How Train Transportation Design Challenges can be addressed with Simulation-based Virtual Prototyping for Distributed Systems

International audienceThe needs to accelerate development of next generation train control technology, while meeting the quality standards and safety requirements demanded for the development of today's distributed, software dominated, train transportation applications, can only be achieved through a novel methodology that addresses analysis and integration validation of subsystems , via simulation-based virtual prototyping. The methodology must be able to address, much earlier in the development cycle, design goals (among others) such as: • Specifications Validation and Quality of Service Analysis, • Systems safety evaluation and commissioning of automated train control systems, • Early Integration Validation, • Fast assessment of derivative designs, • Compliance with transportation standards (EN50128-SIL2). Such methods actually used in some current projects can be seen as exemplary; they are paving the way for other transportation industry domains to adopt in confidence new system design paradigm shifts

Genescene: Biomedical Text and Data Mining

To access the content of digital texts efficiently, it is necessary to provide more sophisticated access than keyword based searching. GeneScene provides biomedical researchers with research findings and background relations automatically extracted from text and experimental data. These provide a more detailed overview of the information available. The extracted relations were evaluated by qualified researchers and are precise. A qualitative ongoing evaluation of the current online interface indicates that this method to search the literature is more useful and efficient than keyword based searching

The plant germplasm and herbarium (WIR) collections maintained at VIR as contributors to grape genetic diversity conservation, expansion and utilization

Improving the standards of collecting and maintaining valuable genetic resources accessions and information about them is currently of crucial importance for the successful development of the world viticulture in the light of the challenges caused by the spread of grape diseases and climate change. This review briefly characterizes the global grapevine gene pool, approaches to its conservation, including base and duplicate conservation techniques, and the current status and prospects of the progress in in vitro and cryogenic preservation methods. The genetic potential of grape wild relatives is assessed focusing on particular species as sources of resistance genes to biotic and abiotic stressors. Achievements in the application of gene editing technologies to increase grape resistance to diseases are discussed. It is noted that a common practice at this stage is to knock out the genes responsible for grapevine susceptibility to diseases, whereas a more advantageous approach in the future will be to make targeted changes in the grape genome based on the knowledge of resistance genes in its wild relatives. Therefore, grape wild relatives need to be studied thoroughly using modern methods of forward and reverse genetics. Regarding the issues of grape genetic diversity conservation and expansion at the current technological stage, the status and significance of the plant germplasm and herbarium (WIR) collections held by VIR are scrutinized in detail. Authentication of grape germplasm accessions is marked as important, along with the role of the WIR herbarium, a unique collection incorporating physical carriers of reference genetic information on the national grapevine gene pool. Promising trends in the development of the WIR herbarium are outlined in connection with the establishment and preservation of nomenclature standards for domestic grape cultivars

Homologous organization of cerebellar pathways to sensory, motor, and associative forebrain.

Cerebellar outputs take polysynaptic routes to reach the rest of the brain, impeding conventional tracing. Here, we quantify pathways between the cerebellum and forebrain by using transsynaptic tracing viruses and a whole-brain analysis pipeline. With retrograde tracing, we find that most descending paths originate from the somatomotor cortex. Anterograde tracing of ascending paths encompasses most thalamic nuclei, especially ventral posteromedial, lateral posterior, mediodorsal, and reticular nuclei. In the neocortex, sensorimotor regions contain the most labeled neurons, but we find higher densities in associative areas, including orbital, anterior cingulate, prelimbic, and infralimbic cortex. Patterns of ascending expression correlate with c-Fos expression after optogenetic inhibition of Purkinje cells. Our results reveal homologous networks linking single areas of the cerebellar cortex to diverse forebrain targets. We conclude that shared areas of the cerebellum are positioned to provide sensory-motor information to regions implicated in both movement and nonmotor function

miRNA Expression Profiling in Migrating Glioblastoma Cells: Regulation of Cell Migration and Invasion by miR-23b via Targeting of Pyk2

Glioblastoma (GB) is the most common and lethal type of primary brain tumor. Clinical outcome remains poor and is essentially palliative due to the highly invasive nature of the disease. A more thorough understanding of the molecular mechanisms that drive glioma invasion is required to limit dispersion of malignant glioma cells.We investigated the potential role of differential expression of microRNAs (miRNA) in glioma invasion by comparing the matched large-scale, genome-wide miRNA expression profiles of migrating and migration-restricted human glioma cells. Migratory and migration-restricted cell populations from seven glioma cell lines were isolated and profiled for miRNA expression. Statistical analyses revealed a set of miRNAs common to all seven glioma cell lines that were significantly down regulated in the migrating cell population relative to cells in the migration-restricted population. Among the down-regulated miRNAs, miR-23b has been reported to target potential drivers of cell migration and invasion in other cell types. Over-expression of miR-23b significantly inhibited glioma cell migration and invasion. A bioinformatics search revealed a conserved target site within the 3' untranslated region (UTR) of Pyk2, a non-receptor tyrosine kinase previously implicated in the regulation of glioma cell migration and invasion. Increased expression of miR-23b reduced the protein expression level of Pyk2 in glioma cells but did not significantly alter the protein expression level of the related focal adhesion kinase FAK. Expression of Pyk2 via a transcript variant missing the 3'UTR in miR-23b-expressing cells partially rescued cell migration, whereas expression of Pyk2 via a transcript containing an intact 3'UTR failed to rescue cell migration.Reduced expression of miR-23b enhances glioma cell migration in vitro and invasion ex vivo via modulation of Pyk2 protein expression. The data suggest that specific miRNAs may regulate glioma migration and invasion to influence the progression of this disease

NHERF-1: Modulator of Glioblastoma Cell Migration and Invasion1,2

The invasive nature of malignant gliomas is a clinical problem rendering tumors incurable by conventional treatment modalities such as surgery, ionizing radiation, and temozolomide. Na+/H+ exchanger regulatory factor 1 (NHERF-1) is a multifunctional adaptor protein, recruiting cytoplasmic signaling proteins and membrane receptors/transporters into functional complexes. This study revealed that NHERF-1 expression is increased in highly invasive cells that reside in the rim of glioblastoma multiforme (GBM) tumors and that NHERF-1 sustains glioma migration and invasion. Gene expression profiles were evaluated from laser capture-microdissected human GBM cells isolated from patient tumor cores and corresponding invaded white matter regions. The role of NHERF-1 in the migration and dispersion of GBM cell lines was examined by reducing its expression with small-interfering RNA followed by radial migration, three-dimensional collagen dispersion, immunofluorescence, and survival assays. The in situ expression of NHERF-1 protein was restricted to glioma cells and the vascular endothelium, with minimal to no detection in adjacent normal brain tissue. Depletion of NHERF-1 arrested migration and dispersion of glioma cell lines and caused an increase in cell-cell cohesiveness. Glioblastoma multiforme cells with depleted NHERF-1 evidenced a marked decrease in stress fibers, a larger cell size, and a more rounded shape with fewer cellular processes. When NHERF-1 expression was reduced, glioma cells became sensitized to temozolomide treatment resulting in increased apoptosis. Taken together, these results provide the first evidence for NHERF-1 as a participant in the highly invasive phenotype of malignant gliomas and implicate NHERF-1 as a possible therapeutic target for treatment of GBM

Deep Behavioral Phenotyping Of Mouse Autism Models using Open-Field Behavior

Download the DATASET_MMM_README.txt file for a detailed description of this dataset's contentThe primary experimental data are in the jointsCON.mat and centroids_velocities_CON.mat consist of body parts and centroid dynamics information during Open-Field Sessions from 60 male and 20 female C57BL/6, as well as from ASD models: 14 Cntnap2 WT, 15 Cntnap2 HET, 10 Cntnap2 KO, 17 L7-Tsc1 WT, 17 L7-Tsc1 HET and 9 L7-Tsc1 HOM mutant mice

Reciprocal Activation of Transcription Factors Underlies the Dichotomy between Proliferation and Invasion of Glioma Cells

<div><p>Histology of malignant glioma depicts dense proliferative areas rich in angiogenesis as well as dissemination of neoplastic cells into adjacent brain tissue. Although the mechanisms that trigger transition from proliferative to invasive phenotypes are complex, the dichotomy of cell proliferation and migration, the “Go or Grow” hypothesis, argues for specific and coordinated regulation of these phenotypes. We investigated transcriptional elements that accompany the phenotypes of migration and proliferation, and consider the therapeutic significance of the “Go or Grow” hypothesis. Interrogation of matched core and rim regions from human glioblastoma biopsy specimens <i>in situ</i> (n = 44) revealed higher proliferation (Ki67 labeling index) in cells residing at the core compared to the rim. Profiling activated transcription factors in a panel of migration-activated versus migration-restricted GBM cells portrayed strong NF-κB activity in the migratory cell population. In contrast, increased c-Myc activity was found in migration-restricted proliferative cells. Validation of transcriptional activity by NF-κB- or c-Myc-driven GFP or RFP, respectively, showed an increased NF-κB activity in the active migrating cells, whereas the proliferative, migration restricted cells displayed increased c-Myc activity. Immunohistochemistry on clinical specimens validated a robust phosphorylated c-Myc staining in tumor cells at the core, whereas increased phosphorylated NF-κB staining was detected in the invasive tumor cells at the rim. Functional genomics revealed that depletion of c-Myc expression by siRNA oligonucleotides reduced cell proliferation <i>in vitro</i>, but surprisingly, cell migration was enhanced significantly. Conversely, inhibition of NF-κB by pharmacological inhibitors, SN50 or BAY-11, decreased both cell migration <i>in vitro</i> and invasion <i>ex vivo</i>. Notably, inhibition of NF-κB was found to have no effect on the proliferation rate of glioma cells. These findings suggest that the reciprocal and coordinated suppression/activation of transcription factors, such as c-Myc and NF-κB may underlie the shift of glioma cells from a “growing-to-going” phenotype.</p></div

Inhibition of NF-κB function suppresses glioma cell migration in vitro and invasion ex vivo.

<p>Treatment with 50 µM SN50 peptide inhibitor suppresses migration of (A) T98G and SNB19 glioma cells in a radial migration assay when compared with untreated (NT) or scrambled peptide treated (SN50M) cells (*; p<0.0001). (B) SNB19 glioma cells stably expressing GFP were implanted into the bilateral putamen on rat organotypic brain slices. Implanted cells were then treated with SN50 peptide inhibitor, scrambled peptide (SN50M) or left untreated (NT) and observed at 48 hrs. Depth of invasion was then calculated from Z-axis images collected by confocal laser scanning microscopy. The mean value of the depth of invasion was obtained from four independent experiments (*; p<0.0001). Treatment with 20 µM NF-κB functional inhibitor (BAY-11-7082) suppresses migration of (C) T98G and SNB19 glioma cells in a radial migration assay when compared with untreated (NT) or DMSO treated (VC) cells (*; p<0.0001). (D) Similar ex vivo brain slice invasion assay as described in B with NF-κB functional inhibitor (BAY-11-7082) demonstrated reduced invasion of T98G and SNB19 glioma cells. The mean value of the depth of invasion was obtained from four independent experiments (*; p<0.0001).</p