Inhibition de la différenciation myogénique par un facteur soluble sécrété par des myoblastes dérivés de muscules squelettiques de sujets atteints de la dystrophie myotonique de type 1

La dystrophie myotonique de type 1 (DM1), la maladie neuromusculaire la plus fréquente chez l’adulte, est causée par une expansion de CTG dans la partie 3’ non traduite du gène codant pour la protéine dystrophy myotonic protein kinase, DMPK. La forme adulte de la maladie est caractérisée, notamment, par une faiblesse musculaire, de la myotonie, des cataractes et des troubles cardiaques. La forme congénitale, la forme la plus sévère de la maladie, est caractérisée par de l’hypotonie, une détresse respiratoire aiguë et un retard psychomoteur important. La régénération des fibres musculaires est déficiente dans la forme adulte de DM1, tandis qu’un retard de maturation du système musculaire est observé dans la forme congénitale. A ce jour, les mécanismes moléculaires par lesquels l’expansion de CTG affecte le développement ou la régénération du système musculaire sont inconnus. Des travaux ont démontré que le sérum de mères ayant un enfant atteint de la forme congénitale de la DM1 contient un facteur soluble inhibant la différenciation terminale des myoblastes. Il est encore indéterminé si ce facteur est produit par la mère ou sécrété par le fœtus. Nous avons émis l’hypothèse qu’un facteur soluble était sécrété par les myoblastes prélevés de patients atteints de forme congénitale de la DM1 qui inhibe la différenciation terminale des précurseurs des cellules musculaires. Les résultats obtenus démontrent que les myoblastes DM1 sécrètent un facteur soluble de masse moléculaire inférieure à 30 kDa inhibant la différentiation myogénique. Cet effet est associé une diminution spécifique de la myogenin. L’effet de ce facteur soluble est proportionnel à la longueur de l’expansion des CTG. L’identification et la caractérisation du facteur soluble sécrété spécifiquement par les myoblastes DM1 permettra une meilleure compréhension des mécanismes moléculaires responsable des défauts de développement du système musculaire observés dans la forme congénitale, et des défauts de régénération des fibres musculaires observés dans la forme adulte de la DM1. L’identification de ce facteur soluble est présentement en cours.Myotonic dystrophy (DM1), the most common form of inherited neuromuscular disease in adults, affects 1 in 8000 individuals worldwide. DM1 is an autosomal dominant muscular dystrophy with very variable symptom presentations. Adult onset DM1 is primarily characterized by myotonia, muscle wasting and weakness, but also affects a number of organs and tissues. One characteristic of the disease is the presence of a severe congenital form (CDM1), which differs from the adult form. CDM1 is characterized by a delay in the development of skeletal muscles. This form is associated with hypotonia, respiratory complications and mental retardation. DM1 is caused by the expansion of an unstable CTG trinucleotide repeat in the 3’untranslated region of the myotonic dystrophy protein kinase (DMPK) gene. To date, the mechanisms by which the DM1 mutation affects skeletal muscles development or regeneration are unknown. A previous study demonstrated that serum produced by mothers of children with congenital myotonic dystrophy inhibits myogenic differentiation. In this study, we hypothesized that CDM1 myoblasts secrete a soluble factor that blocks myogenic differentiation. We provide evidence that this soluble factor is produced by DM1 and CDM1 myoblasts which may be involved in their deficiency to fuse. The inhibitory effect is proportional to the length of the CTG repeat expansion. In addition, the delay in muscle differentiation is associated with a specific reduction in myogenin gene expression. We believe that the DM1 mutation triggers the expression of a soluble factor, which is able to block myogenic differentiation. The identification of this soluble factor is presently under investigation

Towards A Typology Of Parental Behaviors, Attitudes, And Beliefs About School

The social and academic experiences of children and adolescents in school are a major concern for parents and their characteristics as protection or risk factors for their children’s adaptation has been extensively studied. However, few studies have dealt with the behaviors, attitudes and beliefs of parents about the schools their children are enrolled in. The aim of this study was to address that issue. A random sample of 1297 parents drawn from 8 large Canadian school boards took part in standardized individual interviews which yielded both quantitative and qualitative information on demographics, family structure, time management, attitudes, behaviors and beliefs about school, along with data on their children’s school achievement and overall adaptation. A dynamic grouping analysis was applied to salient variables which generated a four group typology of parents: collaborators, critics, overwhelmed, and ill-equipped. Results further indicated that only a very small number of participants did not value education, as opposed to earlier findings where they represented a significant proportion of parents. Practical implications of these results for school administrators, parents and educators will be discussed

An EPID-based method to determine mechanical deformations in a linear accelerator

Purpose: Medical linear accelerators (linac) are delivering increasingly complex treatments using modern techniques in radiation therapy. Complete and precise mechanical QA of the linac is therefore necessary to ensure that there is no unexpected deviation from the gantry's planned course. However, state-of-the-art EPID-based mechanical QA procedures often neglect some degrees of freedom (DOF) like the in-plane rotations of the gantry and imager or the source movements inside the gantry head. Therefore, the purpose of this work is to characterize a 14 DOF method for the mechanical QA of linacs. This method seeks to measure every mechanical deformation in a linac, including source movements, in addition to relevant clinical parameters like mechanical and radiation isocenters. Methods: A widely available commercial phantom and a custom-made accessory inserted in the linac's interface mount are imaged using the electronic portal imaging device (EPID) at multiple gantry angles. Then, simulated images are generated using the nominal geometry of the linac and digitized models of the phantoms. The nominal geometry used to generate these images can be modified using 14 DOF (3 rigid rotations and 3 translations for the imager and the gantry, and 2 in-plane translations of the source) and any change will modify the simulated image. The set of mechanical deformations that minimizes the differences between the simulated and measured image is found using a genetic algorithm coupled with a gradient-descent optimizer. Phantom mispositioning and gantry angular offset were subsequently calculated and extracted from the results. Simulations of the performances of the method for different levels of noise in the phantom models were performed to calculate the absolute uncertainty of the measured mechanical deformations. The measured source positions and the center of collimation were used to define the beam central axis and calculate the radiation isocenter position and radius. Results: After the simultaneous optimization of the 14 DOF, the average distance between the center of the measured and simulated ball bearings on the imager was 0.086 mm. Over the course of a full counter-clockwise gantry rotation, all mechanical deformations were measured, showing sub-millimeter translations and rotations smaller than 1° along every axis. The average absolute uncertainty of the 14 DOF (1 SD) was 0.15 mm or degree. Phantom positioning errors were determined with more than 0.1 mm precision. Errors introduced in the experimental setup like phantom positioning errors, source movements or gantry angular offsets were all successfully detected by our QA method. The mechanical deformations measured are shown to be reproducible over the course of a few weeks and are not sensitive to the experimental setup. Conclusion: This work presents of new method for an accurate mechanical QA of the linacs. It features a 14 DOF model of the mechanical deformations that is both more complete and precise than other available methods. It has demonstrated sub-millimeter accuracy through simulation and experimentation. Introduced errors were successfully detected with high precision

Introduction to the special issue : From RIDGE to Ridge 2000

Author Posting. © The Oceanography Society, 2012. This article is posted here by permission of The Oceanography Society for personal use, not for redistribution. The definitive version was published in Oceanography 25, no. 1 (2012): 12–17, doi:10.5670/oceanog.2012.01.Articles in this special issue of Oceanography represent a compendium of research that spans the disciplinary and thematic breadth of the National Science Foundation's Ridge 2000 Program, as well as its geographic focal points. The mid-ocean ridge (MOR) crest is where much of Earth's volcanism is focused and where most submarine volcanic activity occurs. If we could look down from space at our planet with the ocean drained, the MOR's topography and shape, along with its intervening fracture zones, would resemble the seams on a baseball, with the ocean basins dominating our planetary panorama. The volcanic seafloor is hidden beneath the green-blue waters of the world's ocean, yet therein lie fundamental clues to how our planet works and has evolved over billions of years, something that was not clearly understood 65 years ago—witness the following quote from H.H. Hess (1962) in his essay on "geopoetry" and commentary on J.H.F. Umbgrove's (1947) comprehensive summary of Earth and ocean history: The birth of the oceans is a matter of conjecture, the subsequent history is obscure, and the present structure is just beginning to be understood. Fascinating speculation on these subjects has been plentiful, but not much of it predating the last decade [the 1950s] holds water.This special issue was funded by a supplement to the Ridge 2000 Office grant at the Woods Hole Oceanographic Institution (NSF-OCE-0838923)

Improving the speckle noise attenuation of simultaneous spectral differential imaging with a focal plane holographic diffuser

Direct exoplanet detection is limited by speckle noise in the point spread function (PSF) of the central star. This noise can be reduced by subtracting PSF images obtained simultaneously in adjacent narrow spectral bands using a multi-channel camera (MCC), but only to a limit imposed by differential optical aberrations in the MCC. To alleviate this problem, we suggest the introduction of a holographic diffuser at the focal plane of the MCC to convert the PSF image into an incoherent illumination scene that is then re-imaged with the MCC. The re-imaging is equivalent to a convolution of the scene with the PSF of each spectral channel of the camera. Optical aberrations in the MCC affect only the convolution kernel of each channel and not the PSF globally, resulting in better correlated images. We report laboratory measurements with a dual channel prototype (1.575 micron and 1.625 micron) to validate this approach. A speckle noise suppression factor of 12-14 was achieved, an improvement by a factor ~5 over that obtained without the holographic diffuser. Simulations of realistic exoplanet populations for three representative target samples show that the increase in speckle noise attenuation achieved in the laboratory would roughly double the number of planets that could be detected with current adaptive optics systems on 8-m telescopes.Comment: 9 pages, 8 figure, to be published in ApJ June 20, 200

Reduction of β-amyloid pathology by celastrol in a transgenic mouse model of Alzheimer's disease

<p>Abstract</p> <p>Background</p> <p>Aβ deposits represent a neuropathological hallmark of Alzheimer's disease (AD). Both soluble and insoluble Aβ species are considered to be responsible for initiating the pathological cascade that eventually leads to AD. Therefore, the identification of therapeutic approaches that can lower Aβ production or accumulation remains a priority. NFκB has been shown to regulate BACE-1 expression level, the rate limiting enzyme responsible for the production of Aβ. We therefore explored whether the known NFκB inhibitor celastrol could represent a suitable compound for decreasing Aβ production and accumulation <it>in vivo</it>.</p> <p>Methods</p> <p>The effect of celastrol on amyloid precursor protein (APP) processing, Aβ production and NFκB activation was investigated by western blotting and ELISAs using a cell line overexpressing APP. The impact of celastrol on brain Aβ accumulation was tested in a transgenic mouse model of AD overexpressing the human APP695sw mutation and the presenilin-1 mutation M146L (Tg PS1/APPsw) by immunostaining and ELISAs. An acute treatment with celastrol was investigated by administering celastrol intraperitoneally at a dosage of 1 mg/Kg in 35 week-old Tg PS1/APPsw for 4 consecutive days. In addition, a chronic treatment (32 days) with celastrol was tested using a matrix-driven delivery pellet system implanted subcutaneously in 5 month-old Tg PS1/APPsw to ensure a continuous daily release of 2.5 mg/Kg of celastrol.</p> <p>Results</p> <p><it>In vitro</it>, celastrol dose dependently prevented NFκB activation and inhibited BACE-1 expression. Celastrol potently inhibited Aβ_1-40and Aβ_1-42production by reducing the β-cleavage of APP, leading to decreased levels of APP-CTFβ and APPsβ. <it>In vivo</it>, celastrol appeared to reduce the levels of both soluble and insoluble Aβ_1-38, Aβ_1-40and Aβ_1-42. In addition, a reduction in Aβ plaque burden and microglial activation was observed in the brains of Tg PS1/APPsw following a chronic administration of celastrol.</p> <p>Conclusions</p> <p>Overall our data suggest that celastrol is a potent Aβ lowering compound that acts as an indirect BACE-1 inhibitor possibly by regulating BACE-1 expression level via an NFκB dependent mechanism. Additional work is required to determine whether chronic administration of celastrol can be safely achieved with cognitive benefits in a transgenic mouse model of AD.</p

Etnografía virtual

URN: urn:nbn:de:0114-fqs0703E19URN: urn:nbn:de:0114-fqs0703E19URN: urn:nbn:de:0114-fqs0703E1

La création d’une nouvelle génération d’études épidémiologiques en santé mentale

Grâce à une subvention des Instituts de recherche en santé du Canada (IRSC), il se développe actuellement une nouvelle génération d’études en épidémiologie sociale et psychiatrique dans une zone circonscrite se situant dans le sud-ouest de Montréal où vivent 258 000 personnes. Ce programme de recherche repose sur une étude prospective longitudinale visant à identifier les déterminants de la santé mentale de la population, et sur quatre études spécifiques qui abordent des paramètres importants pour la santé mentale : l’écologie sociale et physique des quartiers, le soutien social, le stigma social et les services en santé mentale. Ce programme est complété par l’utilisation de la dernière génération des outils technologiques et informatiques soit un système d’information géographique (SIG) qui permet d’apprécier les effets du contexte sur la santé mentale. Les bases théoriques sur lesquels repose ce modèle sont présentées de même qu’une description sommaire des méthodes utilisées.The authors were granted funding from the Canadian Institute of Health Research (CIHR) to develop a new generation of epidemiological studies in the field of social and psychiatric epidemiology in a catchment area in Montréal, with a population of around 258 000. This research program will begin with a longitudinal study that will identify mental health determinants and will be followed by four specific studies on important aspects of mental health : service organization, social stigma, and neighbourhood ecology and social support actualization. A Geographic information System based on postal codes will also be used as a mean to evaluate the effects of social and physical environment on mental health and its interactions with individual determinants of mental health. This article describes the research program, its theoretical bases and more briefly, its methodology.Gracias a una subvención de los Institutos de Investigación en Salud de Canadá (IRSC), actualmente se está desarrollando una nueva generación de estudios en epidemiología social y psiquiátrica en una zona circunscrita localizada en el sudoeste de Montreal, donde viven 258,000 personas. Este programa de investigación se apoya en un estudio prospectivo longitudinal, que busca identificar las determinantes de la salud mental de la población, y en cuatro estudios específicos que abordan los parámetros importantes para la salud mental: la ecología social y física de los barrios, el apoyo social, el estigma social y los servicios de salud mental. Este programa se completa con la utilización de la última generación de herramientas tecnológicas e informáticas, es decir, un sistema de información geográfico (SIG) que permite apreciar los efectos del contexto en la salud mental. Se presentan las bases teóricas en las que se apoya este modelo así como una descripción somera de los métodos utilizados.Graças a uma subvenção dos Institutos de Pesquisa em Saúde do Canadá (IRSC), é desenvolvida atualmente uma nova geração de estudos em epidemiologia social e psiquiátrica em uma zona circunscrita situando-se no sudoeste de Montreal, onde vivem 258 mil pessoas. Este programa de pesquisa baseia-se em um estudo prospectivo longitudinal visando identificar os determinantes da saúde mental da população, e sobre quatro estudos específicos que abordam parâmetros importantes para a saúde mental: a ecologia social e física dos bairros, o apoio social, o estigma social e os serviços em saúde mental. Este programa é realizado com a utilização da última geração de ferramentas tecnológicas e informáticas, ou seja, um sistema de informação geográfica (SIG) que permite apreciar os efeitos do contexto na saúde mental. As bases teóricas sobre as quais repousa este modelo são apresentadas, além de uma descrição sumária dos métodos utilizados