Administration intra-vitréenne de liposomes pour la vectorisation de principes actifs [The use of liposomes as intravitreal drug delivery system].

Liposomes are vesicular lipidic systems allowing encapsulation of drugs. This article reviews the relevant issues in liposome structure (composition and size), and their influence on intravitreal pharmacokinetics. Liposome-mediated drug delivery to the posterior segment of the eye via intravitreal administration has been addressed by several authors and remains experimental. Liposomes have been used for intravitreal delivery of antibiotics, antivirals, antifungal drugs, antimetabolites, and cyclosporin. Encapsulation of these drugs within liposomes markedly increased their intravitreal half-life, and reduced their retinal toxicity. Liposomes have also shown an attractive potential for retinal gene transfer by intravitreal delivery of plasmids or oligonucleotides.

Relatedness among arbuscular mycorrhizal fungi drives plant growth and intraspecific fungal coexistence.

Arbuscular mycorrhizal fungi (AMF) form symbioses with most plant species. They are ecologically important determinants of plant growth and diversity. Considerable genetic variation occurs in AMF populations. Thus, plants are exposed to AMF of varying relatedness to each other. Very little is known about either the effects of coexisting AMF on plant growth or which factors influence intraspecific AMF coexistence within roots. No studies have addressed whether the genetics of coexisting AMF, and more specifically their relatedness, influences plant growth and AMF coexistence. Relatedness is expected to influence coexistence between individuals, and it has been suggested that decreasing ability of symbionts to coexist can have negative effects on the growth of the host. We tested the effect of a gradient of AMF genetic relatedness on the growth of two plant species. Increasing relatedness between AMFs lead to markedly greater plant growth (27% biomass increase with closely related compared to distantly related AMF). In one plant species, closely related AMF coexisted in fairly equal proportions but decreasing relatedness lead to a very strong disequilibrium between AMF in roots, indicating much stronger competition. Given the strength of the effects with such a shallow relatedness gradient and the fact that in the field plants are exposed to a steeper gradient, we consider that AMF relatedness can have a strong role in plant growth and the ability of AMF to coexist. We conclude that AMF relatedness is a driver of plant growth and that relatedness is also a strong driver of intraspecific coexistence of these ecologically important symbionts.

L'évaluation actuarielle de la dangerosité: impasses éthiques et dérives sociétales

Le débat qui s'est instauré autour de l'évaluation de la dangerosité par des outils statistiques actuariels s'inscrit dans une évolution préoccupante des pratiques pénales et des attentes sociales. L'instauration de privations de liberté à durée indéterminée et l'utilisation de l'évaluation psychiatrique pour déterminer cette privation peuvent conduire à utiliser ces outils d'évaluation comme facteurs de stigmatisation et d'exclusion. Outils cliniques lorsqu'ils ont été créés, ils sont souvent utilisés comme supports de nouveaux modes de gestion des populations pénales. Ils peuvent aussi contribuer à un renforcement de la stigmatisation sociale à l'égard de la maladie psychique en assimilant celle-ci à un risque de violence. L'évaluation du risque de violence doit donc rester une pratique avant tout clinique où l'usage d'instruments d'aide à la réflexion garde sa pertinence, mais doit faire l'objet d'une interrogation éthique et de définition de règles de bonne pratique.

A 338-bp proximal fragment of the glucose transporter type 2 (GLUT2) promoter drives reporter gene expression in the pancreatic islets of transgenic mice.

The high Km glucose transporter GLUT2 is a membrane protein expressed in tissues involved in maintaining glucose homeostasis, and in cells where glucose-sensing is necessary. In many experimental models of diabetes, GLUT2 gene expression is decreased in pancreatic beta-cells, which could lead to a loss of glucose-induced insulin secretion. In order to identify factors involved in pancreatic beta-cell specific expression of GLUT2, we have recently cloned the murine GLUT2 promoter and identified cis-elements within the 338-bp of the proximal promoter capable of binding islet-specific trans-acting factors. Furthermore, in transient transfection studies, this 338-bp fragment could efficiently drive the expression of the chloramphenicol acetyl transferase (CAT) gene in cell lines derived from the endocrine pancreas, but displayed no promoter activity in non-pancreatic cells. In this report, we tested the cell-specific expression of a CAT reporter gene driven by a short (338 bp) and a larger (1311 bp) fragment of the GLUT2 promoter in transgenic mice. We generated ten transgenic lines that integrated one of the constructs. CAT mRNA expression in transgenic tissues was assessed using the RNAse protection assay and the quantitative reverse transcribed polymerase chain reaction (RT-PCR). Overall CAT mRNA expression for both constructs was low compared to endogenous GLUT2 mRNA levels but the reporter transcript could be detected in all animals in the pancreatic islets and the liver, and in a few transgenic lines in the kidney and the small intestine. The CAT protein was also present in Langerhans islets and in the liver for both constructs by immunocytochemistry. These findings suggest that the proximal 338 bp of the murine GLUT2 promoter contain cis-elements required for the islet-specific expression of GLUT2.

Viral superantigen drives extrafollicular and follicular B cell differentiation leading to virus-specific antibody production.

Mouse mammary tumor virus (MMTV[SW]) encodes a superantigen expressed by infected B cells. It evokes an antibody response specific for viral envelope protein, indicating selective activation of antigen-specific B cells. The response to MMTV(SW) in draining lymph nodes was compared with the response to haptenated chicken gamma globulin (NP-CGG) using flow cytometry and immunohistology. T cell priming occurs in both responses, with T cells proliferating in association with interdigitating dendritic cells in the T zone. T cell proliferation continues in the presence of B cells in the outer T zone, and B blasts then undergo exponential growth and differentiation into plasma cells in the medullary cords. Germinal centers develop in both responses, but those induced by MMTV(SW) appear later and are smaller. Most T cells activated in the T zone and germinal centers in the MMTV(SW) response are superantigen specific and these persist for weeks in lymph nodes draining the site MMTV(SW) injection: this contrasts with the selective loss of superantigen-specific T cells from other secondary lymphoid tissues. The results indicate that this viral superantigen, when expressed by professional antigen-presenting cells, drives extrafollicular and follicular B cell differentiation leading to virus-specific antibody production.

Predation drives interpopulation differences in parental care expression.

Expressing parental care after oviposition or parturition is usually an obligate (evolved) trait within a species, despite evolutionary theory predicting that widespread species should vary in whether or not they express parental care according to local selection pressures. The lizard Eutropis longicaudata expresses maternal care only in a single population throughout its large geographical range, but why this pattern occurs is unknown. We used reciprocal translocation and predator exclusion experiments to test whether this intraspecific variation is a fixed trait within populations and whether predator abundance explains this perplexing pattern. Wild-caught female lizards that were reciprocally translocated consistently guarded or abandoned eggs in line with their population of origin. By contrast, most lizards raised in a common garden environment and subsequently released as adults adopted the maternal care strategy of the recipient population, even when the parents originated from a population lacking maternal care. Egg predation represents a significant fitness cost in the populations where females display egg-guarding behaviour, but guarding eggs outweighs this potential cost by increasing hatching success. These results imply that predators can be a driving force in the expression of parental care in instances where it is normally absent and that local selection pressure is sufficient to cause behavioural divergence in whether or not parental care is expressed.

Length of activity season drives geographic variation in body size of a widely distributed lizard

Understanding the factors that drive geographic variation in life history is an important challenge in evolutionary ecology. Here, we analyze what predicts geographic variation in life-history traits of the common lizard, Zootoca vivipara, which has the globally largest distribution range of all terrestrial reptile species. Variation in body size was predicted by differences in the length of activity season, while we found no effects of environmental temperature per se. Females experiencing relatively short activity season mature at a larger size and remain larger on average than females in populations with relatively long activity seasons. Interpopulation variation in fecundity was largely explained by mean body size of females and reproductive mode, with viviparous populations having larger clutch size than oviparous populations. Finally, body size-fecundity relationship differs between viviparous and oviparous populations, with relatively lower reproductive investment for a given body size in oviparous populations. While the phylogenetic signal was weak overall, the patterns of variation showed spatial effects, perhaps reflecting genetic divergence or geographic variation in additional biotic and abiotic factors. Our findings emphasize that time constraints imposed by the environment rather than ambient temperature play a major role in shaping life histories in the common lizard. This might be attributed to the fact that lizards can attain their preferred body temperature via behavioral thermoregulation across different thermal environments. Length of activity season, defining the maximum time available for lizards to maintain optimal performance, is thus the main environmental factor constraining growth rate and annual rates of mortality. Our results suggest that this factor may partly explain variation in the extent to which different taxa follow ecogeographic rules.

Cancer immunotherapy drives implementation science in oncology.

Cancer immunotherapy has come a long way. The hope that immunological approaches may help cancer patients has sparked many initiatives in research and development (R&D). For many years, progress was modest and disappointments were frequent. Today, the increasing scientific and medical knowledge has established a solid basis for improvements. Considerable clinical success was first achieved for patients with hematological cancers. More recently, immunotherapy has entered center stage in the development of novel therapies against solid cancers. Together with R&D in angiogenesis, the field of immunology has fundamentally extended the scientific scope, which has evolved from a cancer-cell-centered view to a comprehensive and integrated vision of tumor biology. Current R&D is focused on a large array of possible disease mechanisms, driven by cancer cells, and amplified by tumor stroma, inflammatory and immunological actors, blood and lymph vessels, and the "macroenvironment," i.e. systemic mechanisms of the host, particularly of the haematopoietic system. Contrasting to this large spectrum of pathophysiological events promoting tumor growth, only a small number of biological mechanisms, namely of the immune system, have the potential to counteract tumor growth. They are of prime interest because therapeutic enhancement may result in clinical benefit for patients. This special issue is dedicated to immunotherapeutics against cancer, with particular emphasis on vaccination and combination therapies, providing updates and extended insight in this booming field.

The interplay between relatedness and horizontal gene transfer drives the evolution of plasmid-carried public goods.

Plasmids carry a wide range of genes that are often involved in bacterial social behaviour. The question of why such genes are frequently mobile has received increasing attention. Here, we use an explicit population genetic approach to model the evolution of plasmid-borne bacterial public goods production. Our findings highlight the importance of both transmission and relatedness as factors driving the evolution of plasmid-borne public goods production. We partition the effects of plasmid transfer of social traits into those of infectivity and the effect of increased relatedness. Our results demonstrate that, owing to its effect on relatedness, plasmid mobility increases the invasion and stability of public goods, in a way not seen in individually beneficial traits. In addition, we show that plasmid transfer increases relatedness when public goods production is rare but this effect declines when production is common, with both scenarios leading to an increase in the frequency of plasmid-borne public goods. Plasmids remain important vectors for the spread of social genes involved in bacterial virulence thus an understanding of their dynamics is highly relevant from a public health perspective.

Contribution à la cartographie géomorphologique de la dynamique sédimentaire des petits bassins versants torrentiels

Les laves torrentielles sont l'un des vecteurs majeurs de sédiments en milieu montagneux. Leur comportement hydrogéomorphologique est contrôlé par des facteurs géologique, géomorphologique, topographique, hydrologique, climatique et anthropique. Si, en Europe, la recherche s'est plus focalisée sur les aspects hydrologiques que géomorphologiques de ces phénomènes, l'identification des volumes de sédiments potentiellement mobilisables au sein de petits systèmes torrentiels et des processus responsables de leur transfert est d'une importance très grande en termes d'aménagement du territoire et de gestion des dangers naturels. De plus, une corrélation entre des événements pluviométriques et l'occurrence de laves torrentielles n'est pas toujours établie et de nombreux événements torrentiels semblent se déclencher lorsqu'un seuil géomorphologique intrinsèque (degré de remplissage du chenal) au cours d'eau est atteint.Une méthodologie pragmatique a été développée pour cartographier les stocks sédimentaires constituant une source de matériaux pour les laves torrentielles, comme outil préliminaire à la quantification des volumes transportés par ces phénomènes. La méthode s'appuie sur des données dérivées directement d'analyses en environnement SIG réalisées sur des modèles numériques d'altitude de haute précision, de mesures de terrain et d'interprétation de photographies aériennes. La méthode a été conçue pour évaluer la dynamique des transferts sédimentaires, en prenant en compte le rôle des différents réservoirs sédimentaires, par l'application du concept de cascade sédimentaire sous un angle cartographique.Les processus de transferts sédimentaires ont été étudiés dans deux bassins versants des Alpes suisses (torrent du Bruchi, à Blatten beiNaters et torrent du Meretschibach, à Agarn). La cartographie géomorphologique a été couplée avec des mesures complémentaires permettant d'estimer les flux sédimentaires et les taux d'érosion (traçages de peinture, piquets de dénudation et utilisation du LiDAR terrestre). La méthode proposée se révèle innovatrice en comparaison avec la plupart des systèmes de légendes géomorphologiques existants, qui ne sont souvent pas adaptés pour cartographier de manière satisfaisante les systèmes géomorphologiques complexes et actifs que sont les bassins torrentiels. L'intérêt de cette méthode est qu'elle permet l'établissement d'une cascade sédimentaire, mais uniquement pour des systèmes où l'occurrence d'une lave torrentielle est contrôlé par le degré de remplissage en matériaux du chenal. Par ailleurs, le produit cartographique ne peut être directement utilisé pour la création de cartes de dangers - axées sur les zones de dépôt - mais revêt un intérêt pour la mise en place de mesures de correction et pour l'installation de systèmes de monitoring ou d'alerte.La deuxième partie de ce travail de recherche est consacrée à la cartographie géomorphologique. Une analyse a porté sur un échantillon de 146 cartes ou systèmes de légende datant des années 1950 à 2009 et réalisés dans plus de 40 pays. Cette analyse a permis de mettre en évidence la diversité des applications et des techniques d'élaboration des cartes géomorphologiques. - Debris flows are one of the most important vectors of sediment transfer in mountainous areas. Their hydro-geomorphological behaviour is conditioned by geological, geomorphological, topographical, hydrological, climatic and anthropic factors. European research in torrential systems has focused more on hydrological processes than on geomorphological processes acting as debris flow triggers. Nevertheless, the identification of sediment volumes that have the potential to be mobilised in small torrential systems, as well as the recognition of processes responsible for their mobilisation and transfer within the torrential system, are important in terms of land-use planning and natural hazard management. Moreover, a correlation between rainfall and debris flow occurrence is not always established and a number of debris flows seems to occur when a poorly understood geomorphological threshold is reached.A pragmatic methodology has been developed for mapping sediment storages that may constitute source zone of bed load transport and debris flows as a preliminary tool before quantifying their volumes. It is based on data directly derived from GIS analysis using high resolution DEM's, field measurements and aerial photograph interpretations. It has been conceived to estimate sediment transfer dynamics, taking into account the role of different sediment stores in the torrential system applying the concept of "sediment cascade" in a cartographic point of view.Sediment transfer processes were investigated in two small catchments in the Swiss Alps (Bruchi torrent, Blatten bei Naters and Meretschibach torrent, Agarn). Thorough field geomorphological mapping coupled with complementary measurements were conducted to estimate sediment fluxes and denudation rates, using various methods (reference coloured lines, wooden markers and terrestrial LiDAR). The proposed geomorphological mapping methodology is quite innovative in comparison with most legend systems that are not adequate for mapping active and complex geomorphological systems such as debris flow catchments. The interest of this mapping method is that it allows the concept of sediment cascade to be spatially implemented but only for supply-limited systems. The map cannot be used directly for the creation of hazard maps, focused on the deposition areas, but for the design of correction measures and the implementation of monitoring and warning systems.The second part of this work focuses on geomorphological mapping. An analysis of a sample of 146 (extracts of) maps or legend systems dating from the middle of the 20th century to 2009 - realised in more than 40 different countries - was carried out. Even if this study is not exhaustive, it shows a clear renewed interest for the discipline worldwide. It highlights the diversity of applications, techniques (scale, colours and symbology) used for their conception.

Budgeting rockfall and modeling sedimentary delivery in torrent systems

This thesis is a compilation of projects to study sediment processes recharging debris flow channels. These works, conducted during my stay at the University of Lausanne, focus in the geological and morphological implications of torrent catchments to characterize debris supply, a fundamental element to predict debris flows. Other aspects of sediment dynamics are considered, e.g. the coupling headwaters - torrent, as well as the development of a modeling software that simulates sediment transfer in torrent systems. The sediment activity at Manival, an active torrent system of the northern French Alps, was investigated using terrestrial laser scanning and supplemented with geostructural investigations and a survey of sediment transferred in the main torrent. A full year of sediment flux could be observed, which coincided with two debris flows and several bedload transport events. This study revealed that both debris flows generated in the torrent and were preceded in time by recharge of material from the headwaters. Debris production occurred mostly during winter - early spring time and was caused by large slope failures. Sediment transfers were more puzzling, occurring almost exclusively in early spring subordinated to runoffconditions and in autumn during long rainfall. Intense rainstorms in summer did not affect debris storage that seems to rely on the stability of debris deposits. The morpho-geological implication in debris supply was evaluated using DEM and field surveys. A slope angle-based classification of topography could characterize the mode of debris production and transfer. A slope stability analysis derived from the structures in rock mass could assess susceptibility to failure. The modeled rockfall source areas included more than 97% of the recorded events and the sediment budgets appeared to be correlated to the density of potential slope failure. This work showed that the analysis of process-related terrain morphology and of susceptibility to slope failure document the sediment dynamics to quantitatively assess erosion zones leading to debris flow activity. The development of erosional landforms was evaluated by analyzing their geometry with the orientations of potential rock slope failure and with the direction of the maximum joint frequency. Structure in rock mass, but in particular wedge failure and the dominant discontinuities, appear as a first-order control of erosional mechanisms affecting bedrock- dominated catchment. They represent some weaknesses that are exploited primarily by mass wasting processes and erosion, promoting not only the initiation of rock couloirs and gullies, but also their propagation. Incorporating the geological control in geomorphic processes contributes to better understand the landscape evolution of active catchments. A sediment flux algorithm was implemented in a sediment cascade model that discretizes the torrent catchment in channel reaches and individual process-response systems. Each conceptual element includes in simple manner geomorphological and sediment flux information derived from GIS complemented with field mapping. This tool enables to simulate sediment transfers in channels considering evolving debris supply and conveyance, and helps reducing the uncertainty inherent to sediment budget prediction in torrent systems. Cette thèse est un recueil de projets d'études des processus de recharges sédimentaires des chenaux torrentiels. Ces travaux, réalisés lorsque j'étais employé à l'Université de Lausanne, se concentrent sur les implications géologiques et morphologiques des bassins dans l'apport de sédiments, élément fondamental dans la prédiction de laves torrentielles. D'autres aspects de dynamique sédimentaire ont été abordés, p. ex. le couplage torrent - bassin, ainsi qu'un modèle de simulation du transfert sédimentaire en milieu torrentiel. L'activité sédimentaire du Manival, un système torrentiel actif des Alpes françaises, a été étudiée par relevés au laser scanner terrestre et complétée par une étude géostructurale ainsi qu'un suivi du transfert en sédiments du torrent. Une année de flux sédimentaire a pu être observée, coïncidant avec deux laves torrentielles et plusieurs phénomènes de charriages. Cette étude a révélé que les laves s'étaient générées dans le torrent et étaient précédées par une recharge de débris depuis les versants. La production de débris s'est passée principalement en l'hiver - début du printemps, causée par de grandes ruptures de pentes. Le transfert était plus étrange, se produisant presque exclusivement au début du printemps subordonné aux conditions d'écoulement et en automne lors de longues pluies. Les orages d'été n'affectèrent guère les dépôts, qui semblent dépendre de leur stabilité. Les implications morpho-géologiques dans l'apport sédimentaire ont été évaluées à l'aide de MNT et études de terrain. Une classification de la topographie basée sur la pente a permis de charactériser le mode de production et transfert. Une analyse de stabilité de pente à partir des structures de roches a permis d'estimer la susceptibilité à la rupture. Les zones sources modélisées comprennent plus de 97% des chutes de blocs observées et les bilans sédimentaires sont corrélés à la densité de ruptures potentielles. Ce travail d'analyses des morphologies du terrain et de susceptibilité à la rupture documente la dynamique sédimentaire pour l'estimation quantitative des zones érosives induisant l'activité torrentielle. Le développement des formes d'érosion a été évalué par l'analyse de leur géométrie avec celle des ruptures potentielles et avec la direction de la fréquence maximale des joints. Les structures de roches, mais en particulier les dièdres et les discontinuités dominantes, semblent être très influents dans les mécanismes d'érosion affectant les bassins rocheux. Ils représentent des zones de faiblesse exploitées en priorité par les processus de démantèlement et d'érosion, encourageant l'initiation de ravines et couloirs, mais aussi leur propagation. L'incorporation du control géologique dans les processus de surface contribue à une meilleure compréhension de l'évolution topographique de bassins actifs. Un algorithme de flux sédimentaire a été implémenté dans un modèle en cascade, lequel divise le bassin en biefs et en systèmes individuels répondant aux processus. Chaque unité inclut de façon simple les informations géomorpologiques et celles du flux sédimentaire dérivées à partir de SIG et de cartographie de terrain. Cet outil permet la simulation des transferts de masse dans les chenaux, considérants la variabilité de l'apport et son transport, et aide à réduire l'incertitude liée à la prédiction de bilans sédimentaires torrentiels. Ce travail vise très humblement d'éclairer quelques aspects de la dynamique sédimentaire en milieu torrentiel.

What drives invasibility? A multi-model inference test and spatial modelling of alien plant species richness patterns in northern Portugal

Understanding and anticipating biological invasions can focus either on traits that favour species invasiveness or on features of the receiving communities, habitats or landscapes that promote their invasibility. Here, we address invasibility at the regional scale, testing whether some habitats and landscapes are more invasible than others by fitting models that relate alien plant species richness to various environmental predictors. We use a multi-model information-theoretic approach to assess invasibility by modelling spatial and ecological patterns of alien invasion in landscape mosaics and testing competing hypotheses of environmental factors that may control invasibility. Because invasibility may be mediated by particular characteristics of invasiveness, we classified alien species according to their C-S-R plant strategies. We illustrate this approach with a set of 86 alien species in Northern Portugal. We first focus on predictors influencing species richness and expressing invasibility and then evaluate whether distinct plant strategies respond to the same or different groups of environmental predictors. We confirmed climate as a primary determinant of alien invasions and as a primary environmental gradient determining landscape invasibility. The effects of secondary gradients were detected only when the area was sub-sampled according to predictions based on the primary gradient. Then, multiple predictor types influenced patterns of alien species richness, with some types (landscape composition, topography and fire regime) prevailing over others. Alien species richness responded most strongly to extreme land management regimes, suggesting that intermediate disturbance induces biotic resistance by favouring native species richness. Land-use intensification facilitated alien invasion, whereas conservation areas hosted few invaders, highlighting the importance of ecosystem stability in preventing invasions. Plants with different strategies exhibited different responses to environmental gradients, particularly when the variations of the primary gradient were narrowed by sub-sampling. Such differential responses of plant strategies suggest using distinct control and eradication approaches for different areas and alien plant groups.