Tracking Hidden Binding Pockets Along the Molecular Recognition Path of l-Trp to Indoleamine 2,3-Dioxygenase 1

Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the oxidative cleavage of l -Tryptophan (l -Trp) to yield N-formyl-kynurenine in the first and rate limiting step of the kynurenine pathway. Bioactive metabolites, involved in the regulation of important immunological responses and neurological processes, are then produced by downstream enzymes along the pathway. Inhibitors of IDO1 are being designed and developed as therapeutic agents for immuno-oncology. In this work, we investigated the molecular recognition path of l -Trp to IDO1, integrating biophysical methods with supervised molecular dynamics (suMD) and mutagenesis experiments. Results allowed disclosing for the first time high and low dissociation constants of l -Trp to IDO1, and the presence of a metastable interaction site located at the upper part of a channel whose borders are defined by the EF-loop and the C-terminal part of the JK-loop. Collectively, our results provide new clues for the design of next-generation IDO1 ligands.     

Catalytic Reduction of 4-Nitrobenzoic Acid by cis-[Rh(CO)2(Amine)2](PF6) Complexes Under Water–Gas Shift Reaction Conditions: Kinetics Study

Rhodium(I) complexes of the type, cis-[Rh(CO)₂(amine)₂](PF₆) where (amine = 3-picoline, 2-picoline, pyridine, 2,6-lutidina or 3,5-lutidine) dissolved in 80% aqueous amine solutions catalyzed the selective reduction of 4-nitrobenzoic acid to 4-aminobenzoic acid under CO atmosphere. The importance of these catalytic systems is their high chemo selectivity for the aromatic nitro group of the 4-nitrobenzoic acid with respect to the carboxylic group, allowing the production of the desired aromatic amine in high yields. The 4-aminobenzoic acid production depends on the nature of the coordinated amine. The Rh/3,5-lutidine system, the most active catalyst among tested, displays turnover frequencies for 4-aminobenzoic acid production of about 173 moles per mole Rh per day for [Rh] = 1 × 10^?4 mol, [4-nitrobenzoic acid] = 3.82 × 10^?3mol, 10 mL of 80% aqueous 3,5-lutidine, P(CO) = 0.9 atm at 100 °C. Analyses of kinetic results for the Rh/3,5-lutidine system show a first order dependence on 4-nitrobenzoic acid concentration, a non-linear dependence on CO pressure, a segmented Arrhenius plot and dependence on the nature of the reducing gas agent. These data are discussed in terms of a possible mechanism.     

Erythropoietin Modulates Autophagy Signaling in the Developing Rat Brain in an In Vivo Model of Oxygen-Toxicity

Autophagy is a self-degradative process that involves turnover and recycling of cytoplasmic components in healthy and diseased tissue. Autophagy has been shown to be protective at the early stages of programmed cell death but it can also promote apoptosis under certain conditions. Earlier we demonstrated that oxygen contributes to the pathogenesis of neonatal brain damage, which can be ameliorated by intervention with recombinant human erythropoietin (rhEpo). Extrinsic- and intrinsic apoptotic pathways are involved in oxygen induced neurotoxicity but the role of autophagy in this model is unclear. We analyzed the expression of autophagy activity markers in the immature rodent brain after exposure to elevated oxygen concentrations. We observed a hyperoxia-exposure dependent regulation of autophagy-related gene (Atg) proteins Atg3, 5, 12, Beclin-1, microtubule-associated protein 1 light chain 3 (LC3), LC3A-II, and LC3B-II which are all key autophagy activity proteins. Interestingly, a single injection with rhEpo at the onset of hyperoxia counteracted these oxygen-mediated effects. Our results indicate that rhEpo generates its protective effect by modifying the key autophagy activity proteins.     

Metabolic profiling of glucuronides in human urine by LC-MS/MS and partial least-squares discriminant analysis for classification and prediction of gender

Mass spectrometry (MS) is increasingly being used for metabolic profiling, but detection modes such as constant neutral loss or multiple reaction monitoring have not often been reported. These modes allow focusing on structurally related compounds, which could be advantageous for situations in which the trait under investigation is associated with a particular class of metabolites. In this study, we analyzed endogenous glucuronides excreted in human urine by monitoring characteristic transitions of putative steroid glucuronides by LC-MS/MS for discrimination of females from males. Two methods for data extraction were used: (i) a manual procedure based on visual inspection of the chromatograms and selection of 23 peaks and (ii) a software-supported method (MarkerView) set to extract 100 peaks. Data from 10 female and 10 male students were analyzed by principal component analysis (PCA) and partial least-squares discriminant analysis (PLS-DA) using software SIMCA. With PCA, only the manual peak selection resulted in clustering males and females. With PLS-DA, the manual method provided full separation on the basis of one single discriminant; the software-supported approach required a two-component model for complete separation. Loading plots were analyzed for their ability to reveal peaks with high discriminating power, that is, potential biomarkers. The PLS-DA models were validated with urine samples collected from five new females and five new males. Gender was correctly assigned for all. Our results indicate that inclusion of biological criteria for variable selection coupled to class-specific MS analysis and data extraction by appropriate software may constitute a valuable addition to the methods available for metabolomics.     

Fitting in and feeling fine: Conformity and coping motives as mediators of the relationship between social anxiety and problematic drinking.

The present research was conducted to clarify the relationships among social anxiety, alcohol consumption, alcohol-related problems, and negative-reinforcement drinking motives among college students. Heavy drinking students (N = 316, 53.80% female) completed self-report measures of social anxiety, alcohol consumption, alcohol-related problems, and drinking motives. Findings indicated that students higher in social anxiety consumed less alcohol but experienced more negative consequences. Moreover, the relationship between social anxiety and negative consequences was mediated by coping and conformity drinking motives in addition to alcohol consumption. In the context of social anxiety, the current research demonstrates the importance of examining problematic drinking as distinct constructs: alcohol consumption and negative consequences. Findings are also discussed in terms of implications for interventions with socially anxious students. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Can people really “laugh at themselves?”—Experimental and correlational evidence.

Laughing at oneself is considered a core component of the sense of humor in the theories of several authors. In McGhee's (1996) eight-step-training program of the sense of humor, laughing at oneself constitutes one of the most difficult levels. However, until now, only little empirical evidence on laughing at oneself exists. Using a multimethod approach, in the current study, 70 psychology students and a total of 126 peers filled in the Sense of Humor Scale (SHS, McGhee, 1996), containing as a subscale “Laughing at oneself”. In addition, the participants answered the Trait and State forms of the State-Trait-Cheerfulness-Inventory (STCI, Ruch, K?hler, & van Thriel, 1996; Ruch, K?hler, & van Thriel, 1997). They then were confronted with six distorted images of themselves. Facial responses of the participants were videotaped and analyzed using the Facial Action Coding System (FACS, Ekman, Friesen, & Hager, 2002). Four indicators of exhilaration were examined: (a) experienced funniness, (b) AU12 smiles, (c) Duchenne displays, and (d) laughter. Furthermore, fake and masking smiles were studied. Results demonstrated that self- and peer reports of “laughing at oneself” converged moderately. All four indicators of exhilaration were shown, but funniness and laughter seemed to be the most strongly related indicators. Trait cheerfulness and (low) seriousness, and a cheerful mood state formed further characteristics of persons who laugh at themselves. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Assessing the way people look to judge their intentions.

[Correction Notice: An erratum for this article was reported in Vol 11(4) of Emotion (see record 2011-13790-001). Figure 1 should have been printed in color.] [Correction Notice: An erratum for this article was reported in Emotion July 4 2011 (see record 2011-13790-001). Figure 1, which should have been printed in color, was inadvertently printed in black and white. The online version has been corrected.] Faces of unknown persons are processed to infer the intentions of these persons not only when they depict full-blown emotions, but also at rest, or when these faces do not signal any strong feelings. We explored the brain processes involved in these inferences to test whether they are similar to those found when judging full-blown emotions. We recorded the event-related brain potentials (ERPs) elicited by faces of unknown persons who, when they were photographed, were not asked to adopt any particular expression. During the ERP recording, participants had to decide whether each face appeared to be that of a positively, negatively, ambiguously, or neutrally intentioned person. The early posterior negativity, the EPN, was found smaller for neutrally categorized faces than for the other faces, suggesting that the automatic processes it indexes are similar to those evoked by full-blown expressions and thus that these processes might be involved in the decoding of intentions. In contrast, in the same 200–400 ms time window, ERPs were not more negative at anterior sites for neutrally intentioned faces. Second, the peaks of the late positive potentials (LPPs) maximal at parietal sites around 700 ms postonset were not significantly smaller for neutrally intentioned faces. Third, the slow positive waves that followed the LPP were larger for faces that took more time to categorize, that is, for ambiguously intentioned faces. These three series of unexpected results may indicate processes similar to those triggered by full-blown emotions studies, but they question the characteristics of these processes. (PsycINFO Database Record (c) 2011 APA, all rights reserved)