Photo-antagonism of the GABAA receptor

Neurotransmitter receptor trafficking is fundamentally important for synaptic transmission and neural network activity. GABAA receptors and inhibitory synapses are vital components of brain function, yet much of our knowledge regarding receptor mobility and function at inhibitory synapses is derived indirectly from using recombinant receptors, antibody-tagged native receptors and pharmacological treatments. Here we describe the use of a set of research tools that can irreversibly bind to and affect the function of recombinant and neuronal GABAA receptors following ultraviolet photoactivation. These compounds are based on the competitive antagonist gabazine and incorporate a variety of photoactive groups. By using site-directed mutagenesis and ligand-docking studies, they reveal new areas of the GABA binding site at the interface between receptor β and α subunits. These compounds enable the selected inactivation of native GABAA receptor populations providing new insight into the function of inhibitory synapses and extrasynaptic receptors in controlling neuronal excitation

Extended [C I] and (CO)-C-13 (5 -\u3e 4) emission in M17SW

We mapped a 13 × 22 pc region in emission from 492 GHz [C I] and, for the first time, 551 GHz 13CO (5 → 4) in the giant molecular cloud M17SW. The morphologies of the [C I] and 13CO emission are strikingly similar. The extent and intensity of the [C I] and 13CO (5 → 4) emission is explained as arising from photodissociation regions on the surfaces of embedded molecular clumps. Modeling of the 13CO (5 → 4) emission in comparison to 13CO (1 → 0) indicates a temperature gradient across the cloud, peaking to at least 63 K near the M17 ionization front and decreasing to at least 20 K at the western edge of the cloud. We see no correlation between gas density and column density. The beam-averaged column density of C I in the core is 1 × 1018 cm-2, and the mean column density ratio N(C I)/N(CO) is about 0.4. The variations of N(C I)/N(CO) with position in M17SW indicate a similar clump size distribution throughout the cloud

The Dreyfus model of clinical problem-solving skills acquisition: a critical perspective

Context: The Dreyfus model describes how individuals progress through various levels in their acquisition of skills and subsumes ideas with regard to how individuals learn. Such a model is being accepted almost without debate from physicians to explain the ‘acquisition’ of clinical skills. Objectives: This paper reviews such a model, discusses several controversial points, clarifies what kind of knowledge the model is about, and examines its coherence in terms of problem-solving skills. Dreyfus’ main idea that intuition is a major aspect of expertise is also discussed in some detail. Relevant scientific evidence from cognitive science, psychology, and neuroscience is reviewed to accomplish these aims. Conclusions: Although the Dreyfus model may partially explain the ‘acquisition’ of some skills, it is debatable if it can explain the acquisition of clinical skills. The complex nature of clinical problem-solving skills and the rich interplay between the implicit and explicit forms of knowledge must be taken into consideration when we want to explain ‘acquisition’ of clinical skills. The idea that experts work from intuition, not from reason, should be evaluated carefully

What we talk about when we talk about "global mindset": managerial cognition in multinational corporations

Recent developments in the global economy and in multinational corporations have placed significant emphasis on the cognitive orientations of managers, giving rise to a number of concepts such as “global mindset” that are presumed to be associated with the effective management of multinational corporations (MNCs). This paper reviews the literature on global mindset and clarifies some of the conceptual confusion surrounding the construct. We identify common themes across writers, suggesting that the majority of studies fall into one of three research perspectives: cultural, strategic, and multidimensional. We also identify two constructs from the social sciences that underlie the perspectives found in the literature: cosmopolitanism and cognitive complexity and use these two constructs to develop an integrative theoretical framework of global mindset. We then provide a critical assessment of the field of global mindset and suggest directions for future theoretical and empirical research

Embodied Emotion Modulates Neural Signature of Performance Monitoring

BACKGROUND:Recent research on the "embodiment of emotion" implies that experiencing an emotion may involve perceptual, somatovisceral, and motor feedback aspects. For example, manipulations of facial expression and posture appear to induce emotional states and influence how affective information is processed. The present study investigates whether performance monitoring, a cognitive process known to be under heavy control of the dopaminergic system, is modulated by induced facial expressions. In particular, we focused on the error-related negativity, an electrophysiological correlate of performance monitoring. METHODS/PRINCIPAL FINDINGS:During a choice reaction task, participants held a Chinese chop stick either horizontally between the teeth ("smile" condition) or, in different runs, vertically ("no smile") with the upper lip. In a third control condition, no chop stick was used ("no stick"). It could be shown on a separate sample that the facial feedback procedure is feasible to induce mild changes in positive affect. In the ERP sample, the smile condition, hypothesized to lead to an increase in dopaminergic activity, was associated with a decrease of ERN amplitude relative to "no smile" and "no stick" conditions. CONCLUSION:Embodying emotions by induced facial expressions leads to a changes in the neural correlates of error detection. We suggest that this is due to the joint influence of the dopaminergic system on positive affect and performance monitoring

Day-to-day variations during clinical drug monitoring of morphine, morphine-3-glucuronide and morphine-6-glucuronide serum concentrations in cancer patients. A prospective observational study

BACKGROUND: The feasibility of drug monitoring of serum concentrations of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) during chronic morphine therapy is not established. One important factor relevant to drug monitoring is to what extent morphine, M6G and M3G serum concentrations fluctuate during stable morphine treatment. METHODS: We included twenty-nine patients admitted to a palliative care unit receiving oral morphine (n = 19) or continuous subcutaneous (sc) morphine infusions (n = 10). Serum concentrations of morphine, M6G and M3G were obtained at the same time on four consecutive days. If readmitted, the patients were followed for another trial period. Day-to-day variations in serum concentrations and ratios were determined by estimating the percent coefficient of variation (CV = (mean/SD) ×100). RESULTS: The patients' median morphine doses were 90 (range; 20–1460) mg/24 h and 135 (range; 30–440) mg/24 h during oral and sc administration, respectively. Intraindividual fluctuations of serum concentrations estimated by median coefficients of day-to-day variation were in the oral group for morphine 46%, for M6G 25% and for M3G 18%. The median coefficients of variation were lower in patients receiving continuous sc morphine infusions (morphine 10%, M6G 13%, M3G 9%). CONCLUSION: These findings indicate that serum concentrations of morphine and morphine metabolites fluctuate. The fluctuations found in our study are not explained by changes in morphine doses, administration of other drugs or by time for collection of blood samples. As expected the day-to-day variation was lower in patients receiving continuous sc morphine infusions compared with patients receiving oral morphine

Motor Adaptation Scaled by the Difficulty of a Secondary Cognitive Task

Background: Motor learning requires evaluating performance in previous movements and modifying future movements. The executive system, generally involved in planning and decision-making, could monitor and modify behavior in response to changes in task difficulty or performance. Here we aim to identify the quantitative cognitive contribution to responsive and adaptive control to identify possible overlap between cognitive and motor processes. Methodology/Principal Findings: We developed a dual-task experiment that varied the trial-by-trial difficulty of a secondary cognitive task while participants performed a motor adaptation task. Subjects performed a difficulty-graded semantic categorization task while making reaching movements that were occasionally subjected to force perturbations. We find that motor adaptation was specifically impaired on the most difficult to categorize trials. Conclusions/Significance: We suggest that the degree of decision-level difficulty of a particular categorization differentially burdens the executive system and subsequently results in a proportional degradation of adaptation. Our results suggest

A genomic biomarker signature can predict skin sensitizers using a cell-based in vitro alternative to animal tests

<p>Abstract</p> <p>Background</p> <p>Allergic contact dermatitis is an inflammatory skin disease that affects a significant proportion of the population. This disease is caused by an adverse immune response towards chemical haptens, and leads to a substantial economic burden for society. Current test of sensitizing chemicals rely on animal experimentation. New legislations on the registration and use of chemicals within pharmaceutical and cosmetic industries have stimulated significant research efforts to develop alternative, human cell-based assays for the prediction of sensitization. The aim is to replace animal experiments with in vitro tests displaying a higher predictive power.</p> <p>Results</p> <p>We have developed a novel cell-based assay for the prediction of sensitizing chemicals. By analyzing the transcriptome of the human cell line MUTZ-3 after 24 h stimulation, using 20 different sensitizing chemicals, 20 non-sensitizing chemicals and vehicle controls, we have identified a biomarker signature of 200 genes with potent discriminatory ability. Using a Support Vector Machine for supervised classification, the prediction performance of the assay revealed an area under the ROC curve of 0.98. In addition, categorizing the chemicals according to the LLNA assay, this gene signature could also predict sensitizing potency. The identified markers are involved in biological pathways with immunological relevant functions, which can shed light on the process of human sensitization.</p> <p>Conclusions</p> <p>A gene signature predicting sensitization, using a human cell line in vitro, has been identified. This simple and robust cell-based assay has the potential to completely replace or drastically reduce the utilization of test systems based on experimental animals. Being based on human biology, the assay is proposed to be more accurate for predicting sensitization in humans, than the traditional animal-based tests.</p

The method of educational assessment affects children’s neural processing and performance: behavioural and fMRI Evidence.

Standardised educational assessments are now widespread, yet their development has given comparatively more consideration to what to assess than how to optimally assess students’ competencies. Existing evidence from behavioural studies with children and neuroscience studies with adults suggest that the method of assessment may affect neural processing and performance, but current evidence remains limited. To investigate the impact of assessment methods on neural processing and performance in young children, we used functional magnetic resonance imaging to identify and quantify the neural correlates during performance across a range of current approaches to standardised spelling assessment. Results indicated that children’s test performance declined as the cognitive load of assessment method increased. Activation of neural nodes associated with working memory further suggests that this performance decline may be a consequence of a higher cognitive load, rather than the complexity of the content. These findings provide insights into principles of assessment (re)design, to ensure assessment results are an accurate reflection of students’ true levels of competency