Resting-state theta activity is linked to information content-specific coding levels during response inhibition

The neurophysiological processes underlying the inhibition of impulsive responses have been studied extensively. While also the role of theta oscillations during response inhibition is well examined, the relevance of resting-state theta activity for inhibitory control processes is largely unknown. We test the hypothesis that there are specific relationships between resting-state theta activity and sensory/motor coding levels during response inhibition using EEG methods. We show that resting theta activity is specifically linked to the stimulus-related fraction of neurophysiological activity in specific time windows during motor inhibition. In contrast, concomitantly coded processes related to decision-making or response selection as well as the behavioral inhibition performance were not associated with resting theta activity. Even at the peak of task-related theta power, where task-related theta activity and resting theta activity differed the most, there was still predominantly a significant correlation between both types of theta activity. This suggests that aspects similar to resting dynamics are evident in the proportion of inhibition-related neurophysiological activity that reflects an “alarm” signal, whose function is to process and indicate the need for cognitive control. Thus, specific aspects of task-related theta power may build upon resting theta activity when cognitive control is necessary

The basis of the alcohol abstinence

Die empirische Studie im Querschnittdesign untersucht bei Alkoholkranken den Einfluss von Ressourcen auf die subjektive Sicherheit des Alkoholverzichts. Theoretische Grundlage ist die salutogenetische Annahme, dass psychische Ressourcen im Verständnis einer aktivierten individuellen Basisausstattung die Abstinenzsicherheit in kognitiver und emotionaler Hinsicht positiv beeinflussen. Die daraus abgeleiteten Hypothesen werden in der Studie weitgehend bestätigt. Insbesondere die aktuelle Lebenszufriedenheit in diversen Bereichen wie etwa selbst- und fremdbezogene Wertschätzung hat einen signifikant positiven Einfluss auf die rationale Abstinenzzuversicht wie auch auf den emotionalen Abstinenzwert. In multivariaten Detailanalysen wird - trotz komplexer Zusammenhänge als Spiegel der Suchtproblematik an sich - der Stellenwert positiven emotionalen Erlebens bekräftigt. Emotionale Ressourcen sind eine auch therapeutisch bedeutsame und gezielt zu fördernde Alternative zur gestörten Lust-Frust-Balance des Süchtigen.This empirical study looks into the influence of resources and measures conducive to health on the subjective security of alcohol-addict's abstinence in a cross-sectional way. The theoretical basis is the original assumption that mental resources - based on the view of an activated personal and basic endowment - have a positive effect on the addict and on his stability of abstinence in a cognitive and emotional way. The hypotheses deduced from this assumption have been verified to a large extent in the course of my study. It is in particular the current contentment in life in a couple of aspects, as for example being held in high esteem and satisfied with oneself and others, which shows a significant positive influence on the rational hope in abstinence as well as on the emotional value of abstinence. The importance of a positive emotional experience has been confirmed by means of multivariant analyses in detail - despite the fact that the problems of addiction are embedded and reflected in a range of complex coherences. Emotional resources provide an alternative to the addict's unstable balance of frustration and pleasure. Moreover, they are important from a therapeutical point of view and need particular support

Cost comparison of insulin glargine with insulin detemir in a basal-bolus regime with mealtime insulin aspart in type 2 diabetes in Germany

Objective: To compare the treatment costs of insulin glargine (IG; Lantus®) to detemir (ID; Levemir®), both combined with bolus insulin aspart (NovoRapid®) in type 2 diabetes (T2D) in Germany

Off-target effects of siRNA specific for GFP

<p>Abstract</p> <p>Background</p> <p>Gene knock down by RNAi is a highly effective approach to silence gene expression in experimental as well as therapeutic settings. However, this widely used methodology entails serious pitfalls, especially concerning specificity of the RNAi molecules.</p> <p>Results</p> <p>We tested the most widely used control siRNA directed against <it>GFP </it>for off-target effects and found that it deregulates in addition to <it>GFP </it>a set of endogenous target genes. The off-target effects were dependent on the amount of <it>GFP </it>siRNA transfected and were detected in a variety of cell lines. Since the respective siRNA molecule specific for <it>GFP </it>is widely used as negative control for RNAi experiments, we studied the complete set of off-target genes of this molecule by genome-wide expression profiling. The detected modulated mRNAs had target sequences homologous to the siRNA as small as 8 basepairs in size. However, we found no restriction of sequence homology to 3'UTR of target genes.</p> <p>Conclusion</p> <p>We can show that even siRNAs without a physiological target have sequence-specific off-target effects in mammalian cells. Furthermore, our analysis defines the off-target genes affected by the siRNA that is commonly used as negative control and directed against <it>GFP</it>. Since off-target effects can hardly be avoided, the best strategy is to identify false positives and exclude them from the results. To this end, we provide the set of false positive genes deregulated by the commonly used <it>GFP </it>siRNA as a reference resource for future siRNA experiments.</p

Valsartan Improves Adipose Tissue Function in Humans with Impaired Glucose Metabolism: A Randomized Placebo-Controlled Double-Blind Trial

<div><h3>Background</h3><p>Blockade of the renin-angiotensin system (RAS) reduces the incidence of type 2 diabetes mellitus. In rodents, it has been demonstrated that RAS blockade improved adipose tissue (AT) function and glucose homeostasis. However, the effects of long-term RAS blockade on AT function have not been investigated in humans. Therefore, we examined whether 26-wks treatment with the angiotensin II type 1 receptor blocker valsartan affects AT function in humans with impaired glucose metabolism (IGM).</p> <h3>Methodology/Principal Findings</h3><p>We performed a randomized, double-blind, placebo-controlled parallel-group study, in which 38 subjects with IGM were treated with valsartan (VAL, 320 mg/d) or placebo (PLB) for 26 weeks. Before and after treatment, an abdominal subcutaneous AT biopsy was collected for measurement of adipocyte size and AT gene/protein expression of angiogenesis/capillarization, adipogenesis, lipolytic and inflammatory cell markers. Furthermore, we evaluated fasting and postprandial AT blood flow (ATBF) (¹³³Xe wash-out), systemic inflammation and insulin sensitivity (hyperinsulinemic-euglycemic clamp). VAL treatment markedly reduced adipocyte size (<em>P</em><0.001), with a shift toward a higher proportion of small adipocytes. In addition, fasting (<em>P</em> = 0.043) and postprandial ATBF (<em>P</em> = 0.049) were increased, whereas gene expression of angiogenesis/capillarization, adipogenesis and macrophage infiltration markers in AT was significantly decreased after VAL compared with PLB treatment. Interestingly, the change in adipocyte size was associated with alterations in insulin sensitivity and reduced AT gene expression of macrophage infiltration markers. VAL did not alter plasma monocyte-chemoattractant protein (MCP)-1, TNF-α, adiponectin and leptin concentrations.</p> <h3>Conclusions/Significance</h3><p>26-wks VAL treatment markedly reduced abdominal subcutaneous adipocyte size and AT macrophage infiltration markers, and increased ATBF in IGM subjects. The VAL-induced decrease in adipocyte size was associated with reduced expression of macrophage infiltration markers in AT. Our findings suggest that interventions targeting the RAS may improve AT function, thereby contributing to a reduced risk of developing cardiovascular disease and type 2 diabetes.</p> <h3>Trial Registration</h3><p>Trialregister.nl NTR721 (ISRCTN Registry: ISRCTN<a href="http://www.controlled-trials.com/isrctn/pf/42786336">42786336</a>)</p> </div

Functional Diversity of Human Basic Helix-Loop-Helix Transcription Factor TCF4 Isoforms Generated by Alternative 5′ Exon Usage and Splicing

BACKGROUND: Transcription factor 4 (TCF4 alias ITF2, E2-2, ME2 or SEF2) is a ubiquitous class A basic helix-loop-helix protein that binds to E-box DNA sequences (CANNTG). While involved in the development and functioning of many different cell types, recent studies point to important roles for TCF4 in the nervous system. Specifically, human TCF4 gene is implicated in susceptibility to schizophrenia and TCF4 haploinsufficiency is the cause of the Pitt-Hopkins mental retardation syndrome. However, the structure, expression and coding potential of the human TCF4 gene have not been described in detail. PRINCIPAL FINDINGS: In the present study we used human tissue samples to characterize human TCF4 gene structure and TCF4 expression at mRNA and protein level. We report that although widely expressed, human TCF4 mRNA expression is particularly high in the brain. We demonstrate that usage of numerous 5' exons of the human TCF4 gene potentially yields in TCF4 protein isoforms with 18 different N-termini. In addition, the diversity of isoforms is increased by alternative splicing of several internal exons. For functional characterization of TCF4 isoforms, we overexpressed individual isoforms in cultured human cells. Our analysis revealed that subcellular distribution of TCF4 isoforms is differentially regulated: Some isoforms contain a bipartite nuclear localization signal and are exclusively nuclear, whereas distribution of other isoforms relies on heterodimerization partners. Furthermore, the ability of different TCF4 isoforms to regulate E-box controlled reporter gene transcription is varied depending on whether one or both of the two TCF4 transcription activation domains are present in the protein. Both TCF4 activation domains are able to activate transcription independently, but act synergistically in combination. CONCLUSIONS: Altogether, in this study we have described the inter-tissue variability of TCF4 expression in human and provided evidence about the functional diversity of the alternative TCF4 protein isoforms

Quantitative Proteomics Identify Novel miR-155 Target Proteins

Background: MicroRNAs are 22 nucleotides long non-coding RNAs and exert their function either by transcriptional or translational inhibition. Although many microRNA profiles in different tissues and disease states have already been discovered, only little is known about their target proteins. The microRNA miR-155 is deregulated in many diseases, including cancer, where it might function as an oncoMir. Methodology/Principal Findings: We employed a proteomics technique called ‘‘stable isotope labelling by amino acids in cell culture’ ’ (SILAC) allowing relative quantification to reliably identify target proteins of miR-155. Using SILAC, we identified 46 putative miR-155 target proteins, some of which were previously reported. With luciferase reporter assays, CKAP5 was confirmed as a new target of miR-155. Functional annotation of miR-155 target proteins pointed to a role in cell cycle regulation. Conclusions/Significance: To the best of our knowledge we have investigated for the first time miR-155 target proteins in the HEK293T cell line in large scale. In addition, by comparing our results to previously identified miR-155 target proteins i