Implicit methods for qualitative modeling of gene regulatory networks.

Advancements in high-throughput technologies to measure increasingly complex biological phenomena at the genomic level are rapidly changing the face of biological research from the single-gene single-protein experimental approach to studying the behavior of a gene in the context of the entire genome (and proteome). This shift in research methodologies has resulted in a new field of network biology that deals with modeling cellular behavior in terms of network structures such as signaling pathways and gene regulatory networks. In these networks, different biological entities such as genes, proteins, and metabolites interact with each other, giving rise to a dynamical system. Even though there exists a mature field of dynamical systems theory to model such network structures, some technical challenges are unique to biology such as the inability to measure precise kinetic information on gene-gene or gene-protein interactions and the need to model increasingly large networks comprising thousands of nodes. These challenges have renewed interest in developing new computational techniques for modeling complex biological systems. This chapter presents a modeling framework based on Boolean algebra and finite-state machines that are reminiscent of the approach used for digital circuit synthesis and simulation in the field of very-large-scale integration (VLSI). The proposed formalism enables a common mathematical framework to develop computational techniques for modeling different aspects of the regulatory networks such as steady-state behavior, stochasticity, and gene perturbation experiments.

Multimodal MRI analysis of structural and functional networks in the human brain : application to two clinical studies : driving abilities under THC intoxication and early white matter changes in FXTAS

Les approches multimodales dans l'imagerie cérébrale non invasive sont de plus en plus considérées comme un outil indispensable pour la compréhension des différents aspects de la structure et de la fonction cérébrale. Grâce aux progrès des techniques d'acquisition des images de Resonance Magnetique et aux nouveaux outils pour le traitement des données, il est désormais possible de mesurer plusieurs paramètres sensibles aux différentes caractéristiques des tissues cérébraux. Ces progrès permettent, par exemple, d'étudier les substrats anatomiques qui sont à la base des processus cognitifs ou de discerner au niveau purement structurel les phénomènes dégénératifs et développementaux. Cette thèse met en évidence l'importance de l'utilisation d'une approche multimodale pour étudier les différents aspects de la dynamique cérébrale grâce à l'application de cette approche à deux études cliniques: l'évaluation structurelle et fonctionnelle des effets aigus du cannabis fumé chez des consommateurs réguliers et occasionnels, et l'évaluation de l'intégrité de la substance grise et blanche chez des jeunes porteurs de la prémutations du gène FMR1 à risque de développer le FXTAS (Fragile-X Tremor Ataxia Syndrome). Nous avons montré que chez les fumeurs occasionnels de cannabis, même à faible concentration du principal composant psychoactif (THC) dans le sang, la performance lors d'une tâche visuo-motrice est fortement diminuée, et qu'il y a des changements dans l'activité des trois réseaux cérébraux impliqués dans les processus cognitifs: le réseau de saillance, le réseau du contrôle exécutif, et le réseau actif par défaut (Default Mode). Les sujets ne sont pas en mesure de saisir les saillances dans l'environnement et de focaliser leur attention sur la tâche. L'augmentation de la réponse hémodynamique dans le cortex cingulaire antérieur suggère une augmentation de l'activité introspective. Une investigation des ef¬fets au niveau cérébral d'une exposition prolongée au cannabis, montre des changements persistants de la substance grise dans les régions associées à la mémoire et au traitement des émotions. Le niveau d'atrophie dans ces structures corrèle avec la consommation de cannabis au cours des trois mois précédant l'étude. Dans la deuxième étude, nous démontrons des altérations structurelles des décennies avant l'apparition du syndrome FXTAS chez des sujets jeunes, asymptomatiques, et porteurs de la prémutation du gène FMR1. Les modifications trouvées peuvent être liées à deux mécanismes différents. Les altérations dans le réseau moteur du cervelet et dans la fimbria de l'hippocampe, suggèrent un effet développemental de la prémutation. Elles incluent aussi une atrophie de la substance grise du lobule VI du cervelet et l'altération des propriétés tissulaires de la substance blanche des projections afférentes correspondantes aux pédoncules cérébelleux moyens. Les lésions diffuses de la substance blanche cérébrale peu¬vent être un marquer précoce du développement de la maladie, car elles sont liées à un phénomène dégénératif qui précède l'apparition des symptômes du FXTAS. - Multimodal brain imaging is becoming a leading tool for understanding different aspects of brain structure and function. Thanks to the advances in Magnetic Resonance imaging (MRI) acquisition schemes and data processing techniques, it is now possible to measure different parameters sensitive to different tissue characteristics. This allows for example to investigate anatomical substrates underlying cognitive processing, or to disentangle, at a pure structural level degeneration and developmental processes. This thesis highlights the importance of using a multimodal approach for investigating different aspects of brain dynamics by applying this approach to two clinical studies: functional and structural assessment of the acute effects of cannabis smoking in regular and occasional users, and grey and white matter assessment in young FMR1 premutation carriers at risk of developing FXTAS. We demonstrate that in occasional smokers cannabis smoking, even at low concentration of the main psychoactive component (THC) in the blood, strongly decrease subjects' performance on a visuo-motor tracking task, and globally alters the activity of the three brain networks involved in cognitive processing: the Salience, the Control Executive, and the Default Mode networks. Subjects are unable to capture saliences in the environment and to orient attention to the task; the increase in Hemodynamic Response in the Anterior Cingulate Cortex suggests an increase in self-oriented mental activity. A further investigation on long term exposure to cannabis, shows a persistent grey matter modification in brain regions associated with memory and affective processing. The degree of atrophy in these structures also correlates with the estimation of drug use in the three months prior the participation to the study. In the second study we demonstrate structural changes in young asymptomatic premutation carriers decades before the onset of FXTAS that might be related to two different mechanisms. Alteration of the cerebellar motor network and of the hippocampal fimbria/ fornix, may reflect a potential neurodevelopmental effect of the premutation. These include grey matter atrophy in lobule VI and modification of white matter tissue property in the corresponding afferent projections through the Middle Cerebellar Peduncles. Diffuse hemispheric white matter lesions that seem to appear closer to the onset of FXTAS and be related to a neurodegenerative phenomenon may mark the imminent onset of FXTAS.

Is blood still thicker than water? A life-course perspective on the transformation of family and friends' roles in personal networks

This thesis addresses the issue of the moving boundaries between family and friends' roles in personal networks, adopting a life-course perspective and using Switzerland as a case study. In a period of major changes in personal life happening in contemporary Western societies, understanding the organization of personal networks intertwined with the unfolding of individual life courses is of prime importance in facing new challenges with regard to social integration. The data stem from a representative national survey carried out in 2011 named Family tiMes, including 803 individuals born either in 1950-1955 or in 1970-1975. An innovative research design was adopted, combing cross-sectional ego-centered network data and retrospective longitudinal life-course data. The results show continuing boundaries between family and friends' roles and that family keeps a prominent role in personal networks despite the notable importance of friendship ties. One relationship stands out above all, that with the partner, followed quite a few steps behind by those with children. Regarding life courses, de-standardization tendencies were found in family formation and also a persistent gendering of occupational trajectories. Two kinds of life trajectories are particularly intertwined with personal networks, co-residence and partnership trajectories, both related to the unfolding of family life. In particular, transition to parenthood functions as a turning point in individuals' lives, deeply transforming their sociability. Finally, a twofold pluralization process was identified, affecting simultaneously the organization of personal networks and the unfolding of individual life courses. This thesis contributes to the literature on the sociology of family and personal life, and to fruitful interlinkage between the network approach and the life-course perspective.

Structural Brain Connectivity in School-Age Preterm Infants Provides Evidence for Impaired Networks Relevant for Higher Order Cognitive Skills and Social Cognition.

Extreme prematurity and pregnancy conditions leading to intrauterine growth restriction (IUGR) affect thousands of newborns every year and increase their risk for poor higher order cognitive and social skills at school age. However, little is known about the brain structural basis of these disabilities. To compare the structural integrity of neural circuits between prematurely born controls and children born extreme preterm (EP) or with IUGR at school age, long-ranging and short-ranging connections were noninvasively mapped across cortical hemispheres by connection matrices derived from diffusion tensor tractography. Brain connectivity was modeled along fiber bundles connecting 83 brain regions by a weighted characterization of structural connectivity (SC). EP and IUGR subjects, when compared with controls, had decreased fractional anisotropy-weighted SC (FAw-SC) of cortico-basal ganglia-thalamo-cortical loop connections while cortico-cortical association connections showed both decreased and increased FAw-SC. FAw-SC strength of these connections was associated with poorer socio-cognitive performance in both EP and IUGR children.

Beyond contact-based transmission networks: the role of spatial coincidence.

Animal societies rely on interactions between group members to effectively communicate and coordinate their actions. To date, the transmission properties of interaction networks formed by direct physical contacts have been extensively studied for many animal societies and in all cases found to inhibit spreading. Such direct interactions do not, however, represent the only viable pathways. When spreading agents can persist in the environment, indirect transmission via 'same-place, different-time' spatial coincidences becomes possible. Previous studies have neglected these indirect pathways and their role in transmission. Here, we use rock ant colonies, a model social species whose flat nest geometry, coupled with individually tagged workers, allowed us to build temporally and spatially explicit interaction networks in which edges represent either direct physical contacts or indirect spatial coincidences. We show how the addition of indirect pathways allows the network to enhance or inhibit the spreading of different types of agent. This dual-functionality arises from an interplay between the interaction-strength distribution generated by the ants' movement and environmental decay characteristics of the spreading agent. These findings offer a general mechanism for understanding how interaction patterns might be tuned in animal societies to control the simultaneous transmission of harmful and beneficial agents.

La collaboration interprofessionnelle à l'interface des institutions socio-éducative et psychiatrique. Jeux et enjeux de l'intervention auprès de personnes en situation de handicap mental et de troubles psychiques

La prise en charge et le suivi de personnes en situation de handicap mental souffrant de troubles psychiques et se trouvant donc à l'interface des domaines socio:éducatif et psychiatrique, constituent des défis complexes en matière de collaboration interprofessionnelle. Dans le canton de Vaud, les acteurs concernés par ce problème s'efforcent depuis de nombreuses années de créer des réseaux pluridisciplinaires visant un meilleur échange entre professionnels et le développement de compétences et de connaissances permettant d'améliorer le bien:être des bénéficiaires. Ce travail se propose ainsi d'étudier et de questionner ces modalités de travail dans une perspective socioculturelle (Vygotski, 1934/1997), afin d'en comprendre le fonctionnement, d'en éclairer les mécanismes et de fournir des pistes de réflexion aux professionnels. Il repose sur un travail de terrain mené auprès des membres du Dispositif de Collaboration Psychiatrie Handicap Mental (DCPHM) du Département de psychiatrie du CHUV, dont la mission principale est de faciliter la collaboration entre les institutions socio:éducatives et psychiatriques spécialisées dans le suivi des personnes en situation de handicap mental et souffrant de troubles psychiques. Le travail empirique est basé sur une approche qualitative et compréhensive des interactions sociales, et procède par une étude de terrain approfondie. Les données recueillies sont variées : notes de terrain et récolte de documentation, enregistrement de réunions d'équipe au sein du DCPHM et de réunions de réseau, et entretiens de différents types. L'analyse montre que le travail de collaboration qui incombe à l'équipe est constitué d'obstacles qui sont autant d'occasions de développement professionnel et de construction identitaire. Les résultats mettent en lumière des mécanismes discursifs de catégorisation concourant à la fois à la construction des patients comme objets d'activité, et à la construction d'une place qui légitime les interventions de l'équipe dans le paysage socio:éducatif et psychiatrique vaudois et la met au centre de l'arène professionnelle. -- Care and follow:up for people with mental disabilities suffering from psychological disorders : therefore at the interface between the socio:educational and psychiatric fields : represent complex challenges in terms of interprofessional collaboration. In the canton of Vaud, the caregivers involved in this issue have been trying for years to build multidisciplinary networks in order to better exchange between professionals and develop skills and knowledge to improve the recipients' well:being. This work thus proposes to study and question these working methods in a sociocultural perspective (Vygotski, 1934/1997) so as to understand how they operate, highlight inherent mechanisms and provide actionable insights to the professionals. It is based on fieldwork conducted among members of the Dispositif de Collaboration Psychiatrie Handicap Mental (DCPHM), of the Psychiatry Department at the CHUV University Hospital in Lausanne, whose main mission is to facilitate collaboration between the socio:educational and psychiatric institutions specialising in monitoring people presenting with both mental handicap and psychiatric disorder. The empirical work is based on a qualitative and comprehensive approach to social interactions, and conducted based on an in:depth field study. The data collected are varied - field notes and documentation collection, recordings of team meetings within the DCPHM and network meetings, and various types of interviews. The analysis shows that the collaborative work that befalls the team consists of obstacles, all of which provide opportunities for professional development and identity construction. The results highlight discursive strategies of categorisation which contribute both to the construction of the patients as objects of activity and to building a position that legitimates the team's interventions in the socio: educational and psychiatric landscape of canton Vaud and puts it in the centre of the professional arena.