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

Prognostic impact of activin subunit inhibin beta A in gastric and esophageal adenocarcinomas

PURPOSE: Adenocarcinomas of the esophagus (AEG) and stomach (AS) are among the most common cancers worldwide. Novel markers for risk stratification and guiding treatment are strongly needed. Activin is a multi-functional cytokine with context specific pro- and anti-tumorigenic effects. We aimed to investigate the prognostic role of activin tumor protein expression in AEG/ASs. METHODS: Tissue from a retrospective cohort of 277 patients with AEG/AS treated primarily by surgery at the Charité - Universitätsmedizin Berlin was collected and analyzed by immunohistochemistry using a specific antibody to the activin homodimer inhibin beta A. Additionally, we evaluated T-cell infiltration and PD1 expression as well as expression of PD-L1 by immunohistochemistry as possible confounding factors. Clinico-pathologic data were collected and correlated with activin protein expression. RESULTS: Out of 277 tumor samples, 72 (26.0%) exhibited high activin subunit inhibin beta A protein expression. Higher expression was correlated with lower Union for International Cancer Control (UICC) stage and longer overall survival. Interestingly, activin subunit expression correlated with CD4(+) T-cell infiltration, and the correlation with higher overall survival was exclusively seen in tumors with high CD4(+) T-cell infiltration, pointing towards a role of activin in the tumor immune response in AEG/ASs. CONCLUSION: In our cohort of AEG/AS, higher activin subunit levels were correlated with longer overall survival, an effect exclusively seen in tumors with high CD4(+) cell infiltration. Further mechanistic research is warranted discerning the exact effect of this context specific cytokine

Direct control of an active tactile sensor using echo state networks

Krause AF, Bläsing B, Dürr V, Schack T. Direct control of an active tactile sensor using echo state networks. In: Ritter H, Sagerer G, Dillmann R, Buss M, eds. Human Centered Robot Systems. Cognition, Interaction, Technology. Berlin, Heidelberg: Springer; 2009: 11-21.Tactile sensors (antennae) play an important role in the animal kingdom. They are also very useful as sensors in robotic scenarios, where vision systems may fail. Active tactile movements increase the sampling performance. Here we directly control movements of the antenna of a simulated hexapod using an echo state network (ESN). ESNs can store multiple motor patterns as attractors in a single network and generate novel patterns by combining and blending already learned patterns using bifurcation inputs