A common neural scale for the subjective pleasantness of different primary rewards.

When an economic decision is taken, it is between goals with different values, and the values must be on the same scale. Here, we used functional MRI to search for a brain region that represents the subjective pleasantness of two different rewards on the same neural scale. We found activity in the ventral prefrontal cortex that correlated with the subjective pleasantness of two fundamentally different rewards, taste in the mouth and warmth on the hand. The evidence came from two different investigations, a between-group comparison of two independent fMRI studies, and from a within-subject study. In the latter, we showed that neural activity in the same voxels in the ventral prefrontal cortex correlated with the subjective pleasantness of the different rewards. Moreover, the slope and intercept for the regression lines describing the relationship between activations and subjective pleasantness were highly similar for the different rewards. We also provide evidence that the activations did not simply represent multisensory integration or the salience of the rewards. The findings demonstrate the existence of a specific region in the human brain where neural activity scales with the subjective pleasantness of qualitatively different primary rewards. This suggests a principle of brain processing of importance in reward valuation and decision-making

Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD

Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p 10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10−392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group

Vanillin analog - vanillyl mandelic acid, a novel specific inhibitor of snake venom 5'-nucleotidase

Snake venom 5�-nucleotidase (5�NUC) plays a very important role in envenomation strategies; however, apart from its modulation of hemostatic functions, its other pharmacological effects are not yet well characterized. Several studies have used specific inhibitors of enzyme toxins as a biochemical or pharmacological tool to characterize or establish its mechanism of action. We report here for the first time vanillin mandelic acid (VMA), an analog of vanillin, to potentially, selectively, and specifically inhibit venom 5�NUC activity among other enzymes present in venoms. VMA is much more potent in inhibiting 5�NUC activity than vanillyl acid (VA). The experimental results obtained are in good agreement with the in silico molecular docking interaction data. Both VA and VMA are competitive inhibitors as evident by the inhibition-relieving effect upon increasing the substrate concentration. VMA also dose-dependently inhibited the anticoagulant effect in Naja naja venom. In this study, we report novel non-nucleoside specific inhibitors of snake venom 5�NUC and experimentally demonstrate their involvement in the anticoagulant activity of N. naja venom. Hence, we hypothesize that VMA can be used as a molecular tool to evaluate the role of 5�NUC in snake envenomation and to develop prototypes and lead compounds with potential therapeutic applications against snake bites

Homology modeling, molecular dynamics and atomic level interaction study of snake venom 5′ nucleotidase

Abstract 5′ Nucleotidase (5′ NUC) is a ubiquitously distributed enzyme known to be present in snake venoms (SV) that is responsible primarily for causing dysregulation of physiological homeostasis in humans by inducing anticoagulant effects and by inhibiting platelet aggregation. It is also known to act synergistically with other toxins to exert a more pronounced anti-coagulant effect during envenomation. Its structural and functional role is not yet ascertained clearly. The 3D structure of snake venom 5′ nucleotidase (SV-5′ NUC) is not yet known and was predicted by us for the first time using a comparative homology modeling approach using Demansia vestigiata protein sequence. The accuracy and stability of the predicted SV-5′ NUC structure were validated using several computational approaches. Key interactions of SV-5′ NUC were studied using experimental studies/molecular docking analysis of the inhibitors vanillin, vanillic acid and maltol. All these inhibitors were found to dock favorably following pharmacologically relevant absorption, distribution, metabolism and excretion (ADME) profiles. Further, atomic level docking interaction studies using inhibitors of the SV-5′ NUC active site revealed amino acid residues Y65 and T72 as important for inhibitor–(SV-5′ NUC) interactions. Our in silico analysis is in good agreement with experimental inhibition results of SV-5′ NUC with vanillin, vanillic acid and maltol. The present study should therefore play a guiding role in the experimental design of new SV-5′ NUC inhibitors for snake bite management. We also identified a few pharmacophoric features essential for SV-5′ NUC inhibitory activity that can be utilized further for the discovery of putative anti-venom agents of therapeutic value for snake bite management

Blood eosinophil count thresholds and exacerbations in patients with chronic obstructive pulmonary disease

BACKGROUND:Eosinophilic airway inflammation in patients with chronic obstructive pulmonary disease (COPD) is associated with exacerbations and responsivity to steroids, suggesting potential shared mechanisms with eosinophilic asthma. However, there is no consistent blood eosinophil count that has been used to define the increased exacerbation risk. OBJECTIVE:We sought to investigate blood eosinophil counts associated with exacerbation risk in patients with COPD. METHODS:Blood eosinophil counts and exacerbation risk were analyzed in patients with moderate-to-severe COPD by using 2 independent studies of former and current smokers with longitudinal data. The Genetic Epidemiology of COPD (COPDGene) study was analyzed for discovery (n = 1,553), and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study was analyzed for validation (n = 1,895). A subset of the ECLIPSE study subjects were used to assess the stability of blood eosinophil counts over time. RESULTS:COPD exacerbation risk increased with higher eosinophil counts. An eosinophil count threshold of 300 cells/μL or greater showed adjusted incidence rate ratios for exacerbations of 1.32 in the COPDGene study (95% CI, 1.10-1.63). The cutoff of 300 cells/μL or greater was validated for prospective risk of exacerbation in the ECLIPSE study, with adjusted incidence rate ratios of 1.22 (95% CI, 1.06-1.41) using 3-year follow-up data. Stratified analysis confirmed that the increased exacerbation risk associated with an eosinophil count of 300 cells/μL or greater was driven by subjects with a history of frequent exacerbations in both the COPDGene and ECLIPSE studies. CONCLUSIONS:Patients with moderate-to-severe COPD and blood eosinophil counts of 300 cells/μL or greater had an increased risk exacerbations in the COPDGene study, which was prospectively validated in the ECLIPSE study