Structural insights into RNA processing by the human RISC-loading complex.

Targeted gene silencing by RNA interference (RNAi) requires loading of a short guide RNA (small interfering RNA (siRNA) or microRNA (miRNA)) onto an Argonaute protein to form the functional center of an RNA-induced silencing complex (RISC). In humans, Argonaute2 (AGO2) assembles with the guide RNA-generating enzyme Dicer and the RNA-binding protein TRBP to form a RISC-loading complex (RLC), which is necessary for efficient transfer of nascent siRNAs and miRNAs from Dicer to AGO2. Here, using single-particle EM analysis, we show that human Dicer has an L-shaped structure. The RLC Dicer's N-terminal DExH/D domain, located in a short 'base branch', interacts with TRBP, whereas its C-terminal catalytic domains in the main body are proximal to AGO2. A model generated by docking the available atomic structures of Dicer and Argonaute homologs into the RLC reconstruction suggests a mechanism for siRNA transfer from Dicer to AGO2

LipidXplorer: A Software for Consensual Cross-Platform Lipidomics

LipidXplorer is the open source software that supports the quantitative characterization of complex lipidomes by interpreting large datasets of shotgun mass spectra. LipidXplorer processes spectra acquired on any type of tandem mass spectrometers; it identifies and quantifies molecular species of any ionizable lipid class by considering any known or assumed molecular fragmentation pathway independently of any resource of reference mass spectra. It also supports any shotgun profiling routine, from high throughput top-down screening for molecular diagnostic and biomarker discovery to the targeted absolute quantification of low abundant lipid species. Full documentation on installation and operation of LipidXplorer, including tutorial, collection of spectra interpretation scripts, FAQ and user forum are available through the wiki site at: https://wiki.mpi-cbg.de/wiki/lipidx/index.php/Main_Page

Benefits of Stimulus Congruency for Multisensory Facilitation of Visual Learning

Background. Studies of perceptual learning have largely focused on unisensory stimuli. However, multisensory interactions are ubiquitous in perception, even at early processing stages, and thus can potentially play a role in learning. Here, we examine the effect of auditory-visual congruency on visual learning. Methodology/Principle Findings. Subjects were trained over five days on a visual motion coherence detection task with either congruent audiovisual, or incongruent audiovisual stimuli. Comparing performance on visual-only trials, we find that training with congruent audiovisual stimuli produces significantly better learning than training with incongruent audiovisual stimuli or with only visual stimuli. Conclusions/ Significance. This advantage from stimulus congruency during training suggests that the benefits of multisensory training may result from audiovisual interactions at a perceptual rather than cognitive level

Is Task-Irrelevant Learning Really Task-Irrelevant?

In the present study we address the question of whether the learning of task-irrelevant stimuli found in the paradigm of task-irrelevant learning (TIPL) [1]–[9] is truly task irrelevant. To test the hypothesis that associations that are beneficial to task-performance may develop between the task-relevant and task-irrelevant stimuli, or the task-responses and the task-irrelevant stimuli, we designed a new procedure in which correlations between the presentation of task-irrelevant motion stimuli and the identity of task-targets or task-responses were manipulated. We found no evidence for associations developing between the learned (task-irrelevant) motion stimuli and the targets or responses to the letter identification task used during training. Furthermore, the conditions that had the greatest correlations between stimulus and response showed the least amount of TIPL. On the other hand, TIPL was found in conditions of greatest response uncertainty and with the greatest processing requirements for the task-relevant stimuli. This is in line with our previously published model that suggests that task-irrelevant stimuli benefit from the spill-over of learning signals that are released due to processing of task-relevant stimuli

Is Task-Irrelevant Learning Really Task-Irrelevant?

In the present study we address the question of whether the learning of task-irrelevant stimuli found in the paradigm of task-irrelevant learning (TIPL) [1]–[9] is truly task irrelevant. To test the hypothesis that associations that are beneficial to task-performance may develop between the task-relevant and task-irrelevant stimuli, or the task-responses and the task-irrelevant stimuli, we designed a new procedure in which correlations between the presentation of task-irrelevant motion stimuli and the identity of task-targets or task-responses were manipulated. We found no evidence for associations developing between the learned (task-irrelevant) motion stimuli and the targets or responses to the letter identification task used during training. Furthermore, the conditions that had the greatest correlations between stimulus and response showed the least amount of TIPL. On the other hand, TIPL was found in conditions of greatest response uncertainty and with the greatest processing requirements for the task-relevant stimuli. This is in line with our previously published model that suggests that task-irrelevant stimuli benefit from the spill-over of learning signals that are released due to processing of task-relevant stimuli

Endothelial cells regulate p53-dependent apoptosis of neural progenitors after irradiation

Endothelial cells represent an important component of the neurogenic niche and may regulate self-renewal and differentiation of neural progenitor cells (NPCs). Whether they have a role in determining the apoptotic fate of NPCs after stress or injury is unclear. NPCs are known to undergo p53-dependent apoptosis after ionizing radiation, whereas endothelial cell apoptosis after irradiation is dependent on membrane acid sphingomyelinase (ASMase) and is abrogated in sphingomyelin phosphodiesterase 1 (smpd1)- (gene that encodes ASMase) deficient mice. Here we found that p53-dependent apoptosis of NPCs in vivo after irradiation was inhibited in smpd1-deficient mice. NPCs cultured from mice, wild type (+/+) or knockout (−/−), of the smpd1 gene, however, demonstrated no difference in apoptosis radiosensitivity. NPCs transplanted into the hippocampus of smpd1−/− mice were protected against apoptosis after irradiation compared with those transplanted into smpd1+/+ mice. Intravenous administration of basic fibroblast growth factor, which does not cross the blood–brain barrier, known to protect endothelial cells against apoptosis after irradiation also attenuated the apoptotic response of NPCs. These findings provide evidence that endothelial cells may regulate p53-dependent apoptosis of NPCs after genotoxic stress and add support to an important role of endothelial cells in regulating apoptosis of NPCs after injury or in disease

Perceptual Learning in the Absence of Task or Stimulus Specificity

Performance on most sensory tasks improves with practice. When making particularly challenging sensory judgments, perceptual improvements in performance are tightly coupled to the trained task and stimulus configuration. The form of this specificity is believed to provide a strong indication of which neurons are solving the task or encoding the learned stimulus. Here we systematically decouple task- and stimulus-mediated components of trained improvements in perceptual performance and show that neither provides an adequate description of the learning process. Twenty-four human subjects trained on a unique combination of task (three-element alignment or bisection) and stimulus configuration (vertical or horizontal orientation). Before and after training, we measured subjects' performance on all four task-configuration combinations. What we demonstrate for the first time is that learning does actually transfer across both task and configuration provided there is a common spatial axis to the judgment. The critical factor underlying the transfer of learning effects is not the task or stimulus arrangements themselves, but rather the recruitment of commons sets of neurons most informative for making each perceptual judgment

Radiation induced CNS toxicity – molecular and cellular mechanisms

Radiotherapy of tumours proximal to normal CNS structures is limited by the sensitivity of the normal tissue. Prior to the development of prophylactic strategies or treatment protocols a detailed understanding of the mechanisms of radiation induced CNS toxicity is mandatory. Histological analysis of irradiated CNS specimens defines possible target structures prior to a delineation of cellular and molecular mechanisms. Several lesions can be distinguished: Demyelination, proliferative and degenerative glial reactions, endothelial cell loss and capillary occlusion. All changes are likely to result from complex alterations within several functional CNS compartments. Thus, a single mechanism responsible cannot be separated. At least four factors contribute to the development of CNS toxicity: (1) damage to vessel structures; (2) deletion of oligodendrocyte-2 astrocyte progenitors (O-2A) and mature oligodendrocytes; (3) deletion of neural stem cell populations in the hippocampus, cerebellum and cortex; (4) generalized alterations of cytokine expression. Several underlying cellular and molecular mechanisms involved in radiation induced CNS toxicity have been identified. The article reviews the currently available data on the cellular and molecular basis of radiation induced CNS side effects.   http://www.bjcancer.com © 2001 Cancer Research Campaig

Genomic Convergence among ERRα, PROX1, and BMAL1 in the Control of Metabolic Clock Outputs

Metabolic homeostasis and circadian rhythms are closely intertwined biological processes. Nuclear receptors, as sensors of hormonal and nutrient status, are actively implicated in maintaining this physiological relationship. Although the orphan nuclear receptor estrogen-related receptor α (ERRα, NR3B1) plays a central role in the control of energy metabolism and its expression is known to be cyclic in the liver, its role in temporal control of metabolic networks is unknown. Here we report that ERRα directly regulates all major components of the molecular clock. ERRα-null mice also display deregulated locomotor activity rhythms and circadian period lengths under free-running conditions, as well as altered circulating diurnal bile acid and lipid profiles. In addition, the ERRα-null mice exhibit time-dependent hypoglycemia and hypoinsulinemia, suggesting a role for ERRα in modulating insulin sensitivity and glucose handling during the 24-hour light/dark cycle. We also provide evidence that the newly identified ERRα corepressor PROX1 is implicated in rhythmic control of metabolic outputs. To help uncover the molecular basis of these phenotypes, we performed genome-wide location analyses of binding events by ERRα, PROX1, and BMAL1, an integral component of the molecular clock. These studies revealed the existence of transcriptional regulatory loops among ERRα, PROX1, and BMAL1, as well as extensive overlaps in their target genes, implicating these three factors in the control of clock and metabolic gene networks in the liver. Genomic convergence of ERRα, PROX1, and BMAL1 transcriptional activity thus identified a novel node in the molecular circuitry controlling the daily timing of metabolic processes