Similarity in targets with REST points to neural and glioblastoma related miRNAs

There are groups of genes that need coordinated repression in multiple contexts, for example if they code for proteins that work together in a pathway or in a protein complex. Redundancy of biological regulatory networks implies that such coordinated repression might occur at both the pre- and post-transcriptional level, though not necessarily simultaneously or under the same conditions. Here, we propose that such redundancy in the global regulatory network can be detected by the overlap between the putative targets of a transcriptional repressor, as identified by a ChIP-seq experiment, and predicted targets of a microRNA (miRNA). To test this hypothesis, we used publicly available ChIP-seq data of the neural transcriptional repressor RE1 silencing transcription factor (REST) from 15 different cell samples. We found 20 miRNAs, each of which shares a significant amount of predicted targets with REST. The set of predicted associations between these 20 miRNAs and the overlapping REST targets is enriched in known miRNA targets. Many of the detected miRNAs have functions related to neural identity and glioblastoma, which could be expected from their overlap in targets with REST. We propose that the integration of experimentally determined transcription factor binding sites with miRNA-target predictions provides functional information on miRNAs

Targetfinder.org: a resource for systematic discovery of transcription factor target genes

Targetfinder.org (http://targetfinder.org/) provides a web-based resource for finding genes that show a similar expression pattern to a group of user-selected genes. It is based on a large-scale gene expression compendium (>1200 experiments, >13 000 genes). The primary application of Targetfinder.org is to expand a list of known transcription factor targets by new candidate target genes. The user submits a group of genes (the ‘seed’), and as a result the web site provides a list of other genes ranked by similarity of their expression to the expression of the seed genes. Additionally, the web site provides information on a recovery/cross-validation test to check for consistency of the provided seed and the quality of the ranking. Furthermore, the web site allows to analyse affinities of a selected transcription factor to the promoter regions of the top-ranked genes in order to select the best new candidate target genes for further experimental analysis

Reentrant Metallic Behavior of Graphite in the Quantum Limit

Magnetotransport measurements performed on several well-characterized highly oriented pyrolitic graphite and single crystalline Kish graphite samples reveal a reentrant metallic behavior in the basal-plane resistance at high magnetic fields, when only the lowest Landau levels are occupied. The results suggest that the quantum Hall effect and Landau-level-quantization-induced superconducting correlations are relevant to understand the metallic-like state(s) in graphite in the quantum limit.Comment: 4 pages, 5 figure

Experimental and Theoretical Investigation of Recombination Pumped X-ray Lasers Driven by High-Intensity, Short Pulse Lasers

We have experimentally investigated a recombination-pumped soft-x-ray laser on a Lyman-α transition (135 Å) of hydrogenlike lithium. Furthermore, we have modeled the dynamics of this system, including the effects of the multipeaked electron distribution function that is obtained from the sequential, optical-field ionization of an atom. We compare the predictions of our model and our experimental results

Annexin A2 mediates apical trafficking of renal Na(+)-K(+)-2Cl(-)-cotransporter

The furosemide-sensitive Na(+)-K(+)-2Cl(-)-cotransporter (NKCC2) is responsible for urine concentration, and helps maintain systemic salt homeostasis. Its activity depends on trafficking to, and insertion into, the apical membrane, as well as on phosphorylation of conserved N-terminal serine and threonine residues. Vasopressin (AVP), signaling via PKA and other kinases, activates NKCC2. Association of NKCC2 with lipid rafts facilitates its AVP-induced apical translocation and activation at the surface. Lipid raft microdomains typically serve as platforms for membrane proteins to facilitate their interactions with other proteins, but little is known about partners that interact with NKCC2. Yeast two-hybrid screening identified an interaction between NKCC2 and the cytosolic protein, annexin A2 (AnxA2). Annexins mediate lipid raft-dependent trafficking of transmembrane proteins, including the AVP-regulated water channel, aquaporin 2. Here, we demonstrate that AnxA2, which binds to phospholipids in a Ca(2+)-dependent manner and may organize microdomains, is co-distributed with NKCC2 to promote its apical translocation in response to AVP stimulation and low chloride hypotonic stress. NKCC2 and AnxA2 interact in a phosphorylation-dependent manner. Phosphomimetic AnxA2 carrying a mutant, Src-dependent phosphoacceptor (AnxA2-Y24D-GFP), enhanced surface expression and raft association of NKCC2 by 5-fold upon AVP stimulation, whereas PKC-dependent AnxA2-S26D-GFP did not. As the AnxA2 effect involved only non-phosphorylated NKCC2, it appears to affect NKCC2 trafficking. Overexpression or knockdown experiments further supported the role of AnxA2 in the apical translocation and surface expression of NKCC2. In summary, this study identifies AnxA2 as a lipid raft-associated trafficking factor for NKCC2 and provides mechanistic insight into the regulation of this essential cotransporter

Shutdown of achaete-scute homolog-1 expression by heterogeneous nuclear ribonucleoprotein (hnRNP)-A2/B1 in hypoxia

The basic helix-loop-helix transcription factor hASH1, encoded by the ASCL1 gene, plays an important role in neurogenesis and tumor development. Recent findings indicate that the local oxygen tension is a critical determinant for the progression of neuroblastomas. Here we investigated the molecular mechanisms underlying the oxygen-dependent expression of hASH1 in neuroblastoma cells. Exposure of human neuroblastoma-derived Kelly cells to 1% O2 significantly decreased ASCL1 mRNA and hASH1 protein levels. Using reporter gene assays, we show that the response of hASH1 to hypoxia is mediated mainly by post-transcriptional inhibition via the ASCL1 mRNA 5'- and 3'-UTRs, while additional inhibition of the ASCL1 promoter was observed under prolonged hypoxia. By RNA pull-down experiments followed by MALDI/TOF-MS analysis, we identified heterogeneous nuclear ribonucleoprotein (hnRNP)-A2/B1 and hnRNP-R as interactors binding directly to the ASCL1 mRNA 5'- and 3'-UTRs and influencing its expression. We further demonstrate that hnRNP-A2/B1 is a key positive regulator of ASCL1, findings that were also confirmed by analysis of a large compilation of gene expression data. Our data suggest that a prominent down-regulation of hnRNP-A2/B1 during hypoxia is associated with the post-transcriptional suppression of hASH1 synthesis. This novel post-transcriptional mechanism for regulating hASH1 levels will have important implications in neural cell fate development and disease

Magnetic-Field-Driven Superconductor-Insulator-Type Transition in Graphite

A magnetic-field-driven transition from metallic- to semiconducting-type behavior in the basal-plane resistance takes place in highly oriented pyrolytic graphite at a field $H_c \sim 1~$kOe applied along the hexagonal c-axis. The analysis of the data reveals a striking similarity between this transition and that measured in thin-film superconductors and Si MOSFET's. However, in contrast to those materials, the transition in graphite is observable at almost two orders of magnitude higher temperatures.Comment: 4 Figure

L-2-topology and Lagrangians in the space of connections over a Riemann surface

We examine the L²-topology of the gauge orbits over a closed Riemann surface. We prove a subtle local slice theorem based on the div-curl lemma of harmonic analysis, and deduce local pathwise connectedness of the gauge orbits. Based on a quantitative version of the connectivity, we generalize compactness results for anti-self-dual instantons with Lagrangian boundary conditions to general gauge-invariant Lagrangian submanifolds. This provides the foundation for the construction of instanton Floer homology for pairs of a 3-manifold with boundary and a Lagrangian in the configuration space over the boundary