tavoitteena oli myös luoda tutkimuksen case organisaatiolle asiakkuusosaamisen hallinnan malli. Tutkimuksen teoreettisessa osassa yhdistettiin sekä asiakaslähtöisen organisaation (customer orientation) että osaamisen johtamisen (competence-based management) keskustelujen piirissä syntyneitä teorioita ja malleja. Tutkimuksen teoreettisen viitekehyksen perusteella asiakkuusosaaminen koostuu asiakasorientaatiosta, asiakaskonfiguraatiosta ja asiakasinformaatiosta.Asiakkuusosaamisen hallinta puolestaan muodostuu asiakkuusosaamisen hyödyntämisestä, mittaamisesta ja rakentamisesta. Empiirinen tutkimus toteutettiin kvalitatiivisella teemahaastattelumenetelmällä. Tutkimuksen empiirisen osan tavoitteena oli selvittää kohdeorganisaation asiakkuusosaamisen tilaa ja käytössä olevia asiakkuusosaamisen hallinnan menetelmiä. Näistä menetelmistä keskeisimmät olivat asiakkuusosaamisen rakentamisen osalta ihmisten jatkuva kouluttaminen ja työssäoppiminen ja asiakkuusosaamisen hyödyntämisen osalta esimiestyön kehittäminen ja projektiorganisaation käyttäminen. Empiirisen tutkimuksen ja teoreettisen viitekehyksen avulla tutkimuksen case-organisaatiolle luotiin asiakkuusosaamisen hallinnan malli, jonka lähtökohtana on yrityksen asiakkuusstrategiat. Tämä malli koostuu organisaation systeemisestä kehittämisestä, asiakkuusprosessin kehittämisestä ja asiakkuusosaamisen hyödyntämisestä, mittaamisesta ja rakentamisesta osana käytännön työtä.

Brain surface non-rigid registration in auditory processing

Résumé: Le développement rapide de nouvelles technologies comme l'imagerie médicale a permis l'expansion des études sur les fonctions cérébrales. Le rôle principal des études fonctionnelles cérébrales est de comparer l'activation neuronale entre différents individus. Dans ce contexte, la variabilité anatomique de la taille et de la forme du cerveau pose un problème majeur. Les méthodes actuelles permettent les comparaisons interindividuelles par la normalisation des cerveaux en utilisant un cerveau standard. Les cerveaux standards les plus utilisés actuellement sont le cerveau de Talairach et le cerveau de l'Institut Neurologique de Montréal (MNI) (SPM99). Les méthodes de recalage qui utilisent le cerveau de Talairach, ou celui de MNI, ne sont pas suffisamment précises pour superposer les parties plus variables d'un cortex cérébral (p.ex., le néocortex ou la zone perisylvienne), ainsi que les régions qui ont une asymétrie très importante entre les deux hémisphères. Le but de ce projet est d'évaluer une nouvelle technique de traitement d'images basée sur le recalage non-rigide et utilisant les repères anatomiques. Tout d'abord, nous devons identifier et extraire les structures anatomiques (les repères anatomiques) dans le cerveau à déformer et celui de référence. La correspondance entre ces deux jeux de repères nous permet de déterminer en 3D la déformation appropriée. Pour les repères anatomiques, nous utilisons six points de contrôle qui sont situés : un sur le gyrus de Heschl, un sur la zone motrice de la main et le dernier sur la fissure sylvienne, bilatéralement. Evaluation de notre programme de recalage est accomplie sur les images d'IRM et d'IRMf de neuf sujets parmi dix-huit qui ont participés dans une étude précédente de Maeder et al. Le résultat sur les images anatomiques, IRM, montre le déplacement des repères anatomiques du cerveau à déformer à la position des repères anatomiques de cerveau de référence. La distance du cerveau à déformer par rapport au cerveau de référence diminue après le recalage. Le recalage des images fonctionnelles, IRMf, ne montre pas de variation significative. Le petit nombre de repères, six points de contrôle, n'est pas suffisant pour produire les modifications des cartes statistiques. Cette thèse ouvre la voie à une nouvelle technique de recalage du cortex cérébral dont la direction principale est le recalage de plusieurs points représentant un sillon cérébral. Abstract : The fast development of new technologies such as digital medical imaging brought to the expansion of brain functional studies. One of the methodolgical key issue in brain functional studies is to compare neuronal activation between individuals. In this context, the great variability of brain size and shape is a major problem. Current methods allow inter-individual comparisions by means of normalisation of subjects' brains in relation to a standard brain. A largerly used standard brains are the proportional grid of Talairach and Tournoux and the Montreal Neurological Insititute standard brain (SPM99). However, there is a lack of more precise methods for the superposition of more variable portions of the cerebral cortex (e.g, neocrotex and perisyvlian zone) and in brain regions highly asymmetric between the two cerebral hemipsheres (e.g. planum termporale). The aim of this thesis is to evaluate a new image processing technique based on non-linear model-based registration. Contrary to the intensity-based, model-based registration uses spatial and not intensitiy information to fit one image to another. We extract identifiable anatomical features (point landmarks) in both deforming and target images and by their correspondence we determine the appropriate deformation in 3D. As landmarks, we use six control points that are situated: one on the Heschl'y Gyrus, one on the motor hand area, and one on the sylvian fissure, bilaterally. The evaluation of this model-based approach is performed on MRI and fMRI images of nine of eighteen subjects participating in the Maeder et al. study. Results on anatomical, i.e. MRI, images, show the mouvement of the deforming brain control points to the location of the reference brain control points. The distance of the deforming brain to the reference brain is smallest after the registration compared to the distance before the registration. Registration of functional images, i.e fMRI, doesn't show a significant variation. The small number of registration landmarks, i.e. six, is obvious not sufficient to produce significant modification on the fMRI statistical maps. This thesis opens the way to a new computation technique for cortex registration in which the main directions will be improvement of the registation algorithm, using not only one point as landmark, but many points, representing one particular sulcus.

Artificially Intelligent and Adaptive Methods for Prediction and Analysis of Superheater Fireside Corrosion in Fluidized Bed Boilers

Superheater corrosion causes vast annual losses for the power companies. With a reliable corrosion prediction method, the plants can be designed accordingly, and knowledge of fuel selection and determination of process conditions may be utilized to minimize superheater corrosion. Growing interest to use recycled fuels creates additional demands for the prediction of corrosion potential. Models depending on corrosion theories will fail, if relations between the inputs and the output are poorly known. A prediction model based on fuzzy logic and an artificial neural network is able to improve its performance as the amount of data increases. The corrosion rate of a superheater material can most reliably be detected with a test done in a test combustor or in a commercial boiler. The steel samples can be located in a special, temperature-controlled probe, and exposed to the corrosive environment for a desired time. These tests give information about the average corrosion potential in that environment. Samples may also be cut from superheaters during shutdowns. The analysis ofsamples taken from probes or superheaters after exposure to corrosive environment is a demanding task: if the corrosive contaminants can be reliably analyzed, the corrosion chemistry can be determined, and an estimate of the material lifetime can be given. In cases where the reason for corrosion is not clear, the determination of the corrosion chemistry and the lifetime estimation is more demanding. In order to provide a laboratory tool for the analysis and prediction, a newapproach was chosen. During this study, the following tools were generated: · Amodel for the prediction of superheater fireside corrosion, based on fuzzy logic and an artificial neural network, build upon a corrosion database developed offuel and bed material analyses, and measured corrosion data. The developed model predicts superheater corrosion with high accuracy at the early stages of a project. · An adaptive corrosion analysis tool based on image analysis, constructedas an expert system. This system utilizes implementation of user-defined algorithms, which allows the development of an artificially intelligent system for thetask. According to the results of the analyses, several new rules were developed for the determination of the degree and type of corrosion. By combining these two tools, a user-friendly expert system for the prediction and analyses of superheater fireside corrosion was developed. This tool may also be used for the minimization of corrosion risks by the design of fluidized bed boilers.

Stratification of the severity of critically ill patients with classification trees

Background: Development of three classification trees (CT) based on the CART (Classification and Regression Trees), CHAID (Chi-Square Automatic Interaction Detection) and C4.5 methodologies for the calculation of probability of hospital mortality; the comparison of the results with the APACHE II, SAPS II and MPM II-24 scores, and with a model based on multiple logistic regression (LR). Methods: Retrospective study of 2864 patients. Random partition (70:30) into a Development Set (DS) n = 1808 and Validation Set (VS) n = 808. Their properties of discrimination are compared with the ROC curve (AUC CI 95%), Percent of correct classification (PCC CI 95%); and the calibration with the Calibration Curve and the Standardized Mortality Ratio (SMR CI 95%). Results: CTs are produced with a different selection of variables and decision rules: CART (5 variables and 8 decision rules), CHAID (7 variables and 15 rules) and C4.5 (6 variables and 10 rules). The common variables were: inotropic therapy, Glasgow, age, (A-a)O2 gradient and antecedent of chronic illness. In VS: all the models achieved acceptable discrimination with AUC above 0.7. CT: CART (0.75(0.71-0.81)), CHAID (0.76(0.72-0.79)) and C4.5 (0.76(0.73-0.80)). PCC: CART (72(69- 75)), CHAID (72(69-75)) and C4.5 (76(73-79)). Calibration (SMR) better in the CT: CART (1.04(0.95-1.31)), CHAID (1.06(0.97-1.15) and C4.5 (1.08(0.98-1.16)). Conclusion: With different methodologies of CTs, trees are generated with different selection of variables and decision rules. The CTs are easy to interpret, and they stratify the risk of hospital mortality. The CTs should be taken into account for the classification of the prognosis of critically ill patients.

Design and implementation of FPGA-based LQ control of active magnetic bearings

The need for high performance, high precision, and energy saving in rotating machinery demands an alternative solution to traditional bearings. Because of the contactless operation principle, the rotating machines employing active magnetic bearings (AMBs) provide many advantages over the traditional ones. The advantages such as contamination-free operation, low maintenance costs, high rotational speeds, low parasitic losses, programmable stiffness and damping, and vibration insulation come at expense of high cost, and complex technical solution. All these properties make the use of AMBs appropriate primarily for specific and highly demanding applications. High performance and high precision control requires model-based control methods and accurate models of the flexible rotor. In turn, complex models lead to high-order controllers and feature considerable computational burden. Fortunately, in the last few years the advancements in signal processing devices provide new perspective on the real-time control of AMBs. The design and the real-time digital implementation of the high-order LQ controllers, which focus on fast execution times, are the subjects of this work. In particular, the control design and implementation in the field programmable gate array (FPGA) circuits are investigated. The optimal design is guided by the physical constraints of the system for selecting the optimal weighting matrices. The plant model is complemented by augmenting appropriate disturbance models. The compensation of the force-field nonlinearities is proposed for decreasing the uncertainty of the actuator. A disturbance-observer-based unbalance compensation for canceling the magnetic force vibrations or vibrations in the measured positions is presented. The theoretical studies are verified by the practical experiments utilizing a custom-built laboratory test rig. The test rig uses a prototyping control platform developed in the scope of this work. To sum up, the work makes a step in the direction of an embedded single-chip FPGA-based controller of AMBs.

Advances in apple culture worldwide

Over the last 60 years, planting densities for apple have increased as improved management systems have been developed. Dwarfing rootstocks have been the key to the dramatic changes in tree size, spacing and early production. The Malling series of dwarfing rootstocks (M.9 and M.26) have been the most important dwarfing rootstocks in the world but are poorly adapted in some areas of the world and they are susceptible to the bacterial disease fire blight and the soil disease complex, apple replant disease which limits their uses in some areas. Rootstock breeding programs in several parts of the world are developing improved rootstocks with resistance to fire blight, and replant disease, and improved cold hardiness and yield efficiency. A second important trend has been the increasing importance of new cultivars. New cultivars have provided opportunities for higher prices until they are over-produced. A new trend is the "variety club" in which variety owners manage the production and marketing of a new unique cultivar to bring higher prices to the growers and variety owners. This has led to many fruit growers being unable to plant or grow some new cultivars. Important rootstock and cultivar genes have been mapped and can be used in marker assisted selection of future rootstock and cultivar selections. Other important improvements in apple culture include the development of pre-formed trees, the development of minimal pruning strategies and limb angle bending which have also contributed to the dramatic changes in early production in the 2nd-5th years after planting. Studies on light interception and distribution have led to improved tree forms with better fruit quality. Simple pruning strategies and labor positioning platform machines have resulted in partial mechanization of pruning which has reduced management costs. Improved plant growth regulators for thinning and the development of a thinning prediction model based on tree carbohydrate balance have improved the ability to produce the optimum fruit size and crop load. Other new plant growth regulators have also allowed control of shoot growth, control of preharvest fruit drop and control of fruit softening in storage after harvest. As we look to the future, there will be continued incremental improvement in our understanding of plant physiology that will lead to continued incremental improvements in orchard management but there is likely to be dramatic changes in orchard production systems through genomics research and genetic engineering. A greater understanding of the genetic control of dwarfing, precocity, rooting, vegetative growth, flowering, fruit growth and disease resistance which will lead to new varieties and rootstocks which are less expensive to grow and manage.

SAP R/3 -toimimianohjausjärjestelmän käytettävyyden parantaminen metsäteollisuusyrityksessä

Työn tavoitteena on parantaa SAP R/3-järjestelmän käytettävyyttä muutoksenhallintaprosessia mallintamalla. Työn alussa selkeytetään järjestelmän käytön nykytilaa yrityksessä sekä käyttäjien vaatimia parannuskohteita. Työn teoriaosassa käsitellään asiakasnäkökulmasta prosessien kehittämisen sekä niiden mallintamisen teoriaa. Teoriaosassa haetaan vastauksia järjestelmiin liittyviin kysymyksiin: - Kuinka selkeytetään käyttöönottoa sekä hyödynnetään toiminnan prosessilähtöistä kehittämistä? - Kuinka asiakastarpeita kartoittamalla huomioidaan käyttäjien tulevat taipeet? - Miten prosessimallintaminen lisää käyttäjien luottamusta ja yrityksen kilpailukykyä? Soveltavassa osassa tutkitaan vika- ja pienkehityspyyntöjen hallintaa ARIS-mallinnuksen avulla. Toimintoketjun avulla luodaan M-real-konsemissa käyttäjien ja palveluntarjoajan yhteinen toimintamalli. Prosessin omistajuus, käyttäjien liittymäpinta sekä toiminnan organisointi huomioidaan kaikkien osapuolten kesken

Virtauslaskentaa ja energia-analyysiä hyödyntävä huoneilman lämpöolosuhteiden simulointimalli

Huonetilojen lämpöolosuhteiden hallinta on tärkeä osa talotekniikan suunnittelua. Tavallisesti huonetilan lämpöolosuhteita mallinnetaan menetelmillä, joissa lämpödynamiikkaa lasketaan huoneilmassa yhdessä laskentapisteessä ja rakenteissa seinäkohtaisesti. Tarkastelun kohteena on yleensä vain huoneilman lämpötila. Tämän diplomityön tavoitteena oli kehittää huoneilman lämpöolosuhteiden simulointimalli, jossa rakenteiden lämpödynamiikka lasketaan epästationaarisesti energia-analyysilaskennalla ja huoneilman virtauskenttä mallinnetaan valittuna ajanhetkenä stationaarisesti virtauslaskennalla. Tällöin virtauskentälle saadaan jakaumat suunnittelun kannalta olennaisista suureista, joita tyypillisesti ovat esimerkiksi ilman lämpötila ja nopeus. Simulointimallin laskentatuloksia verrattiin testihuonetiloissa tehtyihin mittauksiin. Tulokset osoittautuivat riittävän tarkoiksi talotekniikan suunnitteluun. Mallilla simuloitiin kaksi huonetilaa, joissa tarvittiin tavallista tarkempaa mallinnusta. Vertailulaskelmia tehtiin eri turbulenssimalleilla, diskretointitarkkuuksilla ja hilatiheyksillä. Simulointitulosten havainnollistamiseksi suunniteltiin asiakastuloste, jossa on esitetty suunnittelun kannalta olennaiset asiat. Simulointimallilla saatiin lisätietoa varsinkin lämpötilakerrostumista, joita tyypillisesti on arvioitu kokemukseen perustuen. Simulointimallin kehityksen taustana käsiteltiin rakennusten sisäilmastoa, lämpöolosuhteita ja laskentamenetelmiä sekä mallinnukseen soveltuvia kaupallisia ohjelmia. Simulointimallilla saadaan entistä tarkempaa ja yksityiskohtaisempaa tietoa lämpöolosuhteiden hallinnan suunnitteluun. Mallin käytön ongelmia ovat vielä virtauslaskennan suuri laskenta-aika, turbulenssin mallinnus, tuloilmalaitteiden reunaehtojen tarkka määritys ja laskennan konvergointi. Kehitetty simulointimalli tarjoaa hyvän perustan virtauslaskenta- ja energia-analyysiohjelmien kehittämiseksi ja yhdistämiseksi käyttäjäystävälliseksi talotekniikan suunnittelutyökaluksi.

A microquasar model applied to unidentified gamma-ray sources

Among unidentified gamma-ray sources in the galactic plane, there are some that present significant variability and have been proposed to be high-mass microquasars. To deepen the study of the possible association between variable low galactic latitude gamma-ray sources and microquasars, we have applied a leptonic jet model based on the microquasar scenario that reproduces the gamma-ray spectrum of three unidentified gamma-ray sources, 3EG J1735-1500, 3EG J1828+0142 and GRO J1411-64, and is consistent with the observational constraints at lower energies. We conclude that if these sources were generated by microquasars, the particle acceleration processes could not be as efficient as in other objects of this type that present harder gamma-ray spectra. Moreover, the dominant mechanism of high-energy emission should be synchrotron self-Compton (SSC) scattering, and the radio jets may only be observed at low frequencies. For each particular case, further predictions of jet physical conditions and variability generation mechanisms have been made in the context of the model. Although there might be other candidates able to explain the emission coming from these sources, microquasars cannot be excluded as counterparts. Observations performed by the next generation of gamma-ray instruments, like GLAST, are required to test the proposed model.

Cognitive anatomy of the temporal lobe: Effect of personality in population with mild cognitive impairment & Functional specialization for memory systems in healthy individuals.

Résumé: L'impact de la maladie d'Alzheimer (MA) est dévastateur pour la vie quotidienne de la personne affectée, avec perte progressive de la mémoire et d'autres facultés cognitives jusqu'à la démence. Il n'existe toujours pas de traitement contre cette maladie et il y a aussi une grande incertitude sur le diagnostic des premiers stades de la MA. La signature anatomique de la MA, en particulier l'atrophie du lobe temporal moyen (LTM) mesurée avec la neuroimagerie, peut être utilisée comme un biomarqueur précoce, in vivo, des premiers stades de la MA. Toutefois, malgré le rôle évident du LMT dans les processus de la mémoire, nous savons que les modèles anatomiques prédictifs de la MA basés seulement sur des mesures d'atrophie du LTM n'expliquent pas tous les cas cliniques. Au cours de ma thèse, j'ai conduit trois projets pour comprendre l'anatomie et le fonctionnement du LMT dans (1) les processus de la maladie et dans (2) les processus de mémoire ainsi que (3) ceux de l'apprentissage. Je me suis intéressée à une population avec déficit cognitif léger (« Mild Cognitive Impairment », MCI), à risque pour la MA. Le but du premier projet était de tester l'hypothèse que des facteurs, autres que ceux cognitifs, tels que les traits de personnalité peuvent expliquer les différences interindividuelles dans le LTM. De plus, la diversité phénotypique des manifestations précliniques de la MA provient aussi d'une connaissance limitée des processus de mémoire et d'apprentissage dans le cerveau sain. L'objectif du deuxième projet porte sur l'investigation des sous-régions du LTM, et plus particulièrement de leur contribution dans différentes composantes de la mémoire de reconnaissance chez le sujet sain. Pour étudier cela, j'ai utilisé une nouvelle méthode multivariée ainsi que l'IRM à haute résolution pour tester la contribution de ces sous-régions dans les processus de familiarité (« ou Know ») et de remémoration (ou « Recollection »). Finalement, l'objectif du troisième projet était de tester la contribution du LTM en tant que système de mémoire dans l'apprentissage et l'interaction dynamique entre différents systèmes de mémoire durant l'apprentissage. Les résultats du premier projet montrent que, en plus du déficit cognitif observé dans une population avec MCI, les traits de personnalité peuvent expliquer les différences interindividuelles du LTM ; notamment avec une plus grande contribution du neuroticisme liée à une vulnérabilité au stress et à la dépression. Mon étude a permis d'identifier un pattern d'anormalité anatomique dans le LTM associé à la personnalité avec des mesures de volume et de diffusion moyenne du tissu. Ce pattern est caractérisé par une asymétrie droite-gauche du LTM et un gradient antéro-postérieur dans le LTM. J'ai interprété ce résultat par des propriétés tissulaires et neurochimiques différemment sensibles au stress. Les résultats de mon deuxième projet ont contribué au débat actuel sur la contribution des sous-régions du LTM dans les processus de familiarité et de remémoration. Utilisant une nouvelle méthode multivariée, les résultats supportent premièrement une dissociation des sous-régions associées aux différentes composantes de la mémoire. L'hippocampe est le plus associé à la mémoire de type remémoration et le cortex parahippocampique, à la mémoire de type familiarité. Deuxièmement, l'activation correspondant à la trace mnésique pour chaque type de mémoire est caractérisée par une distribution spatiale distincte. La représentation neuronale spécifique, « sparse-distributed», associée à la mémoire de remémoration dans l'hippocampe serait la meilleure manière d'encoder rapidement des souvenirs détaillés sans interférer les souvenirs précédemment stockés. Dans mon troisième projet, j'ai mis en place une tâche d'apprentissage en IRM fonctionnelle pour étudier les processus d'apprentissage d'associations probabilistes basé sur le feedback/récompense. Cette étude m'a permis de mettre en évidence le rôle du LTM dans l'apprentissage et l'interaction entre différents systèmes de mémoire comme la mémoire procédurale, perceptuelle ou d'amorçage et la mémoire de travail. Nous avons trouvé des activations dans le LTM correspondant à un processus de mémoire épisodique; les ganglions de la base (GB), à la mémoire procédurale et la récompense; le cortex occipito-temporal (OT), à la mémoire de représentation perceptive ou l'amorçage et le cortex préfrontal, à la mémoire de travail. Nous avons également observé que ces régions peuvent interagir; le type de relation entre le LTM et les GB a été interprété comme une compétition, ce qui a déjà été reporté dans des études récentes. De plus, avec un modèle dynamique causal, j'ai démontré l'existence d'une connectivité effective entre des régions. Elle se caractérise par une influence causale de type « top-down » venant de régions corticales associées avec des processus de plus haut niveau venant du cortex préfrontal sur des régions corticales plus primaires comme le OT cortex. Cette influence diminue au cours du de l'apprentissage; cela pourrait correspondre à un mécanisme de diminution de l'erreur de prédiction. Mon interprétation est que cela est à l'origine de la connaissance sémantique. J'ai également montré que les choix du sujet et l'activation cérébrale associée sont influencés par les traits de personnalité et des états affectifs négatifs. Les résultats de cette thèse m'ont amenée à proposer (1) un modèle expliquant les mécanismes possibles liés à l'influence de la personnalité sur le LTM dans une population avec MCI, (2) une dissociation des sous-régions du LTM dans différents types de mémoire et une représentation neuronale spécifique à ces régions. Cela pourrait être une piste pour résoudre les débats actuels sur la mémoire de reconnaissance. Finalement, (3) le LTM est aussi un système de mémoire impliqué dans l'apprentissage et qui peut interagir avec les GB par une compétition. Nous avons aussi mis en évidence une interaction dynamique de type « top -down » et « bottom-up » entre le cortex préfrontal et le cortex OT. En conclusion, les résultats peuvent donner des indices afin de mieux comprendre certains dysfonctionnements de la mémoire liés à l'âge et la maladie d'Alzheimer ainsi qu'à améliorer le développement de traitement. Abstract: The impact of Alzheimer's disease is devastating for the daily life of the affected patients, with progressive loss of memory and other cognitive skills until dementia. We still lack disease modifying treatment and there is also a great amount of uncertainty regarding the accuracy of diagnostic classification in the early stages of AD. The anatomical signature of AD, in particular the medial temporal lobe (MTL) atrophy measured with neuroimaging, can be used as an early in vivo biomarker in early stages of AD. However, despite the evident role of MTL in memory, we know that the derived predictive anatomical model based only on measures of brain atrophy in MTL does not explain all clinical cases. Throughout my thesis, I have conducted three projects to understand the anatomy and the functioning of MTL on (1) disease's progression, (2) memory process and (3) learning process. I was interested in a population with mild cognitive impairment (MCI), at risk for AD. The objective of the first project was to test the hypothesis that factors, other than the cognitive ones, such as the personality traits, can explain inter-individual differences in the MTL. Moreover, the phenotypic diversity in the manifestations of preclinical AD arises also from the limited knowledge of memory and learning processes in healthy brain. The objective of the second project concerns the investigation of sub-regions of the MTL, and more particularly their contributions in the different components of recognition memory in healthy subjects. To study that, I have used a new multivariate method as well as MRI at high resolution to test the contribution of those sub-regions in the processes of familiarity and recollection. Finally, the objective of the third project was to test the contribution of the MTL as a memory system in learning and the dynamic interaction between memory systems during learning. The results of the first project show that, beyond cognitive state of impairment observed in the population with MCI, the personality traits can explain the inter-individual differences in the MTL; notably with a higher contribution of neuroticism linked to proneness to stress and depression. My study has allowed identifying a pattern of anatomical abnormality in the MTL related to personality with measures of volume and mean diffusion of the tissue. That pattern is characterized by right-left asymmetry in MTL and an anterior to posterior gradient within MTL. I have interpreted that result by tissue and neurochemical properties differently sensitive to stress. Results of my second project have contributed to the actual debate on the contribution of MTL sub-regions in the processes of familiarity and recollection. Using a new multivariate method, the results support firstly a dissociation of the subregions associated with different memory components. The hippocampus was mostly associated with recollection and the surrounding parahippocampal cortex, with familiarity type of memory. Secondly, the activation corresponding to the mensic trace for each type of memory is characterized by a distinct spatial distribution. The specific neuronal representation, "sparse-distributed", associated with recollection in the hippocampus would be the best way to rapidly encode detailed memories without overwriting previously stored memories. In the third project, I have created a learning task with functional MRI to sudy the processes of learning of probabilistic associations based on feedback/reward. That study allowed me to highlight the role of the MTL in learning and the interaction between different memory systems such as the procedural memory, the perceptual memory or priming and the working memory. We have found activations in the MTL corresponding to a process of episodic memory; the basal ganglia (BG), to a procedural memory and reward; the occipito-temporal (OT) cortex, to a perceptive memory or priming and the prefrontal cortex, to working memory. We have also observed that those regions can interact; the relation type between the MTL and the BG has been interpreted as a competition. In addition, with a dynamic causal model, I have demonstrated a "top-down" influence from cortical regions associated with high level cortical area such as the prefrontal cortex on lower level cortical regions such as the OT cortex. That influence decreases during learning; that could correspond to a mechanism linked to a diminution of prediction error. My interpretation is that this is at the origin of the semantic knowledge. I have also shown that the subject's choice and the associated brain activation are influenced by personality traits and negative affects. Overall results of this thesis have brought me to propose (1) a model explaining the possible mechanism linked to the influence of personality on the MTL in a population with MCI, (2) a dissociation of MTL sub-regions in different memory types and a neuronal representation specific to each region. This could be a cue to resolve the actual debates on recognition memory. Finally, (3) the MTL is also a system involved in learning and that can interact with the BG by a competition. We have also shown a dynamic interaction of « top -down » and « bottom-up » types between the pre-frontal cortex and the OT cortex. In conclusion, the results could give cues to better understand some memory dysfunctions in aging and Alzheimer's disease and to improve development of treatment.

Consequences of lineage-specific gene loss on functional evolution of surviving paralogs: ALDH1A and retinoic acid signaling in vertebrate genomes

Genome duplications increase genetic diversity and may facilitate the evolution of gene subfunctions. Little attention, however, has focused on the evolutionary impact of lineage-specific gene loss. Here, we show that identifying lineage-specific gene loss after genome duplication is important for understanding the evolution of gene subfunctions in surviving paralogs and for improving functional connectivity among human and model organism genomes. We examine the general principles of gene loss following duplication, coupled with expression analysis of the retinaldehyde dehydrogenase Aldh1a gene family during retinoic acid signaling in eye development as a case study. Humans have three ALDH1A genes, but teleosts have just one or two. We used comparative genomics and conserved syntenies to identify loss of ohnologs (paralogs derived from genome duplication) and to clarify uncertain phylogenies. Analysis showed that Aldh1a1 and Aldh1a2 form a clade that is sister to Aldh1a3-related genes. Genome comparisons showed secondarily loss of aldh1a1 in teleosts, revealing that Aldh1a1 is not a tetrapod innovation and that aldh1a3 was recently lost in medaka, making it the first known vertebrate with a single aldh1a gene. Interestingly, results revealed asymmetric distribution of surviving ohnologs between co-orthologous teleost chromosome segments, suggesting that local genome architecture can influence ohnolog survival. We propose a model that reconstructs the chromosomal history of the Aldh1a family in the ancestral vertebrate genome, coupled with the evolution of gene functions in surviving Aldh1a ohnologs after R1, R2, and R3 genome duplications. Results provide evidence for early subfunctionalization and late subfunction-partitioning and suggest a mechanistic model based on altered regulation leading to heterochronic gene expression to explain the acquisition or modification of subfunctions by surviving ohnologs that preserve unaltered ancestral developmental programs in the face of gene loss.

CFD simulation of complex phenomena containing suspensions and flow throughporous media

There is an increasing reliance on computers to solve complex engineering problems. This is because computers, in addition to supporting the development and implementation of adequate and clear models, can especially minimize the financial support required. The ability of computers to perform complex calculations at high speed has enabled the creation of highly complex systems to model real-world phenomena. The complexity of the fluid dynamics problem makes it difficult or impossible to solve equations of an object in a flow exactly. Approximate solutions can be obtained by construction and measurement of prototypes placed in a flow, or by use of a numerical simulation. Since usage of prototypes can be prohibitively time-consuming and expensive, many have turned to simulations to provide insight during the engineering process. In this case the simulation setup and parameters can be altered much more easily than one could with a real-world experiment. The objective of this research work is to develop numerical models for different suspensions (fiber suspensions, blood flow through microvessels and branching geometries, and magnetic fluids), and also fluid flow through porous media. The models will have merit as a scientific tool and will also have practical application in industries. Most of the numerical simulations were done by the commercial software, Fluent, and user defined functions were added to apply a multiscale method and magnetic field. The results from simulation of fiber suspension can elucidate the physics behind the break up of a fiber floc, opening the possibility for developing a meaningful numerical model of the fiber flow. The simulation of blood movement from an arteriole through a venule via a capillary showed that the model based on VOF can successfully predict the deformation and flow of RBCs in an arteriole. Furthermore, the result corresponds to the experimental observation illustrates that the RBC is deformed during the movement. The concluding remarks presented, provide a correct methodology and a mathematical and numerical framework for the simulation of blood flows in branching. Analysis of ferrofluids simulations indicate that the magnetic Soret effect can be even higher than the conventional one and its strength depends on the strength of magnetic field, confirmed experimentally by Völker and Odenbach. It was also shown that when a magnetic field is perpendicular to the temperature gradient, there will be additional increase in the heat transfer compared to the cases where the magnetic field is parallel to the temperature gradient. In addition, the statistical evaluation (Taguchi technique) on magnetic fluids showed that the temperature and initial concentration of the magnetic phase exert the maximum and minimum contribution to the thermodiffusion, respectively. In the simulation of flow through porous media, dimensionless pressure drop was studied at different Reynolds numbers, based on pore permeability and interstitial fluid velocity. The obtained results agreed well with the correlation of Macdonald et al. (1979) for the range of actual flow Reynolds studied. Furthermore, calculated results for the dispersion coefficients in the cylinder geometry were found to be in agreement with those of Seymour and Callaghan.