Serotonin or 5-hydroxytryptamine (5-HT) regulates a wide spectrum of human physiology through the 5-HT receptor family. We report the crystal structures of the human 5-HT1B G protein-coupled receptor bound to the agonist antimigraine medications ergotamine and dihydroergotamine. The structures reveal similar binding modes for these ligands, which occupy the orthosteric pocket and an extended binding pocket close to the extracellular loops. The orthosteric pocket is formed by residues conserved in the 5-HT receptor family, clarifying the family-wide agonist activity of 5-HT. Compared with the structure of the 5-HT2B receptor, the 5-HT1B receptor displays a 3 angstrom outward shift at the extracellular end of helix V, resulting in a more open extended pocket that explains subtype selectivity. Together with docking and mutagenesis studies, these structures provide a comprehensive structural basis for understanding receptor-ligand interactions and designing subtype-selective serotonergic drugs.

Activation of G protein-coupled receptors upon agonist binding is a critical step in the signaling cascade for this family of cell surface proteins. We report the crystal structure of the A(2A) adenosine receptor (A(2A)AR) bound to an agonist UK-432097 at 2.7 angstrom resolution. Relative to inactive, antagonist-bound A(2A)AR, the agonist-bound structure displays an outward tilt and rotation of the cytoplasmic half of helix VI, a movement of helix V, and an axial shift of helix III, resembling the changes associated with the active-state opsin structure. Additionally, a seesaw movement of helix VII and a shift of extracellular loop 3 are likely specific to A(2A)AR and its ligand. The results define the molecule UK-432097 as a "conformationally selective agonist" capable of receptor stabilization in a specific active-state configuration.

We investigate in this paper global convergence properties of the augmented Lagrangian method for nonlinear semidefinite programming (NLSDP). Four modified augmented Lagrangian methods for solving NLSDP based on different algorithmic strategies are proposed. Possibly infeasible limit points of the proposed methods are characterized. It is proved that feasible limit points that satisfy the Mangasarian-Fromovitz constraint qualification are KKT points of NLSDP without requiring the boundedness condition of the multipliers. Preliminary numerical results are reported to compare the performance of the modified augmented Lagrangian methods.

The Eurasian perch (Perca fluviatilis L.) is a very important freshwater species in the Eurasian Continent. We characterized 12 microsatellite markers in this species and evaluated their usefulness for identifying genetic variation in 40 perch individuals from the Ulungur and Taitun-4 Lakes in the Xinjiang province of China. The number of alleles per locus ranged from 2 to 7, the observed (H-O) and expected (H-E) heterozygosities were 0.053-1.000 and 0.053-0.813, respectively. These microsatellite loci will be useful for assessment of genetic variation in Perca fluviatilus.

Climatic changes in Arid Central Asia (ACA) over the past two millennia have been widely concerned. However, less attention has been paid to those in the High Central Asia (HCA), where the Asian water tower nurtures the numerous oases by glacier and/or snow melt. Here, we present a new reconstruction of the temperature and precipitation change over the past two millennia based on grain size of a well-dated glacial lake sediment core in the central of southern Tianshan Mountains. The results show that the glacial lake catchment has experienced cold-wet climate conditions during the Dark Age Cold Period (similar to 300-600 AD; DACP) and the Little Ice Age (similar to 1300-1870 AD; LIA), whereas warm-dry conditions during the Medieval Warm Period (similar to 700-1270 AD; MWP). Integration of our results with those of previously published lake sediment records, stalagmite delta O-18 records, ice core net accumulation rates, tree-ring based temperature reconstructions, and mountain glacier activities suggest that there has a broadly similar hydroclimatic pattern over the HCA areas on centennial time scale during the past two millennia. Comparison between hydroclimatic pattern of the HCA and that of the ACA areas suggests a prevailing 'warm-dry and cold-wet' hydroclimatic pattern over the whole westerlies-dominated central Asia areas during the past two millennia. We argue that the position and intensity of the westerlies, which are closely related to the phase of the North Atlantic Oscillation (NAO), and the strength of the Siberian High pressure (SH), could have jointly modulated the late Holocene central Asia hydroclimatic changes. (C) 2017 Elsevier Ltd and INQUA. All rights reserved.

The Eurasian perch (Perca fluviatilis L.) is widely distributed in the European continent and restrictedly ranges at the lrtse River drainage in China. To understand the population structure of this species in China, the Asian edge of its natural range, samples of eight natural populations and one colonized population were analyzed using microsatellite markers. The Eurasian perch in China was found to possess high allelic richness (7.097-8.662) and heterozygosities (H-O = 0.734-0.856, H-E = 0.798-0.876). Significant bottleneck signatures for six populations were found. Significant genetic differentiation among populations was revealed from pairwise F-ST values, as well as analysis of molecular variance (AMOVA), Bayesian clustering in STRUCTURE, and Principal coordinate analysis (PCA). The hierarchical analysis for selection sweep suggested local adaptation to habitat conditions. The current results imply the occurrence of habitat fragmentation in the Eurasian perch in China. Management and conservation implications are also presented in this study. (C) 2011 Elsevier Ltd. All rights reserved.

Molecular modeling of agonist binding to the human A(2A) adenosine receptor (AR) was assessed and extended in light of crystallographic structures. Heterocyclic adenine nitrogens of cocrystallized agonist overlaid corresponding positions of the heterocyclic base of a bound triazolotriazine antagonist, and ribose moiety was coordinated in a hydrophilic region, as previously predicted based on modeling using the inactive receptor. Automatic agonist docking of 20 known potent nucleoside agonists to agonist-bound A(2A)AR crystallographic structures predicted new stabilizing protein interactions to provide a structural basis for previous empirical structure activity relationships consistent with previous mutagenesis results. We predicted binding of novel C2 terminal amino acid conjugates of A(2A)AR agonist CGS21680 and used these models to interpret effects on binding affinity of newly synthesized agonists. D-Amino acid conjugates were generally more potent than L-stereoisomers and free terminal carboxylates more potent than corresponding methyl esters. Amino acid moieties were coordinated close to extracellular loops 2 and 3. Thus, molecular modeling is useful in probing ligand recognition and rational design of GPCR-targeting compounds with specific pharmacological profiles.

Advances in human genetics have dramatically expanded our understanding of complex heritable diseases. Genome-wide association studies have identified an allelic series of CARD9 variants associated with increased risk of or protection from inflammatory bowel disease (IBD). The predisposing variant of CARD9 is associated with increased NF-kappa B-mediated cytokine production. Conversely, the protective variant lacks a functional C-terminal domain and is unable to recruit the E3 ubiquitin ligase TRIM62. Here, we used biochemical insights into CARD9 variant proteins to create a blueprint for IBD therapeutics and recapitulated the mechanism of the CARD9 protective variant using small molecules. We developed a multiplexed bead-based technology to screen compounds for disruption of the CARD9-TRIM62 interaction. We identified compounds that directly and selectively bind CARD9, disrupt TRIM62 recruitment, inhibit TRIM62-mediated ubiquitinylation of CARD9, and demonstrate cellular activity and selectivity in CARD9-dependent pathways. Taken together, small molecules targeting CARD9 illustrate a path toward improved IBD therapeutics.

Multi-proxy indices retrieved from sediments in Lake Chaonaqiu, an alpine lake on the western Loess Plateau (LP) of China, were used to reconstruct a precipitation history over the last similar to 300 years. The results correlate well with records from tree rings and historical documents in neighboring regions. We show that the lake oscillated between two states, i.e. wetter climatic conditions, which favored denser vegetation cover, and promoted weaker catchment soil erosion; and drier climatic conditions, which lead to less vegetation coverage, correlate with stronger surface soil erosion. Several intensive soil erosion events were identified in the sediment cores, and most of these occurred during decadal/multi-decadal dry periods, and correlate well with flood events documented in historical literature. The results of this study show that soil erosion by flood events is particularly intense during dry periods, and further highlights the role of vegetation cover in the conservation of water and soil in small lake basins on the Chinese LP. Copyright (c) 2016 John Wiley & Sons, Ltd.

With continuous scaling of gate dielectrics with technology scaling to nanoscale regime, an accurate direct tunneling modeling is critical and necessary to understand the scaling limits. In this paper, direct tunneling model based on WKB approximation, and three-subband quantum mechanical simulations have been used to calculate the inversion layer charge density and then model the gate leakage current for SiO2 and several different high-k gate dielectrics. The scaling limits of high-k gate dielectrics are then explored based on their direct tunneling characteristics. The gate voltage and surface potential dependence of the gate current density for SiO2 and several high-k materials are studied as well. The effects of effective oxide thickness, dielectric constant and barrier height on the direct tunneling current are studied as a function of gate voltages. Simulation results show that high-k dielectrics such as HfO2, Al2O3, La2O3 demonstrate significant gate leakage reduction. (c) 2006 Elsevier Ltd. All rights reserved.

The Smoothened receptor (SMO) mediates signal transduction in the hedgehog pathway, which is implicated in normal development and carcinogenesis. SMO antagonists can suppress the growth of some tumours; however, mutations at SMO have been found to abolish their antitumour effects, a phenomenon known as chemoresistance. Here we report three crystal structures of human SMO bound to the antagonists SANT1 and Anta XV, and the agonist, SAG1.5, at 2.6-2.8A resolution. The long and narrow cavity in the transmembrane domain of SMO harbours multiple ligand binding sites, where SANT1 binds at a deeper site as compared with other ligands. Distinct interactions at D473(6.54f) elucidated the structural basis for the differential effects of chemoresistance mutations on SMO antagonists. The agonist SAG1.5 induces a conformational rearrangement of the binding pocket residues, which could contribute to SMO activation. Collectively, these studies reveal the structural basis for the modulation of SMO by small molecules. =20

Recently, various concepts of D-eta-properly prequasi-invex functions were introduced and characterizations of D-eta-properly prequasi-invex functions were presented under a certain set of conditions. In this paper, we show that the same results can be obtained under weaker assumptions.