Divinyl ether fatty acid synthesis in late blight-diseased potato leaves.

We conducted a study of the patterns and dynamics of oxidized fatty acid derivatives (oxylipins) in potato leaves infected with the late-blight pathogen Phytophthora infestans. Two 18-carbon divinyl ether fatty acids, colneleic acid and colnelenic acid, accumulated during disease development. To date, there are no reports that such compounds have been detected in higher plants. The divinyl ether fatty acids accumulate more rapidly in potato cultivar Matilda (a cultivar with increased resistance to late blight) than in cultivar Bintje, a susceptible cultivar. Colnelenic acid reached levels of up to approximately 24 nmol (7 microgram) per g fresh weight of tissue in infected leaves. By contrast, levels of members of the jasmonic acid family did not change significantly during pathogenesis. The divinyl ethers also accumulated during the incompatible interaction of tobacco with tobacco mosaic virus. Colneleic and colnelenic acids were found to be inhibitory to P. infestans, suggesting a function in plant defense for divinyl ethers, which are unstable compounds rarely encountered in biological systems.

Magnetic pill tracking : a novel non-invasive tool for investigation of human digestive motility

RESUME Les améliorations méthodologiques des dernières décennies ont permis une meilleure compréhension de la motilité gastro-intestinale. Il manque toutefois une méthode qui permette de suivre la progression du chyme le long du tube gastro-intestinal. Pour permettre l'étude de la motilité de tout le tractus digestif humain, une nouvelle technique, peu invasive, a été élaborée au Département de Physiologie, en collaboration avec l'EPFL. Appelée "Magnet Tracking", la technique est basée sur la détection du champ magnétique généré par des matériaux ferromagnétiques avalés. A cet usage, une pilule magnétique, une matrice de capteurs et un logiciel ont été développés. L'objet de ce travail est de démontrer la faisabilité d'un examen de la motilité gastro-intestinale chez l'Homme par cette méthode. L'aimant est un cylindre (ø 6x7 mm, 0.2 cm3) protégé par une gaine de silicone. Le système de mesure est constitué d'une matrice de 4x4 capteurs et d'un ordinateur portable. Les capteurs fonctionnent sur l'effet Hall. Grâce à l'interface informatique, l'évolution de la position de l'aimant est suivie en temps réel à travers tout le tractus digestif. Sa position est exprimée en fonction du temps ou reproduite en 3-D sous forme d'une trajectoire. Différents programmes ont été crées pour analyser la dynamique des mouvements de l'aimant et caractériser la motilité digestive. Dix jeunes volontaires en bonne santé ont participé à l'étude. L'aimant a été avalé après une nuit de jeûne et son séjour intra digestif suivi pendant 2 jours consécutifs. Le temps moyen de mesure était de 34 heures. Chaque sujet a été examiné une fois sauf un qui a répété sept fois l'expérience. Les sujets restaient en décubitus dorsal, tranquilles et pouvaient interrompre la mesure s'ils le désiraient. Ils sont restés à jeûne le premier jour. L'évacuation de l'aimant a été contrôlée chez tous les sujets. Tous les sujets ont bien supporté l'examen. Le marqueur a pu être détecté de l'oesophage au rectum. La trajectoire ainsi constituée représente une conformation de l'anatomie digestive : une bonne superposition de celle-ci à l'anatomie est obtenue à partir des images de radiologie conventionnelle (CT-scan, lavement à la gastrografine). Les mouvements de l'aimant ont été caractérisés selon leur périodicité, leur amplitude ou leur vitesse pour chaque segment du tractus digestif. Ces informations physiologiques sont bien corrélées à celles obtenues par des méthodes établies d'étude de la motilité gastro-intestinale. Ce travail démontre la faisabilité d'un examen de la motilité gastro-intestinal chez l'Homme par la méthode de Magnet Tracking. La technique fournit les données anatomiques et permet d'analyser en temps réel la dynamique des mouvements du tube digestif. Cette méthode peu invasive ouvre d'intéressantes perspectives pour l'étude de motilité dans des conditions physiologiques et pathologiques. Des expériences visant à valider cette approche en tant que méthode clinique sont en voie de réalisation dans plusieurs centres en Suisse et à l'étranger. SUMMARY Methodological improvements realised over the last decades have permitted a better understanding of gastrointestinal motility. Nevertheless, a method allowing a continuous following of lumina' contents is still lacking. In order to study the human digestive tract motility, a new minimally invasive technique was developed at the Department of Physiology in collaboration with Swiss Federal Institute of Technology. The method is based on the detection of magnetic field generated by swallowed ferromagnetic materials. The aim of our work was to demonstrate the feasibility of this new approach to study the human gastrointestinal motility. The magnet used was a cylinder (ø6x7mm, 0.2 cm3) coated with silicon. The magnet tracking system consisted of a 4x4 matrix of sensors based on the Hall effect Signals from the sensors were digitised and sent to a laptop computer for processing and storage. Specific software was conceived to analyse in real time the progression of the magnet through the gastrointestinal tube. Ten young and healthy volunteers were enrolled in the study. After a fasting period of 12 hours, they swallowed the magnet. The pill was then tracked for two consecutive days for 34 hours on average. Each subject was studied once except one who was studied seven times. Every subject laid on his back for the entire experiment but could interrupt it at anytime. Evacuation of the magnet was controlled in all subjects. The examination was well tolerated. The pill could be followed from the esophagus to the rectum. The trajectory of the magnet represented a "mould" of the anatomy of the digestive tube: a good superimposition with radiological anatomy (gastrografin contrast and CT) was obtained. Movements of the magnet were characterized by periodicity, velocity, and amplitude of displacements for every segment of the digestive tract. The physiological information corresponded well to data from current methods of studying gastrointestinal motility. This work demonstrates the feasibility of the new approach in studies of human gastrointestinal motility. The technique allows to correlate in real time the dynamics of digestive movements with the anatomical data. This minimally invasive method is ready for studies of human gastrointestinal motility under physiological as well as pathological conditions. Studies aiming at validation of this new approach as a clinically relevant tool are being realised in several centres in Switzerland and abroad. Abstract: A new minimally invasive technique allowing for anatomical mapping and motility studies along the entire human digestive system is presented. The technique is based on continuous tracking of a small magnet progressing through the digestive tract. The coordinates of the magnet are calculated from signals recorded by 16 magnetic field sensors located over the abdomen. The magnet position, orientation and trajectory are displayed in real time. Ten young healthy volunteers were followed during 34 h. The technique was well tolerated and no complication was encountered, The information obtained was 3-D con-figuration of the digestive tract and dynamics of the magnet displacement (velocity, transit time, length estimation, rhythms). In the same individual, repea-ted examination gave very reproducible results. The anatomical and physiological information obtained corresponded well to data from current methods and imaging. This simple, minimally invasive technique permits examination of the entire digestive tract and is suitable for both research and clinical studies. In combination with other methods, it may represent a useful tool for studies of Cl motility with respect to normal and pathological conditions.

Contribution of recombination to the evolutionary history of HIV.

PURPOSE OF REVIEW: An improved understanding of how recombination affects the evolutionary history of HIV is crucial to understand its current and future evolution. The present review aims to disentangle the manifold effects of recombination on HIV by discussing its effects on the evolutionary history and the adaptive potential of HIV in the context of concepts from evolutionary genetics and genomics. RECENT FINDINGS: The increasing occurrence of secondary contacts between divergent subtype populations (during coinfection) results in increased observations of recombinants worldwide. Recombination is heterogeneous along the HIV genome. Consequences of recombination of HIV evolution are, in combination with other demographic processes, expected to either homogenize the genetic composition of HIV populations (homogenization) or provide the potential for novel adaptations (diversification). New methods in population genomics allow deep characterization of recombinant genome (the segment composition and origin) and their evolutionary trajectories. SUMMARY: HIV recombinants increase worldwide and invade geographical regions where pure subtypes were previously predominant. This trend is expected to continue in the future, as ease to travel worldwide increases opportunities for recombination between divergent HIV strains. While the effects of recombination in HIV are much researched, more effort is required to characterize current HIV recombinant composition and dynamics. This can be achieved with new population genetic and genomic methods.

Assignment strategies for large proteins by magic-angle spinning NMR: the 21-kDa disulfide-bond-forming enzyme DsbA.

We present strategies for chemical shift assignments of large proteins by magic-angle spinning solid-state NMR, using the 21-kDa disulfide-bond-forming enzyme DsbA as prototype. Previous studies have demonstrated that complete de novo assignments are possible for proteins up to approximately 17 kDa, and partial assignments have been performed for several larger proteins. Here we show that combinations of isotopic labeling strategies, high field correlation spectroscopy, and three-dimensional (3D) and four-dimensional (4D) backbone correlation experiments yield highly confident assignments for more than 90% of backbone resonances in DsbA. Samples were prepared as nanocrystalline precipitates by a dialysis procedure, resulting in heterogeneous linewidths below 0.2 ppm. Thus, high magnetic fields, selective decoupling pulse sequences, and sparse isotopic labeling all improved spectral resolution. Assignments by amino acid type were facilitated by particular combinations of pulse sequences and isotopic labeling; for example, transferred echo double resonance experiments enhanced sensitivity for Pro and Gly residues; [2-(13)C]glycerol labeling clarified Val, Ile, and Leu assignments; in-phase anti-phase correlation spectra enabled interpretation of otherwise crowded Glx/Asx side-chain regions; and 3D NCACX experiments on [2-(13)C]glycerol samples provided unique sets of aromatic (Phe, Tyr, and Trp) correlations. Together with high-sensitivity CANCOCA 4D experiments and CANCOCX 3D experiments, unambiguous backbone walks could be performed throughout the majority of the sequence. At 189 residues, DsbA represents the largest monomeric unit for which essentially complete solid-state NMR assignments have so far been achieved. These results will facilitate studies of nanocrystalline DsbA structure and dynamics and will enable analysis of its 41-kDa covalent complex with the membrane protein DsbB, for which we demonstrate a high-resolution two-dimensional (13)C-(13)C spectrum.

How useful is satellite positioning system (GPS) to track gait parameters? A review.

Over the last century, numerous techniques have been developed to analyze the movement of humans while walking and running. The combined use of kinematics and kinetics methods, mainly based on high speed video analysis and forceplate, have permitted a comprehensive description of locomotion process in terms of energetics and biomechanics. While the different phases of a single gait cycle are well understood, there is an increasing interest to know how the neuro-motor system controls gait form stride to stride. Indeed, it was observed that neurodegenerative diseases and aging could impact gait stability and gait parameters steadiness. From both clinical and fundamental research perspectives, there is therefore a need to develop techniques to accurately track gait parameters stride-by-stride over a long period with minimal constraints to patients. In this context, high accuracy satellite positioning can provide an alternative tool to monitor outdoor walking. Indeed, the high-end GPS receivers provide centimeter accuracy positioning with 5-20 Hz sampling rate: this allows the stride-by-stride assessment of a number of basic gait parameters--such as walking speed, step length and step frequency--that can be tracked over several thousand consecutive strides in free-living conditions. Furthermore, long-range correlations and fractal-like pattern was observed in those time series. As compared to other classical methods, GPS seems a promising technology in the field of gait variability analysis. However, relative high complexity and expensiveness--combined with a usability which requires further improvement--remain obstacles to the full development of the GPS technology in human applications.

Visuo-motor pathways in humans revealed by event-related fMRI.

Whether different brain networks are involved in generating unimanual responses to a simple visual stimulus presented in the ipsilateral versus contralateral hemifield remains a controversial issue. Visuo-motor routing was investigated with event-related functional magnetic resonance imaging (fMRI) using the Poffenberger reaction time task. A 2 hemifield x 2 response hand design generated the "crossed" and "uncrossed" conditions, describing the spatial relation between these factors. Both conditions, with responses executed by the left or right hand, showed a similar spatial pattern of activated areas, including striate and extrastriate areas bilaterally, SMA, and M1 contralateral to the responding hand. These results demonstrated that visual information is processed bilaterally in striate and extrastriate visual areas, even in the "uncrossed" condition. Additional analyses based on sorting data according to subjects' reaction times revealed differential crossed versus uncrossed activity only for the slowest trials, with response strength in infero-temporal cortices significantly correlating with crossed-uncrossed differences (CUD) in reaction times. Collectively, the data favor a parallel, distributed model of brain activation. The presence of interhemispheric interactions and its consequent bilateral activity is not determined by the crossed anatomic projections of the primary visual and motor pathways. Distinct visuo-motor networks need not be engaged to mediate behavioral responses for the crossed visual field/response hand condition. While anatomical connectivity heavily influences the spatial pattern of activated visuo-motor pathways, behavioral and functional parameters appear to also affect the strength and dynamics of responses within these pathways.

IDENTITÉ, PROJET, CHANGEMENT : DES REPRÉSENTATIONS SOCIALES AUX LEVIERS DE L'ACTION PUBLIQUE. POUR UN MODE DE GOUVERNANCE AXÉ SUR LE DÉVELOPPEMENT TERRITORIAL. ETUDE DE CAS : CANTON DU JURA (SUISSE)

Thirty years after the Canton of Jura entered sovereignty, it has to be admited that the creation of the newly canton did't fullfill the hopes of economic and demografic growth that many could have expected from political independance. Through a plurality of complementary approaches, the research suggest a closer look at, on one hand, the position of the Canton in its territorial context as well as its structure and dynamics and on the other hand, the representations of the territory and its evolution by the social actors. This in order to formulate a set of social demands (of debate, of openness and of overcoming cleavages) which augurs for a new territoriality regime and testify of a requirement of reflexivity toward the state institutions and actions. The analysis allowed to set in evidence the central role of the couple identity-project in the dynamics of change, and to identifiy three main periods in the recent past of the Canton: a period of territorialization, during which grew a strong collective identity, coupled with a major project of society (the creation of the canton of Jura); then followed a period of deterritorialization, with the fragmentation of the collective identity and the lack of a project of society. Then, the third period, with a paradoxical event, the failure in public vote of the the project Jura open Land (Jura Pays ouvert), which was meant to give a second wind to the Canton. We consider this turning point as the start of a new period (of reterritorialization), with an issue linked with the outlines of a renewed "jurassian" identity and the elaboration of a shared territory project.Trente ans après l'entrée en souveraineté, force est de constater que la création du canton du Jura n'a pas permis de répondre aux espérances de développement économique et démographique que l'indépendance politique devait entraîner dans son sillage. Cette recherche se propose, à travers une pluralité d'approches complémentaires, d'examiner d'une part la position du Canton dans son contexte territorial ainsi que sa structure et sa dynamique; d'autre part, les représentations que se font les acteurs du territoire et de son évolution, pour déboucher sur une série de demandes sociales (de débat, d'ouverture et de dépassement des clivages) qui augurent de la transition vers un nouveau régime de territorialité et témoignent d'une exigence de réflexivité envers les institutions et les actions de l'Etat. L'analyse a permis de mettre en évidence le rôle central du couple identité-projet dans la dynamique de changement et d'identifier trois temps forts dans l'évolution récente du Canton, une phase de territorialisation au cours de laquelle s'est constituée une identité forte doublée d'un projet de société majeur, suivie d'une phase de déterritorialisation avec une fragmentation de l'identité collective et l'absence de projet mobilisateur. Enfin, un moment paradoxal, l'échec du projet Jura Pays ouvert, censé redonner un second souffle au Canton, qui amorce une nouvelle étape (de reterritorialisation) avec un questionnement lié aux contours d'une identité jurassienne renouvelée et à l'élaboration d'un projet de territoire partagé.Les ressorts de la production du territoire et de son développement sont analysés à travers le rôle des représentations sociales dans la constitution identitaire et le projet territorial, à l'exemple du canton du Jura. La mise en évidence du rôle central du couple identité-projet dans la dynamique de changement a permis d'identifier trois temps forts dans l'évolution récente du Canton. Une première phase (la création du canton du Jura), au cours de laquelle s'est constituée une identité forte doublée d'un projet de société majeur, suivie d'une phase au cours de laquelle l'identité collective s'est fragmentée en l'absence de projet mobilisateur (la phase de « gestion » de l'Etat). Puis un moment de rupture (l'échec du projet Jura Pays ouvert) et l'amorce d'une transition vers une nouvelle étape, avec un questionnement lié aux contours d'une identité jurassienne renouvelée, à l'élaboration d'un projet de territoire partagé, et à l'action des pouvoirs publics dans un contexte de repositionnement du Canton.

Objective evaluation of shoulder function using body-fixed sensors: a new way to detect early treatment failures?

Background: Variable definitions of outcome (Constant score, Simple Shoulder Test [SST]) have been used to assess outcome after shoulder treatment, although none has been accepted as the universal standard. Physicians lack an objective method to reliably assess the activity of their patients in dynamic conditions. Our purpose was to clinically validate the shoulder kinematic scores given by a portable movement analysis device, using the activities of daily living described in the SST as a reference. The secondary objective was to determine whether this device could be used to document the effectiveness of shoulder treatments (for glenohumeral osteoarthritis and rotator cuff disease) and detect early failures.Methods: A clinical trial including 34 patients and a control group of 31 subjects over an observation period of 1 year was set up. Evaluations were made at baseline and 3, 6, and 12 months after surgery by 2 independent observers. Miniature sensors (3-dimensional gyroscopes and accelerometers) allowed kinematic scores to be computed. They were compared with the regular outcome scores: SST; Disabilities of the Arm, Shoulder and Hand; American Shoulder and Elbow Surgeons; and Constant.Results: Good to excellent correlations (0.61-0.80) were found between kinematics and clinical scores. Significant differences were found at each follow-up in comparison with the baseline status for all the kinematic scores (P < .015). The kinematic scores were able to point out abnormal patient outcomes at the first postoperative follow-up.Conclusion: Kinematic scores add information to the regular outcome tools. They offer an effective way to measure the functional performance of patients with shoulder pathology and have the potential to detect early treatment failures.Level of evidence: Level II, Development of Diagnostic Criteria, Diagnostic Study. (C) 2011 Journal of Shoulder and Elbow Surgery Board of Trustees.

Reggies/flotillins regulate E-cadherin-mediated cell contact formation by affecting EGFR trafficking.

The reggie/flotillin proteins are implicated in membrane trafficking and, together with the cellular prion protein (PrP), in the recruitment of E-cadherin to cell contact sites. Here, we demonstrate that reggies, as well as PrP down-regulation, in epithelial A431 cells cause overlapping processes and abnormal formation of adherens junctions (AJs). This defect in cell adhesion results from reggie effects on Src tyrosine kinases and epidermal growth factor receptor (EGFR): loss of reggies reduces Src activation and EGFR phosphorylation at residues targeted by Src and c-cbl and leads to increased surface exposure of EGFR by blocking its internalization. The prolonged EGFR signaling at the plasma membrane enhances cell motility and macropinocytosis, by which junction-associated E-cadherin is internalized and recycled back to AJs. Accordingly, blockage of EGFR signaling or macropinocytosis in reggie-deficient cells restores normal AJ formation. Thus, by promoting EGFR internalization, reggies restrict the EGFR signaling involved in E-cadherin macropinocytosis and recycling and regulate AJ formation and dynamics and thereby cell adhesion.

Transcranial direct current stimulation for the treatment of focal hand dystonia.

The treatment of writer's cramp, a task-specific focal hand dystonia, needs new approaches. A deficiency of inhibition in the motor cortex might cause writer's cramp. Transcranial direct current stimulation modulates cortical excitability and may provide a therapeutic alternative. In this randomized, double-blind, sham-controlled study, we investigated the efficacy of cathodal stimulation of the contralateral motor cortex in 3 sessions in 1 week. Assessment over a 2-week period included clinical scales, subjective ratings, kinematic handwriting analysis, and neurophysiological evaluation. Twelve patients with unilateral dystonic writer's cramp were investigated; 6 received transcranial direct current and 6 sham stimulation. Cathodal transcranial direct current stimulation had no favorable effects on clinical scales and failed to restore normal handwriting kinematics and cortical inhibition. Subjective worsening remained unexplained, leading to premature study termination. Repeated sessions of cathodal transcranial direct current stimulation of the motor cortex yielded no favorable results supporting a therapeutic potential in writer's cramp.

Evolutionary ecology of the colour-dimorphic rewardless orchid "Dactylorhiza sambucina"

Abstract Phenotypic polymorphism is an ideal system to study natural selection in wild populations, because it allows tracking population genetic changes by means of phenotypic changes. A wide variety of polymorphic traits have been studied in numerous animals and plants, as for example colour patterns in moths, snails and birds, human laterality, male reproductive strategies, plant morphology or mating systems. This thesis focused on Dactylorhiza sarnbucina, a rewardless European orchid species, showing a striking flower colour polymorphism, with either yellow or red flowered individuals co-occurring in natural populations. Several studies have investigated its evolutionary ecology since Nilsson's seminal paper in 1980, with a particular emphasis in the evolution and maintenance of its colour polymorphism. One of the main selective forces proposed to maintain this colour polymorphism was pollinator driven negative frequency-dependent selection (NFDS), when each morph is advantaged when rare, and comparatively disadvantaged when common. However, other investigators have recently questioned the occurrence of NFDS, and proposed alternatively that fluctuating selection may maintain this colour polymorphism. In this thesis, we aimed at reviewing and synthesizing these different studies, and also brought our contribution on D. sambucina reproductive ecology. Because numerous hypotheses have still to be tested, we concluded by saying that we are a long way from understanding the evolution and dynamics of colour polymorphism in natural D. sambucina populations. Beside the debated question of colour polymorphism maintenance, one question remained to be tested: what are the consequences of polymorphism per se. We experimentally addressed this question using artificial populations of D. sambucina, and found no relationship between population phenotypic diversity and orchid pollination success. This finding suggest that polymorphism itself was not an advantage for deceptive species such D sambucina, contrarily to the expectations. Finally, we suggest potential research perspectives that could allow a better understanding of the evolutionary ecology of this species. Résumé Le polymorphisme phénotypique est un système biologique idéal pour étudier l'action de la sélection en populations naturelles, grâce à la possibilité de suivre les changements génétiques de la population en étudiant les phénotypes des individus. De très nombreuses études ont montré du polymorphisme phénotypique chez les animaux, par exemple la latéralité chez l'Homme, la coloration des escargots ou des oiseaux. Dans le règne végétal, le polymorphisme est souvent associé à des traits du système de reproduction. Cette thèse est centrée sur une espèce d'orchidée Européenne qui ne produit pas de nectar, Dactylorhiza sambucina. Cette espèce présente des individus à fleurs jaunes et des individus à fleurs rouge, généralement présents en mélange dans les populations naturelles. Plusieurs études ont investigué l'écologie évolutive de cette espèce depuis 25 ans, avec comme thème central l'évolution et le maintien de ce polymorphisme. La principale force sélective proposée pour maintenir ce polymorphisme de couleur est la sélection fréquence-dépendante, exercée par le comportement des pollinisateurs. Chacun des deux variants de couleur est favorisé quand il est rare, et défavorisé quand il devient commun. Bien que ce mécanisme semble agir, certains auteurs doutent de son importance, et ont proposé que les variations temporelles ou spatiales des forces de sélection puisse maintenir le polymorphisme de couleur chez D. sambucina. Dans cette thèse, nous avons voulu résumer et synthétiser les résultats de ces différentes études, et aussi présenter des données nouvelles concernant la reproduction de cette espèce. À la vue de ces résultats, il apparait que de nombreux points nécessitent des expériences complémentaires, et que la compréhension de ce système biologique est encore fragmentaire. Nous nous sommes également intéressés à une question laissée en suspens dans la littérature: le polymorphisme de couleur en soit confère-t-il un avantage à l'espèce, comme proposé par certains auteurs? En construisant des populations artificielles de D. sambucina, nous avons pu montrer que le polymorphisme de couleur n'augmente pas le succès reproducteur de l'espèce. Nous terminons ce travail de recherche en proposant plusieurs axes de recherche pouvant conduire à une meilleure compréhension de l'écologie et de l'évolution de cette espèce.

Social trust : a public good?

Combining theories on social trust and social capital with sociopsychological approaches and applying contextual analyses to Swiss and European survey data, this thesis examines under what circumstances generalised trust, often understood as public good, may not benefit everyone, but instead amplify inequality. The empirical investigation focuses on the Swiss context, but considers different scales of analysis. Two broader questions are addressed. First, might generalised trust imply more or less narrow visions of community and solidarity in different contexts? Applying nonlinear principal component analysis to aggregate indicators, Study 1 explores inclusive and exclusive types of social capital in Europe, measured as regional configurations of generalised trust, civic participation and attitudes towards diversity. Study 2 employs multilevel models to examine how generalised trust, as an individual predisposition and an aggregate climate at the level of Swiss cantons, is linked to equality- directed collective action intention versus radical right support. Second, might high-trust climates impact negatively on disadvantaged members of society, precisely because they reflect a normative discourse of social harmony that impedes recognition of inequality? Study 3 compares how climates of generalised trust at the level of Swiss micro-regions and subjective perceptions of neighbourhood cohesion moderate the negative relationship between socio-economic disadvantage and mental health. Overall, demonstrating beneficial, as well as counterintuitive effects of social trust, this thesis proposes a critical and contextualised approach to the sources and dynamics of social cohesion in democratic societies. -- Cette thèse combine des théories sur le capital social et la confiance sociale avec des approches psychosociales et s'appuie sur des analyses contextuelles de données d'enquêtes suisses et européennes, afin d'étudier dans quelles circonstances la confiance généralisée, souvent présentée comme un bien public, pourrait ne pas bénéficier à tout le monde, mais amplifier les inégalités. Les études empiriques, centrées sur le contexte suisse, intègrent différentes échelles d'analyse et investiguent deux questions principales. Premièrement, la confiance généralisée implique-t-elle des visions plus ou moins restrictives de la communauté et de la solidarité selon le contexte? Dans l'étude 1, une analyse à composantes principales non-linéaire sur des indicateurs agrégés permet d'explorer des types de capital social inclusif et exclusif en Europe, mesurés par des configurations régionales de confiance généralisée, de participation civique, et d'attitudes envers la diversité. L'étude 2 utilise des modèles multiniveaux afin d'analyser comment la confiance généralisée, en tant que prédisposition individuelle et climat agrégé au niveau des cantons suisses, est associée à l'intention de participer à des actions collectives en faveur de l'égalité ou, au contraire, à l'intention de voter pour la droite radicale. Deuxièmement, des climats de haute confiance peuvent-ils avoir un impact négatif sur des membres désavantagés de la société, précisément parce qu'ils reflètent un discours normatif d'harmonie sociale qui empêche la reconnaissance des inégalités? L'étude 3 analyse comment des climats de confiance au niveau des micro-régions suisses et la perception subjective de faire partie d'un environnement cohésif modèrent la relation négative entre le désavantage socio-économique et la santé mentale. En démontrant des effets bénéfiques mais aussi contre-intuitifs de la confiance sociale, cette thèse propose une approche critique et contextualisée des sources et dynamiques de la cohésion sociale dans les sociétés démocratiques.

Dynamic single cell measurements of kinase activity by synthetic kinase activity relocation sensors.

BACKGROUND: Mitogen activated protein kinases (MAPK) play an essential role in integrating extra-cellular signals and intra-cellular cues to allow cells to grow, adapt to stresses, or undergo apoptosis. Budding yeast serves as a powerful system to understand the fundamental regulatory mechanisms that allow these pathways to combine multiple signals and deliver an appropriate response. To fully comprehend the variability and dynamics of these signaling cascades, dynamic and quantitative single cell measurements are required. Microscopy is an ideal technique to obtain these data; however, novel assays have to be developed to measure the activity of these cascades. RESULTS: We have generated fluorescent biosensors that allow the real-time measurement of kinase activity at the single cell level. Here, synthetic MAPK substrates were engineered to undergo nuclear-to-cytoplasmic relocation upon phosphorylation of a nuclear localization sequence. Combination of fluorescence microscopy and automated image analysis allows the quantification of the dynamics of kinase activity in hundreds of single cells. A large heterogeneity in the dynamics of MAPK activity between individual cells was measured. The variability in the mating pathway can be accounted for by differences in cell cycle stage, while, in the cell wall integrity pathway, the response to cell wall stress is independent of cell cycle stage. CONCLUSIONS: These synthetic kinase activity relocation sensors allow the quantification of kinase activity in live single cells. The modularity of the architecture of these reporters will allow their application in many other signaling cascades. These measurements will allow to uncover new dynamic behaviour that previously could not be observed in population level measurements.