The underlying causes of variability in the electrical activity of hearts from individuals of the same species are not well understood. Understanding this variability is important to enable prediction of the response of individual hearts to diseases and therapies. Current experimental and computational methods for investigating the behaviour of the heart do not incorporate biological variation between individuals. In experimental studies, experimental results are averaged together to control errors and determine the average behaviour of the studied organism. In computational studies, averaged experimental data is usually used to develop models, and these models therefore represent a 'typical' organism, with all information on variability within the species having been lost. In this thesis we develop a methodology for modelling variability between individuals of the same species in cardiac cellular electrophysiology, motivated by the inability of traditional computational modelling approaches to capture experimental variability. A first study is conducted using traditional modelling approaches to investigate potentially pro-arrhythmic abnormalities in rabbit Purkinje fibres. A comparison with experimental recordings highlights their wide variability and the inability of existing computer modelling approaches to capture it. This leads to the development of a novel methodology that integrates the variability observed in experimental data with computational modelling and simulation, by building experimentally-calibrated populations of computational models, that collectively span the variability seen in experimental data. We apply this methodology to construct a population of rabbit Purkinje cell models. We show that our population of models can quantitatively predict the range of responses, not just the average response, to application of the potassium channel blocking drug dofetilide. This demonstrates an important potential application of our methodology, for predicting pro-arrhythmic drug effects in safety pharmacology. We then analyse a data set of experimental recordings from human ventricular tissue preparations, and use this data to develop a population of human ventricular cell models. We apply this population to study how variability between individuals alters the susceptibility of cardiac cells to developing drug-induced repolarisation abnormalities. These abnormalities can increase the chance of fatal arrhythmias, but the mechanisms that determine individual susceptibility are not well-understood.

Cette thèse est organisée en trois parties principales. La première partie de cette thèse a permis de mettre en évidence l’existence de coping style chez le bar, révélant des liens entre réponses comportementales et physiologiques suite à un stress. Les individus proactifs montraient une plus faible activation de l’axe HPI, résultant en une moindre augmentation des taux de cortisol plasmatique après un stress que les individus réactifs. Cependant, les liens entre traits de personnalité et activation des systèmes dopaminergiques et sérotoninergiques n’ont pas pu être clairement mis en évidence. Les tests individuels se sont révélés discriminants de la personnalité, mais n’ont pas permis d’observer des réponses cohérentes dans le temps en raison du caractère stressant de l’isolement chez cette espèce sociale. L’utilisation de tests en groupe est apparue mieux adaptée et a permis de caractériser un nombre important d’individus, étape nécessaire à toutes études visant à caractériser la variabilité génétique des traits comportementaux. La variabilité observée met en avant d’importantes capacités d’adaptation chez cette espèce. La seconde partie a mis en avant l’existence de liens entre traits de personnalité et stratégies d’approvisionnement en nourriture. L’analyse de la structure sociale chez cette espèce a mis en évidence une stratégie coopérative concernant l’acquisition de la nourriture avec une spécialisation de certains individus dans le groupe. Enfin, la troisième partie a permis l’observation de liens génétiques entre traits de personnalité et caractères phénotypiques, laissant entrevoir une possible sélection des caractères de personnalité dans un contexte de production piscicole. Le niveau de domestication s’est révélé avoir une influence sur les liens entre personnalité et potentiel de croissance. L’utilisation de ces coping styles et traits de personnalité pourrait être un outil supplémentaire pour améliorer le processus de domestication, permettant par exemple la sélection de coping styles divergents qui pourraient correspondre à des individus plus résistants aux maladies, ou mieux adaptés à leur environnement. / This thesis is organized in three principal parts. The first part of this thesis highlights the existence of coping style in seabass, revealing links between behavioral and physiological responses following a stress. The proactive individuals showed a weaker activation of the HPI axis, resulting in a lesser increase of plasmatic cortisol levels after a stress compared to reactive fish. However, the links between personality traits and activation of the dopaminergic and serotonergic systems could not be clearly demonstrated. The individual tests appeared discriminating personality, but did not allow observing coherent responses in time likely because of the stressing character of the isolated situation in this social species. The use of tests in group appeared better adapted and made it possible to characterize a significant number of individual, a necessary step when one aims at characterizing the genetic variability of the behavioural traits. Finally, variability observed underlined important adaptation capacities of this species. The second part demonstrated the existence of links between personality traits and feeding strategies. The analysis of the social structure highlighted a cooperative strategy concerning the acquisition of food with a specialization of certain individuals in the group. Lastly, the third part showed genetic correlations between coping styles, personality traits and phenotypes, letting foresee a possible selection of the personality traits in a production context. The level of domestication proved to have an influence on the links between personality and growth potential. The use of all these coping style and personality traits could be an additional tool to improve the process of domestication, allowing for example the selection of divergent coping styles which could correspond to individuals more resistant to diseases, or better adapted to their environment.

Les Anelloviridae sont de petits virus à ADN simple brin de découverte récente, très largement répandus chez les vertébrés. Chez l'homme, 3 genres distincts ont été caractérisés : Alphatorquevirus (TTV), Betatorquevirus (TTMV), Gammatorquevirus (TTMDV), engendrant une infection chronique mais dont le pouvoir pathogène potentiel demeure encore méconnu. Leur épidémiologie est en constante réévaluation du fait de leur extrême variabilité et diversité génétique. Au cours de cette recherche à l'interface entre virologie et paléomicrobiologie, nous avons exploré l'histoire naturelle de ces virus via 2 axes interconnectés. D'une part la diversité génétique a été analysée lors d'une étude transversale au sein de populations contemporaines (française et afghane) et de populations anciennes datant du néolithique à l'époque moderne. D'autre part, leur évolution a été étudiée à l'échelle individuelle par une étude longitudinale au sein de 2 corpus (suivis de patient transplanté et de patient hémodialysé). Dans le but de compléter les données concernant cette famille virale unique, un travail méthodologique a été mis en oeuvre afin d'apporter des améliorations et de standardiser les protocoles d'analyse existants. La comparaison de distribution des Anelloviridae parmi plusieurs populations contemporaines, nous a permis d'observer des différences significatives de profils, notamment dans la population afghane. Notre méthodologie d'analyse d'échantillons anciens a mis en évidence la présence de souches Anelloviridae, attestant ainsi leur ancestralité et révélant également l'existence de variabilités inter- et intra-individuelles, similaires à l'infection des populations modernes. / Anelloviridae are small single-stranded DNA viruses, recently discovered, and widely spread among vertebrates. In humans, three distinct genera were characterised: Alphatorquevirus (TTV), Betatorquevirus (TTMV), Gammatorquevirus (TTMDV), leading to a chronic infection whose pathogenicity remains unknown. Their epidemiology is constantly evolving due to their extreme variability and genetic diversity. In this multidisciplinary research, combining virology, bioanthropology and palaeomicrobiology, we have used genetic analysis to explore the natural history of those viruses via two linked issues. On the one hand, the genetic diversity was analysed by way of a cross-sectional study within contemporary populations (French and Afghan) and ancient populations from the Neolithic period to Modern times. On the other hand, their evolution was studied at the individual level through a longitudinal study in two corpora (follow-ups of a transplanted patient and haemodialysis patients). In order to complement data regarding this unique viral family, a methodological process was established to improve and standardize existing analysis protocols. Comparison of Anelloviridae's distributions among several healthy contemporary populations allowed us to notice significant differences of partitions, especially an almost complete absence of TTMDV in the Afghan sample. Our methodology dedicated to ancient remains displayed the presence of Anelloviridae strains, testifying their ancestral origin and highlighting inter- and intra-individual variations, similar to infections in modern populations.

Le polymorphisme génétique du virus de l’hépatite B (VHB) a déjà été étudié pourtenter de comprendre les facteurs viraux influençant l'évolution de la maladie, mais les étudessont discordantes. Ceci peut être lié au fait que les précédents travaux n’ont été menés quedans des populations avec une faible variété de génotypes et présentant des charges viralesplasmatiques (CVP) élevées.Nous avons donc étudié la variabilité du génome complet du VHB chez 422 individusinfectés chroniquement, naïfs de traitements anti-viraux et dont 38% présentaient une CVPinférieure à 103 UI/mL. L’optimisation de l’amplification par PCR du génome complet duVHB nous a permis de séquencer en technique Sanger plus de 90% du génome pour 320échantillons. Le séquençage direct a mis en évidence des co-infections. Ceci a été confirmé enséquençage clonal par pyroséquençage de 27 échantillons qui a montré des proportions departicules défectives variables mais toujours en co-infections avec des sous-populationssauvages. Le génotypage des séquences obtenues par technique Sanger a montré une grandereprésentativité des génotypes les plus fréquents (A à E) ainsi que 60 potentiels recombinantsinter-génotypiques. Cependant le séquençage clonal par pyroséquençage et clonage vectorielclassique de ces derniers montre la présence de co-infections de plusieurs génotypes ou laprésence de génotypes intermédiaires entre génotypes proches. Ceci est en défaveur derecombinaison par échange de matériel génétique comme ce qui a été suggéré dans lalittérature.Cette étude sera complétée par l’analyse de corrélation entre les polymorphismes et lesmarqueurs de mauvaise évolution de la pathologie. / The genetic polymorphism of hepatitis B virus (HBV) has been investigated tounderstand its impact on disease evolution, with discordant results. This could be due to thenarrow range of genotype and plasmatic viral load in these studies.We analysed complete genome variability of circulating HBV, in 422 chronicallyinfected patients. All were naive of anti-viral treatement and 38% had a plasmatic viral loadbelow 103 UI/mL. After optimisation of full length genome PCR amplification, we obtainedSanger sequences for more than 90% of HBV genome in 320 samples. We detected by directsequencing multiples co-infections that were confirmed by clonal pyrosequencing in 27samples. Defective viruses were always observed in co-infection with wild type virus. Directsequences showed a large representation of the most frequent genotypes (A to E), but also 60potential inter-genotypic recombinants. Clonal pyrosequencing and vectorial sequencingshowed that these potential recombinants were co-infections with different genotypes orintermediate genotypes located between close genotypes. These observations are incontradiction with the hypothesis described in the literature on recombination by geneticmaterial exchange.This study will be completed by a correlation analysis between the polymorphisms andmarkers of bad prognosis during HBV-induced disease.

Introduction: The current development strategy of population pharmacokinetic models is a complex and iterative process that is manually performed by modellers. Such a strategy is time-demanding, subjective, and dependent on the modellers’ experience. This thesis presents a novel model building tool that automates the development process of pharmacokinetic (PK) structural models. Methods: Modelsearch is a tool in Pharmpy library, an open-source package for pharmacometrics modelling, that searches for the best structural model using an exhaustive stepwise search algorithm. Given a dataset, a starting model and a pre-specified model search space of structural model features, the tool creates and fits a series of candidate models that are then ranked based on a selection criterion, leading to the selection of the best model. The Modelsearch tool was used to develop structural models for 10 clinical PK datasets (5 orally and 5 i.v. administered drugs). A starting model for each dataset was generated using the assemblerr package in R, which included a first-order (FO) absorption without any absorption delay for oral drugs, one-compartment disposition, FO elimination, a proportional residual error model, and inter-individual variability on the starting model parameters with a correlation between clearance (CL) and central volume of distribution (VC). The model search space included aspects of absorption and absorption delay (for oral drugs), distribution and elimination. In order to understand the effects of different IIV structures on structural model selection, five model search approaches were investigated that differ in the IIV structure of candidate models: 1. naïve pooling, 2. IIV on starting model parameters only, 3. additional IIV on mean delay time parameter, 4. additional diagonal IIVs on newly added parameters, and 5. full block IIVs. Additionally, the implementation of structural model selection in the workflow of the fully automatic model development was investigated. Three strategies were evaluated: SIR, SRI, and RSI depending on the development order of structural model (S), IIV model (I) and residual error model (R). Moreover, the NONMEM errors encountered when using the tool were investigated and categorized in order to be handled in the automatic model building workflow. Results: Differences in the final selected structural models for each drug were observed between the five different model search approaches. The same distribution components were selected through Approaches 1 and 2 for 6/10 drugs. Approach 2 has also identified an absorption delay component in 4/5 oral drugs, whilst the naïve pooling approach only identified an absorption delay model in 2 drugs. Compared to Approaches 1 and 2, Approaches 3, 4 and 5 tended to select more complex models and more often resulted in minimization errors during the search. For the SIR, SRI and RSI investigations, the same structural model was selected in 9/10 drugs with a significant higher run time in RSI strategy compared to the other strategies. The NONMEM errors were categorized into four categories based on the handling suggestions which is valuable to further improve the tool in its automatic error handling. Conclusions: The Modelsearch tool was able to automatically select a structural model with different strategies of setting the IIV model structure. This novel tool enables the evaluation of numerous combinations of model components, which would not be possible using a traditional manual model building strategy. Furthermore, the tool is flexible and can support multiple research investigations for how to best implement structural model selection in a fully automatic model development workflow.

<p>  </p> <p>Appetitive sensations are widely viewed as important signals for eating decisions. Intra- and inter-individual variability have been reported in short-term studies, but it is still unknown whether individual differences are consistent over time and, whether individuals at the appetite extremes vary in energy intake. Therefore, a seventeen-week observational study was conducted to examine the stability of appetitive sensations (hunger, fullness, and thirst), implications of individual differences in appetite on energy intake and eating patterns, as well as associations between appetitive sensations and selected individual characteristics (age, gender, BMI). </p> <p>Ninety-seven (90 completers) healthy adults recorded the intensity of their hunger, fullness, and thirst hourly during all waking hours and reported their energy intake  for three days at weeks 1, 9 and 17. There were marked and stable inter-individual differences for each sensation over the 17 weeks: hunger (ANOVA, p<0.001, correlation coefficients of ratings between weeks: week 1 vs week 9, r=0.72 (p<0.001), week 1 vs week 17, r=0.67 (p<0.001), week 9 vs week 17, r=0.77 (p<0.001)), fullness (ANOVA, p<0.001, correlation coefficients of ratings between weeks: week 1 vs week 9 r=0.74 (p<0.001), week 1 vs week 17, r=0.71 (p<0.001), week 9 vs week 17, r=0.81 (p<0.001)), and thirst (ANOVA, p<0.001, correlation coefficients of ratings between weeks: week 1 vs week 9 r=0.82 (p<0.001), week 1 vs week 17, r=0.81 (p<0.001), week 9 vs week 17, r=0.88 (p<0.001)). Cross-correlation functions revealed energy intake and eating pattern exerted stronger effects on appetitive sensations than the reverse. However, the absolute effect sizes of the directional effects were small. No robust effects of the studied individual characteristics (gender, age, BMI) were observed. The primary finding is that acute and chronic sensations of hunger, fullness and thirst are stable across individuals, but are poor predictors of energy intake. </p> <p>This dissertation focuses on the study above, but as part of the training experience, two additional studies were conducted. One entailed appetite concept training to improve the validity of appetite measurements. A potential barrier to accurate appetite measurement is low conceptual understanding by study participants and resulting poor sensitivity and accuracy of responses. While each appetitive sensation is independent and has a unique definition, reported similar patterns between appetitive sensations in multiple studies raise questions about whether participants fully comprehend appetite concepts and provide accurate responses. To overcome this potential limitation, appetite concept materials were developed, and two groups of individuals were provided training either with these materials or unrelated sensory information followed by measurement of appetite responses to five different pre-loads. This study terminated early due to the COVID-19 pandemic and thus we cannot draw a conclusion for now due to the limited number of participants.  </p> <p>A second study sought to gain insights on the sensory qualities of fatty acids as part of an effort to determine if oral fat detection is based, in part, on gustatory cues. It has been argued that if fat taste is a primary, the sensations imparted by fats should yield unique percepts and these may be determined by fatty acid chain length. In particular, because acids impart a sour taste, free fatty acids may simply be detected as sour. The fat taste study entailed measurement of intensity ratings with or without sour adaptation (to assess sour notes), tongue locations of taste detection, and subjective descriptors of fatty acids. This study examined intensity and quality ratings of NEFA's ranging from C2 to C18. Oral sites and the time course of sensations were also monitored. Given all NEFA contain carboxylic acid moieties capable of donating hydrogen ions, the primary stimulus for sour taste, testing was conducted with and without sour adaptation to explore the contribution of sour taste across the range of NEFA. Short chain NEFA (C2-C6) were rated as predominantly sour, and this was diminished in C2 and C4 by sour adaptation. Medium chain NEFA (C8-C12) were rated as mainly irritating with long chain NEFA (C18) described mostly as bitter. The latter may reflect the lack of “fatty” lexicon to describe the sensation. Short chain NEFA were mostly localized to the anterior tongue and were of rapid onset. The sensation from medium chain NEFA was attributed to the lateral tongue while medium and long chain NEFA sensations were predominantly localized to the back of the tongue and throat and had a longer lag time. The findings indicate there is a systematic transition of NEFA taste quality and irritation with increments in chain length and this is consistent with multiple modes of transduction.</p>

Although the research literature supports the notion of language growth trajectories, primarily in monolingual English children, the shape and direction of English-language learners' (ELLs) language growth trajectories are largely unknown. The present study examined the shape of ELLs' language growth trajectories by estimating the initial status and the growth rates of specific oral language skills (mean length of utterance in words (MLUw), number of different words (NDW), and words per minute (WPM)) in each language during the first 3 years of formal schooling. This study was framed from the perspective of language as a dynamic system, composed of linguistic subsystems that change over time. This study utilized secondary data from a larger project, the Bilingual Language Literacy Project (BLLP), which collected narrative retell language samples produced in Spanish and English from ELL children. The final longitudinal dataset used in this study consisted of 12,248 oral narrative language samples (6,516 Spanish; 5,732 English) that were produced by 1,723 ELLs. This study examined the effect of three predictors on language growth: academic semester (metric of time), gender, and schooling. Growth curve model (GCM) testing was used to profile the longitudinal growth of the ELLs' oral language skills in Spanish and English over time. This study had a number of important findings regarding change over time, intra- and inter-individual variability, and the impact of initial status on growth. With regard to change over time: MLUw, NDW, and WPM demonstrated growth over time in Spanish and English; the shapes of Spanish (curvilinear, non-monotonic, and continuous) and English growth (linear, non-monotonic, and discontinuous) were similar within-language; language growth in Spanish was predicted by academic semester and gender; and language growth in English was predicted by academic semester, gender, and schooling. With regard to intra- and inter-individual variability: significant intra-individual differences in the growth of all the oral language measures, across each wave of measurement, were found for both languages; significant intra-individual differences in the initial status of participants for all the oral language measures were found for both languages; significant inter-individual differences in the growth rates were found for WPM-Spanish; and significant inter-individual differences in the growth rates were found for all the oral language measures in English. With regard to the impact of initial status on growth: the growth of MLUw-Spanish was systematically related to initial status (lower performers at initial status may not catch up to higher performers); the growth of NDW- and WPM-Spanish were unrelated to its initial status (lower performers at initial status may, or may not catch up to higher performers); and the growth of MLUw-, NDW-, and WPM-English was systematically related to initial status (lower performers at initial status may catch up to higher performers). With regard to the co-development of interconnected subsystems, qualitative observations (non-empirically tested) based on visual inspection and GCM estimates provided initial insight into the possible co-development occurring within- and across-languages. The present study broke new ground by specifying the shape of growth for MLUw, NDW, and WPM in the Spanish and English of ELLs during their first 3 years of formal schooling. The study had a number of methodological limitations that will guide and motivate future work on the language growth of ELLs. / Communication Sciences

Il y a de plus en plus de preuves que les animaux diffèrent de façon constante dans leur tendance à se servir de l’information sociale et de l’information personnelle, et ces différences interindividuelles sont corrélées avec des traits de personnalité tels que l’hardiesse et l’exploration. Le lien entre la personnalité et l’utilisation d’information sociale serait attribué au fait que les performances cognitives des individus affectent non seulement leur personnalité, mais aussi leur habileté à acquérir de l’information personnelle fiable. La présente étude cherchait à déterminer si les femelles diamant mandarin qui ont tendance à se fier à l’information sociale dans des contextes de choix de partenaire et d’alimentation démontrent également un niveau de contrôle de soi plus faible, une mesure que nous avons utilisée pour évaluer leur capacité à discriminer entre deux alternatives. Nous avons observé que les femelles plus impulsives ont une plus grande tendance à se servir de l’information sociale que celles qui démontrent un degré de contrôle de soi plus élevé. Ainsi, nos résultats suggèrent fortement que les différences individuelles dans les capacités cognitives auraient contribué à l'émergence et au maintien des personnalités animales. / There is increasing evidence that animals differ consistently in their tendency to weight social and personal information and these inter-individual differences have been found to correlate with personality traits, such as boldness or exploratory tendency. One reason that could explain the relationship between personality and social information use is that cognitive capacities of individuals affect both their personality and their ability to acquire reliable personal information. Our study aimed to determine if female zebra finches that relied on social information in a mating and a foraging context also demonstrated a low level of self-control, used as a measure of their ability to discriminate accurately among alternatives. Supporting our expectations, we found that the most impulsive females consistently relied on social information to a greater extent than those that demonstrated higher levels of self control. Thus, our findings strongly suggest that individual differences in cognitive abilities have contributed to the emergence and maintenance of animal personalities.

Dans un contexte de fluctuation des prix des intrants et d’une demande croissante en produits à base de lait de chèvre issus de pratiques respectueuses de l’environnement et des animaux, le pâturage peut retrouver une place plus importante dans l’alimentation des chèvres laitières. D’après la synthèse bibliographique, les facteurs de variation de l’ingestion et des performances au pâturage ont été très peu étudiés chez les chèvres laitières en conditions tempérées. L’objectif de la thèse a été de comprendre quelle est l’influence des pratiques de gestion du pâturage (disponibilité en herbe et en temps pour pâturer) sur la régulation de l’ingestion et les performances des chèvres laitières, dans le but d’affiner les recommandations aux éleveurs et d’élaborer les bases d’un modèle de prévision de l’ingestion. D’après les 6 essais réalisés : (1) les chèvres recevant entre 0,6 et 1,0 kg/j de compléments s’adaptent à des restrictions de temps d’accès de 11 à 6 h/j, en augmentant leur vitesse d’ingestion et surtout le pourcentage du temps passé à pâturer jusqu’à 95 % du temps d’accès, (2) les chèvres recevant 0,6 kg de concentrés et un temps d’accès d’au moins 11 h/j peuvent s’adapter à une restriction de quantité d’herbe offerte jusqu’à 2,3-2,6 kg MS/chèvre/j, (3), le poids vif et la production laitière sont des paramètres déterminant de la quantité d’herbe ingérée alors que la parité et le stade de lactation n’ont pas montré d’effet significatif. Ce travail a permis d’établir les premières lois de réponse d’ingestion, de production laitière et d’adaptation comportementale des chèvres laitières à des variations de temps d’accès et de quantité d’herbe offerte au pâturage. / In the context of prices volatility and growing demand for goat's milk products from respectful practices of the environment and animals, grazing can become more important in the diet of dairy goats. According to the literature review, the factors of variation of intake and performance of grazing dairy goats have been poorly studied under temperate conditions. The aim of this thesis was to understand the influence of grazing management practices (availability of pasture and access time to grazing) on the regulation of intake and performance of dairy goats, with the aim of refining recommendations for farmers and to elaborate a model of intake prediction. Based on the six trials conducted: (1) goats receiving between 0.6 and 1.0 kg/day of supplements adapt themselves to access time restrictions from 11 to 6 h/d, by increasing their intake rate and especially the percentage of time spent grazing up to 95% of access time, (2) goats receiving 0.6 kg of concentrates and an access time of at least 11 h/day can adapt to a restriction of pasture allowance up to 2.3-2.6 kg DM/goat/day, (3) live weight and milk production are the main variables affecting intake while parity and stage of lactation had no significant effect. This work provides the first response laws of intake, milk production and behavioural adaptation of grazing dairy goats to variations of access time to pasture and to pasture allowance.

No description available.