Raf Kinase Inhibitory Protein regulates the cAMP-dependent protein kinase signaling pathway through a positive feedback loop.

Raf Kinase Inhibitory Protein (RKIP) maintains cellular robustness and prevents the progression of diseases such as cancer and heart disease by regulating key kinase cascades including MAP kinase and protein kinase A (PKA). Phosphorylation of RKIP at S153 by Protein Kinase C (PKC) triggers a switch from inhibition of Raf to inhibition of the G protein coupled receptor kinase 2 (GRK2), enhancing signaling by the ß-adrenergic receptor (ß-AR) that activates PKA. Here we report that PKA-phosphorylated RKIP promotes ß-AR-activated PKA signaling. Using biochemical, genetic, and biophysical approaches, we show that PKA phosphorylates RKIP at S51, increasing S153 phosphorylation by PKC and thereby triggering feedback activation of PKA. The S51V mutation blocks the ability of RKIP to activate PKA in prostate cancer cells and to induce contraction in primary cardiac myocytes in response to the ß-AR activator isoproterenol, illustrating the functional importance of this positive feedback circuit. As previously shown for other kinases, phosphorylation of RKIP at S51 by PKA is enhanced upon RKIP destabilization by the P74L mutation. These results suggest that PKA phosphorylation at S51 may lead to allosteric changes associated with a higher-energy RKIP state that potentiates phosphorylation of RKIP at other key sites. This allosteric regulatory mechanism may have therapeutic potential for regulating PKA signaling in disease states.

Ni/Al-Hybrid Cellular Foams: An Interface Study by Combination of 3D-Phase Morphology Imaging, Microbeam Fracture Mechanics and In Situ Synchrotron Stress Analysis.

Nickel(Ni)/aluminium(Al) hybrid foams are Al base foams coated with Ni by electrodeposition. Hybrid foams offer an enhanced energy absorption capacity. To ensure a good adhering Ni coating, necessary for a shear resistant interface, the influence of a chemical pre-treatment of the base foam was investigated by a combination of an interface morphology analysis by focused ion beam (FIB) tomography and in situ mechanical testing. The critical energy for interfacial decohesion from these microbending fracture tests in the scanning electron microscope (SEM) were contrasted to and the results validated by depth-resolved measurements of the evolving stresses in the Ni coating during three-point bending tests at the energy-dispersive diffraction (EDDI) beamline at the synchrotron BESSY II. Such a multi-method assessment of the interface decohesion resistance with respect to the interface morphology provides a reliable investigation strategy for further improvement of the interface morphology.

Modification of N170 by different emotional expression of schematic faces.

The N170 is widely regarded as a face sensitive potential, having its maximum at occipito-temporal sites, with right-hemisphere dominance. However, it is debatable whether the N170 is modulated by different emotional expressions of a face. The aim of this study was to analyze the N170 elicited by schematic happy and angry faces when the emotional expression is semantically processed. To investigate the influence of different emotional expressions of schematic faces, we used a Prime-Probe procedure with the N400 effect as an indicator for a semantic processing. Eighteen subjects were presented the German word "happiness" or "anger" followed by happy and angry faces. The word-face pair could be congruent or incongruent in emotional meaning. Subjects were instructed to compare the emotional meaning of the words and faces and to count the congruent trials. Event-related potentials were recorded from 124 sites. Congruent faces elicited a smaller negativity in the N400 time range than incongruent faces, indicating that the facial emotional expression was cognitively processed. The face sensitive N170 was most pronounced at posterior and occipital sites, and N170 amplitudes were larger following the angry as compared to the happy faces. It is concluded that different emotional expressions of schematic faces can modulate the N170.

Combining electrodermal responses and cardiovascular measures for probing adaptive automation during simulated flight.

Adaptive automation increases the operator's workload in case of hypovigilance and takes over more responsibility if workload becomes too high. Two consecutive studies were conducted to construct a biocybernetic adaptive system for a professional flight simulator, based on autonomic measures. Workload was varied through different stages of turbulences. In a first study with 18 participants, electrodermal responses of experimental subjects oscillated very close to the individual set point, demonstrating that workload level was adjusted as a result of adaptive control, which was not the case in yoked control subjects without adaptive automation. Combining electrodermal responses with heart rate variability in a second study with 48 participants further enhanced the adaptive power which was seen in even smaller set point deviations for the experimental compared to the yoked control group. We conclude that the level of arousal can be adjusted to avoid hypovigilance by combining autonomic measures in a closed loop.

Dissociation of decision-making under ambiguity and decision-making under risk in patients with Parkinson's disease: a neuropsychological and psychophysiological study.

Decision-making impairments in Parkinson's disease (PD) are most likely associated with dysfunctions in fronto-striatal loops. Recent studies examined decision-making in PD either in ambiguous situations with implicit rules, using the Iowa Gambling Task (IGT), or in risky situations with explicit rules, using the Game of Dice Task (GDT). Both tasks have been associated with the limbic-orbitofrontal-striatal loop, involved in emotional processing. However, the GDT has additionally been highly associated with the dorsolateral prefrontal-striatal loop, being involved in executive functions. The present study is the first one which examined decision-making in PD patients with both, IGT and GDT. We studied 21 non-demented PD patients on dopaminergic medication and 23 healthy controls with both tasks and a neuropsychological test battery with focus on executive functions. To analyse possible abnormalities in emotional processing, electrodermal responses (EDRs) were assessed while performing the tasks. We found that PD patients were significantly impaired in the GDT, but not in the IGT. Executive dysfunctions correlated with GDT but not with IGT performance. In both tasks, PD patients showed significantly reduced feedback EDRs after losses, but not after gains, indicating a primary decline of sensitivity to negative feedback. Our behavioural data suggest that dysfunctions in the dorsolateral prefrontal loop might be stronger than in the limbic loop, resulting in deficits in executive functions and GDT performance but unimpaired IGT performance. Reduced sensitivity to negative feedback is discussed with regard to dysfunctions in the limbic loop, which may result from pathology of limbic structures or dopaminergic medication.