Calpain-mediated cleavage generates a ZBTB18 N-terminal product that regulates HIF1A signaling and glioblastoma metabolism

Proteolytic cleavage is an important post-translational mechanism to increase protein variability and functionality. In cancer, this process can be deregulated to shut off tumor-suppressive functions. Here, we report that in glioblastoma (GBM), the tumor suppressor ZBTB18 is targeted for protein cleavage by the intracellular protease calpain. The N-terminal (Nte) ZBTB18 cleaved fragment localizes to the cytoplasm and thus, is unable to exert the gene expression repressive function of the uncleaved protein. Mass spectrometry (MS) analysis indicates that the Nte ZBTB18 short form (SF) interacts with C-terminal (Cte) binding proteins 1 and 2 (CTBP1/2), which appear to be involved in HIF1A signaling activation. In fact, we show that the new ZBTB18 product activates HIF1A-regulated genes, which in turn lead to increased lipid uptake, lipid droplets (LD) accumulation, and enhanced metabolic activity. We propose that calpain-mediated ZBTB18 cleavage represents a new mechanism to counteract ZBTB18 tumor suppression and increase tumor-promoting functions in GBM cells

Effects of an Alpha-4 Integrin Inhibitor on Restenosis in a New Porcine Model Combining Endothelial Denudation and Stent Placement

Restenosis remains the main complication of balloon angioplasty and/or stent implantation. Preclinical testing of new pharmacologic agents preventing restenosis largely rely on porcine models, where restenosis is assessed after endothelial abrasion of the arterial wall or stent implantation. We combined endothelial cell denudation and implantation of stents to develop a new clinically relevant porcine model of restenosis, and used this model to determine the effects of an α4 integrin inhibitor, ELN 457946, on restenosis. Balloon-angioplasty endothelial cell denudation and subsequent implantation of bare metal stents in the left anterior descending coronary, iliac, and left common carotid arteries was performed in domestic pigs, treated with vehicle or ELN 457946, once weekly via subcutaneous injections, for four weeks. After 1 month, histopathology and morphometric analyses of the arteries showed complete healing and robust, consistent restenotic response in stented arteries. Treatment with ELN 457946 resulted in a reduction in the neointimal response, with decreases in area percent stenosis between 12% in coronary arteries and 30% in peripheral vessels. This is the first description of a successful pig model combining endothelial cell denudation and bare metal stent implantation. This new double injury model may prove particularly useful to assess pharmacological effects of drug candidates on restenosis, in coronary and/or peripheral arteries. Furthermore, the ELN 457946 α4 integrin inhibitor, administered subcutaneously, reduced inflammation and restenosis in stented coronary and peripheral arteries in pigs, therefore representing a promising systemic therapeutic approach in reducing restenosis in patients undergoing angioplasty and/or stent implantation

A new species of Stenobiella Tillyard (Neuroptera, Berothidae) from Australia

Stenobiella variola sp. n., a new species of beaded lacewing (Neuroptera: Berothidae), is described and figured from south-eastern Australia. A preliminary key to Stenobiella species is presented

The Emergence of Emotions

Emotion is conscious experience. It is the affective aspect of consciousness. Emotion arises from sensory stimulation and is typically accompanied by physiological and behavioral changes in the body. Hence an emotion is a complex reaction pattern consisting of three components: a physiological component, a behavioral component, and an experiential (conscious) component. The reactions making up an emotion determine what the emotion will be recognized as. Three processes are involved in generating an emotion: (1) identification of the emotional significance of a sensory stimulus, (2) production of an affective state (emotion), and (3) regulation of the affective state. Two opposing systems in the brain (the reward and punishment systems) establish an affective value or valence (stimulus-reinforcement association) for sensory stimulation. This is process (1), the first step in the generation of an emotion. Development of stimulus-reinforcement associations (affective valence) serves as the basis for emotion expression (process 2), conditioned emotion learning acquisition and expression, memory consolidation, reinforcement-expectations, decision-making, coping responses, and social behavior. The amygdala is critical for the representation of stimulus-reinforcement associations (both reward and punishment-based) for these functions. Three distinct and separate architectural and functional areas of the prefrontal cortex (dorsolateral prefrontal cortex, orbitofrontal cortex, anterior cingulate cortex) are involved in the regulation of emotion (process 3). The regulation of emotion by the prefrontal cortex consists of a positive feedback interaction between the prefrontal cortex and the inferior parietal cortex resulting in the nonlinear emergence of emotion. This positive feedback and nonlinear emergence represents a type of working memory (focal attention) by which perception is reorganized and rerepresented, becoming explicit, functional, and conscious. The explicit emotion states arising may be involved in the production of voluntary new or novel intentional (adaptive) behavior, especially social behavior

Serum 25-hydroxyvitamin D levels and intramuscular vitamin D3 supplementation among Eritrean migrants recently arrived in Switzerland.

In a cross-sectional screening programme, we assessed serum vitamin D levels in adult Eritrean refugees recently arrived in Switzerland. Median vitamin D level among 107 participants (95 males and 12 females) was 27 nmol/l (interquartile range 23-42 nmol/l), 86% had insufficient vitamin D levels (≤50 nmol/l) and 36% severe deficiency (<25 nmol/l). In 29 participants who received single-dose intramuscular vitamin D substitution (300 000 IU), median vitamin D levels increased from 25 to 35 nmol/l after 3 months (p = 0.005); only 11 (38%) reached sufficient vitamin D levels. Eritrean migrants should be routinely screened for vitamin D deficiency. Single-dose intramuscular supplementation appeared to be insufficient to achieve optimal levels in the majority of participants

Hypofrontality in Schizophrenia. A meta-analysis of functional imaging studies

The definitive version is available at www.blackwell-synergy.com '--Copyright Blackwell PublishingObjective: Hypofrontality is not a well-replicated finding in schizophrenia either at rest or under conditions of task activation. Method: Studies comparing whole brain and frontal blood flow/ metabolism in schizophrenic patients and normal controls were pooled.Voxel-based studies were also combined to examine the pattern of prefrontal activation in schizophrenia. Results: Whole brain flow/metabolism was reduced in schizophrenia to only a small extent.Restin g and activation frontal flow/metabolism were both reduced with a medium effect size.Duration of illness significantly moderated resting hypofrontality, but the moderating effects of neuroleptic treatment were consistent with an influence on global flow/metabolism only.Pooling of voxel-based studies did not suggest an abnormal pattern of activation in schizophrenia. Conclusion: Meta-analysis supports resting hypofrontality in schizophrenia.Task-activated hypofrontality is also supported, but there is little from voxel-based studies to suggest that this is associated with an altered pattern of regional functional architecture.Peer reviewe