Effectiveness of antioxidants in preventing oxidation of palm oil enriched with heme iron: A model for iron fortification in baked products

Bakery products such as biscuits, cookies, and pastries represent a good medium for iron fortification in food products, since they are consumed by a large proportion of the population at risk of developing iron deficiency anemia, mainly children. The drawback, however, is that iron fortification can promote oxidation. To assess the extent of this, palm oil added with heme iron and different antioxidants was used as a model for evaluating the oxidative stability of some bakery products, such as baked goods containing chocolate. The palm oil samples were heated at 220°C for 10 min to mimic the conditions found during a typical baking processing. The selected antioxidants were a free radical scavenger (tocopherol extract (TE), 0 and 500 mg/kg), an oxygen scavenger (ascorbyl palmitate (AP), 0 and 500 mg/kg), and a chelating agent (citric acid (CA), 0 and 300 mg/kg). These antioxidants were combined using a factorial design and were compared to a control sample, which was not supplemented with antioxidants. Primary (peroxide value and lipid hydroperoxide content) and secondary oxidation parameters (p-anisidine value, p-AnV) were monitored over a period of 200 days in storage at room temperature. The combination of AP and CA was the most effective treatment in delaying the onset of oxidation. TE was not effective in preventing oxidation. The p-AnV did not increase during the storage period, indicating that this oxidation marker was not suitable for monitoring oxidation in this model.

Linking landscape- and population ecology for large population management modelling: the case of Ibex (capra ibex) in Switzerland

La biologie de la conservation est communément associée à la protection de petites populations menacées d?extinction. Pourtant, il peut également être nécessaire de soumettre à gestion des populations surabondantes ou susceptibles d?une trop grande expansion, dans le but de prévenir les effets néfastes de la surpopulation. Du fait des différences tant quantitatives que qualitatives entre protection des petites populations et contrôle des grandes, il est nécessaire de disposer de modèles et de méthodes distinctes. L?objectif de ce travail a été de développer des modèles prédictifs de la dynamique des grandes populations, ainsi que des logiciels permettant de calculer les paramètres de ces modèles et de tester des scénarios de gestion. Le cas du Bouquetin des Alpes (Capra ibex ibex) - en forte expansion en Suisse depuis sa réintroduction au début du XXème siècle - servit d?exemple. Cette tâche fut accomplie en trois étapes : En premier lieu, un modèle de dynamique locale, spécifique au Bouquetin, fut développé : le modèle sous-jacent - structuré en classes d?âge et de sexe - est basé sur une matrice de Leslie à laquelle ont été ajoutées la densité-dépendance, la stochasticité environnementale et la chasse de régulation. Ce modèle fut implémenté dans un logiciel d?aide à la gestion - nommé SIM-Ibex - permettant la maintenance de données de recensements, l?estimation automatisée des paramètres, ainsi que l?ajustement et la simulation de stratégies de régulation. Mais la dynamique d?une population est influencée non seulement par des facteurs démographiques, mais aussi par la dispersion et la colonisation de nouveaux espaces. Il est donc nécessaire de pouvoir modéliser tant la qualité de l?habitat que les obstacles à la dispersion. Une collection de logiciels - nommée Biomapper - fut donc développée. Son module central est basé sur l?Analyse Factorielle de la Niche Ecologique (ENFA) dont le principe est de calculer des facteurs de marginalité et de spécialisation de la niche écologique à partir de prédicteurs environnementaux et de données d?observation de l?espèce. Tous les modules de Biomapper sont liés aux Systèmes d?Information Géographiques (SIG) ; ils couvrent toutes les opérations d?importation des données, préparation des prédicteurs, ENFA et calcul de la carte de qualité d?habitat, validation et traitement des résultats ; un module permet également de cartographier les barrières et les corridors de dispersion. Le domaine d?application de l?ENFA fut exploré par le biais d?une distribution d?espèce virtuelle. La comparaison à une méthode couramment utilisée pour construire des cartes de qualité d?habitat, le Modèle Linéaire Généralisé (GLM), montra qu?elle était particulièrement adaptée pour les espèces cryptiques ou en cours d?expansion. Les informations sur la démographie et le paysage furent finalement fusionnées en un modèle global. Une approche basée sur un automate cellulaire fut choisie, tant pour satisfaire aux contraintes du réalisme de la modélisation du paysage qu?à celles imposées par les grandes populations : la zone d?étude est modélisée par un pavage de cellules hexagonales, chacune caractérisée par des propriétés - une capacité de soutien et six taux d?imperméabilité quantifiant les échanges entre cellules adjacentes - et une variable, la densité de la population. Cette dernière varie en fonction de la reproduction et de la survie locale, ainsi que de la dispersion, sous l?influence de la densité-dépendance et de la stochasticité. Un logiciel - nommé HexaSpace - fut développé pour accomplir deux fonctions : 1° Calibrer l?automate sur la base de modèles de dynamique (par ex. calculés par SIM-Ibex) et d?une carte de qualité d?habitat (par ex. calculée par Biomapper). 2° Faire tourner des simulations. Il permet d?étudier l?expansion d?une espèce envahisseuse dans un paysage complexe composé de zones de qualité diverses et comportant des obstacles à la dispersion. Ce modèle fut appliqué à l?histoire de la réintroduction du Bouquetin dans les Alpes bernoises (Suisse). SIM-Ibex est actuellement utilisé par les gestionnaires de la faune et par les inspecteurs du gouvernement pour préparer et contrôler les plans de tir. Biomapper a été appliqué à plusieurs espèces (tant végétales qu?animales) à travers le Monde. De même, même si HexaSpace fut initialement conçu pour des espèces animales terrestres, il pourrait aisément être étndu à la propagation de plantes ou à la dispersion d?animaux volants. Ces logiciels étant conçus pour, à partir de données brutes, construire un modèle réaliste complexe, et du fait qu?ils sont dotés d?une interface d?utilisation intuitive, ils sont susceptibles de nombreuses applications en biologie de la conservation. En outre, ces approches peuvent également s?appliquer à des questions théoriques dans les domaines de l?écologie des populations et du paysage.<br/><br/>Conservation biology is commonly associated to small and endangered population protection. Nevertheless, large or potentially large populations may also need human management to prevent negative effects of overpopulation. As there are both qualitative and quantitative differences between small population protection and large population controlling, distinct methods and models are needed. The aim of this work was to develop theoretical models to predict large population dynamics, as well as computer tools to assess the parameters of these models and to test management scenarios. The alpine Ibex (Capra ibex ibex) - which experienced a spectacular increase since its reintroduction in Switzerland at the beginning of the 20th century - was used as paradigm species. This task was achieved in three steps: A local population dynamics model was first developed specifically for Ibex: the underlying age- and sex-structured model is based on a Leslie matrix approach with addition of density-dependence, environmental stochasticity and culling. This model was implemented into a management-support software - named SIM-Ibex - allowing census data maintenance, parameter automated assessment and culling strategies tuning and simulating. However population dynamics is driven not only by demographic factors, but also by dispersal and colonisation of new areas. Habitat suitability and obstacles modelling had therefore to be addressed. Thus, a software package - named Biomapper - was developed. Its central module is based on the Ecological Niche Factor Analysis (ENFA) whose principle is to compute niche marginality and specialisation factors from a set of environmental predictors and species presence data. All Biomapper modules are linked to Geographic Information Systems (GIS); they cover all operations of data importation, predictor preparation, ENFA and habitat suitability map computation, results validation and further processing; a module also allows mapping of dispersal barriers and corridors. ENFA application domain was then explored by means of a simulated species distribution. It was compared to a common habitat suitability assessing method, the Generalised Linear Model (GLM), and was proven better suited for spreading or cryptic species. Demography and landscape informations were finally merged into a global model. To cope with landscape realism and technical constraints of large population modelling, a cellular automaton approach was chosen: the study area is modelled by a lattice of hexagonal cells, each one characterised by a few fixed properties - a carrying capacity and six impermeability rates quantifying exchanges between adjacent cells - and one variable, population density. The later varies according to local reproduction/survival and dispersal dynamics, modified by density-dependence and stochasticity. A software - named HexaSpace - was developed, which achieves two functions: 1° Calibrating the automaton on the base of local population dynamics models (e.g., computed by SIM-Ibex) and a habitat suitability map (e.g. computed by Biomapper). 2° Running simulations. It allows studying the spreading of an invading species across a complex landscape made of variously suitable areas and dispersal barriers. This model was applied to the history of Ibex reintroduction in Bernese Alps (Switzerland). SIM-Ibex is now used by governmental wildlife managers to prepare and verify culling plans. Biomapper has been applied to several species (both plants and animals) all around the World. In the same way, whilst HexaSpace was originally designed for terrestrial animal species, it could be easily extended to model plant propagation or flying animals dispersal. As these softwares were designed to proceed from low-level data to build a complex realistic model and as they benefit from an intuitive user-interface, they may have many conservation applications. Moreover, theoretical questions in the fields of population and landscape ecology might also be addressed by these approaches.

Can wild ungulate carcasses provide enough biomass to maintain avian scavenger populations? An empirical assessment using a bio-inspired computational model

Background: The reduction in the amount of food available for European avian scavengers as a consequence of restrictive public health policies is a concern for managers and conservationists. Since 2002, the application of several sanitary regulations has limited the availability of feeding resources provided by domestic carcasses, but theoretical studies assessing whether the availability of food resources provided by wild ungulates are enough to cover energetic requirements are lacking. Methodology/Findings: We assessed food provided by a wild ungulate population in two areas of NE Spain inhabited by three vulture species and developed a P System computational model to assess the effects of the carrion resources provided on their population dynamics. We compared the real population trend with to a hypothetical scenario in which only food provided by wild ungulates was available. Simulation testing of the model suggests that wild ungulates constitute an important food resource in the Pyrenees and the vulture population inhabiting this area could grow if only the food provided by wild ungulates would be available. On the contrary, in the Pre-Pyrenees there is insufficient food to cover the energy requirements of avian scavenger guilds, declining sharply if biomass from domestic animals would not be available. Conclusions/Significance: Our results suggest that public health legislation can modify scavenger population trends if a large number of domestic ungulate carcasses disappear from the mountains. In this case, food provided by wild ungulates could be not enough and supplementary feeding could be necessary if other alternative food resources are not available (i.e. the reintroduction of wild ungulates), preferably in European Mediterranean scenarios sharing similar and socio-economic conditions where there are low densities of wild ungulates. Managers should anticipate the conservation actions required by assessing food availability and the possible scenarios in order to make the most suitable decisions.

Increased risk of cardiovascular disease (CVD) with age in HIV-positive men : a comparison of the D:A:D CVD risk equation and general population CVD risk equations

OBJECTIVES: The aim of the study was to statistically model the relative increased risk of cardiovascular disease (CVD) per year older in Data collection on Adverse events of anti-HIV Drugs (D:A:D) and to compare this with the relative increased risk of CVD per year older in general population risk equations. METHODS: We analysed three endpoints: myocardial infarction (MI), coronary heart disease (CHD: MI or invasive coronary procedure) and CVD (CHD or stroke). We fitted a number of parametric age effects, adjusting for known risk factors and antiretroviral therapy (ART) use. The best-fitting age effect was determined using the Akaike information criterion. We compared the ageing effect from D:A:D with that from the general population risk equations: the Framingham Heart Study, CUORE and ASSIGN risk scores. RESULTS: A total of 24 323 men were included in analyses. Crude MI, CHD and CVD event rates per 1000 person-years increased from 2.29, 3.11 and 3.65 in those aged 40-45 years to 6.53, 11.91 and 15.89 in those aged 60-65 years, respectively. The best-fitting models included inverse age for MI and age + age(2) for CHD and CVD. In D:A:D there was a slowly accelerating increased risk of CHD and CVD per year older, which appeared to be only modest yet was consistently raised compared with the risk in the general population. The relative risk of MI with age was not different between D:A:D and the general population. CONCLUSIONS: We found only limited evidence of accelerating increased risk of CVD with age in D:A:D compared with the general population. The absolute risk of CVD associated with HIV infection remains uncertain.

A model for the evolution of reinforcement learning in fluctuating games

Many species are able to learn to associate behaviours with rewards as this gives fitness advantages in changing environments. Social interactions between population members may, however, require more cognitive abilities than simple trial-and-error learning, in particular the capacity to make accurate hypotheses about the material payoff consequences of alternative action combinations. It is unclear in this context whether natural selection necessarily favours individuals to use information about payoffs associated with nontried actions (hypothetical payoffs), as opposed to simple reinforcement of realized payoff. Here, we develop an evolutionary model in which individuals are genetically determined to use either trial-and-error learning or learning based on hypothetical reinforcements, and ask what is the evolutionarily stable learning rule under pairwise symmetric two-action stochastic repeated games played over the individual's lifetime. We analyse through stochastic approximation theory and simulations the learning dynamics on the behavioural timescale, and derive conditions where trial-and-error learning outcompetes hypothetical reinforcement learning on the evolutionary timescale. This occurs in particular under repeated cooperative interactions with the same partner. By contrast, we find that hypothetical reinforcement learners tend to be favoured under random interactions, but stable polymorphisms can also obtain where trial-and-error learners are maintained at a low frequency. We conclude that specific game structures can select for trial-and-error learning even in the absence of costs of cognition, which illustrates that cost-free increased cognition can be counterselected under social interactions.

Population pharmacokinetic study to evaluate dosing strategies of imipenem in neonates and infants

Objective: Imipenem is a broad spectrum antibiotic used to treat severe infections in critically ill patients. Imipenem pharmacokinetics (PK) was evaluated in a cohort of neonates treated in the Neonatal Intensive Care Unit of the Lausanne University Hospital. The objective of our study was to identify key demographic and clinical factors influencing imipenem exposure in this population. Method: PK data from neonates and infants with at least one imipenem concentration measured between 2002 and 2013 were analyzed applying population PK modeling methods. Measurement of plasma concentrations were performed upon the decision of the physician within the frame of a therapeutic drug monitoring (TDM) programme. Effects of demographic (sex, body weight, gestational age, postnatal age) and clinical factors (serum creatinine as a measure of kidney function; co-administration of furosemide, spironolactone, hydrochlorothiazide, vancomycin, metronidazole and erythromycin) on imipenem PK were explored. Model-based simulations were performed (with a median creatinine value of 46 μmol/l) to compare various dosing regimens with respect to their ability to maintain drug levels above predefined minimum inhibitory concentrations (MIC) for at least 40 % of the dosing interval. Results: A total of 144 plasma samples was collected in 68 neonates and infants, predominantly preterm newborns, with median gestational age of 27 weeks (24 - 41 weeks) and postnatal age of 21 days (2 - 153 days). A two-compartment model best characterized imipenem disposition. Actual body weight exhibited the greatest impact on PK parameters, followed by age (gestational age and postnatal age) and serum creatinine on clearance. They explain 19%, 9%, 14% and 9% of the interindividual variability in clearance respectively. Model-based simulations suggested that 15 mg/kg every 12 hours maintain drug concentrations over a MIC of 2 mg/l for at least 40% of the dosing interval during the first days of life, whereas neonates older than 14 days of life required a dose of 20 mg/kg every 12 hours. Conclusion: Dosing strategies based on body weight and post-natal age are recommended for imipenem in all critically ill neonates and infants. Most current guidelines seem adequate for newborns and TDM should be restricted to some particular clinical situations.

5C.09: Heritability of renal function parameters and electrolyte levels in the Swiss population

OBJECTIVE: Electrolytes handling by the kidney is essential for volume and blood pressure (BP) homeostasis but their distribution and heritability are not well described. We estimated the heritability of kidney function as well as of serum and urine concentrations, renal clearances and fractional excretions for sodium, chloride, potassium, calcium, phosphate and magnesium in a Swiss population-based study. DESIGN AND METHOD: Nuclear families were randomly selected from the general population in Switzerland. We estimated glomerular filtration rate (eGFR) using the CKD-EPI and MDRD equations. Urine was collected separately during day and night over 24-hour. We used the ASSOC program (S.A.G.E.) to estimate narrow sense heritability, including as covariates in the model: age, sex, body mass index and study center. RESULTS: The 1128 participants (537 men and 591 women from 273 families), had mean (sd) age of 47.4(17.5) years, body mass index of 25.0 (4.5) kg/m2 and CKD-EPI of 98.0(18.5) mL/min/1.73 m2. Heritability estimates (SE) were 46.0% (0.06), 48.0% (0.06) and 18.0% (0.06) for CKD-EPI, MDRD and 24-hour creatinine clearance (P < 0.05), respectively. Heritability [SE] of serum concentration was highest for calcium (37%[0.06]) and lowest for sodium (13%[0.05]). Heritabilities [SE] of 24-h urine concentrations and excretions, and of fractional excretions were highest for calcium (51%[0.06], 44%[0.06] and 51%[0.06], respectively) and lowest for potassium (11%[0.05], 10%[0.05] and 16%[0.06], respectively). All results were statistically different from zero.(Figure is included in full-text article.) CONCLUSIONS: : Serum and urine levels, urinary excretions and renal handling of electrolytes, particularly calcium, are heritable in the general adult population. Identifying genetic variants involved in electrolytes homeostasis may provide useful insight into the pathophysiological mechanisms involved in common chronic diseases such as kidney diseases, hypertension and diabetes.

4B.05: Plasma Lasma copeptin is associated with insulin resistance in a Swiss population-based study

OBJECTIVE: Previous studies suggest that arginine vasopressin may have a role in metabolic syndrome (MetS) and diabetes by altering liver glycogenolysis, insulin, and glucagon secretion and pituitary ACTH release. We tested whether plasma copeptin, the stable C-terminal fragment of arginine vasopressin prohormone, was associated with insulin resistance and MetS in a Swiss population-based study. DESIGN AND METHOD: We analyzed data from the population-based Swiss Kidney Project on Genes in Hypertension. Copeptin was assessed by an immunoluminometric assay. Insulin resistance was derived from the HOMA model and calculated as follows: (FPI x FPG)/22.5, where FPI is fasting plasma insulin concentration (mU/L) and FPG fasting plasma glucose (mmol/L). Subjects were classified as having the MetS according to the National Cholesterol Education Program Adult Treatment Panel III criteria. Mixed multivariate linear regression models were built to explore the association of insulin resistance with copeptin. In addition, multivariate logistic regression models were built to explore the association between MetS and copeptin. In the two analyses, adjustment was done for age, gender, center, tobacco and alcohol consumption, socioeconomic status, physical activity, intake of fruits and vegetables and 24 h urine flow rate. Copeptin was log-transformed for the analyses. RESULTS: Among the 1,089 subjects included in this analysis, 47% were male. Mean (SD) age and body mass index were 47.4 (17.6) years 25.0 (4.5) kg/m2. The prevalence of MetS was 10.5%. HOMA-IR was higher in men (median 1.3, IQR 0.7-2.1) than in women (median 1.0, IQR 0.5-1.6,P < 0.0001). Plasma copeptin was higher in men (median 5.2, IQR 3.7-7.8 pmol/L) than in women (median 3.0, IQR 2.2-4.3 pmol/L), P < 0.0001. HOMA-IR was positively associated with log-copeptin after full adjustment (β (95% CI) 0.19 (0.09-0.29), P < 0.001). MetS was not associated with copeptin after full adjustment (P = 0.92). CONCLUSIONS: Insulin resistance, but not MetS, was associated with higher copeptin levels. Further studies should examine whether modifying pharmacologically the arginine vasopressin system might improve insulin resistance, thereby providing insight into the causal nature of this association.

Gamma-ray emission from microquasars: a numerical model for LSI+61º303

We explore the possible association between the microquasar LSI +61°303 and the EGRET source 2CG 135+01/3EG J0241+6103 by studying, with a detailed numerical model, whether this system can produce the emission and the variability detected by EGRET (>100 MeV) through inverse Compton (IC) scattering. Our numerical approach considers a population of relativistic electrons entrained in a cylindrical inhomogeneous jet, interacting with both the radiation and the magnetic fields, taking into account the Thomson and Klein-Nishina regimes of interaction. Our results reproduce the observed spectral characteristics and variability at γ-rays, thus strengthening the identification of LSI +61°303 as a high-energy γ-ray source.

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.

A statistical shape model of the human second cervical vertebra.

PURPOSE: Statistical shape and appearance models play an important role in reducing the segmentation processing time of a vertebra and in improving results for 3D model development. Here, we describe the different steps in generating a statistical shape model (SSM) of the second cervical vertebra (C2) and provide the shape model for general use by the scientific community. The main difficulties in its construction are the morphological complexity of the C2 and its variability in the population. METHODS: The input dataset is composed of manually segmented anonymized patient computerized tomography (CT) scans. The alignment of the different datasets is done with the procrustes alignment on surface models, and then, the registration is cast as a model-fitting problem using a Gaussian process. A principal component analysis (PCA)-based model is generated which includes the variability of the C2. RESULTS: The SSM was generated using 92 CT scans. The resulting SSM was evaluated for specificity, compactness and generalization ability. The SSM of the C2 is freely available to the scientific community in Slicer (an open source software for image analysis and scientific visualization) with a module created to visualize the SSM using Statismo, a framework for statistical shape modeling. CONCLUSION: The SSM of the vertebra allows the shape variability of the C2 to be represented. Moreover, the SSM will enable semi-automatic segmentation and 3D model generation of the vertebra, which would greatly benefit surgery planning.

The Besançon Galaxy Model renewed. I. Constraints on the Galactic thin disc evolution from Tycho data

Context. The understanding of Galaxy evolution can be facilitated by the use of population synthesis models, which allow to test hypotheses on the star formation history, star evolution, as well as chemical and dynamical evolution of the Galaxy. Aims. The new version of the Besanc¸on Galaxy Model (hereafter BGM) aims to provide a more flexible and powerful tool to investigate the Initial Mass Function (IMF) and Star Formation Rate (SFR) of the Galactic disc. Methods. We present a new strategy for the generation of thin disc stars which assumes the IMF, SFR and evolutionary tracks as free parameters. We have updated most of the ingredients for the star count production and, for the first time, binary stars are generated in a consistent way. We keep in this new scheme the local dynamical self-consistency as in Bienayme et al (1987). We then compare simulations from the new model with Tycho-2 data and the local luminosity function, as a first test to verify and constrain the new ingredients. The effects of changing thirteen different ingredients of the model are systematically studied. Results. For the first time, a full sky comparison is performed between BGM and data. This strategy allows to constrain the IMF slope at high masses which is found to be close to 3.0, excluding a shallower slope such as Salpeter"s one. The SFR is found decreasing whatever IMF is assumed. The model is compatible with a local dark matter density of 0.011 M pc−3 implying that there is no compelling evidence for significant amount of dark matter in the disc. While the model is fitted to Tycho2 data, a magnitude limited sample with V<11, we check that it is still consistent with fainter stars. Conclusions. The new model constitutes a new basis for further comparisons with large scale surveys and is being prepared to become a powerful tool for the analysis of the Gaia mission data.

Planarians as a model to assess in vivo the role of matrix metalloproteinase genes during homeostasis and regeneration

Matrix metalloproteinases (MMPs) are major executors of extracellular matrix remodeling and, consequently, play key roles in the response of cells to their microenvironment. The experimentally accessible stem cell population and the robust regenerative capabilities of planarians offer an ideal model to study how modulation of the proteolytic system in the extracellular environment affects cell behavior in vivo. Genome-wide identification of Schmidtea mediterranea MMPs reveals that planarians possess four mmp-like genes. Two of them (mmp1 and mmp2) are strongly expressed in a subset of secretory cells and encode putative matrilysins. The other genes (mt-mmpA and mt-mmpB) are widely expressed in postmitotic cells and appear structurally related to membrane-type MMPs. These genes are conserved in the planarian Dugesia japonica. Here we explore the role of the planarian mmp genes by RNA interference (RNAi) during tissue homeostasis and regeneration. Our analyses identify essential functions for two of them. Following inhibition of mmp1 planarians display dramatic disruption of tissues architecture and significant decrease in cell death. These results suggest that mmp1 controls tissue turnover, modulating survival of postmitotic cells. Unexpectedly, the ability to regenerate is unaffected by mmp1(RNAi). Silencing of mt-mmpA alters tissue integrity and delays blastema growth, without affecting proliferation of stem cells. Our data support the possibility that the activity of this protease modulates cell migration and regulates anoikis, with a consequent pivotal role in tissue homeostasis and regeneration. Our data provide evidence of the involvement of specific MMPs in tissue homeostasis and regeneration and demonstrate that the behavior of planarian stem cells is critically dependent on the microenvironment surrounding these cells. Studying MMPs function in the planarian model provides evidence on how individual proteases work in vivo in adult tissues. These results have high potential to generate significant information for development of regenerative and anti cancer therapies.

The effect of learning on the evolution of new courtship behavior: a simulation model

The fact that individuals learn can change the relationship between genotype and phenotype in the population, and thus affect the evolutionary response to selection. Here we ask how male ability to learn from female response affects the evolution of a novel male behavioral courtship trait under pre-existing female preference (sensory drive). We assume a courtship trait which has both a genetic and a learned component, and a two-level female response to males. With individual-based simulations we show that, under this scenario, learning generally increases the strength of selection on the genetic component of the courtship trait, at least when the population genetic mean is still low. As a consequence, learning not only accelerates the evolution of the courtship trait, but also enables it when the trait is costly, which in the absence of learning results in an adaptive valley. Furthermore, learning can enable the evolution of the novel trait in the face of gene flow mediated by immigration of males that show superior attractiveness to females based on another, non-heritable trait. However, rather than increasing monotonically with the speed of learning, the effect of learning on evolution is maximized at intermediate learning rates. This model shows that, at least under some scenarios, the ability to learn can drive the evolution of mating behaviors through a process equivalent to Waddington's genetic assimilation.

Association between parental history and genetic risk scores for coronary heart disease prediction: The population-based CoLaus study.

BACKGROUND AND AIMS: Parental history (PH) and genetic risk scores (GRSs) are separately associated with coronary heart disease (CHD), but evidence regarding their combined effects is lacking. We aimed to evaluate the joint associations and predictive ability of PH and GRSs for incident CHD. METHODS: Data for 4283 Caucasians were obtained from the population-based CoLaus Study, over median follow-up time of 5.6 years. CHD was defined as incident myocardial infarction, angina, percutaneous coronary revascularization or bypass grafting. Single nucleotide polymorphisms for CHD identified by genome-wide association studies were used to construct unweighted and weighted versions of three GRSs, comprising of 38, 53 and 153 SNPs respectively. RESULTS: PH was associated with higher values of all weighted GRSs. After adjustment for age, sex, smoking, diabetes, systolic blood pressure, low and high density lipoprotein cholesterol, PH was significantly associated with CHD [HR 2.61, 95% CI (1.47-4.66)] and further adjustment for GRSs did not change this estimate. Similarly, one standard deviation change of the weighted 153-SNPs GRS was significantly associated with CHD [HR 1.50, 95% CI (1.26-1.80)] and remained so, after further adjustment for PH. The weighted, 153-SNPs GRS, but not PH, modestly improved discrimination [(C-index improvement, 0.016), p = 0.048] and reclassification [(NRI improvement, 8.6%), p = 0.027] beyond cardiovascular risk factors. After including both the GRS and PH, model performance improved further [(C-index improvement, 0.022), p = 0.006]. CONCLUSION: After adjustment for cardiovascular risk factors, PH and a weighted, polygenic GRS were jointly associated with CHD and provided additive information for coronary events prediction.