OpenCCM : une infrastructure à composants pour le déploiement d'applications à base de composants CORBA

Le déploiement de composants logiciels pour la construction d'applications réparties consiste à coordonner un ensemble de tâches élémentaires comme le téléchargement des binaires sur les sites d'exécution, leur chargement en mémoire, la création d'instances de composants, l'interconnexion de leurs ports, la configuration de leurs propriétés métiers et techniques. Automatiser le processus de déploiement nécessite alors la présence d'une infrastructure logicielle elle-même répartie sur les différents sites d'exécution. Cet article présente les caractéristiques d'une telle infrastructure pour le déploiement d'applications à base de composants CORBA. Cette dernière a été conçue et réalisée dans le cadre de notre plate-forme OpenCCM, une implantation libre du modèle de composants CORBA. La principale caractéristique de cette infrastructure est qu'elle est elle-même conçue sous la forme d'assemblages de composants CORBA. Ceci autorise son assemblage dynamique lors de son déploiement sur les sites d'exécution.––––– Deployment of software components for building distributed applications consists of the coordination of a set of basic tasks like uploading component binaries to the execution sites, loading them in memory, instantiating components, interconnecting their ports, setting their business and technical attributes. The automation of the deployment process then requires the presence of a software infrastructure distributed itself on the different execution sites. This paper presents the characteristics of such an infrastructure for the deployment of CORBA component-based applications. This latter is designed and implemented in the context of our OpenCCM platform, an open source implementation of the CORBA Component Model. The main characteristic lays on the fact that this infrastructure is itself designed as a set of CORBA component assemblies. This allows its dynamic assembly during its deployment over the execution site

Buffer layers inhomogeneity and coupling with epitaxial graphene unravelled by Raman scattering and graphene peeling

The so-called buffer layer (BL) is a carbon rich reconstructed layer formed during the sublimation of SiC (0001). The existence of covalent bonds between some of the carbon atoms in this layer and the underlying silicon atoms makes it different from epitaxial graphene. We report a systematical and statistical investigation of the BL signature and its coupling with epitaxial graphene by Raman spectroscopy. Three different kinds of BLs are studied: bare buffer layer obtained by direct growth (BL 0), interfacial buffer layer situated between graphene and SiC (c-BL 1) and the interfacial buffer layer without graphene above (u-BL 1). To obtain the latter, we develop a mechanical exfoliation of graphene by depositing and subsequently removing an epoxy-based resin or nickel layer. The observed BLs are ordered-like on the whole BL growth temperature range. BL 0 Raman signature may vary from sample to sample but also forms patches on the same terrace. u-BL 1 share similar properties with BL 0 , albeit with more variability. These BLs have a strikingly larger overall intensity than BL with graphene on top. The signal onset on the high frequency side upshifts upon graphene coverage, that cannot be explained by a simple strain effect. Two fine peaks situated at 1235 and 1360 cm-1 are present for epitaxial monolayer while absent for BL and transferred graphene. These findings point to a coupling between graphene and BL

Microprocessor, Setx, Xrn2, and Rrp6 Co-operate to Induce Premature Termination of Transcription by RNAPII

SummaryTranscription elongation is increasingly recognized as an important mechanism of gene regulation. Here, we show that microprocessor controls gene expression in an RNAi-independent manner. Microprocessor orchestrates the recruitment of termination factors Setx and Xrn2, and the 3′–5′ exoribonuclease, Rrp6, to initiate RNAPII pausing and premature termination at the HIV-1 promoter through cleavage of the stem-loop RNA, TAR. Rrp6 further processes the cleavage product, which generates a small RNA that is required to mediate potent transcriptional repression and chromatin remodeling at the HIV-1 promoter. Using chromatin immunoprecipitation coupled to high-throughput sequencing (ChIP-seq), we identified cellular gene targets whose transcription is modulated by microprocessor. Our study reveals RNAPII pausing and premature termination mediated by the co-operative activity of ribonucleases, Drosha/Dgcr8, Xrn2, and Rrp6, as a regulatory mechanism of RNAPII-dependent transcription elongation

Identification of a New Cholesterol-Binding Site within the IFN-gamma Receptor that is Required for Signal Transduction

[EN] The cytokine interferon-gamma (IFN-gamma) is a master regulator of innate and adaptive immunity involved in a broad array of human diseases that range from atherosclerosis to cancer. IFN-gamma exerts it signaling action by binding to a specific cell surface receptor, the IFN-gamma receptor (IFN-gamma R), whose activation critically depends on its partition into lipid nanodomains. However, little is known about the impact of specific lipids on IFN-gamma R signal transduction activity. Here, a new conserved cholesterol (chol) binding motif localized within its single transmembrane domain is identified. Through direct binding, chol drives the partition of IFN-gamma R2 chains into plasma membrane lipid nanodomains, orchestrating IFN-gamma R oligomerization and transmembrane signaling. Bioinformatics studies show that the signature sequence stands for a conserved chol-binding motif presented in many mammalian membrane proteins. The discovery of chol as the molecular switch governing IFN-gamma R transmembrane signaling represents a significant advance for understanding the mechanism of lipid selectivity by membrane proteins, but also for figuring out the role of lipids in modulating cell surface receptor function. Finally, this study suggests that inhibition of the chol-IFN gamma R2 interaction may represent a potential therapeutic strategy for various IFN-gamma-dependent diseases.This work was supported by grants from the Spanish Ministry of Science, Innovation, and Universities (BFU-2015-68981-P and PID2020-117405GB-I00) and the Basque Government (IT1264-19, IT1625-22) to F.-X.C. and M.L. F.-X.C. acknowledge the generous support of Fundacion Ramon Areces (grant CIVP20S11276). O.T. was supported by a Basque Government grant (IT1270-19) I.R.-B., O.M., J.A.N.-G., and D.C. were supported by the Fundacion Biofisica Bizkaia. The Lamaze laboratory was supported from Agence Nationale de la Recherche grants ANR-11-LABX-0038, ANR-10-IDEX-0001-02, and ANR NanoGammaR-15-CE11-0025-01. The Bernardino de la Serna Lab acknowledges support from Belinda and Bill Gates Foundation and BBSRC (INV-016631 and BB/V019791/1, respectively). This work was supported in part by the Fundacion Biofisica Bizkaia and the Basque Excellence Research Centre (BERC) program of the Basque Government. The authors thank J. M. Gonzalez Manas for helpful comments on the manuscript. The authors thank the technical and human support provided by the analytical and high-resolution microscopy facility (SGIker) of UPV/EHU and European funding (ERDF and ESF)

Estradiol Regulates Energy Balance by Ameliorating Hypothalamic Ceramide-Induced ER Stress

Compelling evidence has shown that, besides its putative effect on the regulation of the gonadal axis, estradiol (E2) exerts a dichotomic effect on the hypothalamus to regulate food intake and energy expenditure. The anorectic effect of E2 is mainly mediated by its action on the arcuate nucleus (ARC), whereas its effects on brown adipose tissue (BAT) thermogenesis occur in the ventromedial nucleus (VMH). Here, we demonstrate that central E2 decreases hypothalamic ceramide levels and endoplasmic reticulum (ER) stress. Pharmacological or genetic blockade of ceramide synthesis and amelioration of ER stress selectively occurring in the VMH recapitulate the effect of E2, leading to increased BAT thermogenesis, weight loss, and metabolic improvement. These findings demonstrate that E2 regulation of ceramide-induced hypothalamic lipotoxicity and ER stress is an important determinant of energy balance, suggesting that dysregulation of this mechanism may underlie some changes in energy homeostasis seen in femalesThe research leading to these results has received funding from Xunta de Galicia (R.N.: 2015-CP080 and 2016-PG057; M.L.: 2015-CP079), MINECO co-funded by the FEDER Program of EU (R.N.: BFU2015-70664R; D.P.: SAF2016-77526-R; C.D.: BFU2017-87721; M.L.: SAF2015-71026-R and BFU2015-70454-REDT/Adipoplast). The CiMUS is supported by the Xunta de Galicia (2016-2019, ED431G/05). L.L.-P. is a recipient of a fellowship from Xunta de Galicia (ED481A-2016/094); E.R.-P. is a recipient of a fellowship from MINECO (BES-2015-072743); A.E.-S. is a recipient of a fellowship from MINECO (FPI/BES-2016-077439); C.R. is a recipient of a fellowship from MINECO (FPU16/04582). CIBER Fisiopatología de la Obesidad y Nutrición is an initiative of ISCIIIS

Specific and Sensitive Detection of H. pylori in Biological Specimens by Real-Time RT-PCR and In Situ Hybridization

PCR detection of H. pylori in biological specimens is rendered difficult by the extensive polymorphism of H. pylori genes and the suppressed expression of some genes in many strains. The goal of the present study was to (1) define a domain of the 16S rRNA sequence that is both highly conserved among H. pylori strains and also specific to the species, and (2) to develop and validate specific and sensitive molecular methods for the detection of H. pylori. We used a combination of in silico and molecular approaches to achieve sensitive and specific detection of H. pylori in biologic media. We sequenced two isolates from patients living in different continents and demonstrated that a 546-bp domain of the H. pylori 16S rRNA sequence was conserved in those strains and in published sequences. Within this conserved sequence, we defined a 229-bp domain that is 100% homologous in most H. pylori strains available in GenBank and also is specific for H. pylori. This sub-domain was then used to design (1) a set of high quality RT-PCR primers and probe that encompassed a 76-bp sequence and included at least two mismatches with other Helicobacter sp. 16S rRNA; and (2) in situ hybridization antisense probes. The sensitivity and specificity of the approaches were then demonstrated by using gastric biopsy specimens from patients and rhesus monkeys. This H. pylori-specific region of the 16S rRNA sequence is highly conserved among most H. pylori strains and allows specific detection, identification, and quantification of this bacterium in biological specimens

Long-Term Clinical Protection from Falciparum Malaria Is Strongly Associated with IgG3 Antibodies to Merozoite Surface Protein 3

Using data from malaria cases in Senegal, Pierre Druilhe and colleagues found that antibodies of the IgG3 isotype directed to merozoite surface protein 3 (MSP3) were strongly predictive of clinical outcome

High Content Screening Identifies Decaprenyl-Phosphoribose 2′ Epimerase as a Target for Intracellular Antimycobacterial Inhibitors

A critical feature of Mycobacterium tuberculosis, the causative agent of human tuberculosis (TB), is its ability to survive and multiply within macrophages, making these host cells an ideal niche for persisting microbes. Killing the intracellular tubercle bacilli is a key requirement for efficient tuberculosis treatment, yet identifying potent inhibitors has been hampered by labor-intensive techniques and lack of validated targets. Here, we present the development of a phenotypic cell-based assay that uses automated confocal fluorescence microscopy for high throughput screening of chemicals that interfere with the replication of M. tuberculosis within macrophages. Screening a library of 57,000 small molecules led to the identification of 135 active compounds with potent intracellular anti-mycobacterial efficacy and no host cell toxicity. Among these, the dinitrobenzamide derivatives (DNB) showed high activity against M. tuberculosis, including extensively drug resistant (XDR) strains. More importantly, we demonstrate that incubation of M. tuberculosis with DNB inhibited the formation of both lipoarabinomannan and arabinogalactan, attributable to the inhibition of decaprenyl-phospho-arabinose synthesis catalyzed by the decaprenyl-phosphoribose 2′ epimerase DprE1/DprE2. Inhibition of this new target will likely contribute to new therapeutic solutions against emerging XDR-TB. Beyond validating the high throughput/content screening approach, our results open new avenues for finding the next generation of antimicrobials