The Impact of Memory Organization in Hybrid DSM

Hybrid Distributed Shared Memory (DSM) systems are shared-memory multiprocessor architectures with software-implemented coherence protocols and hardware support for fine-grain sharing. In this paper we compare the design issues and performance consequences for adopting in hybrid DSM four memory organizations inspired from existing architectures: CC-NUMA, RC-NUMA, S-COMA, and COMA. The performance of these architectures has been analyzed for hardware implementations. However, there are many competing trade-offs which require careful re-evaluations for hybrid implementations. To do so, on a common platform, we have completely implemented the software protocol handlers for the four architectures. These handlers run on the same processor as the application; however, our findings can be easily interpreted in the context of systems with dedicated protocol processors. We base our evaluations on detailed execution-driven simulations of six complete benchmarks with both coarse-grain and fine-gr..

Hardware vs. Software Implementation of COMA

Traditionally, cache coherence in multiprocessors has been maintained in hardware. However, the cost-effectiveness of hardwired protocols is questionable. Virtual Shared Memory systems have highlighted the many advantages of softwareimplemented protocols, albeit at a performance price. The performance gap is narrowed by hybrid systems with the addition of hardware support for fine-grain sharing. We have developed a software protocol for a COMA (Cache-Only Memory Architecture). We call the system SCCOMA for Software-Controlled COMA, to emphasize that the protocol engine is emulated by software executed on the main processor. Contrary to user-level protocols, the software handling coherence events in SC-COMA runs in sub-kernel mode, transparently providing the same services to applications as a hardware counterpart. The software emulation layer has been written and we compare SC-COMA to an idealized hardware COMA through detailed simulations. Our results show that SC-COMA is competitive...

Memory Organizations in Hybrid DSM: A Performance Comparison

Hybrid Distributed Shared Memory (DSM) systems are shared-memory multiprocessor architectures with software-implemented coherence protocols and hardware support for fine-grain sharing. In this paper we compare the designs of three possible hybrid architectures inspired from three hardware DSMs: CC-NUMA, COMA and Simple COMA. The corresponding hybrids are called SCC-NUMA, SC-COMA and SS-COMA. There are several competing trade-offs in these three architectures, which require careful evaluations. We have completely implemented the software protocol handlers for the three architectures. In the target systems, these handlers run on the same processor as the application; however, our findings can be easily interpreted in the context of machines with dedicated protocol processors. We base our evaluations on detailed execution-driven simulations of six complete benchmarks with both coarse-grain and fine-grain sharing. The major difference between SCC-NUMA and the two hybrid COMAs is that both ..

Multiprocessor Emulation With RPM: Early Experience

Field-Programmable Gate Arrays is an emerging technology which promises easy hardware reconfigurability by software at low cost. Entire systems can be built in which some parts are easily programmable. Such systems are flexible hardware platforms or emulators, which are then tailored to implement various architectures. The performance of these architectures can be compared on the same hardware substrate. Besides having a large speedup advantage over software simulation, the emulator is a detailed hardware implementation of the architecture --including I/O-- on which complex software systems can be run without code instrumentation and it is a more convincing proof of concept. On the other hand it is much more cost-effective than a full-fledged prototype. We have built a multiprocessor emulator called RPM --Rapid Prototyping engine for Multiprocessor systems. RPM can emulate various configurations of shared-memory and message-passing systems. The bandwidth and latency of various componen..

Neryl acetate, the major component of Corsican Helichrysum italicum essential oil, mediates its biological activities on skin barrier.

Corsican Helichrysum italicum essential oil (HIEO) is characterized by high concentrations of neryl acetate, and we previously demonstrated that Corsican HIEO increases the expression of genes that are part of the differentiation complex (involucrin, small proline rich proteins, late cornified envelope, S100 protein family). The biological activities of HIEO and neryl acetate (NA) were compared to identify how NA contributes to HIEO activity on human skin. NA, as a part component of HIEO, was tested on skin explant models for 24 hours and 5 days in comparison with HIEO. We analyzed the biological regulations in the skin explant by transcriptomic analysis, skin barrier protein immunofluorescence, lipid staining and ceramide analysis by liquid chromatography-mass spectrometry. Transcriptomic analysis revealed that 41.5% of HIEO-modulated genes were also regulated by NA and a selected panel of genes were confirmed by qquantitative reverse transcription PCR analysis. Those genes are involved in epidermal differentiation, skin barrier formation and ceramide synthesis. Involucrin (IVL), involved in formation of the cornified envelope (CE), was upregulated at both gene and protein levels after 24 hours and 5 days respectively. After 5 days of treatment, total lipids and ceramides were also increased. Our results demonstrate that NA mediates a large part of Corsican HIEO activity on skin barrier formation

The Actin-Based Motor Myosin Vb Is Crucial to Maintain Epidermal Barrier Integrity

International audienceMyosin Vb (Myo5b) is an unconventional myosin involved in the actin-dependent transport and tethering of intracellular organelles. In the epidermis, granular keratinocytes accumulate cytoplasmic lamellar bodies (LBs), secretory vesicles released at the junction with the stratum corneum that participate actively in the maintenance of the epidermal barrier. We have previously demonstrated that LB biogenesis is controlled by the Rab11a guanosine triphosphate hydrolase, known for its ability to recruit the Myo5b motor. In order to better characterize the molecular pathway that controls LB trafficking, we analyzed the role of F-actin and Myo5b in the epidermis. We demonstrated that LB distribution in granular keratinocytes was dependent on a dynamic F-actin cytoskeleton. Myo5b was shown to be highly expressed in granular keratinocytes and associated with corneodesmosin-loaded LB. In reconstructed human epidermis, Myo5b silencing led to epidermal barrier defects associated with structural alterations of the stratum corneum and a reduced pool of LB showing signs of disordered maturation. Myo5b depletion also disturbed the expression and distribution of both LB cargoes and junctional components, such as claudin-1, which demonstrates its action on both LB trafficking and junctional complex composition. Together, our data reveal the essential role of Myo5b in maintaining the epidermal barrier integrity

Rab11a Is Essential for Lamellar Body Biogenesis in the Human Epidermis

International audienceMost of the skin barrier function is attributable to the outermost layer of the epidermis, the stratum corneum, which is composed of flattened, anucleated cells called corneocytes surrounded by a lipid-enriched lamellar matrix. The composition of the stratum corneum is directly dependent on the underlying granular keratinocytes, which are the last living cells in the stratified epidermis. Many components present in the intercorneocyte matrix are delivered by the underlying granular keratinocytes through a secretion process dependent on lysosome-related organelles called lamellar bodies. Because of the importance of lamellar bodies in the maintenance of the epidermal barrier, the mechanisms regulating their biogenesis must be better understood. In this study, we show that the Rab11a GTPase is highly expressed in terminally differentiated keratinocytes, where it is partly associated with lamellar bodies. Rab11a silencing in three-dimensional in vitro reconstructed human epidermis induces a barrier defect, a decrease in the amount of lipid found in the stratum corneum, a reduction in lamellar body density and secretion areas in granular keratinocytes, and the mis-sorting of lamellar body cargoes being driven to the lysosomal degradation pathway. Our results highlight the importance of Rab11a-dependent regulation of lamellar body biogenesis in keratinocytes and consequently on epidermal barrier homeostasis

Autologous Th2-polarized lymphocytes induce atopic dermatitis lesions in non-atopic human skin xenotransplants

The key signals that suffice to induce atopic dermatitis (AD) in human skin remain incompletely understood. Also, current mouse models reflect human AD only unsatisfactorily. Therefore, we have asked whether a humanized AD mouse model can be developed that reflects human AD more faithfully and permit to identify key signals that suffice to induce AD lesions in previously healthy human skin in vivo. Healthy human skin from non-atopic donors was transplanted onto SCID/beige mice. After xenotransplant reinnervation by mouse sensory nerve fibers had occurred, mixed autologous human Th2 CD4+ and Tc2 CD8+ T cells that had been pretreated in vitro with IL-2, IL-4- and LPS were injected intradermally into the xenotransplants without skin barrier disruption. Injected non-atopic xenotransplants rapidly developed a morphological, functional, and immunological phenocopy of human AD lesions regarding skin barrier defects, immunopathology including intraepidermal eosinophils, mast cell activation, increase of thymic stromal lymphopoietin, eotaxin-1 and type 2 cytokine circuits, and even showed characteristic neuroimmunological abnormalities such as ß2-adrenergic receptor downregulation. The experimentally induced AD lesions in human skin responded to standard AD therapy (topical dexamethasone or tacrolimus; systemic anti-IL-4Rα antibody [dupilumab]), and relapsed when neurogenic skin inflammation was induced by exposing mice to perceived stress. This new animal model uniquely mimics the complexity of human AD and its clinical response to standard therapy and psychoemotional stressors in vivo, and shows that Th2-polarized lymphocytes associated with excessive IL-4Rα-mediated signaling suffice to induce human AD skin lesions, while atopy and epidermal barrier disruption are dispensable

Non-invasive diagnosis and follow-up of chronic infection with Hepatitis C Virus

International audienceHepatitis C virus (HCV) infection is a major cause of chronic liver disease. Clinical care for patients with HCV-related liver disease has advanced considerably with developments in screening, diagnostic procedures to evaluate liver fibrosis and improvements in therapy with pangenotypic direct antivirals and prevention. These AFEF guidelines on the non-invasive diagnosis and follow up of chronic infection with HCV describe the optimal management of HCV positive patients with non-invasive methods in screening, in assessing viral disease and liver fibrosis and the follow-up of these patients according to the value of FibroScan Ò , Fibrotest Ò or Fibrometer Ò. Hepatocellular carcinoma screening must continue in patients with liver stiffness by FibroScan Ò 10 kPa or Fibrotest Ò >0.58 or Fibrometer Ò >0.78 prior to treatment initiation. After reaching sustained virologic response, patients with a measurement of liver stiffness by FibroScan Ò <10 kPa or Fibrotest Ò 0.58 or Fibrometer Ò 0.78 before treatment initiation and without liver comorbidity (alcohol consumption, metabolic syndrome, HBV co-infection etc.) no longer require specific monitoring. The role of liver biopsy is discussed in some rare situations