Recognition of hepatitis C virus RNA by toll like receptors 7 and 8 : implications for the initiation of innate immune response

Le virus de l’hépatite C (VHC) est un virus à ARN simple brin positif (ssARN) qui se replique dans le foie. Deux cents millions de personnes sont infectées par le virus dans le monde et environ 80% d’entre elles progresseront vers un stade chronique de l’infection. Les thérapies anti-virales actuelles comme l’interféron (IFN) ou la ribavirin sont de plus en plus utilisées mais ne sont efficaces que dans la moitié des individus traités et sont souvent accompagnées d’une toxicité ou d’effets secondaires indésirables. Le système immunitaire inné est essentiel au contrôle des infections virales. Les réponses immunitaires innées sont activées suite à la reconnaissance par les Pathogen Recognition Receptors (PRRs), de motifs macromoléculaires dérivés du virus appelés Pathogen-Associated Molecular Patterns (PAMPs). Bien que l'activation du système immunitaire par l'ARN ou les protéines du VHC ait été largement étudiée, très peu de choses sont actuellement connues concernant la détection du virus par le système immunitaire inné. Et même si l’on peut très rapidement déceler des réponses immunes in vivo après infection par le VHC, l’augmentation progressive et continue de la charge virale met en évidence une incapacité du système immunitaire à contrôler l’infection virale. Une meilleure compréhension des mécanismes d’activation du système immunitaire par le VHC semble, par conséquent, essentielle au développement de stratégies antivirales plus efficaces. Dans le présent travail nous montrons, dans un modèle de cellule primaire, que le génome ARN du VHC contient des séquences riches en GU capables de stimuler spécifiquement les récepteurs de type Toll (TLR) 7 et 8. Cette stimulation a pour conséquence la maturation des cellules dendritiques plasmacytoïdes (pDCs), le production d’interféron de type I (IFN) ainsi que l’induction de chémokines et cytokines inflammatoires par les différentes types de cellules présentatrices d’antigènes (APCs). Les cytokines produites après stimulation de monocytes ou de pDCs par ces séquences ssARN virales, inhibent la production du virus de façon dépendante de l’IFN. En revanche, les cytokines produites après stimulation de cellules dendritiques myéloïdes (mDCs) ou de macrophages par ces mêmes séquences n’ont pas d’effet inhibiteur sur la production virale car les séquences ssARN virales n’induisent pas la production d’IFN par ces cellules. Les cytokines produites après stimulation des TLR 7/8 ont également pour effet de diminuer, de façon indépendante de l’IFN, l’expression du récepteur au VHC (CD81) sur la lignée cellulaire Huh7.5, ce qui pourrait avoir pour conséquence de restreindre l’infection par le VHC. Quoiqu’il en soit, même si les récepteurs au VHC comme le CD81 sont largement exprimés à la surface de différentes sous populations lymphocytaires, les DCs et les monocytes ne répondent pas aux VHC, Nos résultats indiquent que seuls les macrophages sont capables de reconnaître le VHC et de produire des cytokines inflammatoires en réponse à ce dernier. La reconnaissance du VHC par les macrophages est liée à l’expression membranaire de DC-SIGN et l’engagement des TLR 7/8 qui en résulte. Comme d’autres agonistes du TLR 7/8, le VHC stimule la production de cytokines inflammatoires (TNF-α, IL-8, IL-6 et IL-1b) mais n’induit pas la production d’interféron-beta par les macrophages. De manière attendue, la production de cytokines par des macrophages stimulés par les ligands du TLR 7/8 ou les séquences ssARN virales n’inhibent pas la réplication virale. Nos résultats mettent en évidence la capacité des séquences ssARN dérivées du VHC à stimuler les TLR 7/8 dans différentes populations de DC et à initier une réponse immunitaire innée qui aboutit à la suppression de la réplication virale de façon dépendante de l’IFN. Quoiqu’il en soit, le VHC est capable d’échapper à sa reconnaissance par les monocytes et les DCs qui ont le potentiel pour produire de l’IFN et inhiber la réplication virale après engagement des TLR 7/8. Les macrophages possèdent quant à eux la capacité de reconnaître le VHC grâce en partie à l’expression de DC-SIGN à leur surface, mais n’inhibent pas la réplication du virus car ils ne produisent pas d’IFN. L’échappement du VHC aux défenses antivirales pourrait ainsi expliquer l’échec du système immunitaire inné à contrôler l’infection par le VHC. De plus, la production de cytokines inflammatoires observée après stimulation in vitro des macrophages par le VHC suggère leur potentielle contribution dans l’inflammation que l’on retrouve chez les individus infectés par le VHC.

Simulation on the process of fatigue crack initiation in a martensitic stainless steel

Die vorliegende Arbeit beschäftigt sich mit der Computersimulation des Rissinitiierungsprozesses für einen martensitischen Stahl, der der niederzyklischen Ermüdung unterworfen wurde. Wie auf der Probenoberfläche beobachtet wurde, sind die Initiierung und das frühe Wachstum dieser Mikrorisse in hohem Grade von der Mikrostruktur abhängig. Diese Tatsache wurde in mesoskopischen Schädigungsmodellen beschrieben, wobei die Körner als einzelne Kristalle mit anisotropem Materialverhalten modelliert wurden. Das repräsentative Volumenelement (RVE), das durch einen Voronoi-Zerlegung erzeugt wurde, wurde benutzt, um die Mikrostruktur des polykristallinen Materials zu simulieren. Spannungsverteilungen wurden mit Hilfe der Finiten-Elemente-Methode mit elastischen und elastoplastischen Materialeigenschaften analysiert. Dazu wurde die Simulation zunächst an zweidimensionalen Modellen durchgeführt. Ferner wurde ein vereinfachtes dreidimensionales RVE hinsichtlich des sowohl dreidimensionalen Gleitsystems als auch Spannungszustandes verwendet. Die kontinuierliche Rissinitiierung wurde simuliert, indem der Risspfad innerhalb jedes Kornes definiert wurde. Die Zyklenanzahl bis zur Rissinitiierung wurde auf Grundlage der Tanaka-Mura- und Chan-Gleichungen ermittelt. Die Simulation lässt auf die Flächendichten der einsegmentige Risse in Relation zur Zyklenanzahl schließen. Die Resultate wurden mit experimentellen Daten verglichen. Für alle Belastungsdehnungen sind die Simulationsergebnisse mit denen der experimentellen Daten vergleichbar.

You can canoe!: a book of sporting activities.

Explica los fundamentos de la canoa, kayak, gimnasia, equitación, artes marciales, escalada, rodeo, patinaje, y la natación. Hace un énfasis en los deportes de seguridad y definiciones claras de la terminología especializada asociadas a cada deporte. Para trabajar en clase: explorar cómo se organizan por escrito las instrucciones. Lectura de sencillas instrucciones. Reconocer palabras compuestas, y utilizar este conocimiento para apoyar su ortografía. Resumir oralmente el contenido de un pasaje o texto.

Patrocínios no Desporto Como Meio de Comunicação : caso Sporting Clube de Portugal

Este trabalho tem como objectivo perceber se o patrocínio começa cada vez mais a ser visto como um meio de comunicação viável para as empresas inseridas no mundo do desporto. Foi feita uma revisão de literatura em que abordaremos os tópicos de marketing, desporto em Portugal, marketing desportivo e patrocínio, e faremos a associação devida entre eles para que possamos perceber como estes temas se relacionam e quais os resultados finais. Iremos também abordar as visões sobre o patrocínio, tanto do patrocinado como do patrocinador, e quais os seus objectivos e diferenças, com um exemplo prático do Sporting Clube de Portugal e de três dos seus patrocinadores: Puma, Portugal Telecom e a Caixa Geral de Depósitos.

Flight initiation distances of nesting Piping Plovers (Charadrius melodus) in response to human disturbance

Birds frequently interact with people when they occur in coupled human-ecological or anthropogenic environments, which makes the protection of legally protected species a challenge. Flight initiation distances (FIDs) are often used to inform development of appropriate buffer distances required for human exclusion zones used to protect birds nesting in anthropogenic landscapes. Piping Plovers (Charadrius melodus) are protected by the Endangered Species Act in the United States and often nest in areas used by humans. Studies evaluating Piping Plover FIDs are limited and implementation of exclusion zones has been inconsistent across the species’ range. We measured Piping Plover response and FIDs to naturally occurring stimuli on public beaches at Lake McConaughy, Nebraska, USA. Piping Plover FIDs differed most by stimulus class (vehicle, human, dog, human with dog), Julian day, and hour of day. Piping Plover FIDs were greatest for dog and human with dog compared to humans and vehicles. For all types of stimuli, Piping Plover FIDs decreased over time during the nesting season and increased slightly during each day. In the majority of instances in which Piping Plovers left their nests, return times to the nest were relatively short (less than three minutes). These results suggest Piping Plovers become habituated to the presence of human-related stimuli over the course of a nesting season, but other explanations such as parental investment and risk allocation cannot be excluded. Additional research and improved guidance regarding the implementation of exclusion zones is needed so managers can implement effective protection programs in anthropogenic landscapes.

The Convective Storm Initiation Project

The Convective Storm Initiation Project (CSIP) is an international project to understand precisely where, when, and how convective clouds form and develop into showers in the mainly maritime environment of southern England. A major aim of CSIP is to compare the results of the very high resolution Met Office weather forecasting model with detailed observations of the early stages of convective clouds and to use the newly gained understanding to improve the predictions of the model. A large array of ground-based instruments plus two instrumented aircraft, from the U.K. National Centre for Atmospheric Science (NCAS) and the German Institute for Meteorology and Climate Research (IMK), Karlsruhe, were deployed in southern England, over an area centered on the meteorological radars at Chilbolton, during the summers of 2004 and 2005. In addition to a variety of ground-based remote-sensing instruments, numerous rawin-sondes were released at one- to two-hourly intervals from six closely spaced sites. The Met Office weather radar network and Meteosat satellite imagery were used to provide context for the observations made by the instruments deployed during CSIP. This article presents an overview of the CSIP field campaign and examples from CSIP of the types of convective initiation phenomena that are typical in the United Kingdom. It shows the way in which certain kinds of observational data are able to reveal these phenomena and gives an explanation of how the analyses of data from the field campaign will be used in the development of an improved very high resolution NWP model for operational use.

On the initiation of surface waves by turbulent shear flow

An analytical model is developed for the initial stage of surface wave generation at an air-water interface by a turbulent shear flow in either the air or in the water. The model treats the problem of wave growth departing from a flat interface and is relevant for small waves whose forcing is dominated by turbulent pressure fluctuations. The wave growth is predicted using the linearised and inviscid equations of motion, essentially following Phillips [Phillips, O.M., 1957. On the generation of waves by turbulent wind. J. Fluid Mech. 2, 417-445], but the pressure fluctuations that generate the waves are treated as unsteady and related to the turbulent velocity field using the rapid-distortion treatment of Durbin [Durbin, P.A., 1978. Rapid distortion theory of turbulent flows. PhD thesis, University of Cambridge]. This model, which assumes a constant mean shear rate F, can be viewed as the simplest representation of an oceanic or atmospheric boundary layer. For turbulent flows in the air and in the water producing pressure fluctuations of similar magnitude, the waves generated by turbulence in the water are found to be considerably steeper than those generated by turbulence in the air. For resonant waves, this is shown to be due to the shorter decorrelation time of turbulent pressure in the air (estimated as proportional to 1/Gamma), because of the higher shear rate existing in the air flow, and due to the smaller length scale of the turbulence in the water. Non-resonant waves generated by turbulence in the water, although being somewhat gentler, are still steeper than resonant waves generated by turbulence in the air. Hence, it is suggested that turbulence in the water may have a more important role than previously thought in the initiation of the surface waves that are subsequently amplified by feedback instability mechanisms.

Water deficits promote flowering in Rhododendron via regulation of pre and post initiation development

Flowering is generally considered to be advanced by water deficits in many woody perennial species. A long-standing paradigm being that as a plant senses severe environmental conditions resources are diverted away from vegetative growth and towards reproduction before death. It is demonstrated that in Rhododendron flowering is promoted under water deficit treatments. However, the promotion of flowering is not achieved via all increase in floral initiation, but through separate developmental responses. If regulated deficit irrigation (RDI) is imposed prior to the time of initiation, fewer vegetative nodes are formed before the apical meristems switch to floral initiation, and chronologically, floral initiation occurs earlier. Both RDI and partial rootzone drying (PRD) treatments stimulate the development of more flowers Oil each inflorescence if the treatments are continued after the plant has undergone floral initiation. However, floral initiation is inhibited by soil water deficits. If the soil water deficit continues beyond the stages of floral development then anthesis call occur prematurely oil the fully formed floral buds without a need for a winter chilling treatment. It is hypothesised that inhibition of floral initiation in plants experiencing severe soil water deficits results from the inhibitory action Of ABA transportation to the apical meristem from stressed roots. It is demonstrated that ABA applications to well-watered Rhododendron inhibit floral initiation. (c) 2008 Elsevier B.V. All rights reserved.

Calicivirus translation initiation requires an interaction between VPg and eIF4E

Unlike other positive-stranded RNA viruses that use either a 5'-cap structure or an internal ribosome entry site to direct translation of their messenger RNA, calicivirus translation is dependent on the presence of a protein covalently linked to the 50 end of the viral genome (VPg). We have shown a direct interaction of the calicivirus VPg with the cap-binding protein eIF4E. This interaction is required for calicivirus mRNA translation, as sequestration of eIF4E by 4E-BP1 inhibits translation. Functional analysis has shown that VPg does not interfere with the interaction between eIF4E and the cap structure or 4E-BP1, suggesting that VPg binds to eIF4E at a different site from both cap and 4E-BP1. This work lends support to the idea that calicivirus VPg acts as a novel 'cap substitute' during initiation of translation on virus mRNA.

Involuntary inhibition of movement initiation alters oculomotor competition resolution

Identifying a stimulus as the target for a goal-directed movement involves inhibiting competing responses. Separable inhibitory interconnections bias local competition to ensure only one stimulus is selected and to alter movement initiation. Behavioural evidence of these inhibitory processes comes from the effects of distracters on oculomotor landing positions and saccade latencies. Here, we investigate the relationship between these two sources of inhibition. Targets were presented with or without close and remote distracters. In separate experiments the possible position and identity of the target and distracters were manipulated. In all cases saccade landing position was found to be less affected by the presence of the close distracter when remote distracters were also present. The involuntary increase in the latency of saccade initiation caused by the presence of the remote distracters alters the state of competitive processes involved in selecting the saccade target thus changing its landing position.

Evidence that indirect inhibition of saccade initiation improves saccade accuracy

Saccadic eye-movements to a visual target are less accurate if there are distracters close to its location (local distracters). The addition of more distracters, remote from the target location (remote distracters), invokes an involuntary increase in the response latency of the saccade and attenuates the effect of local distracters on accuracy. This may be due to the target and distracters directly competing (direct route) or to the remote distracters acting to impair the ability to disengage from fixation (indirect route). To distinguish between these we examined the development of saccade competition by recording saccade latency and accuracy responses made to a target and local distracter compared with those made with an addition of a remote distracter. The direct route would predict that the remote distracter impacts on the developing competition between target and local distracter, while the indirect route would predict no change as the accuracy benefit here derives from accessing the same competitive process but at a later stage. We found that the presence of the remote distracter did not change the pattern of accuracy improvement. This suggests that the remote distracter was acting along an indirect route that inhibits disengagement from fixation, slows saccade initiation, and enables more accurate saccades to be made.

The role of seeds and airborne inoculum in the initiation of leaf blotch (Rhynchosporium secalis) epidemics in winter barley

Both airborne spores of Rhynchosporium secalis and seed infection have been implied as major sources of primary inoculum for barley leaf blotch (scald) epidemics in fields without previous history of barley cropping. However, little is known about their relative importance in the onset of disease. Results from both quantitative real-time PCR and visual assessments indicated that seed infection was the main source of inoculum in the field trial conducted in this study. Glasshouse studies established that the pathogen can be transmitted from infected seeds into roots, shoots and leaves without causing symptoms. Plants in the field trial remained symptomless for approximately four months before symptoms were observed in the crop. Covering the crop during part of the growing season was shown to prevent pathogen growth, despite the use of infected seed, indicating that changes in the physiological condition of the plant and/or environmental conditions may trigger disease development. However, once the disease appeared in the field it quickly became uniform throughout the cropping area. Only small amounts of R. secalis DNA were measured in 24 h spore-trap tape samples using PCR. Inoculum levels equivalent to spore concentrations between 30 and 60 spores per m3 of air were only detected on three occasions during the growing season. The temporal pattern and level of detection of R. secalis DNA in spore tape samples indicated that airborne inoculum was limited and most likely represented rain-splashed conidia rather than putative ascospores.