ORION-VIRCAT: a tool for mapping ICTV and NCBI taxonomies

Viruses, viroids and prions are the smallest infectious biological entities that depend on their host for replication. The number of pathogenic viruses is considerably large and their impact in human global health is well documented. Currently, the International Committee on the Taxonomy of Viruses (ICTV) has classified ∼4379 virus species while the National Center for Biotechnology Information Viral Genomes Resource (NCBI-VGR) database has mapped 617 705 proteins to eight large taxonomic groups. Despite these efforts, an automated approach for mapping the ICTV master list and its officially accepted virus naming to the NCBI-VGR’s taxonomical classification is not available. Due to metagenomic sequencing, it is likely that the discovery and naming of new viral species will increase by at least ten fold. Unfortunately, existing viral databases are not adequately prepared to scale, maintain and annotate automatically ultra-high throughput sequences and place this information into specific taxonomic categories. ORION-VIRCAT is a scalable and interoperable object-relational database designed to serve as a resource for the integration and verification of taxonomical classifications generated by the ICTV and NCBI-VGR. The current release (v1.0) of ORION-VIRCAT is implemented in PostgreSQL and it has been extended to ORACLE, MySQL and SyBase. ORION-VIRCAT automatically mapped and joined 617 705 entries from the NCBI-VGR to the viral naming of the ICTV. This detailed analysis revealed that 399 095 entries from the NCBI-VGR can be mapped to the ICTV classification and that one Order, 10 families, 35 genera and 503 species listed in the ICTV disagree with the the NCBI-VGR classification schema. Nevertheless, we were eable to correct several discrepancies mapping 234 000 additional entries

Theory of Coexistence of Superconductivity and Ferroelectricity : A Dynamical Symmetry Model

We propose and investigate a model for the coexistence of Superconductivity (SC) and Ferroelectricity (FE) based on the dynamical symmetries $su(2)$ for the pseudo-spin SC sector, $h(4)$ for the displaced oscillator FE sector, and $su(2) \otimes h(4)$ for the composite system. We assume a minimal symmetry-allowed coupling, and simplify the hamiltonian using a double mean field approximation (DMFA). A variational coherent state (VCS) trial wave-function is used for the ground state: the energy, and the relevant order parameters for SC and FE are obtained. For positive sign of the SC-FE coupling coefficient, a non-zero value of either order parameter can suppress the other (FE polarization suppresses SC and vice versa). This gives some support to "Matthias' Conjecture" [1964], that SC and FE tend to be mutually exclusive. For such a Ferroelectric Superconductor we predict: a) the SC gap $\Delta$ (and $T_c$) will increase with increasing applied pressure when pressure quenches FE as in many ferroelectrics, and b) the FE polarization will increase with increaesing magnetic field up to $H_c$. The last result is equivalent to the prediction of a new type of Magneto-Electric Effect in a coexistent SC-FE material. Some discussion will be given of the relation of these results to the cuprate superconductors.Comment: 46 page

Effects of sacubitril/valsartan on N-terminal pro-B-type natriuretic peptide in heart failure with preserved ejection fraction

Objectives: The authors sought to evaluate the prognostic significance of baseline N-terminal pro–B-type natriuretic peptide (NT-proBNP), whether NT-proBNP modified the treatment response to sacubitril/valsartan, and the treatment effect of sacubitril/valsartan on NT-proBNP overall and in key subgroups. Background: Sacubitril/valsartan reduces NT-proBNP in heart failure (HF) with both reduced and preserved ejection fraction (EF), but did not significantly reduce total HF hospitalizations and cardiovascular death compared with valsartan in patients with HF with preserved EF (HFpEF). Methods: In the PARAGON-HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial, 4,796 patients with HFpEF and elevated NT-proBNP were randomized to sacubitril/valsartan or valsartan. NT-proBNP was measured at screening in all patients and at 5 subsequent times in >2,700 patients: before, between, and after sequential valsartan and sacubitril/valsartan run-in periods, and 16 and 48 weeks post-randomization. Results: Median NT-proBNP was 911 pg/ml (interquartile range: 464 to 1,613 pg/ml) at screening. Screening NT-proBNP was strongly associated with the primary endpoint, total HF hospitalizations and cardiovascular death (rate ratio [RR]: 1.68 per log increase in NT-proBNP, 95% confidence interval [CI]: 1.53 to 1.85; p < 0.001). This relationship was stronger in patients with atrial fibrillation (adjusted RR: 2.33 [95% CI: 1.89 to 2.87] vs. 1.58 [95% CI: 1.42 to 1.75] in patients without atrial fibrillation; p interaction <0.001) and weaker in obese patients (adjusted RR: 1.50 [95% CI: 1.31 to 1.71] vs. 1.92 [95% CI: 1.70 to 2.17] in nonobese patients; p interaction <0.001). Screening NT-proBNP did not modify the treatment effect of sacubitril/valsartan compared with valsartan (p interaction = 0.96). Sacubitril/valsartan reduced NT-proBNP by 19% (95% CI: 14% to 23%; p < 0.001) compared with valsartan 16 weeks post-randomization, with similar reductions in men (20%) and women (18%), and in patients with left ventricular EF ≤57% (20%) and >57% (18%). Decreases in NT-proBNP predicted lower subsequent risk of the primary endpoint. Conclusions: Baseline NT-proBNP predicted HF events but did not modify the sacubitril/valsartan treatment effect in patients with HFpEF. Sacubitril/valsartan reduced NT-proBNP consistently in men and women, and in patients with lower or higher EF. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711

Allosteric “beta-blocker” isolated from a DNA-encoded small molecule library

The present study reports the discovery of a small-molecule negative allosteric modulator for the β2-adrenergic receptor (β2AR) via in vitro affinity-based iterative selection of highly diverse DNA-encoded small-molecule libraries. Characterization of the compound demonstrates its selectivity for the β2AR and that it negatively modulates a wide range of receptor functions. More importantly, our findings establish a generally applicable, proof-of-concept strategy for screening DNA-encoded small-molecule libraries against purified G-protein–coupled receptors (GPCRs), which holds great potential for discovering therapeutic molecules

Comparative Analysis of the Heptahelical Transmembrane Bundles of G Protein-Coupled Receptors

Background: G protein-coupled receptors represent a large family of eukaryotic membrane proteins, and are involved in almost all physiological processes in humans. Recent advances in the crystallographic study of these receptors enable a detailed comparative analysis of the commonly shared heptahelical transmembrane bundle. Systematic comparison of the bundles from a variety of receptors is indispensable for understanding not only of the structural diversification optimized for the binding of respective ligands but also of the structural conservation required for the common mechanism of activation accompanying the interaction changes among the seven helices. Methodology/Principal Findings: We have examined the bundles of 94 polypeptide chains from almost all available structures of 11 receptors, which we classified into either inactivated chain or activated chain, based on the type of bound ligand. For the inactivated chains, superposition of 200 residue bundles by secondary structure matching demonstrated that the bound ligands share a laterally limited cavity in the extracellular section of the bundle. Furthermore, a distinct feature was found for helix III of bovine rhodopsin, which might have evolved to lower its activity in the presence of 11-cis-retinal, to a level that other receptors could hardly achieve with any currently available ligands. Conclusions/Significance: Systematic analysis described here would be valuable for understanding of the rearrangement o