Exploring the rate-limiting steps in visual phototransduction recovery by bottom-up kinetic modeling

Phototransduction in vertebrate photoreceptor cells represents a paradigm of signaling pathways mediated by G-protein-coupled receptors (GPCRs), which share common modules linking the initiation of the cascade to the final response of the cell. In this work, we focused on the recovery phase of the visual photoresponse, which is comprised of several interacting mechanisms. We employed current biochemical knowledge to investigate the response mechanisms of a comprehensive model of the visual phototransduction pathway. In particular, we have improved the model by implementing a more detailed representation of the recoverin (Rec)-mediated calcium feedback on rhodopsin kinase and including a dynamic arrestin (Arr) oligomerization mechanism. The model was successfully employed to investigate the rate limiting steps in the recovery of the rod photoreceptor cell after illumination. Simulation of experimental conditions in which the expression levels of rhodospin kinase (RK), of the regulator of the G-protein signaling (RGS), of Arr and of Rec were altered individually or in combination revealed severe kinetic constraints to the dynamics of the overall network. Our simulations confirm that RGS-mediated effector shutdown is the rate-limiting step in the recovery of the photoreceptor and show that the dynamic formation and dissociation of Arr homodimers and homotetramers at different light intensities significantly affect the timing of rhodopsin shutdown. The transition of Arr from its oligomeric storage forms to its monomeric form serves to temper its availability in the functional state. Our results may explain the puzzling evidence that overexpressing RK does not influence the saturation time of rod cells at bright light stimuli. The approach presented here could be extended to the study of other GPCR signaling pathways.

Exchange rate predictability

The main goal of this article is to provide an answer to the question: "Does anything forecast exchange rates, and if so, which variables?". It is well known thatexchange rate fluctuations are very difficult to predict using economic models, andthat a random walk forecasts exchange rates better than any economic model (theMeese and Rogoff puzzle). However, the recent literature has identified a series of fundamentals/methodologies that claim to have resolved the puzzle. This article providesa critical review of the recent literature on exchange rate forecasting and illustratesthe new methodologies and fundamentals that have been recently proposed in an up-to-date, thorough empirical analysis. Overall, our analysis of the literature and thedata suggests that the answer to the question: "Are exchange rates predictable?" is,"It depends" -on the choice of predictor, forecast horizon, sample period, model, andforecast evaluation method. Predictability is most apparent when one or more of thefollowing hold: the predictors are Taylor rule or net foreign assets, the model is linear, and a small number of parameters are estimated. The toughest benchmark is therandom walk without drift.

Understanding the gains from wage flexibility: The exchange rate connection

We study the gains from increased wage flexibility and their dependence on exchange rate policy, using a small open economy model with staggered price andwage setting. Two results stand out: (i) the impact of wage adjustments on employment is smaller the more the central bank seeks to stabilize the exchange rate,and (ii) an increase in wage flexibility often reduces welfare, and more likely so ineconomies under an exchange rate peg or an exchange rate-focused monetary policy.Our findings call into question the common view that wage flexibility is particularlydesirable in a currency union.

Estimation of a maximum Lu diffusion rate in a natural eclogite garnet

Lutetium zoning in garnet within eclogites from the Zermatt-Saas Fee zone, Western Alps, reveal sharp, exponentially decreasing central peaks. They can be used to constrain maximum Lu volume diffusion in garnets. A prograde garnet growth temperature interval of 450-600 A degrees C has been estimated based on pseudosection calculations and garnet-clinopyroxene thermometry. The maximum pre-exponential diffusion coefficient which fits the measured central peak is in the order of D-0= 5.7*10(-6) m(2)/s, taking an estimated activation energy of 270 kJ/mol based on diffusion experiments for other rare earth elements in garnet. This corresponds to a maximum diffusion rate of D (600 A degrees C) = 4.0*10(-22) m(2)/s. The diffusion estimate of Lu can be used to estimate the minimum closure temperature, T-c, for Sm-Nd and Lu-Hf age data that have been obtained in eclogites of the Western Alps, postulating, based on a literature review, that D (Hf) < D (Nd) < D (Sm) a parts per thousand currency sign D (Lu). T-c calculations, using the Dodson equation, yielded minimum closure temperatures of about 630 A degrees C, assuming a rapid initial exhumation rate of 50A degrees/m.y., and an average crystal size of garnets (r = 1 mm). This suggests that Sm/Nd and Lu/Hf isochron age differences in eclogites from the Western Alps, where peak temperatures did rarely exceed 600 A degrees C must be interpreted in terms of prograde metamorphism.

A Generalized Model Study of Scour Around Bridge Piers and Abutments, HR-24, 1953

Four classes of variables are apparent in the problem of scour around bridge piers and abutments--geometry of piers and abutments, stream-flow characteristics, sediment characteristics, and geometry of site. The laboratory investigation, from its inception, has been divided into four phases based on these classes. In each phase the variables in three of the classes are held constant and those in the pertinent class are varied. To date, the first three phases have been studied. Typical scour bole patterns related to the geometry of the pier or abutment have been found. For equilibrium conditions of scour with uniform sand, the velocity of flow and the sand size do not appear to have any measurable effects on the depth of scour. This result is especially encouraging in the search for correlation between model and prototype since it would indicate that, primarily, only the depth of flow might be involved in the scale effect. The technique of model testing has been simplified, therefore, because rate of sediment transportation does not need to be scaled. Prior to the establishment of equilibrium conditions, however, depths of scour in excess of those for equilibrium conditions have been found. A concept of active scour as an imbalance between sediment transport capacity and rate of sediment supply has been used to explain the laboratory observations.

Scale Effects in Hydraulic Model Tests of Rock Protected Structures, HR-119, 1970

A laboratory investigation was undertaken to determine the limiting model Reynolds number above which the scour behavior of rock protected structures can be reproduced in hydraulic models scaled according to the Froude criterion. A submerged jet was passed over an initially full scour pocket containing uniform glass spheres and the rate of scour was measured as a function of time. The dimensions of the scour pocket and jet and the particle diameters were varied as needed to maintain strict geometric similarity. For each of two different Froude numbers the Reynolds number was varied over a wide range. The normalized scour rate was found to be practically independent of the Reynolds number, R, (based on the jet velocity and particle diameter) at values of R above about 2.5 x 10^3, and to decrease with Rat smaller values. A grid placed in the jet was found to have a very strong effect on the scour rate. In an attempt to explain the effect of R on the scour behavior, turbulent pressure and velocity fluctuations were measured in air flows and water flows, respectively, over rigid scour pockets having the same geometry as those formed in the scour experiments. The normalized spectra of the fluctuations were found to be nearly independent of R, but the flow pattern was found to be very sensitive to the inlet condition, the jet deflecting upward or downward in a not wholly explainable manner. This indicates that scour behavior can be modeled only if the approach flow is also accurately modeled.

Statistical properties of population differentiation estimators under stepwise mutation in a finite island model.

Microsatellite loci mutate at an extremely high rate and are generally thought to evolve through a stepwise mutation model. Several differentiation statistics taking into account the particular mutation scheme of the microsatellite have been proposed. The most commonly used is R(ST) which is independent of the mutation rate under a generalized stepwise mutation model. F(ST) and R(ST) are commonly reported in the literature, but often differ widely. Here we compare their statistical performances using individual-based simulations of a finite island model. The simulations were run under different levels of gene flow, mutation rates, population number and sizes. In addition to the per locus statistical properties, we compare two ways of combining R(ST) over loci. Our simulations show that even under a strict stepwise mutation model, no statistic is best overall. All estimators suffer to different extents from large bias and variance. While R(ST) better reflects population differentiation in populations characterized by very low gene-exchange, F(ST) gives better estimates in cases of high levels of gene flow. The number of loci sampled (12, 24, or 96) has only a minor effect on the relative performance of the estimators under study. For all estimators there is a striking effect of the number of samples, with the differentiation estimates showing very odd distributions for two samples.

Specific inhibition of HCN channels slows rhythm differently in atria, ventricle and outflow tract and stabilizes conduction in the anoxic-reoxygenated embryonic heart model.

The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are expressed in pacemaker cells very early during cardiogenesis. This work aimed at determining to what extent these channels are implicated in the electromechanical disturbances induced by a transient oxygen lack which may occur in utero. Spontaneously beating hearts or isolated ventricles and outflow tracts dissected from 4-day-old chick embryos were exposed to a selective inhibitor of HCN channels (ivabradine 0.1-10microM) to establish a dose-response relationship. The effects of ivabradine on electrocardiogram, excitation-contraction coupling and contractility of hearts submitted to anoxia (30min) and reoxygenation (60min) were also determined. The distribution of the predominant channel isoform, HCN4, was established in atria, ventricle and outflow tract by immunoblotting. Intrinsic beating rate of atria, ventricle and outflow tract was 164+/-22 (n=10), 78+/-24 (n=8) and 40+/-12bpm (n=23, mean+/-SD), respectively. In the whole heart, ivabradine (0.3microM) slowed the firing rate of atria by 16% and stabilized PR interval. These effects persisted throughout anoxia-reoxygenation, whereas the variations of QT duration, excitation-contraction coupling and contractility, as well as the types and duration of arrhythmias were not altered. Ivabradine (10microM) reduced the intrinsic rate of atria and isolated ventricle by 27% and 52%, respectively, whereas it abolished activity of the isolated outflow tract. Protein expression of HCN4 channels was higher in atria and ventricle than in the outflow tract. Thus, HCN channels are specifically distributed and control finely atrial, ventricular and outflow tract pacemakers as well as conduction in the embryonic heart under normoxia and throughout anoxia-reoxygenation.

Development of a Subgrade Drainage Model for Unpaved Roads, TR-654, 2015

With over 68 thousand miles of gravel roads in Iowa and the importance of these roads within the farm-to-market transportation system, proper water management becomes critical for maintaining the integrity of the roadway materials. However, the build-up of water within the aggregate subbase can lead to frost boils and ultimately potholes forming at the road surface. The aggregate subbase and subgrade soils under these gravel roads are produced with material opportunistically chosen from local sources near the site and, many times, the compositions of these sublayers are far from ideal in terms of proper water drainage with the full effects of this shortcut not being fully understood. The primary objective of this project was to provide a physically-based model for evaluating the drainability of potential subbase and subgrade materials for gravel roads in Iowa. The Richards equation provided the appropriate framework to study the transient unsaturated flow that usually occurs through the subbase and subgrade of a gravel road. From which, we identified that the saturated hydraulic conductivity, Ks, was a key parameter driving the time to drain of subgrade soils found in Iowa, thus being a good proxy variable for accessing roadway drainability. Using Ks, derived from soil texture, we were able to identify potential problem areas in terms of roadway drainage . It was found that there is a threshold for Ks of 15 cm/day that determines if the roadway will drain efficiently, based on the requirement that the time to drain, Td, the surface roadway layer does not exceed a 2-hr limit. Two of the three highest abundant textures (loam and silty clay loam), which cover nearly 60% of the state of Iowa, were found to have average Td values greater than the 2-hr limit. With such a large percentage of the state at risk for the formation of boils due to the soil with relatively low saturated hydraulic conductivity values, it seems pertinent that we propose alternative design and/or maintenance practices to limit the expensive repair work in Iowa. The addition of drain tiles or French mattresses my help address drainage problems. However, before pursuing this recommendation, a comprehensive cost-benefit analysis is needed.

Characterization of cerebral glucose dynamics in vivo with a four-state conformational model of transport at the blood-brain barrier.

Determination of brain glucose transport kinetics in vivo at steady-state typically does not allow distinguishing apparent maximum transport rate (T(max)) from cerebral consumption rate. Using a four-state conformational model of glucose transport, we show that simultaneous dynamic measurement of brain and plasma glucose concentrations provide enough information for independent and reliable determination of the two rates. In addition, although dynamic glucose homeostasis can be described with a reversible Michaelis-Menten model, which is implicit to the large iso-inhibition constant (K(ii)) relative to physiological brain glucose content, we found that the apparent affinity constant (K(t)) was better determined with the four-state conformational model of glucose transport than with any of the other models tested. Furthermore, we confirmed the utility of the present method to determine glucose transport and consumption by analysing the modulation of both glucose transport and consumption by anaesthesia conditions that modify cerebral activity. In particular, deep thiopental anaesthesia caused a significant reduction of both T(max) and cerebral metabolic rate for glucose consumption. In conclusion, dynamic measurement of brain glucose in vivo in function of plasma glucose allows robust determination of both glucose uptake and consumption kinetics.

A biophysical model of atrial fibrillation ablation: what can a surgeon learn from a computer model?

AIMS: Surgical ablation procedures for treating atrial fibrillation have been shown to be highly successful. However, the ideal ablation pattern still remains to be determined. This article reports on a systematic study of the effectiveness of the performance of different ablation line patterns. METHODS AND RESULTS: This study of ablation line patterns was performed in a biophysical model of human atria by combining basic lines: (i) in the right atrium: isthmus line, line between vena cavae and appendage line and (ii) in the left atrium: several versions of pulmonary vein isolation, connection of pulmonary veins, isthmus line, and appendage line. Success rates and the presence of residual atrial flutter were documented. Basic patterns yielded conversion rates of only 10-25 and 10-55% in the right and the left atria, respectively. The best result for pulmonary vein isolation was obtained when a single closed line encompassed all veins (55%). Combination of lines in the right/left atrium only led to a success rate of 65/80%. Higher rates, up to 90-100%, could be obtained if right and left lines were combined. The inclusion of a left isthmus line was found to be essential for avoiding uncommon left atrial flutter. CONCLUSION: Some patterns studied achieved a high conversion rate, although using a smaller number of lines than those of the Maze III procedure. The biophysical atrial model is shown to be effective in the search for promising alternative ablation strategies.

Weber's law in decision making: integrating behavioral data in humans with a neurophysiological model

Recent single-cell studies in monkeys (Romo et al., 2004) show that the activity of neurons in the ventral premotor cortex covaries with the animal's decisions in a perceptual comparison task regarding the frequency of vibrotactile events. The firing rate response of these neurons was dependent only on the frequency differences between the two applied vibrations, the sign of that difference being the determining factor for correct task performance. We present a biophysically realistic neurodynamical model that can account for the most relevant characteristics of this decision-making-related neural activity. One of the nontrivial predictions of this model is that Weber's law will underlie the perceptual discrimination behavior. We confirmed this prediction in behavioral tests of vibrotactile discrimination in humans and propose a computational explanation of perceptual discrimination that accounts naturally for the emergence of Weber's law. We conclude that the neurodynamical mechanisms and computational principles underlying the decision-making processes in this perceptual discrimination task are consistent with a fluctuation-driven scenario in a multistable regime.

Factors associated with 56-day non-return rate in dairy cattle

The objective of this work was to identify factors associated with the 56-day non-return rate (56-NRR) in dairy herds in the Galician region, Spain, and to estimate it for individual Holstein bulls. The experiment was carried out in herds originated from North-West Spain, from September 2008 to August 2009. Data of the 76,440 first inseminations performed during this period were gathered. Candidate factors were tested for their association with the 56-NRR by using a logistic model (binomial). Afterwards, 37 sires with a minimum of 150 first performed inseminations were individually evaluated. Logistic models were also estimated for each bull, and predicted individual 56-NRR rate values were calculated as a solution for the model parameters. Logistic regression found four major factors associated with 56-NRR in lactating cows: age at insemination, days from calving to insemination, milk production level at the time of insemination, and herd size. First-service conception rate, when a particular sire was used, was higher for heifers (0.71) than for lactating cows (0.52). Non-return rates were highly variable among bulls. Asignificant part of the herd-level variation of 56-NRR of Holstein cattle seems attributable to the service sire. High correlation level between observed and predicted 56-NRR was found.

Outcrossing rate between 'Haden' and 'Tommy Atkins' mangoes estimated using microsatellite and AFLP markers

The objective of this work was to estimate outcrossing rates between Haden and Tommy Atkins mango cultivars, using AFLP and microsatellite markers. Progenies of an isolated 'Haden' plant, identified in a 'Tommy Atkins' commercial orchard, in Petrolina, PE, Brazil, were analyzed. Total DNA was isolated from the progeny leaves and used for AFLP and microsatellite reactions. Multilocus outcrossing rates (t m) were estimated by direct count of AFLP or microsatellite markers and by the mLTR software. Outcrossing rates ranged from 0.85 to 0.87 with the analysis based on seven AFLP markers, and from 0.83 to 0.91 based on three microsatellite primers. No unexpected band patterns were observed for 'Haden' and 'Tommy Atkins'. The estimates obtained with the mLTR software were close to those obtained by direct AFLP and microsatellite allele counting, which indicates that the multilocus model was appropriate for this kind of study. The microsatellites mMiCIR005, mMiCIR030, and mMiCIR036 can be used to elucidate the origin of 'Haden' and 'Tommy Atkins' seedlings.

Bactericidal synergism between daptomycin and the phage lysin Cpl-1 in a mouse model of pneumococcal bacteraemia.

Combination therapy may improve the outcome of Streptococcus pneumoniae-induced bacteraemia. Here we tested the combination of two antipneumococcal agents, daptomycin and Cpl-1 (the pneumococcal Cp-1 bacteriophage lysin), in a mouse model of pneumococcal bacteraemia. Mice were challenged intraperitoneally (i.p.) with 10(6)CFU of the extremely virulent serotype 2 S. pneumoniae D39 isolate. Subtherapeutic doses of daptomycin (0.4mg/kg) and Cpl-1 (0.4mg/kg and 1mg/kg) were administrated i.p. either alone or in combination by a single bolus injection 1h after bacterial challenge. Survival rates of animals were followed over a period of 7 days. Daptomycin (0.4mg/kg) in combination with Cpl-1 (0.4mg/kg) significantly increased the percentage of surviving mice at Day 7 (80%) compared with the untreated control (0%) and daptomycin or Cpl-1 monotherapy (35% and 0%, respectively). Whilst increasing the concentration of Cpl-1 to 1.0mg/kg did not improve survival when injected alone, its combination with 0.4mg/kg daptomycin further increased the survival rate to 95%. Thus, it was found that the combination of daptomycin with Cpl-1 was synergistic and bactericidal against S. pneumoniae in a mouse model of pneumococcal bacteraemia. To our knowledge, this is the first report of synergism between daptomycin and a phage lysin demonstrated in vivo. Such a combination could represent an interesting alternative therapy for the treatment of pneumococcal bacteraemia/sepsis and possibly other severe pneumococcal infections.