Biased signalling is an essential feature of TLR4 in glioma cells

A distinct feature of the Toll-like receptor 4 (TLR4) is its ability to trigger both MyD88-dependent and MyD88-independent signalling, culminating in activation of pro-inflammatory NF-κB and/or the antiviral IRF3. Although TLR4 agonists (lipopolysaccharides; LPSs) derived from different bacterial species have different endotoxic activity, the impact of LPS chemotype on the downstream signalling is not fully understood. Notably, different TLR4 agonists exhibit anti-tumoural activity in animal models of glioma, but the underlying molecular mechanisms are largely unknown. Thus, we investigated the impact of LPS chemotype on the signalling events in the human glioma cell line U251. We found that LPS of Escherichia coli origin (LPSEC) leads to NF-κB-biased downstream signalling compared to Salmonella minnesota-derived LPS (LPSSM). Exposure of U251 cells to LPSEC resulted in faster nuclear translocation of the NF-κB subunit p65, higher NF-κB-activity and expression of its targets genes, and higher amount of secreted IL-6 compared to LPSSM. Using super-resolution microscopy we showed that the biased agonism of TLR4 in glioma cells is neither a result of differential regulation of receptor density nor of formation of higher order oligomers. Consistent with previous reports, LPSEC-mediated NF-κB activation led to significantly increased U251 proliferation, whereas LPSSM-induced IRF3 activity negatively influenced their invasiveness. Finally, treatment with methyl-β-cyclodextrin (MCD) selectively increased LPSSM-induced nuclear translocation of p65 and NF-κB activity without affecting IRF3. Our data may explain how TLR4 agonists differently affect glioma cell proliferation and migration

A short-term plastic adherence incubation of the stromal vascular fraction leads to a predictable GMP-compliant cell-product

Introduction: Mesenchymal stromal/stem cells (MSCs) derived from fat tissue are an encouraging tool for regenerative medicine. They share properties similar to the bone marrow-derived MSCs, but the amount of MSCs per gram of fat tissue is 500x higher. The fat tissue can easily be digested by collagenase, releasing a heterogeneous cell fraction called stromal vascular fraction (SVF) which contains a variable amount of stromal/stem cells. In Europe, cell products like the SVF derived from fat tissue are considered advanced therapy medicinal product (ATMPs). As a consequence, the manufacturing process has to be approved via GMP-compliant process validation. The problem of the process validation for SVF is the heterogeneity of this fraction. Methods: Here, we modified existing purification strategies by adding an additional plastic adherence incubation of maximal 20 hours after SVF isolation. The resulting cell fraction was characterized and compared to SVF as well as cultivated adipose-derived stromal/stem cells (ASCs) with respect to viability and cell yield, the expression of surface markers, differentiation potential and cytokine expression. Results: Short-term incubation significantly reduced the heterogeneity of the resulting cell fraction compared to SVF. The cells were able to differentiate into adipocytes, chondrocytes, and osteoblasts. More importantly, they expressed trophic proteins which have been previously associated with the beneficial effects of MSCs. Furthermore, GMP compliance of the production process described herein was acknowledged by the national regulatory agencies (DE_BB_01_GMP_2017_1018). Conclusion: Addition of a short purification-step after the SVF isolation is a cheap and fast strategy to isolate a homogeneous uncultivated GMP-compliant cell fraction of ASCs

Development of an IS change reason - IS change type combination matrix

Firms change their information systems (IS) for various reasons, ranging from compliance with government regulations to the development of new capabilities. When making these changes a firm can choose between four different IS change types: IS introduction, IS extension, IS replacement, and IS merger. This paper proposes that change reasons and change types are interrelated, and that certain reason-type combinations are more likely than others to result in a successful IS change. To identify these combinations, an IS change reason–IS change type matrix is developed. While the matrix is created from prior IS research, we conducted a focus group study of IS professionals to further explore and refine the matrix. The findings from the focus group study reveal that some IS change reason–IS change type combinations are more appropriate than others to carry out the IS change project successfully. We also present three examples of IS change projects to illustrate the use and value of the matrix in practice

Confidence in uncertainty: Error cost and commitment in early speech hypotheses

© 2018 Loth et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Interactions with artificial agents often lack immediacy because agents respond slower than their users expect. Automatic speech recognisers introduce this delay by analysing a user’s utterance only after it has been completed. Early, uncertain hypotheses of incremental speech recognisers can enable artificial agents to respond more timely. However, these hypotheses may change significantly with each update. Therefore, an already initiated action may turn into an error and invoke error cost. We investigated whether humans would use uncertain hypotheses for planning ahead and/or initiating their response. We designed a Ghost-in-the-Machine study in a bar scenario. A human participant controlled a bartending robot and perceived the scene only through its recognisers. The results showed that participants used uncertain hypotheses for selecting the best matching action. This is comparable to computing the utility of dialogue moves. Participants evaluated the available evidence and the error cost of their actions prior to initiating them. If the error cost was low, the participants initiated their response with only suggestive evidence. Otherwise, they waited for additional, more confident hypotheses if they still had time to do so. If there was time pressure but only little evidence, participants grounded their understanding with echo questions. These findings contribute to a psychologically plausible policy for human-robot interaction that enables artificial agents to respond more timely and socially appropriately under uncertainty

Risk preferences and predictions about others: no association with 2D:4D ratio

Abstract: Prenatal androgen exposure affects the brain development of the fetus which may facilitate certain behaviors and decision patterns in the later life. The ratio between the lengths of second and the fourth fingers (2D:4D) is a negative biomarker of the ratio between prenatal androgen and estrogen exposure and men typically have lower ratios than women. In line with the typical findings suggesting that women are more risk averse than men, several studies have also shown negative relationships between 2D:4D and risk taking although the evidence is not conclusive. Previous studies have also reported that both men and women believe women are more risk averse than men. In the current study, we re-test the relationship between 2D:4D and risk preferences in a German student sample and also investigate whether the 2D:4D ratio is associated with people’s perceptions about others’ risk preferences. Following an incentivized risk elicitation task, we asked all participants their predictions about (i) others’ responses (without sex specification), (ii) men’s responses, and (iii) women’s responses; then measured their 2D:4D ratios. In line with the previous findings, female participants in our sample were more risk averse. While both men and women underestimated other participants’ (non sex-specific) and women’s risky decisions on average, their predictions about men were accurate. We also found evidence for the false consensus effect, as risky choices are positively correlated with predictions about other participants’ risky choices. The 2D:4D ratio was not directly associated either with risk preferences or the predictions of other participants’ choices. An unexpected finding was that women with mid-range levels of 2D:4D estimated significantly larger sex differences in participants’ decisions. This finding needs further testing in future studies

Resting autonomic nervous system activity is unrelated to antisocial behaviour dimensions in adolescents: Cross-sectional findings from a European multi-centre study

Purpose: Autonomic nervous system (ANS) functioning has long been studied in relation to antisocial behaviour, but relevant measures (heart rate, heart rate variability, pre-ejection period, respiration rate) have rarely been considered together. This study investigated the relationship between these measures and antisocial behaviour. Methods: Using a sample of 1010 youths with (47.8%) and without conduct disorder (52.2%) aged between 9 and 18. years (659 females, 351 males, mean age = 14.2. years, SD = 2.4), principal component analysis (PCA) was applied to various measures of psychopathology and antisocial behavior. Structural equation modelling was performed in order to test whether the ANS measures predicted PCA-dimensions. Cluster analysis was used in order to classify patterns of ANS activity. Analyses were performed separately for males/females and controlled for body-mass-index, age, caffeine use, cigarette smoking, sports, socioeconomic status, medication, cardiac problems. Results: The PCA yielded three components: antisocial behaviour/comorbid psychopathology, narcissistic traits, and callous-unemotional traits. ANS measures were only weakly correlated with these components. Cluster analysis yielded high and low arousal clusters in both sexes. When controlling for covariates, all associations disappeared. Conclusion: Our findings suggest that resting ANS measures are only weakly related to antisocial behaviour and indicate that smoking should be considered as an important covariate in future psychophysiological studies

Evaluation of the HadGEM3-A simulations in view of detection and attribution of human influence on extreme events in Europe

A detailed analysis is carried out to assess the HadGEM3-A global atmospheric model skill in simulating extreme temperatures, precipitation and storm surges in Europe in the view of their attribution to human influence. The analysis is performed based on an ensemble of 15 atmospheric simulations forced with observed Sea Surface Temperature of the 54 year period 1960-2013. These simulations, together with dual simulations without human influence in the forcing, are intended to be used in weather and climate event attribution. The analysis investigates the main processes leading to extreme events, including atmospheric circulation patterns, their links with temperature extremes, land-atmosphere and troposphere-stratosphere interactions. It also compares observed and simulated variability, trends and generalized extreme value theory parameters for temperature and precipitation. One of the most striking findings is the ability of the model to capture North Atlantic atmospheric weather regimes as obtained from a cluster analysis of sea level pressure fields. The model also reproduces the main observed weather patterns responsible for temperature and precipitation extreme events. However, biases are found in many physical processes. Slightly excessive drying may be the cause of an overestimated summer interannual variability and too intense heat waves, especially in central/northern Europe. However, this does not seem to hinder proper simulation of summer temperature trends. Cold extremes appear well simulated, as well as the underlying blocking frequency and stratosphere-troposphere interactions. Extreme precipitation amounts are overestimated and too variable. The atmospheric conditions leading to storm surges were also examined in the Baltics region. There, simulated weather conditions appear not to be leading to strong enough storm surges, but winds were found in very good agreement with reanalyses. The performance in reproducing atmospheric weather patterns indicates that biases mainly originate from local and regional physical processes. This makes local bias adjustment meaningful for climate change attribution

Self-Regulation of Amygdala Activation Using Real-Time fMRI Neurofeedback

Real-time functional magnetic resonance imaging (rtfMRI) with neurofeedback allows investigation of human brain neuroplastic changes that arise as subjects learn to modulate neurophysiological function using real-time feedback regarding their own hemodynamic responses to stimuli. We investigated the feasibility of training healthy humans to self-regulate the hemodynamic activity of the amygdala, which plays major roles in emotional processing. Participants in the experimental group were provided with ongoing information about the blood oxygen level dependent (BOLD) activity in the left amygdala (LA) and were instructed to raise the BOLD rtfMRI signal by contemplating positive autobiographical memories. A control group was assigned the same task but was instead provided with sham feedback from the left horizontal segment of the intraparietal sulcus (HIPS) region. In the LA, we found a significant BOLD signal increase due to rtfMRI neurofeedback training in the experimental group versus the control group. This effect persisted during the Transfer run without neurofeedback. For the individual subjects in the experimental group the training effect on the LA BOLD activity correlated inversely with scores on the Difficulty Identifying Feelings subscale of the Toronto Alexithymia Scale. The whole brain data analysis revealed significant differences for Happy Memories versus Rest condition between the experimental and control groups. Functional connectivity analysis of the amygdala network revealed significant widespread correlations in a fronto-temporo-limbic network. Additionally, we identified six regions — right medial frontal polar cortex, bilateral dorsomedial prefrontal cortex, left anterior cingulate cortex, and bilateral superior frontal gyrus — where the functional connectivity with the LA increased significantly across the rtfMRI neurofeedback runs and the Transfer run. The findings demonstrate that healthy subjects can learn to regulate their amygdala activation using rtfMRI neurofeedback, suggesting possible applications of rtfMRI neurofeedback training in the treatment of patients with neuropsychiatric disorders

Single-cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene

The etiology of Parkinson disease (PD) is complex and multifactorial, with hereditary and environmental factors contributing. Monogenic forms have provided molecular clues to disease mechanisms but genetic modifiers of idiopathic PD are still to be determined. METHODS: We carried out whole-genome expression profiling of isolated human substantia nigra (SN) neurons from patients with PD vs. controls followed by association analysis of tagging single-nucleotide polymorphisms (SNPs) in differentially regulated genes. Association was investigated in a German PD sample and confirmed in Italian and British cohorts. RESULTS: We identified four differentially expressed genes located in PD candidate pathways, ie, MTND2 (mitochondrial, p = 7.14 x 10(-7)), PDXK (vitamin B6/dopamine metabolism, p = 3.27 x 10(-6)), SRGAP3 (axon guidance, p = 5.65 x 10(-6)), and TRAPPC4 (vesicle transport, p = 5.81 x 10(-6)). We identified a DNA variant (rs2010795) in PDXK associated with an increased risk of PD in the German cohort (p = 0.00032). This association was confirmed in the British (p = 0.028) and Italian (p = 0.0025) cohorts individually and reached a combined value of p = 1.2 x 10(-7) (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.18-1.44). INTERPRETATION: We provide an example of how microgenomic genome-wide expression studies in combination with association analysis can aid to identify genetic modifiers in neurodegenerative disorders. The detection of a genetic variant in PDXK, together with evidence accumulating from clinical studies, emphasize the impact of vitamin B6 status and metabolism on disease risk and therapy in PD