Decreased Neutrophil Apoptosis in Quiescent ANCA-Associated Systemic Vasculitis

Background: ANCA-Associated Systemic Vasculitis (AASV) is characterized by leukocytoclasis, accumulation of unscavenged apoptotic and necrotic neutrophils in perivascular tissues. Dysregulation of neutrophil cell death may contribute directly to the pathogenesis of AASV. less thanbrgreater than less thanbrgreater thanMethods: Neutrophils from Healthy Blood Donors (HBD), patients with AASV most in complete remission, Polycythemia Vera (PV), Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA) and renal transplant recipients (TP) were incubated in vitro, and the rate of spontaneous apoptosis was measured by FACS. Plasma levels of cytokines and sFAS were measured with cytometric bead array and ELISA. Expression of pro/anti-apoptotic factors, transcription factors C/EBP-alpha, C/EBP-beta and PU.1 and inhibitors of survival/JAK2-pathway were measured by real-time-PCR. less thanbrgreater than less thanbrgreater thanResults: AASV, PV and RA neutrophils had a significantly lower rate of apoptosis compared to HBD neutrophils (AASV 50 +/- 14% vs. HBD 64 +/- 11%, p andlt; 0.0001). In RA but not in AASV and PV, low apoptosis rate correlated with increased plasma levels of GM-CSF and high mRNA levels of anti-apoptotic factors Bcl-2A1 and Mcl-1. AASV patients had normal levels of G-CSF, GM-CSF and IL-3. Both C/EBP-alpha, C/EBP-beta were significantly higher in neutrophils from AASV patients than HBD. Levels of sFAS were significantly higher in AASV compared to HBD. less thanbrgreater than less thanbrgreater thanConclusion: Neutrophil apoptosis rates in vitro are decreased in AASV, RA and PV but mechanisms seem to differ. Increased mRNA levels of granulopoiesis-associated transcription factors and increased levels of sFAS in plasma were observed in AASV. Additional studies are required to define the mechanisms behind the decreased apoptosis rates, and possible connections with accumulation of dying neutrophils in regions of vascular lesions in AASV patients.Funding Agencies|Swedish Research Council|71X-15152|Crafoord Foundation||</p

Deconstructing Insight: EEG Correlates of Insightful Problem Solving

Background: Cognitive insight phenomenon lies at the core of numerous discoveries. Behavioral research indicates four salient features of insightful problem solving: (i) mental impasse, followed by (ii) restructuring of the problem representation, which leads to (iii) a deeper understanding of the problem, and finally culminates in (iv) an “Aha!” feeling of suddenness and obviousness of the solution. However, until now no efforts have been made to investigate the neural mechanisms of these constituent features of insight in a unified framework. Methodology/Principal Findings: In an electroencephalographic study using verbal remote associate problems, we identified neural correlates of these four features of insightful problem solving. Hints were provided for unsolved problems or after mental impasse. Subjective ratings of the restructuring process and the feeling of suddenness were obtained on trial-by-trial basis. A negative correlation was found between these two ratings indicating that sudden insightful solutions, where restructuring is a key feature, involve automatic, subconscious recombination of information. Electroencephalogram signals were analyzed in the space×time×frequency domain with a nonparametric cluster randomization test. First, we found strong gamma band responses at parieto-occipital regions which we interpreted as (i) an adjustment of selective attention (leading to a mental impasse or to a correct solution depending on the gamma band power level) and (ii) encoding and retrieval processes for the emergence of spontaneous new solutions. Secondly, we observed an increased upper alpha band response in right temporal regions (suggesting active suppression of weakly activated solution relevant information) for initially unsuccessful trials that after hint presentation led to a correct solution. Finally, for trials with high restructuring, decreased alpha power (suggesting greater cortical excitation) was observed in right prefrontal area. Conclusions/Significance: Our results provide a first account of cognitive insight by dissociating its constituent components and potential neural correlates

Metabolomic profiles of hepatocellular carcinoma in a European prospective cohort

Background: Hepatocellular carcinoma (HCC), the most prevalent form of liver cancer, is difficult to diagnose and has limited treatment options with a low survival rate. Aside from a few key risk factors, such as hepatitis, high alcohol consumption, smoking, obesity, and diabetes, there is incomplete etiologic understanding of the disease and little progress in identification of early risk biomarkers. Methods: To address these aspects, an untargeted nuclear magnetic resonance metabolomic approach was applied to pre-diagnostic serum samples obtained from first incident, primary HCC cases (n = 114) and matched controls (n = 222) identified from amongst the participants of a large European prospective cohort. Results: A metabolic pattern associated with HCC risk comprised of perturbations in fatty acid oxidation and amino acid, lipid, and carbohydrate metabolism was observed. Sixteen metabolites of either endogenous or exogenous origin were found to be significantly associated with HCC risk. The influence of hepatitis infection and potential liver damage was assessed, and further analyses were made to distinguish patterns of early or later diagnosis. Conclusion: Our results show clear metabolic alterations from early stages of HCC development with application for better etiologic understanding, prevention, and early detection of this increasingly common cancer.This work was supported by the French National Cancer Institute (L’Institut National du Cancer; INCA; grant number 2009-139; PI: M. Jenab). AF received financial support (BDI fellowship) from the Centre National de la Recherche Scientifique (CNRS) and Bruker Biospin. The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, and Institut National de la Santé et de la Recherche Médicale (INSERM) (France); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum (DKFZ), and Federal Ministry of Education and Research (Germany); Hellenic Health Foundation (Greece); Italian Association for Research on Cancer (AIRC), National Research Council, Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, and AIRE-ONLUS Ragusa, AVIS Ragusa, Sicilian Government (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), and Statistics Netherlands (the Netherlands); European Research Council (ERC; grant number ERC-2009-AdG 232997) and Nordforsk, and Nordic Center of Excellence Programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), Regional Governments of Andalucía, Asturias, Basque Country, Murcia (No. 6236) and Navarra, and ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Scientific Council, and Regional Government of Skåne and Västerbotten (Sweden); Cancer Research UK, Medical Research Council, Stroke Association, British Heart Foundation, Department of Health, Food Standards Agency, and Wellcome Trust (UK)

Analytical approximation of the neutrino oscillation matter effects at large θ 13

We argue that the neutrino oscillation probabilities in matter are best understood by allowing the mixing angles and mass-squared differences in the standard parametrization to `run' with the matter effect parameter $a=2\sqrt{2}G_F N_e E$, where $N_e$ is the electron density in matter and $E$ is the neutrino energy. We present simple analytical approximations to these `running' parameters. We show that for the moderately large value of $\theta_{13}$, as discovered by the reactor experiments, the running of the mixing angle $\theta_{23}$ and the CP violating phase $\delta$ can be neglected. It simplifies the analysis of the resulting expressions for the oscillation probabilities considerably. Approaches which attempt to directly provide approximate analytical expressions for the oscillation probabilities in matter suffer in accuracy due to their reliance on expansion in $\theta_{13}$, or in simplicity when higher order terms in $\theta_{13}$ are included. We demonstrate the accuracy of our method by comparing it to the exact numerical result, as well as the direct approximations of Cervera et al., Akhmedov et al., Asano and Minakata, and Freund. We also discuss the utility of our approach in figuring out the required baseline lengths and neutrino energies for the oscillation probabilities to exhibit certain desirable features.Comment: 43 pages, 51 pdf figures. Uses jheppub.sty. Revised figs 5, 6, and

Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer

We performed a multistage genome-wide association study (GWAS) including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT; per-allele odds ratio [OR] = 0.79; 95% confidence interval [CI] = 0.74–0.84; P = 3.0×10−12), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2; OR = 1.46; 95% CI = 1.30–1.65; P = 1.1×10−10), rs9581943 at 13q12.2 (PDX1; OR = 1.15; 95% CI = 1.10–1.20; P = 2.4×10−9), and rs16986825 at 22q12.1 (ZNRF3; OR = 1.18; 95% CI = 1.12–1.25; P = 1.2×10−8). An independent signal was identified in exon 2 of TERT at the established region 5p15.33 (rs2736098; OR = 0.80; 95% CI = 0.76–0.85; P = 9.8×10−14). We also identified a locus at 8q24.21 (rs1561927; P = 1.3×10−7) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study has identified multiple new susceptibility alleles for pancreatic cancer worthy of follow-up studies

A Study of the Mean Field Approach to Knapsack Problems

: The mean field theory (MFT) approach to knapsack problems is extended to multiple knapsacks and generalized assignment problems with Potts mean field equations governing the dynamics. Numerical tests against &quot;state of the art&quot; conventional algorithms shows good performance for the mean field approach. The inherently parallelism of the MFT equations makes them suitable for direct implementations in micro-chips. It is demonstrated numerically that the performance is essentially not affected when only a limited number of bits is used in the mean field equations. Also, a hybrid algorithm with linear programming and mean field components is showed to further improve the performance for the difficult homogeneous NxM knapsack problem. 1 [email protected] 2 [email protected] 1 Motivation and Results Suppose you want to go hill climbing carrying a knapsack filled with a selection of possible items. Which items should you choose, as to maximize your comfort, when the knapsack is bound..

A study of the mean field approach to knapsack problems

The mean field theory approach to knapsack problems is extended to multiple knapsacks and generalized assignment problems with Potts mean field equations governing the dynamics. Numerical tests against 'state of the art' conventional algorithms shows good performance for the mean field approach. The inherently parallelism of the mean field equations makes them suitable for direct implementations in microchips. It is demonstrated numerically that the performance is essentially not affected when only a limited number of bits is used in the mean field equations. Also, a hybrid algorithm with linear programming and mean field components is showed to further improve the performance for the difficult homogeneous N x M knapsack problem

Predicting System loads with Artificial Neural Networks : Method and Result from "the Great Energy Predictor Shootout"

We devise a feed-forward Artificial Neural Network (ANN) procedure for predicting utility loads and present the resulting predictions for two test problems given by ``The Great Energy Predictor Shootout - The First Building Data Analysis and Prediction Competition''. Key ingredients in our approach are a method ($\delta$ -test) for determiningrelevant inputs and the Multilayer Perceptron. These methods are briefly reviewed together with comments on alternative schemes like fitting to polynomials and the use of recurrent networks

Predicting System Loads with Artificial Neural Networks - Methods and Results from &quot;the Great Energy Predictor Shootout&quot;

: We devise a feed-forward Artificial Neural Network (ANN) procedure for predicting utility loads and present the resulting predictions for two test problems given by &quot;The Great Energy Predictor Shootout - The First Building Data Analysis and Prediction Competition&quot; [1]. Key ingredients in our approach are a method (ffi -test) for determining relevant inputs and the Multilayer Perceptron. These methods are briefly reviewed together with comments on alternative schemes like fitting to polynomials and the use of recurrent networks. 1 [email protected] 2 [email protected] 3 [email protected] 4 [email protected] 5 [email protected] 1 Introduction This paper concerns methods and results in making predictions for two test problems (A and B) given by &quot;The Great Energy Predictor Shootout - The First Building Data Analysis and Prediction Competition&quot; [1]. The present approach scored # 1 on set B and # 2 on set A. Both problems were given to the contestants in terms of tables of histori..