Structure and function of an irreversible agonist-β(2) adrenoceptor complex

G-protein-coupled receptors (GPCRs) are eukaryotic integral membrane proteins that modulate biological function by initiating cellular signalling in response to chemically diverse agonists. Despite recent progress in the structural biology of GPCRs, the molecular basis for agonist binding and allosteric modulation of these proteins is poorly understood. Structural knowledge of agonist-bound states is essential for deciphering the mechanism of receptor activation, and for structure-guided design and optimization of ligands. However, the crystallization of agonist-bound GPCRs has been hampered by modest affinities and rapid off-rates of available agonists. Using the inactive structure of the human β(2) adrenergic receptor (β(2)AR) as a guide, we designed a β(2)AR agonist that can be covalently tethered to a specific site on the receptor through a disulphide bond. The covalent β(2)AR-agonist complex forms efficiently, and is capable of activating a heterotrimeric G protein. We crystallized a covalent agonist-bound β(2)AR-T4L fusion protein in lipid bilayers through the use of the lipidic mesophase method, and determined its structure at 3.5?? resolution. A comparison to the inactive structure and an antibody-stabilized active structure (companion paper) shows how binding events at both the extracellular and intracellular surfaces are required to stabilize an active conformation of the receptor. The structures are in agreement with long-timescale (up to 30?μs) molecular dynamics simulations showing that an agonist-bound active conformation spontaneously relaxes to an inactive-like conformation in the absence of a G protein or stabilizing antibody.     

Misspecified prediction for time series

Let {X_t} be a stationary process with spectral density g(λ).It is often that the true structure g(λ) is not completely specified. This paper discusses the problem of misspecified prediction when a conjectured spectral density f_θ(λ), θ∈Θ, is fitted to g(λ). Then, constructing the best linear predictor based on f_θ(λ), we can evaluate the prediction error M(θ). Since θ is unknown we estimate it by a quasi‐MLE . The second‐order asymptotic approximation of is given. This result is extended to the case when X_t contains some trend, i.e. a time series regression model. These results are very general. Furthermore we evaluate the second‐order asymptotic approximation of for a time series regression model having a long‐memory residual process with the true spectral density g(λ). Since the general formulae of the approximated prediction error are complicated, we provide some numerical examples. Then we illuminate unexpected effects from the misspecification of spectra. Copyright © 2001 John Wiley & Sons, Ltd.     

A new algorithm for building the GSA-form

Gated Single Assignment (GSA) form is used to transform an imperative program into a form suitable for dataflow interpretation. We describe a GSA-formed Control Flow Graph (CFG) that contains gating functions and the information of switches. We also present an algorithm to transform an imperative program into a GSA-formed CFG. Transformation of an imperative program into a GSA-formed CFG provides the basis for generating dataflow graphs(DFG). By using GSA-formed CFG, we can transform an imperative program into a DFG more simply comparing with previous methods, and show an expectation of use with demand- and control-driven model. As we create an intermediate form which has essential information for translation, it will be used to do transformations for various kinds of dataflow models.     

Forecasts for leverage heterogeneous autoregressive models with jumps and other covariates

For leverage heterogeneous autoregressive (LHAR) models with jumps and other covariates, called LHARX models, multistep forecasts are derived. Some optimal properties of forecasts in terms of conditional volatilities are discussed, which tells us to model conditional volatility for return but not for the LHARX regression error and other covariates. Forecast standard errors are constructed for which we need to model conditional volatilities both for return and for LHAR regression error and other blue covariates. The proposed methods are well illustrated by forecast analysis for the realized volatilities of the US stock price indexes: the S&P 500, the NASDAQ, the DJIA, and the RUSSELL indexes.     

The action of the cholecystokinin-A receptor antagonist,devazepide, on the digestive system of the chicken

The influence of the cholecystokinin (CCK)-A receptor antagonist, devazepide (DVZ), on the chicken digestive tract was investigated. The passage of food from the crops of birds treated with DVZ was not significantly different from that of the control. DVZ treatment did not inhibit the biliary flow stimulated by the CCK analogue, caerulein. Dispersed chicken pancreatic acini stimulated with CCK were treated with various concentrations of DVZ. At 10^–5 M, DVZ completely inhibited amylase release; this concentration was much higher than those reported to have similar effects in mammals. The results suggest that the action DVZ as a CCK antagonist in the chicken is very weak.     

Rate of molecular evolution of the seminal protein gene SEMG2 correlates with levels of female promiscuity

Postcopulatory sperm competition is a key aspect of sexual selection and is believed to drive the rapid evolution of both reproductive physiology and reproduction-related genes. It is well-established that mating behavior determines the intensity of sperm competition, with polyandry (i.e., female promiscuity) leading to fiercer sperm competition than monandry. Studies in mammals, particularly primates, showed that, owing to greater sperm competition, polyandrous taxa generally have physiological traits that make them better adapted for fertilization than monandrous species, including bigger testes, larger seminal vesicles, higher sperm counts, richer mitochondrial loading in sperm and more prominent semen coagulation. Here, we show that the degree of polyandry can also impact the dynamics of molecular evolution. Specifically, we show that the evolution of SEMG2, the gene encoding semenogelin II, a main structural component of semen coagulum, is accelerated in polyandrous primates relative to monandrous primates. Our study showcases the intimate relationship between sexual selection and the molecular evolution of reproductive genes.     

Genome-wide association study identifies susceptibility loci for IgA nephropathy

We carried out a genome-wide association study of IgA nephropathy, a major cause of kidney failure worldwide. We studied 1,194 cases and 902 controls of Chinese Han ancestry, with targeted follow up in Chinese and European cohorts comprising 1,950 cases and 1,920 controls. We identified three independent loci in the major histocompatibility complex, as well as a common deletion of CFHR1 and CFHR3 at chromosome 1q32 and a locus at chromosome 22q12 that each surpassed genome-wide significance (P values for association between 1.59 × 10?2? and 4.84 × 10?? and minor allele odds ratios of 0.63-0.80). These five loci explain 4-7% of the disease variance and up to a tenfold variation in interindividual risk. Many of the alleles that protect against IgA nephropathy impart increased risk for other autoimmune or infectious diseases, and IgA nephropathy risk allele frequencies closely parallel the variation in disease prevalence among Asian, European and African populations, suggesting complex selective pressures.