β-Adrenoceptor mediated signal transduction in congestive heart failure in cardiomyopathic (UMX7.1) hamsters

In view of the lack of information regarding the status of -adrenoceptor mediated signal transduction mechanisms at severe stages of congestive heart failure, the status of -adrenoceptors, G-proteins and adenylyl cyclase activities was examined in 2202–275 day old cardiomyopathic hamster hearts. Although no changes in the Kd values for ₁- and ₂-adrenoceptors were seen, the number of ₁-adrenoceptors, unlike that of R2-adrenoceptors, was markedly decreased in cardiac membranes from failing hearts. The activation of adenylyl cyclase in the failing hearts by different concentrations of isoproterenol was also attenuated in comparison to the control preparations. The basal adenylyl cyclase activity in cardiac membranes from the failing hearts was not altered; however, the stimulated enzyme activities, when measured in the presence of forskolin, NaF or Gpp(NH)p were depressed significantly. The functional activity of Gs-proteins (measured by cholera toxin stimulation of adenylyl cyclase) was depressed whereas that of Gi-proteins (measured by pertussis toxin stimulation of adenylyl cyclase) was increased in the failing hearts. Not only were the Gs- and Gi-protein contents (measured by immunoblotting) increased, the bioactivities of these proteins as determined by ADP-ribosylations in the presence of cholera toxin and pertussis toxin, respectively, were also higher in failing hearts in comparison to the control values. Northern blot analysis revealed that the signals for Gs- and Gi-protein mRNAs were augmented at this stage of heart failure. These results indicate that the loss of adrenergic support at severe stages of congestive heart failure in cardiomyopathic hamsters may involve a reduction in the number of ₁-adrenoceptors, and an increase in Gi-protein contents as well as bioactivities in addition to an uncoupling of Gs-proteins from the catalytic site of adenylyl cyclase in cardiac membrane.     

Parameterizing Spatial Models of Infectious Disease Transmission that Incorporate Infection Time Uncertainty Using Sampling-Based Likelihood Approximations

A class of discrete-time models of infectious disease spread, referred to as individual-level models (ILMs), are typically fitted in a Bayesian Markov chain Monte Carlo (MCMC) framework. These models quantify probabilistic outcomes regarding the risk of infection of susceptible individuals due to various susceptibility and transmissibility factors, including their spatial distance from infectious individuals. The infectious pressure from infected individuals exerted on susceptible individuals is intrinsic to these ILMs. Unfortunately, quantifying this infectious pressure for data sets containing many individuals can be computationally burdensome, leading to a time-consuming likelihood calculation and, thus, computationally prohibitive MCMC-based analysis. This problem worsens when using data augmentation to allow for uncertainty in infection times. In this paper, we develop sampling methods that can be used to calculate a fast, approximate likelihood when fitting such disease models. A simple random sampling approach is initially considered followed by various spatially-stratified schemes. We test and compare the performance of our methods with both simulated data and data from the 2001 foot-and-mouth disease (FMD) epidemic in the U.K. Our results indicate that substantial computation savings can be obtained—albeit, of course, with some information loss—suggesting that such techniques may be of use in the analysis of very large epidemic data sets.     

Attenuation of cellular antioxidant defense mechanisms in kidney of rats intoxicated with carbofuran

Carbofuran, an anticholinestrase carbamate, is commonly used as an insecticide. Its toxic effect on kidney is less established. The present study was designed to investigate the effect of carbofuran on kidneys and to understand the mechanism involved in its nephrotoxicity. Male Wistar rats were divided into two groups of eight animals each; control animals received sunflower oil (vehicle) and carbofuran exposed animals were treated with carbofuran (1 mg/kg body weight) orally for 28 days. At the end of the treatment, significant increase was observed in urea and creatinine levels in serum along with the inhibition of acetylcholinesterase, suggesting nephrotoxicity. The antioxidant defense system of animals treated with carbofuran was altered in terms of increased lipid peroxidation, reduced glutathione, and total thiols and decreased activity of antioxidant enzymes (superoxide dismutase and catalase). The results indicate that carbofuran is nephrotoxic and increased oxidative stress appears to be involved in its nephrotoxic effects. © 2012 Wiley Periodicals, Inc. J Biochem Mol Toxicol 26:393–398, 2012; View this article online at wileyonlinelibrary.com . DOI 10.1002/jbt.21433     

Cholesterol Interaction Sites on the Transmembrane Domain of the Hedgehog Signal Transducer and Class F G Protein-Coupled Receptor Smoothened

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