Protein geometry and placement in the cardiac dyad influence macroscopic properties of calcium-induced calcium release

In cardiac ventricular myocytes, events crucial to excitation-contraction coupling take place in spatially restricted microdomains known as dyads. The movement and dynamics of calcium (Ca2+) ions in the dyad have often been described by assigning continuously valued Ca2+ concentrations to one or more dyadic compartments. However, even at its peak, the estimated number of free Ca2+ ions present in a single dyad is small (approximately 10-100 ions). This in turn suggests that modeling dyadic calcium dynamics using laws of mass action may be inappropriate. In this study, we develop a model of stochastic molecular signaling between L-type Ca2+ channels (LCCs) and ryanodine receptors (RyR2s) that describes: a), known features of dyad geometry, including the space-filling properties of key dyadic proteins; and b), movement of individual Ca2+ ions within the dyad, as driven by electrodiffusion. The model enables investigation of how local Ca2+ signaling is influenced by dyad structure, including the configuration of key proteins within the dyad, the location of Ca2+ binding sites, and membrane surface charges. Using this model, we demonstrate that LCC-RyR2 signaling is influenced by both the stochastic dynamics of Ca2+ ions in the dyad as well as the shape and relative positioning of dyad proteins. Results suggest the hypothesis that the relative placement and shape of the RyR2 proteins helps to "funnel" Ca2+ ions to RyR2 binding sites, thus increasing excitation-contraction coupling gain.     

A Semiempirical QM/MM Implementation and its Application to the Absorption of Organic Molecules in Zeolites

An intermolecular hybrid semiempirical MO/molecular mechanics technique is described. The model allows polarisation of the quantum mechanical molecule(s), but not of the molecular mechanics part and is shown to be relatively insensitive to the size of the molecular mechanics environment. It has been validated by comparison of calculated and experimental absorption energies of small organic molecules in various zeolites. This validation gives us confidence that the method is also appropriate for experimentally less well characterised problems, such as solvation or ligand/enzyme complexation.     

A Comparison of Body Size Evaluations of Obesity Surgery Patients and General Population Adults

RAND, COLLEEN S. W., JAQUELYN LISS RESNIK, AND ALEX M. C. MACGREGOR. A comparison of body size evaluations of obesity surgery patients and general population adults. Obes Res. Objective: To compare post-operative obesity surgery patients and general population adults in their assessments of a wide range of body sizes. Research Methods and Procedures: Obesity surgery patients (n = 274) and general population adults (n = 326) rated ideal and socially acceptable body sizes in separate arrays of babies, children, young adults, and middle-aged and older adults. Nine line figure drawings ranging from very thin to very obese were rated for each array. Results: Both groups selected the same ideal body size for all arrays except for babies. Both groups rejected obese and very thin body sizes as socially acceptable. However, the obesity surgery patients were more restrictive than general population adults in their ratings of socially acceptable body sizes. Current obesity status did not impact ratings for the patient or general population subjects. In the patient sample, time since surgery did not influence body size evaluations. Discussion: The study of body size ratings limited only to the “ideal” size may be misleading because it may mask subtle but meaningful differences between groups. The consistent difference in more restrictive ratings of obesity surgery patients compared to general population adults may be due to patients' greater psychological investment in endorsing the societal ideal body size. It may also be due to patients' status as peripheral group members of the normal weight community. The inability of some patients to maintain their post-operative weight loss may be particularly problematic for those who have defined “socially acceptable” body size most narrowly.     

Indian red scorpion venom modulates spontaneous activity of rat right atria through the involvement of cholinergic and adrenergic systems.

The effect of Indian red scorpion (Mesobuthus tamulus concanesis, Pocock; MBT) venom was investigated on isolated rat right atrial preparations. MBT venom (0.001-3.0 micrograms/ml) exhibited a peculiar concentration-response pattern with respect to rate. The venom concentrations between 0.001-0.01 microgram/ml increased the atrial rate (phase I), followed by a relative decrease with 0.03-0.3 microgram/ml (phase II), and then an abrupt increase with 0.6-3.0 micrograms/ml (phase III). On the other hand, the force was unaltered by venom at phases I and II, while an increase was seen at phase III (3.0 micrograms/ml). Propranolol (0.1 microM) completely blocked the cardiostimulant action of venom at phase III. Further, this stimulant action of venom was absent in atria obtained from reserpinized animals. Pretreatment with atropine (0.3 microM), produced tachycardia at concentrations 0.1-0.3 microgram/ml of venom. But, hexamethonium (30 microM) had no influence on the venom (0.1 microgram/ml)-induced alterations in rate. However, MBT venom increased the acetylcholinesterase (AChE) activity (2-3 fold) in a concentration-dependent manner. Tetrodotoxin (2 microM), did not block the increase in rate produced by 0.01 microgram/ml of venom. Results suggest that, MBT venom-induced alterations of cardiac rhythmicity are mediated through cholinergic as well as adrenergic mechanisms depending upon the concentrations. The modulation of atrial rate at very low concentrations may be due to the direct action of venom on the atrium.     

AnCF, the CCAAT Binding Complex of Aspergillus nidulans, Contains Products of the hapB, hapC, and hapE Genes and Is Required for Activation by the Pathway-Specific Regulatory Gene amdR

CCAAT binding factors (CBFs) positively regulating the expression of the amdS gene (encoding acetamidase) and two penicillin biosynthesis genes (ipnA and aatA) have been previously found in Aspergillus nidulans. The factors were called AnCF and PENR1, respectively. Deletion of the hapC gene, encoding a protein with significant similarity to Hap3p of Saccharomyces cerevisiae, eliminated both AnCF and PENR1 binding activities. We now report the isolation of the genes hapB and hapE, which encode proteins with central regions of high similarity to Hap2p and Hap5p of S. cerevisiae and to the CBF-B and CBF-C proteins of mammals. An additional fungus-specific domain present in HapE was revealed by comparisons with the homologs from S. cerevisiae, Neurospora crassa, and Schizosaccharomyces pombe. The HapB, HapC, and HapE proteins have been shown to be necessary and sufficient for the formation of a CCAAT binding complex in vitro. Strains with deletions of each of the hapB, hapC, and hapE genes have identical phenotypes of slow growth, poor conidiation, and reduced expression of amdS. Furthermore, induction of amdS by omega amino acids, which is mediated by the AmdR pathway-specific activator, is abolished in the hap deletion mutants, as is growth on γ-aminobutyric acid as a sole nitrogen or carbon source. AmdR and AnCF bind to overlapping sites in the promoters of the amdS and gatA genes. It is known that AnCF can bind independently of AmdR. We suggest that AnCF binding is required for AmdR binding in vivo.     

Male mating strategies under predation risk: do females call the shots?

Many authors have reported that, under elevated risk of predation,male guppies (Poecilia reticulata) alter their behavior fromcourtship to forced copulation (gonopodial thrusts not precededby sigmoid displays). This shift is presumed to benefit thebrightly colored male, whose intense courting activity mightotherwise increase his risk of detection and attack by predators.However, there is some evidence that females engaged in reproductiveactivity with males may be even more vulnerable to predatorsthan the males themselves, which suggests an alternative hypothesis:females in high-risk situations are less receptive to male courtship,and this leads males to change their behavior. We tested thishypothesis by providing either males and females separately,or both sexes concurrently, with information about elevatedpredation risk from a cichlid (Crenicichla sp.). We found thatwhen only females were provided with information about increased risk,males performed fewer courtship displays and fewer thrusts.They did not perform more forced copulations in any treatmentgroup. Nonetheless, our results suggest that the female's perceptionof predation risk can be at least as important as the male'sin changing male mating behavior.