IFN stimulated gene expression in the liver is a better predictor of treatment response in chronic hepatitis c than the IL28b (IFN lambda 3) genotype

Background: Therapy of chronic hepatitis C (CHC) with pegIFNa/ribavirin achieves sustained virologic response (SVR) in ~55%. Pre-activation of the endogenous interferon system in the liver is associated non-response (NR). Recently, genome-wide association studies described associations of allelic variants near the IL28B (IFNλ3) gene with treatment response and with spontaneous clearance of the virus. We investigated if the IL28B genotype determines the constitutive expression of IFN stimulated genes (ISGs) in the liver of patients with CHC. Methods: We genotyped 93 patients with CHC for 3 IL28B single nucleotide polymorphisms (SNPs, rs12979860, rs8099917, rs12980275), extracted RNA from their liver biopsies and quantified the expression of IL28B and of 8 previously identified classifier genes which discriminate between SVR and NR (IFI44L, RSAD2, ISG15, IFI22, LAMP3, OAS3, LGALS3BP and HTATIP2). Decision tree ensembles in the form of a random forest classifier were used to calculate the relative predictive power of these different variables in a multivariate analysis. Results: The minor IL28B allele (bad risk for treatment response) was significantly associated with increased expression of ISGs, and, unexpectedly, with decreased expression of IL28B. Stratification of the patients into SVR and NR revealed that ISG expression was conditionally independent from the IL28B genotype, i.e. there was an increased expression of ISGs in NR compared to SVR irrespective of the IL28B genotype. The random forest feature score (RFFS) identified IFI27 (RFFS = 2.93), RSAD2 (1.88) and HTATIP2 (1.50) expression and the HCV genotype (1.62) as the strongest predictors of treatment response. ROC curves of the IL28B SNPs showed an AUC of 0.66 with an error rate (ERR) of 0.38. A classifier with the 3 best classifying genes showed an excellent test performance with an AUC of 0.94 and ERR of 0.15. The addition of IL28B genotype information did not improve the predictive power of the 3-gene classifier. Conclusions: IL28B genotype and hepatic ISG expression are conditionally independent predictors of treatment response in CHC. There is no direct link between altered IFNλ3 expression and pre-activation of the endogenous system in the liver. Hepatic ISG expression is by far the better predictor for treatment response than IL28B genotype

Hydrophobic and ionic-interactions in bulk and confined water with implications for collapse and folding of proteins

Water and water-mediated interactions determine thermodynamic and kinetics of protein folding, protein aggregation and self-assembly in confined spaces. To obtain insights into the role of water in the context of folding problems, we describe computer simulations of a few related model systems. The dynamics of collapse of eicosane shows that upon expulsion of water the linear hydrocarbon chain adopts an ordered helical hairpin structure with 1.5 turns. The structure of dimer of eicosane molecules has two well ordered helical hairpins that are stacked perpendicular to each other. As a prelude to studying folding in confined spaces we used simulations to understand changes in hydrophobic and ionic interactions in nano droplets. Solvation of hydrophobic and charged species change drastically in nano water droplets. Hydrophobic species are localized at the boundary. The tendency of ions to be at the boundary where water density is low increases as the charge density decreases. Interaction between hydrophobic, polar, and charged residue are also profoundly altered in confined spaces. Using the results of computer simulations and accounting for loss of chain entropy upon confinement we argue and then demonstrate, using simulations in explicit water, that ordered states of generic amphiphilic peptide sequences should be stabilized in cylindrical nanopores

Spatial distribution of photoelectrons participating in formation of x-ray absorption spectra

Interpretation of x-ray absorption near-edge structure (XANES) experiments is often done via analyzing the role of particular atoms in the formation of specific peaks in the calculated spectrum. Typically, this is achieved by calculating the spectrum for a series of trial structures where various atoms are moved and/or removed. A more quantitative approach is presented here, based on comparing the probabilities that a XANES photoelectron of a given energy can be found near particular atoms. Such a photoelectron probability density can be consistently defined as a sum over squares of wave functions which describe participating photoelectron diffraction processes, weighted by their normalized cross sections. A fine structure in the energy dependence of these probabilities can be extracted and compared to XANES spectrum. As an illustration of this novel technique, we analyze the photoelectron probability density at the Ti K pre-edge of TiS2 and at the Ti K-edge of rutile TiO2.Comment: Journal abstract available on-line at http://link.aps.org/abstract/PRB/v65/e20511

Effects of follicular phase exercise on luteinizing hormone pulse characteristics in sedentary eumenorrhoeic women

OBJECTIVE Current studies reveal little regarding the Inception of exercise-induced LH changes during physical training. This study aimed to assess the susceptibility of the hypothalamic–pituitary axis to the acute physical stress of exercise in untrained, physically inactive women. The acute effects of submaximal endurance exercise upon the pulsatile LH secretion in the follicular phase were compared with those accompanying leisurely strolling for a similar time period. SUBJECTS All subjects were eumenorrhoelc, as determined by biphasic temperature patterns, detection of the urinary LH surge, and mid-luteal serum progesterone levels. Subjects were not physically active and had little history of strenuous exercise ( V o 2 max = 38·0 ± 1·8) (mean ± SEM) ml/kg/min). DESIGN All women completed a 13·5-hour pulsatility test which included three consecutive 20-minute runs on a treadmill at 50, 60 and 70% of the subjects’maximum oxygen uptake ( n = 16). Six of these same subjects completed a separate test on another occasion in which one hour of leisurely strolling was substituted for exercise. Blood was sampled every 10 minutes via an indwelling cannula for 4·5 hours before and 8 hours after one hour of exercise and or strolling. MEASUREMENTS A pulse algorithm (Pulsar) was used to quantify LH pulse characteristics. RESULTS Exercise produced no significant effects upon LH pulse frequency or mean serum LH concentration. However, exercise of moderate intensity caused a significant increase in LH pulse amplitude ( P < 0·05). Strolling produced no significant changes in LH secretion. CONCLUSION Acute exercise of moderate intensity in the follicular phase of untrained women is an insufficient stimulus to inhibit the GnRH pulse generator in the post-exercise period, yet may produce a slight stimulatory effect on the amount of LH released per pulsePeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73507/1/j.1365-2265.1994.tb02794.x.pd

Model-Based Verification, Optimization, Synthesis and Performance Evaluation of Real-Time Systems

International audienceThis article aims at providing a concise and precise Travellers Guide, Phrase Book or Reference Manual to the timed automata modeling formalism introduced by Alur and Dill [8, 9]. The paper gives comprehensive definitions of timed automata, priced (or weighted) timed automata, and timed games and highlights a number of results on associated decision problems related to model checking, equivalence checking, optimal scheduling, the existence of winning strategies, and then statistical model checking

Five Determinisation Algorithms

Abstract. Determinisation of nondeterministic finite automata is a well-studied problem that plays an important role in compiler theory and system verification. In the latter field, one often encounters automata consisting of millions or even billions of states. On such input, the memory usage of analysis tools becomes the major bottleneck. In this paper we present several determinisation algorithms, all variants of the well-known subset construction, that aim to reduce memory usage and produce smaller output automata. One of them produces automata that are already minimal. We apply our algorithms to determinise automata that describe the possible sequences appearing after a fixed-length run of cellular automaton 110, and obtain a significant improvement in both memory and time efficiency.