The Supercore for Normal Form Games

We study the supercore of a system derived from a normal form game. For the case of a finite game with pure strategies, we define a sequence of games and show that the supercore of that system coincides with the set of Nash equilibrium strategy profiles of the last game in the sequence. This result is illustrated with the characterization of the supercore for the n-person prisoners’ dilemma. With regard to the mixed extension of a normal form game, we show that the set of Nash equilibrium profiles coincides with the supercore for games with a finite number of Nash equilibria. For games with an infinite number of Nash equilibria this need not be no longer the case. Yet, it is not difficult to find a binary relation which guarantees the coincidence of these two sets.

USP1 deubiquitinase: cellular functions, regulatory mechanisms and emerging potential as target in cancer therapy

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Janus-faced microglia: beneficial and detrimental consequences of microglial phagocytosis

Microglia are the resident brain macrophages and they have been traditionally studied as orchestrators of the brain inflammatory response during infections and disease. In addition, microglia has a more benign, less explored role as the brain professional phagocytes. Phagocytosis is a term coined from the Greek to describe the receptor-mediated engulfment and degradation of dead cells and microbes. In addition, microglia phagocytoses brain-specific cargo, such as axonal and myelin debris in spinal cord injury or multiple sclerosis, amyloid-beta deposits in Alzheimer's disease, and supernumerary synapses in postnatal development. Common mechanisms of recognition, engulfment, and degradation of the different types of cargo are assumed, but very little is known about the shared and specific molecules involved in the phagocytosis of each target by microglia. More importantly, the functional consequences of microglial phagocytosis remain largely unexplored. Overall, phagocytosis is considered a beneficial phenomenon, since it eliminates dead cells and induces an anti-inflammatory response. However, phagocytosis can also activate the respiratory burst, which produces toxic reactive oxygen species (ROS). Phagocytosis has been traditionally studied in pathological conditions, leading to the assumption that microglia have to be activated inorder to become efficient phagocytes. Recent data, however, has shown that unchallenged microglia phagocytose apoptotic cells during development and in adult neurogenic niches, suggesting an overlooked role in brain remodeling throughout the normal lifespan. The present review will summarize the current state of the literature regarding the role of microglial phagocytosis in maintaining tissue homeostasis in health as in disease.

The E2F2 Transcription Factor Sustains Hepatic Glycerophospholipid Homeostasis in Mice

Increasing evidence links metabolic signals to cell proliferation, but the molecular wiring that connects the two core machineries remains largely unknown. E2Fs are master regulators of cellular proliferation. We have recently shown that E2F2 activity facilitates the completion of liver regeneration after partial hepatectomy (PH) by regulating the expression of genes required for S-phase entry. Our study also revealed that E2F2 determines the duration of hepatectomy-induced hepatic steatosis. A transcriptomic analysis of normal adult liver identified "lipid metabolism regulation" as a major E2F2 functional target, suggesting that E2F2 has a role in lipid homeostasis. Here we use wild-type (E2F2(+/+)) and E2F2 deficient (E2F2(-/-)) mice to investigate the in vivo role of E2F2 in the composition of liver lipids and fatty acids in two metabolically different contexts: quiescence and 48-h post-PH, when cellular proliferation and anabolic demands are maximal. We show that liver regeneration is accompanied by large triglyceride and protein increases without changes in total phospholipids both in E2F2(+/+) and E2F2(-/-) mice. Remarkably, we found that the phenotype of quiescent liver tissue from E2F2(-/-) mice resembles the phenotype of proliferating E2F2(+/+) liver tissue, characterized by a decreased phosphatidylcholine to phosphatidylethanolamine ratio and a reprogramming of genes involved in generation of choline and ethanolamine derivatives. The diversity of fatty acids in total lipid, triglycerides and phospholipids was essentially preserved on E2F2 loss both in proliferating and non-proliferating liver tissue, although notable exceptions in inflammation-related fatty acids of defined phospholipid classes were detected. Overall, our results indicate that E2F2 activity sustains the hepatic homeostasis of major membrane glycerolipid components while it is dispensable for storage glycerolipid balance.

Landscape Genetics for the Empirical Assessment of Resistance Surfaces: The European Pine Marten (Martes martes) as a Target-Species of a Regional Ecological Network

Coherent ecological networks (EN) composed of core areas linked by ecological corridors are being developed worldwide with the goal of promoting landscape connectivity and biodiversity conservation. However, empirical assessment of the performance of EN designs is critical to evaluate the utility of these networks to mitigate effects of habitat loss and fragmentation. Landscape genetics provides a particularly valuable framework to address the question of functional connectivity by providing a direct means to investigate the effects of landscape structure on gene flow. The goals of this study are (1) to evaluate the landscape features that drive gene flow of an EN target species (European pine marten), and (2) evaluate the optimality of a regional EN design in providing connectivity for this species within the Basque Country (North Spain). Using partial Mantel tests in a reciprocal causal modeling framework we competed 59 alternative models, including isolation by distance and the regional EN. Our analysis indicated that the regional EN was among the most supported resistance models for the pine marten, but was not the best supported model. Gene flow of pine marten in northern Spain is facilitated by natural vegetation, and is resisted by anthropogenic landcover types and roads. Our results suggest that the regional EN design being implemented in the Basque Country will effectively facilitate gene flow of forest dwelling species at regional scale.

Prediction of Multi-Target Networks of Neuroprotective Compounds with Entropy Indices and Synthesis, Assay, and Theoretical Study of New Asymmetric 1,2-Rasagiline Carbamates

In a multi-target complex network, the links (L-ij) represent the interactions between the drug (d(i)) and the target (t(j)), characterized by different experimental measures (K-i, K-m, IC50, etc.) obtained in pharmacological assays under diverse boundary conditions (c(j)). In this work, we handle Shannon entropy measures for developing a model encompassing a multi-target network of neuroprotective/neurotoxic compounds reported in the CHEMBL database. The model predicts correctly >8300 experimental outcomes with Accuracy, Specificity, and Sensitivity above 80%-90% on training and external validation series. Indeed, the model can calculate different outcomes for >30 experimental measures in >400 different experimental protocolsin relation with >150 molecular and cellular targets on 11 different organisms (including human). Hereafter, we reported by the first time the synthesis, characterization, and experimental assays of a new series of chiral 1,2-rasagiline carbamate derivatives not reported in previous works. The experimental tests included: (1) assay in absence of neurotoxic agents; (2) in the presence of glutamate; and (3) in the presence of H2O2. Lastly, we used the new Assessing Links with Moving Averages (ALMA)-entropy model to predict possible outcomes for the new compounds in a high number of pharmacological tests not carried out experimentally.

Differential activity of GSK-3 isoforms regulates NF-kappa B and TRAIL- or TNF alpha induced apoptosis in pancreatic cancer cells

While TRAIL is a promising anticancer agent due to its ability to selectively induce apoptosis in neoplastic cells, many tumors, including pancreatic ductal adenocarcinoma (PDA), display intrinsic resistance, highlighting the need for TRAIL-sensitizing agents. Here we report that TRAIL-induced apoptosis in PDA cell lines is enhanced by pharmacological inhibition of glycogen synthase kinase-3 (GSK-3) or by shRNA-mediated depletion of either GSK-3 alpha or GSK-3 beta. In contrast, depletion of GSK-3 beta, but not GSK-3 alpha, sensitized PDA cell lines to TNF alpha-induced cell death. Further experiments demonstrated that TNF alpha-stimulated I kappa B alpha phosphorylation and degradation as well as p65 nuclear translocation were normal in GSK-3 beta-deficient MEFs. Nonetheless, inhibition of GSK-3 beta function in MEFs or PDA cell lines impaired the expression of the NF-kappa B target genes Bcl-xL and cIAP2, but not I kappa B alpha. Significantly, the expression of Bcl-xL and cIAP2 could be reestablished by expression of GSK-3 beta targeted to the nucleus but not GSK-3 beta targeted to the cytoplasm, suggesting that GSK-3 beta regulates NF-kappa B function within the nucleus. Consistent with this notion, chromatin immunoprecipitation demonstrated that GSK-3 inhibition resulted in either decreased p65 binding to the promoter of BIR3, which encodes cIAP2, or increased p50 binding as well as recruitment of SIRT1 and HDAC3 to the promoter of BCL2L1, which encodes Bcl-xL. Importantly, depletion of Bcl-xL but not cIAP2, mimicked the sensitizing effect of GSK-3 inhibition on TRAIL-induced apoptosis, whereas Bcl-xL overexpression ameliorated the sensitization by GSK-3 inhibition. These results not only suggest that GSK-3 beta overexpression and nuclear localization contribute to TNF alpha and TRAIL resistance via anti-apoptotic NF-kappa B genes such as Bcl-xL, but also provide a rationale for further exploration of GSK-3 inhibitors combined with TRAIL for the treatment of PDA.

Transverse target single-spin asymmetry in inclusive electroproduction of charged pions and kaons

Single-spin asymmetries were investigated in inclusive electroproduction of charged pions and kaons from transversely polarized protons at the HERMES experiment. The asymmetries were studied as a function of the azimuthal angle psi about the beam direction between the target-spin direction and the hadron production plane, the transverse hadron momentum P-T relative to the direction of the incident beam, and the Feynman variable x(F). The sin psi* amplitudes are positive for pi(+) and K+ slightly negative for pi(-) and consistent with zero for K-, with particular P-T but weak x(F) dependences. Especially large asymmetries are observed for two small subsamples of events, where also the scattered electron was recorded by the spectrometer. (C) 2013 The Authors. Published by Elsevier B.V. All rights reserved.

Feedback on the Rate and Depth of Chest Compressions during Cardiopulmonary Resuscitation Using Only Accelerometers

Background Quality of cardiopulmonary resuscitation (CPR) is key to increase survival from cardiac arrest. Providing chest compressions with adequate rate and depth is difficult even for well-trained rescuers. The use of real-time feedback devices is intended to contribute to enhance chest compression quality. These devices are typically based on the double integration of the acceleration to obtain the chest displacement during compressions. The integration process is inherently unstable and leads to important errors unless boundary conditions are applied for each compression cycle. Commercial solutions use additional reference signals to establish these conditions, requiring additional sensors. Our aim was to study the accuracy of three methods based solely on the acceleration signal to provide feedback on the compression rate and depth. Materials and Methods We simulated a CPR scenario with several volunteers grouped in couples providing chest compressions on a resuscitation manikin. Different target rates (80, 100, 120, and 140 compressions per minute) and a target depth of at least 50 mm were indicated. The manikin was equipped with a displacement sensor. The accelerometer was placed between the rescuer's hands and the manikin's chest. We designed three alternatives to direct integration based on different principles (linear filtering, analysis of velocity, and spectral analysis of acceleration). We evaluated their accuracy by comparing the estimated depth and rate with the values obtained from the reference displacement sensor. Results The median (IQR) percent error was 5.9% (2.8-10.3), 6.3% (2.9-11.3), and 2.5% (1.2-4.4) for depth and 1.7% (0.0-2.3), 0.0% (0.0-2.0), and 0.9% (0.4-1.6) for rate, respectively. Depth accuracy depended on the target rate (p < 0.001) and on the rescuer couple (p < 0.001) within each method. Conclusions Accurate feedback on chest compression depth and rate during CPR is possible using exclusively the chest acceleration signal. The algorithm based on spectral analysis showed the best performance. Despite these encouraging results, further research should be conducted to asses the performance of these algorithms with clinical data.