Predicting postdischarge opiate abstinence from admission measures of motivation and confidence.

Admission scores from a model comprising 3 motivation factors concerning the cessation of heroin use and a confidence scale concerning postdischarge abstinence were tested for their ability to predict postdischarge outcomes in patients beginning inpatient opiate detoxification. Statistically significant prediction of abstinence from heroin 30 days after discharge and the number of heroin-free days in the 3 months following admission was based on the confidence scale and a factor concerned with externally imposed constraints on continued heroin use. The single-scale confidence measure made the largest contribution to each prediction, indicating that such scales may be potentially useful outcome predictors for postdischarge abstinence. External constraints on heroin use may not provide a basis for success in this treatment modality. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Improved sooting tendency measurements for aromatic hydrocarbons and their implications for naphthalene formation pathways

Sooting tendencies have been determined for aromatic hydrocarbons using a new definition: the maximum soot volume fraction fv,max measured in a coflow methane/air nonpremixed flame whose fuel is doped with 400 ppm of the test hydrocarbon. These fv,max were converted into apparatus-independent yield sooting indices (YSIs) by the equation YSI=C×fv,max+D, where C and D are apparatus-specific parameters chosen so that YSI-benzene = 30 and YSI-1,2-dihydronaphthalene = 100. The dopants were added to the fuel mixture with a syringe pump and fv,max was measured with laser-induced incandescence. YSI was determined for 6 cycloaliphatics and for 62 aromatics, which included 28 alkylbenzenes, 10 alkenylbenzenes, 10 alkynylbenzenes, 25 multiply substituted benzenes, 6 two-ring aromatics, and 6 substituted benzenes with heteroatoms in the side chains. The YSIs correlate well with literature values of threshold sooting index (TSI), which is a more traditional sooting tendency based on the height of pure-fuelled flames at the smoke point. This agreement indicates that fv,max and smoke height are equivalent measures of sooting tendency and that YSI is largely apparatus-independent. However, the YSIs have a total uncertainty of ±3%, which is substantially better than the TSIs, and the number of aromatic YSIs reported here is more than double the number of aromatic TSIs in the literature. The YSIs depend strongly on molecular structure; thus they provide information about the chemical kinetic reaction mechanisms responsible for fuel decomposition and hydrocarbon growth from a broad cross section of one-ring aromatics. Important naphthalene formation pathways appear to include acetylene addition to ethynylphenyl, propargyl addition to benzyl, and methyl addition to indenyl. This last pathway is particularly significant because it converts indene quantitatively to naphthalene and because the side chains in many alkenylbenzenes and alkynylbenzenes cyclize to form five-membered rings.     

Automated zebrafish chorion removal and single embryo placement: optimizing throughput of zebrafish developmental toxicity screens

The potential of the developing zebrafish model for toxicology and drug discovery is limited by inefficient approaches to manipulating and chemically exposing zebrafish embryos-namely, manual placement of embryos into 96- or 384-well plates and exposure of embryos while still in the chorion, a barrier of poorly characterized permeability enclosing the developing embryo. We report the automated dechorionation of 1600 embryos at once at 4 h postfertilization (hpf) and placement of the dechorionated embryos into 96-well plates for exposure by 6 hpf. The process removed ≥95% of the embryos from their chorions with 2% embryo mortality by 24 hpf, and 2% of the embryos malformed at 120 hpf. The robotic embryo placement allocated 6-hpf embryos to 94.7% ± 4.2% of the wells in multiple 96-well trials. The rate of embryo mortality was 2.8% (43 of 1536) from robotic handling, the rate of missed wells was 1.2% (18 of 1536), and the frequency of multipicks was <0.1%. Embryo malformations observed at 24 hpf occurred nearly twice as frequently from robotic handling (16 of 864; 1.9%) as from manual pipetting (9 of 864; 1%). There was no statistical difference between the success of performing the embryo placement robotically or manually.     

A GRL-compliant iStar extension for collaborative cyber-physical systems

Requirements Engineering - Collaborative cyber-physical systems are capable of forming networks at runtime to achieve goals that are unachievable for individual systems. They do so by connecting to...     

Randomized function evaluation on a ring

LetR be a unidirectional asynchronous ring ofn identical processors each with a single input bit. Letf be any cyclic nonconstant function ofn boolean variables. Moran and Warmuth (1986) prove that anydeterministic algorithm that evaluatesf onR has communication complexity (n logn) bits. They also construct a family of cyclic nonconstant boolean functions that can be evaluated inO(n logn) bits by a deterministic algorithm.This contrasts with the following new results:

Multi-Omics Revealed Molecular Mechanisms Underlying Guard Cell Systemic Acquired Resistance

Systemic Acquired Resistance (SAR) improves immunity of plant systemic tissue after local exposure to a pathogen. Guard cells that form stomatal pores on leaf surfaces recognize bacterial pathogens via pattern recognition receptors, such as Flagellin Sensitive 2 (FLS2). However, how SAR affects stomatal immunity is not known. In this study, we aim to reveal molecular mechanisms underlying the guard cell response to SAR using multi-omics of proteins, metabolites and lipids. Arabidopsis plants previously exposed to pathogenic bacteria Pseudomonas syringae pv. tomato DC3000 (Pst) exhibit an altered stomatal response compared to control plants when they are later exposed to the bacteria. Reduced stomatal apertures of SAR primed plants lead to decreased number of bacteria in leaves. Multi-omics has revealed molecular components of SAR response specific to guard cells functions, including potential roles of reactive oxygen species (ROS) and fatty acid signaling. Our results show an increase in palmitic acid and its derivative in the primed guard cells. Palmitic acid may play a role as an activator of FLS2, which initiates stomatal immune response. Improved understanding of how SAR signals affect stomatal immunity can aid biotechnology and marker-based breeding of crops for enhanced disease resistance.     

Polycyclic Aromatic Hydrocarbons Activate the Aryl Hydrocarbon Receptor and the Constitutive Androstane Receptor to Regulate Xenobiotic Metabolism in Human Liver Cells

Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants produced by incomplete combustion of organic matter. They induce their own metabolism by upregulating xenobiotic-metabolizing enzymes such as cytochrome P450 monooxygenase 1A1 (CYP1A1) by activating the aryl hydrocarbon receptor (AHR). However, previous studies showed that individual PAHs may also interact with the constitutive androstane receptor (CAR). Here, we studied ten PAHs, different in carcinogenicity classification, for their potential to activate AHR- and CAR-dependent luciferase reporter genes in human liver cells. The majority of investigated PAHs activated AHR, while non-carcinogenic PAHs tended to activate CAR. We further characterized gene expression, protein abundancies and activities of the AHR targets CYP1A1 and 1A2, and the CAR target CYP2B6 in human HepaRG hepatoma cells. Enzyme induction patterns strongly resembled the profiles obtained at the receptor level, with AHR-activating PAHs inducing CYP1A1/1A2 and CAR-activating PAHs inducing CYP2B6. In summary, this study provides evidence that beside well-known activation of AHR, some PAHs also activate CAR, followed by subsequent expression of respective target genes. Furthermore, we found that an increased PAH ring number is associated with AHR activation as well as the induction of DNA double-strand breaks, whereas smaller PAHs activated CAR but showed no DNA-damaging potential.     

Functional and Molecular Properties of DYT-SGCE Myoclonus-Dystonia Patient-Derived Striatal Medium Spiny Neurons

Myoclonus-dystonia (DYT-SGCE, formerly DYT11) is characterized by alcohol-sensitive, myoclonic-like appearance of fast dystonic movements. It is caused by mutations in the SGCE gene encoding ε-sarcoglycan leading to a dysfunction of this transmembrane protein, alterations in the cerebello-thalamic pathway and impaired striatal plasticity. To elucidate underlying pathogenic mechanisms, we investigated induced pluripotent stem cell (iPSC)-derived striatal medium spiny neurons (MSNs) from two myoclonus-dystonia patients carrying a heterozygous mutation in the SGCE gene (c.298T>G and c.304C>T with protein changes W100G and R102X) in comparison to two matched healthy control lines. Calcium imaging showed significantly elevated basal intracellular Ca²⁺ content and lower frequency of spontaneous Ca²⁺ signals in SGCE MSNs. Blocking of voltage-gated Ca²⁺ channels by verapamil was less efficient in suppressing KCl-induced Ca²⁺ peaks of SGCE MSNs. Ca²⁺ amplitudes upon glycine and acetylcholine applications were increased in SGCE MSNs, but not after GABA or glutamate applications. Expression of voltage-gated Ca²⁺ channels and most ionotropic receptor subunits was not altered. SGCE MSNs showed significantly reduced GABAergic synaptic density. Whole-cell patch-clamp recordings displayed elevated amplitudes of miniature postsynaptic currents and action potentials in SGCE MSNs. Our data contribute to a better understanding of the pathophysiology and the development of novel therapeutic strategies for myoclonus-dystonia.     

Characterization of Apo-Form Selective Inhibition of Indoleamine 2,3-Dioxygenase**

Indoleamine-2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme that catalyzes the rate-limiting step in the kynurenine pathway of tryptophan (TRP) metabolism. As it is an inflammation-induced immunoregulatory enzyme, pharmacological inhibition of IDO1 activity is currently being pursued as a potential therapeutic tool for the treatment of cancer and other disease states. As such, a detailed understanding of the mechanism of action of IDO1 inhibitors with various mechanisms of inhibition is of great interest. Comparison of an apo-form-binding IDO1 inhibitor (GSK5628) to the heme-coordinating compound, epacadostat (Incyte), allows us to explore the details of the apo-binding inhibition of IDO1. Herein, we demonstrate that GSK5628 inhibits IDO1 by competing with heme for binding to a heme-free conformation of the enzyme (apo-IDO1), whereas epacadostat coordinates its binding with the iron atom of the IDO1 heme cofactor. Comparison of these two compounds in cellular systems reveals a long-lasting inhibitory effect of GSK5628, previously undescribed for other known IDO1 inhibitors. Detailed characterization of this apo-binding mechanism for IDO1 inhibition might help design superior inhibitors or could confer a unique competitive advantage over other IDO1 inhibitors vis-à-vis specificity and pharmacokinetic parameters.