Both Ligand- and Cell-Specific Parameters Control Ligand Agonism in a Kinetic Model of G Protein–Coupled Receptor Signaling

G protein–coupled receptors (GPCRs) exist in multiple dynamic states (e.g., ligand-bound, inactive, G protein–coupled) that influence G protein activation and ultimately response generation. In quantitative models of GPCR signaling that incorporate these varied states, parameter values are often uncharacterized or varied over large ranges, making identification of important parameters and signaling outcomes difficult to intuit. Here we identify the ligand- and cell-specific parameters that are important determinants of cell-response behavior in a dynamic model of GPCR signaling using parameter variation and sensitivity analysis. The character of response (i.e., positive/neutral/inverse agonism) is, not surprisingly, significantly influenced by a ligand's ability to bias the receptor into an active conformation. We also find that several cell-specific parameters, including the ratio of active to inactive receptor species, the rate constant for G protein activation, and expression levels of receptors and G proteins also dramatically influence agonism. Expressing either receptor or G protein in numbers several fold above or below endogenous levels may result in system behavior inconsistent with that measured in endogenous systems. Finally, small variations in cell-specific parameters identified by sensitivity analysis as significant determinants of response behavior are found to change ligand-induced responses from positive to negative, a phenomenon termed protean agonism. Our findings offer an explanation for protean agonism reported in β2-adrenergic and α2A-adrenergic receptor systems

Inverse targeting -- an effective immunization strategy

We propose a new method to immunize populations or computer networks against epidemics which is more efficient than any method considered before. The novelty of our method resides in the way of determining the immunization targets. First we identify those individuals or computers that contribute the least to the disease spreading measured through their contribution to the size of the largest connected cluster in the social or a computer network. The immunization process follows the list of identified individuals or computers in inverse order, immunizing first those which are most relevant for the epidemic spreading. We have applied our immunization strategy to several model networks and two real networks, the Internet and the collaboration network of high energy physicists. We find that our new immunization strategy is in the case of model networks up to 14%, and for real networks up to 33% more efficient than immunizing dynamically the most connected nodes in a network. Our strategy is also numerically efficient and can therefore be applied to large systems

Microwave conductivity of d-wave superconductors with extended impurities

We investigate the influence of extended scatterers on the finite temperature and finite frequency microwave conductivity of d-wave superconductors. For this purpose we generalize a previous treatment by Durst and Lee, which is based on a nodal approximation of the quasiparticle excitations and scattering processes, and apply it to the analysis of experimental spectra of YBCO-123 and BSCCO-2212. For YBCO, we find that accounting for a slight spatial extension of the strong scattering in-plane defects improves the fit of the low temperature microwave conductivity to experiment. With respect to BSCCO we conclude that it is necessary to include a large concentration of weak-to-intermediate strength extended scatterers, which we attribute to the out-of plane disorder introduced by doping. These findings for BSCCO are consistent with similar analyses of the normal state ARPES spectra and of STM spectra in the superconducting state, where an enhanced forward scattering has been inferred as well.Comment: 10 pages, 11 figure

Bone: An Acute Buffer of Plasma Sodium during Exhaustive Exercise?

Both hyponatremia and osteopenia separately have been well documented in endurance athletes. Although bone has been shown to act as a “sodium reservoir” to buffer severe plasma sodium derangements in animals, recent data have suggested a similar function in humans. We aimed to explore if acute changes in bone mineral content were associated with changes in plasma sodium concentration in runners participating in a 161 km mountain footrace. Eighteen runners were recruited. Runners were tested immediately pre- and post-race for the following main outcome measures: bone mineral content (BMC) and density (BMD) via dual-energy X-ray absorptiometry (DEXA); plasma sodium concentration ([Na+]p), plasma arginine vasopressin ([AVP]p), serum aldosterone concentration ([aldosterone]s), and total sodium intake. Six subjects finished the race in a mean time of 27.0±2.3 h. All subjects started and finished the race with [Na+]p within the normal range (137.7±2.3 and 136.7±1.6 mEq/l, pre- and post-race, respectively). Positive correlations were noted between change (Δ; post-race minus pre-race) in total BMC (grams) and [Na+]p (mEq/l) (r=0.99;

Association of Gastrointestinal Distress in Ultramarathoners with Race Diet

Context: Gastrointestinal (GI) distress is common during ultrarunning. Purpose: To determine if race diet is related to GI distress in a 161-km ultramarathon. Methods: Fifteen (10 male, 5 female) consenting runners in the Javelina Jundred (6.5 loops on a desert trail) participated. Body mass was measured immediately pre-race and after each loop. Runners reported if they had nausea, vomiting, abdominal cramps, and/or diarrhea after each loop. Subjects were interviewed after each loop to record food, fluid, and electrolyte consumption. Race diets were analyzed using Nutritionist Pro. Results: Nine (8 male, 1 female) of 15 runners experienced GI distress including nausea (89%), abdominal cramps (44%), diarrhea (44%), and vomiting (22%). Fluid consumption rate was higher (p = .001) in runners without GI distress (10.9 ± 3.2 ml · kg–1 · hr–1) than in those with GI distress (5.9 ± 1.6 ml · kg–1 · hr–1). Runners without GI distress consumed a higher percentage fat (p = .03) than runners with GI distress (16.5 ± 2.6 vs. 11.1 ± 5.0). In addition, fat intake rate was higher (p = .01) in runners without GI distress (0.06 ± 0.03 g · kg–1 · hr–1) than in runners with GI distress (0.03 ± 0.01 g · kg–1 · hr–1). Lower fluid and fat intake rates were evident in those developing GI distress before the onset of symptoms. Conclusions: A race diet with higher percentage fat and higher intake rates of fat and fluid may protect ultramarathoners from GI distress. However, these associations do not indicate cause and effect, and factors other than race diet may have contributed to GI distress

Experimental evaluation of heat transfer on a 1030:1 area ratio rocket nozzle

A 1030:1 carbon steel, heat-sink nozzle was tested. The test conditions included a nominal chamber pressure of 2413 kN/sq m and a mixture ratio range of 2.78 to 5.49. The propellants were gaseous oxygen and gaseous hydrogen. Outer wall temperature measurements were used to calculate the inner wall temperature and the heat flux and heat rate to the nozzle at specified axial locations. The experimental heat fluxes were compared to those predicted by the Two-Dimensional Kinetics (TDK) computer model analysis program. When laminar boundary layer flow was assumed in the analysis, the predicted values were within 15% of the experimental values for the area ratios of 20 to 975. However, when turbulent boundary layer conditions were assumed, the predicted values were approximately 120% higher than the experimental values. A study was performed to determine if the conditions within the nozzle could sustain a laminar boundary layer. Using the flow properties predicted by TDK, the momentum-thickness Reynolds number was calculated, and the point of transition to turbulent flow was predicted. The predicted transition point was within 0.5 inches of the nozzle throat. Calculations of the acceleration parameter were then made to determine if the flow conditions could produce relaminarization of the boundary layer. It was determined that if the boundary layer flow was inclined to transition to turbulent, the acceleration conditions within the nozzle would tend to suppress turbulence and keep the flow laminar-like

Comparison of theoretical and experimental thrust performance of a 1030:1 area ratio rocket nozzle at a chamber pressure of 2413 kN/m2 (350 psia)

The joint Army. Navy, NASA. Air Force (JANNAF) rocket engine peformnace prediction procedure is based on the use of various reference computer programs. One of the reference programs for nozzle analysis is the Two-Dimensional Kinetics (TDK) Program. The purpose of this report is to calibrate the JANNAF procedure incorporated into the December l984 version of the TDK program for the high-area-ratio rocket engine regime. The calibration was accomplished by modeling the performance of a 1030:1 rocket nozzle tested at NASA Lewis Research Center. A detailed description of the experimental test conditions and TDK input parameters is given. The results show that the computer code predicts delivered vacuum specific impulse to within 0.12 to 1.9 percent of the experimental data. Vacuum thrust coefficient predictions were within + or - 1.3 percent of experimental results. Predictions of wall static pressure were within approximately + or - 5 percent of the measured values. An experimental value for inviscid thrust was obtained for the nozzle extension between area ratios of 427.5 and 1030 by using an integration of the measured wall static pressures. Subtracting the measured thrust gain produced by the nozzle between area ratios of 427.5 and 1030 from the inviscid thrust gain yielded experimental drag decrements of 10.85 and 27.00 N (2.44 and 6.07 lb) for mixture ratios of 3.04 and 4.29, respectively. These values correspond to 0.45 and 1.11 percent of the total vacuum thrust. At a mixture ratio of 4.29, the TDK predicted drag decrement was 16.59 N (3.73 lb), or 0.71 percent of the predicted total vacuum thrust

Dopant-modulated pair interaction in cuprate superconductors

Comparison of recent experimental STM data with single-impurity and many-impurity Bogoliubov-de Gennes calculations strongly suggests that random out-of-plane dopant atoms in cuprates modulate the pair interaction locally. This type of disorder is crucial to understanding the nanoscale electronic structure inhomogeneity observed in BSCCO-2212, and can reproduce observed correlations between the positions of impurity atoms and various aspects of the local density of states such as the gap magnitude and the height of the coherence peaks. Our results imply that each dopant atom modulates the pair interaction on a length scale of order one lattice constant.Comment: 5 pages, 4 figure