3D Structure Prediction of TAS2R38 Bitter Receptors Bound to Agonists Phenylthiocarbamide (PTC) and 6-n-Propylthiouracil (PROP)

The G protein-coupled receptor (GPCR) TAS2R38 is a bitter taste receptor that can respond to bitter compounds such as phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP). This receptor was chosen because its four haplotypes (based on three residue site polymorphism) hTAS2R38_PAV, hTAS2R38_AVI, hTAS2R38_AAI, and hTAS2R38_PVV are known to have dramatically different responses to PTC and PROP. We aimed to identify the protein–ligand interaction features that determine whether the bitter taste signal from this receptor is sent to the cortex. To do this we predicted the 3D structures of the TAS2R38 bitter taste receptor using our new BiHelix and SuperBiHelix Monte Carlo methods (No experimental determinations of the 3D structure have been reported for any taste receptors.). We find that residue 262 (2nd position in the polymorphism) is involved in the interhelical hydrogen bond network stabilizing the GPCR structure in tasters (hTAS2R38_PAV, hTAS2R38_AAI, and hTAS2R38_PVV), while it is not in the nontaster (hTAS2R38_AVI). This suggests that the hydrogen bond interactions between TM3 and TM6 or between TM5 and TM6 may play a role in activating this GPCR. To further validate these structures, we used the DarwinDock method to predict the binding sites and 3D structures for PTC and PROP bound to hTAS2R38_PAV, hTAS2R38_AVI, hTAS2R38_AAI, and hTAS2R38_PVV, respectively. Our results show that PTC and PROP can form H-bonds with the backbone of residue 262 in the tasters (hTAS2R38_PAV, hTAS2R38_AAI, and hTAS2R38_PVV) but not in the nontaster (hTAS2R38_AVI). Thus it appears that the hydrogen bond interaction between TM3 and TM6 may activate the receptor to pass the ligand binding signal to intracellular processes and that the H-bond between agonists and residue 262 in tasters is involved in the bitter tasting. This is in agreement with experimental observations, providing validation of the predicted ligand-protein complexes and also a potential activation mechanism for the TAS2R38 receptor

Causal inference in paired two-arm experimental studies under non-compliance with application to prognosis of myocardial infarction

Motivated by a study about prompt coronary angiography in myocardial infarction, we propose a method to estimate the causal effect of a treatment in two-arm experimental studies with possible non-compliance in both treatment and control arms. The method is based on a causal model for repeated binary outcomes (before and after the treatment), which includes individual covariates and latent variables for the unobserved heterogeneity between subjects. Moreover, given the type of non-compliance, the model assumes the existence of three subpopulations of subjects: compliers, never-takers, and always-takers. The model is estimated by a two-step estimator: at the first step the probability that a subject belongs to one of the three subpopulations is estimated on the basis of the available covariates; at the second step the causal effects are estimated through a conditional logistic method, the implementation of which depends on the results from the first step. Standard errors for this estimator are computed on the basis of a sandwich formula. The application shows that prompt coronary angiography in patients with myocardial infarction may significantly decrease the risk of other events within the next two years, with a log-odds of about -2. Given that non-compliance is significant for patients being given the treatment because of high risk conditions, classical estimators fail to detect, or at least underestimate, this effect

Measuring Market Power in Professional Baseball, Basketball, Football, and Hockey

Using Forbes magazine’s estimates of the current value and revenues of professional sports teams, we derive a long-run variant of the Lerner Index. We apply the strategy to professional teams in baseball, basketball, football, and hockey over the 2006–2019 period. All teams have positive and significant price-cost margins over the entire period. Analysis of variance shows that local market factors and past team performance have less impact on a team’s market power than do common league-wide effects. The strongest market power is in leagues with more aggressive revenue sharing policies. Price-cost margins are higher for professional teams in North American than for the most valuable European soccer teams, consistent with the stronger exemption from antitrust law in the United States and the weaker revenue sharing policies in Europe

Predicted Structures for Kappa Opioid G‑Protein Coupled Receptor Bound to Selective Agonists

Human kappa opioid receptor (κ-OR), a G protein-coupled receptor (GPCR), has been identified as a drug target for treatment of such human disorders as pain perception, neuroendocrine physiology, affective behavior, and cognition. In order to find more selective and active agonists, one would like to do structure based drug design. Indeed, there is an X-ray structure for an antagonist bound to κ-OR, but structures for activated GPCRs are quite different from those for the inactive GPCRs. Here we predict the ensemble of 24 low-energy structures of human kappa opioid receptor (κ-OR), obtained by application of the GEnSeMBLE (GPCR Ensemble of Structures in Membrane Bilayer Environment) complete sampling method, which evaluates 13 trillion combinations of tilt and rotation angles for κ-OR to select the best 24. To validate these structures, we used the DarwinDock complete sampling method to predict the binding sites for five known agonists (ethylketocyclazocine, bremazocine, pentazocine, nalorphine, and morphine) bound to all 24 κ-OR conformations. We find that some agonists bind selectively to receptor conformations that lack the salt bridge between transmembrane domains 3 and 6 as expected for active conformations. These 3D structures for κ-OR provide a structural basis for understanding ligand binding and activation of κ-OR, which should be useful for guiding subtype specific drug design

Nonparametric nonlinear model predictive control

Model Predictive Control (MPC) has recently found wide acceptance in industrial applications, but its potential has been much impeded by linear models due to the lack of a similarly accepted nonlinear modeling or databased technique. Aimed at solving this problem, the paper addresses three issues: (i) extending second-order Volterra nonlinear MPC (NMPC) to higher-order for improved prediction and control; (ii) formulating NMPC directly with plant data without needing for parametric modeling, which has hindered the progress of NMPC; and (iii) incorporating an error estimator directly in the formulation and hence eliminating the need for a nonlinear state observer. Following analysis of NMPC objectives and existing solutions, nonparametric NMPC is derived in discrete-time using multidimensional convolution between plant data and Volterra kernel measurements. This approach is validated against the benchmark van de Vusse nonlinear process control problem and is applied to an industrial polymerization process by using Volterra kernels of up to the third order. Results show that the nonparametric approach is very efficient and effective and considerably outperforms existing methods, while retaining the original data-based spirit and characteristics of linear MPC

On the selection and design of proteins and peptide derivatives for the production of photoluminescent, red-emitting gold quantum clusters

Novel pathways of the synthesis of photoluminescent gold quantum clusters (AuQCs) using biomolecules as reactants provide biocompatible products for biological imaging techniques. In order to rationalize the rules for the preparation of red-emitting AuQCs in aqueous phase using proteins or peptides, the role of different organic structural units was investigated. Three systems were studied: proteins, peptides, and amino acid mixtures, respectively. We have found that cysteine and tyrosine are indispensable residues. The SH/S-S ratio in a single molecule is not a critical factor in the synthesis, but on the other hand, the stoichiometry of cysteine residues and the gold precursor is crucial. These observations indicate the importance of proper chemical behavior of all species in a wide size range extending from the atomic distances (in the AuI-S semi ring) to nanometer distances covering the larger sizes of proteins assuring the hierarchical structure of the whole self-assembled system

A biosensor for the determination of high density lipoprotein cholesterol employing combined surfactant-derived selectivity and sensitivity enhancements

High density lipoprotein cholesterol (HDL-C) is a modifiable risk factor in cardiovascular disease and devices suitable for its determination at the point of care are critical to the future management of hypercholesterolaemia. An electrochemical biosensor for measuring HDL-C was developed. The biosensor was based on a homogeneous assay methodology for selective determination of HDL-C in combination with a printed electrochemical sensor for measuring the reduction of hydrogen peroxide at a silver paste electrode. The polyoxyethylene alkylene tribenzylphenyl ether surfactant (Emulgen B-66) was found to be capable of both the selective dissolution of HDL particles, as well as the enhanced electrocatalytic reduction of hydrogen peroxide. The resulting biosensor was shown to have a linear response to HDL-C from 0.5 to 4 mM (r2=0.998) with an average r.s.d. of 7%. The biosensor was also used to analyse HDL-C in thirteen serum samples and had good agreement with a commercial spectrophotometric precipitation-based assay (r=0.7222; p < 0.058)

Thin-Film Metamaterials called Sculptured Thin Films

Morphology and performance are conjointed attributes of metamaterials, of which sculptured thin films (STFs) are examples. STFs are assemblies of nanowires that can be fabricated from many different materials, typically via physical vapor deposition onto rotating substrates. The curvilinear--nanowire morphology of STFs is determined by the substrate motions during fabrication. The optical properties, especially, can be tailored by varying the morphology of STFs. In many cases prototype devices have been fabricated for various optical, thermal, chemical, and biological applications.Comment: to be published in Proc. ICTP School on Metamaterials (Augsut 2009, Sibiu, Romania