Competition between beta-subunits of cardiac L-type calcium channels

Cardiac L-type Ca (CaV1.2) channels are composed of a pore forming CaV1.2-α1 subunit and auxiliary β- and α2δ-subunits. β-subunits are important not only for surface expression of the channel pore but also for modulation of channel gating properties. Different β-subunits differentially modulate channel activity (Hullin et al., PLOSone, 2007) and thus L-type Ca2+ channel gating is altered when β-subunit expression pattern is changed. In human heart failure increased activity of single ventricular L-type Ca2+-channels is associated with an increased expression of β2-subunits. Interestingly, induction of β2-subunit over-expression in hearts of transgenic mice resembled this heart failure phenotype of hyperactive single L-type Ca2+-channel channels (Beetz et al., Cardiovasc Res. 2009). We hypothesised that competition of less stimulating β-subunits (e.g. β1) with β-subunits causing strong channel stimulation (e.g. β2) might be a means to treat dysfunctional L-type Ca2+-channel activity. To test this hypothesis, we performed whole-cell and single-channel measurements employing recombinant CaV1.2 channels expressed in HEK293 cells together with both β- and β1a2b-subunits. Whole-cell analysis revealed no differences of maximum L-type Ca2+-current densities [pA/pF] with coexpression of either β1a-subunits (-52±3.8), β2b-subunits (-61.5±6.6) or the mixtures of β- and β1a2b-subunits with the plasmid transfection ratio of 2:1 (-60.2±1.6) and 1:1 (-56.7±2.6) respectively. However, steady state inactivation kinetics differed between particular β-subunit and the relative amount of β-subunit presence in the mixtures (β1a1a-subunit (-41.1±1.0), β2b-subunits (-35.1±1.1), mixture 2:1 (-40.3±1.5), and mixture 1:1 (-38.4±2.0); [mV]; p<0.05, students t-test). Using a novel single-channel analysis, switching of gating between β1-like and β2-like modes was monitored on a minute time-scale when both β-subunits were co-expressed in the same cells, but the larger amount of β1a-subunits is required for the effective switching of gating. Our results indicate a model of mutually exclusive binding and effective competition between several β-subunits suggesting that hyperactive channel gating mediated e.g. by β2-subunits can be normalized by β1-subunits. Therefore, competitive replacement between different L-type Ca2+-channel β-subunits might serve as a novel therapeutic strategy for e.g. heart failure.

Defect dynamics in viscous fingering

We study the dynamics of Staffman-Taylor fingering in terms of topological defects of the flow field. The defects are created and/or annihilated at the interface. The route towards the single-finger steady state is characterized by a detailed mechanism for defect annihilation. For small viscosity contrast this mechanism is impeded, and creation of new defects leads the system away from a single-finger solution. Strong evidence for a drastic reduction of the basin of attraction of the Saffman-Taylor finger is presented.

Effects of small surface tension in Hele-Shaw multifinger dynamics: an analytical and numerical study

We study the singular effects of vanishingly small surface tension on the dynamics of finger competition in the Saffman-Taylor problem, using the asymptotic techniques described by Tanveer [Philos. Trans. R. Soc. London, Ser. A 343, 155 (1993)] and Siegel and Tanveer [Phys. Rev. Lett. 76, 419 (1996)], as well as direct numerical computation, following the numerical scheme of Hou, Lowengrub, and Shelley [J. Comput. Phys. 114, 312 (1994)]. We demonstrate the dramatic effects of small surface tension on the late time evolution of two-finger configurations with respect to exact (nonsingular) zero-surface-tension solutions. The effect is present even when the relevant zero-surface-tension solution has asymptotic behavior consistent with selection theory. Such singular effects, therefore, cannot be traced back to steady state selection theory, and imply a drastic global change in the structure of phase-space flow. They can be interpreted in the framework of a recently introduced dynamical solvability scenario according to which surface tension unfolds the structurally unstable flow, restoring the hyperbolicity of multifinger fixed points.

Phase-field model of Hele-Shaw flows in the high-viscosity contrast regime

A one-sided phase-field model is proposed to study the dynamics of unstable interfaces of Hele-Shaw flows in the high viscosity contrast regime. The corresponding macroscopic equations are obtained by means of an asymptotic expansion from the phase-field model. Numerical integrations of the phase-field model in a rectangular Hele-Shaw cell reproduce finger competition with the final evolution to a steady-state finger.

Front propagation in spatially modulated media

A two-dimensional reaction-diffusion front which propagates in a modulated medium is studied. The modulation consists of a spatial variation of the local front velocity in the transverse direction to that of the front propagation. We study analytically and numerically the final steady-state velocity and shape of the front, resulting from a nontrivial interplay between the local curvature effects and the global competition process between different maxima of the control parameter. The transient dynamics of the process is also studied numerically and analytically by means of singular perturbation techniques.

Wave competition in excitable modulated media.

The propagation of an initially planar front is studied within the framework of the photosensitive Belousov-Zhabotinsky reaction modulated by a smooth spatial variation of the local front velocity in the direction perpendicular to front propagation. Under this modulation, the wave front develops several fingers corresponding to the local maxima of the modulation function. After a transient, the wave front achieves a stationary shape that does not necessarily coincide with the one externally imposed by the modulation. Theoretical predictions for the selection criteria of fingers and steady-state velocity are experimentally validated.

Experiments of periodic forcing of Saffman-Taylor fingers

We report on an experimental study of long normal Saffman-Taylor fingers subject to periodic forcing. The sides of the finger develop a low amplitude, long wavelength instability. We discuss the finger response in stationary and nonstationary situations, as well as the dynamics towards the stationary states. The response frequency of the instability increases with forcing frequency at low forcing frequencies, while, remarkably, it becomes independent of forcing frequency at large forcing frequencies. This implies a process of wavelength selection. These observations are in good agreement with previous numerical results reported in [Ledesma-Aguilar et al., Phys. Rev. E 71, 016312 (2005)]. We also study the average value of the finger width, and its fluctuations, as a function of forcing frequency. The average finger width is always smaller than the width of the steady-state finger. Fluctuations have a nonmonotonic behavior with a maximum at a particular frequency.

Brownian pump powered by a white-noise flasing ratchet

A Brownian pump of particles powered by a stochastic flashing ratchet mechanism is studied. The pumping device is embedded in a finite region and bounded by particle reservoirs. In the steady state, we exactly calculate the spatial density profile, the concentration ratio between both reservoirs and the particle flux. We propose a simulation framework for the consistent evaluation of such observable quantities.

Colored noise in spatially extended systems

We study the effects of time and space correlations of an external additive colored noise on the steady-state behavior of a time-dependent Ginzburg-Landau model. Simulations show the existence of nonequilibrium phase transitions controlled by both the correlation time and length of the noise. A Fokker-Planck equation and the steady probability density of the process are obtained by means of a theoretical approximation.

Phosphorus transformation in poultry litter and litter-treated Oxisol of Brazil assessed by 31P-NMR and wet chemical fractionation

Large quantities of poultry litter are being produced in Brazil, which contain appreciable amounts of phosphorus (P) that could be of environmental concern. To assess the immediate environmental threat, five poultry litters composed of diverse bedding material were incubated for 43 days under greenhouse conditions. The litters consisted of: coffee bean husk (CH); wood chips (WC); rice husk (RH); ground corn cobs (CC) and ground napier grass (NG) (Pennisetum purpureum Schum.), in which the change in forms of soluble P was evaluated using 31P NMR spectroscopy. On average, 80.2 and 19.8 % of the total P in the extract, respectively, accounted for the inorganic and organic forms before incubation and 48 % of the organic P was mineralized to inorganic P in 43 days of incubation. Wide variation in the organic P mineralization rate (from 82 % -WC to 4 % - NG) was observed among litters. Inorganic orthophosphate (99.9 %) and pyrophosphate (0.1 %) were the only inorganic P forms, whereas the organic P forms orthophosphate monoesters (76.3 %) and diester (23.7 %) were detected. Diester P compounds were mineralized almost completely in all litters, except in the CH litter, within the incubation period. Pyrophosphates contributed with less than 0.5% and remained unaltered during the incubation period. Wood-chip litter had a higher organic P (40 %) content and a higher diester: monoester ratio; it was therefore mineralized rapidly, within the first 15 days, achieving steady state by the 29th day. Distinct mineralization patterns were observed in the litter when incubated with a clayey Oxisol. The substantial decrease observed in the organic P fraction (Po) of the litter types followed the order: CH (45 %) > CC (25 %) > RH (13 %) ≈ NG (12 %) > WC (5 %), whereas the Pi fraction increased. Incubation of RH litter in soil slowed down the mineralization of organic P.

Effets extra-rénaux du facteur natriurétique auriculaire [Extrarenal effects of the atrial natriuretic factor]

The synthesis of peptides which have the natriuretic and vasodilator properties of the atrial natriuretic factor has made it possible to study the physiological role of this recently discovered hormonal system. In addition to renal effects, atrial natriuretic peptides exert vascular, hemodynamic and endocrine actions which may participate in the regulation of plasma and interstitial volume as well as arterial blood pressure. Its acute hypotensive effect, which was observed in normal volunteers and in patients with cardiac failure or hypertension, is not entirely explained by its direct vasodilator effect. The complexity of its role is demonstrated by its inhibiting action on the synthesis and/or the activity of other vasoactive hormones. The observed increase in hematocrit suggests that vascular permeability may be enhanced; the resulting consequences, e.g. on blood viscosity, still need to be elucidated. When infusing atrial natriuretic peptides, there exists a clear delay between the moment steady-state plasma levels are achieved and peak effect occurs. This renders the interpretation of the results very difficult. At this moment, the physiological role of atrial natriuretic peptides as well as their potential future use as therapeutic agents cannot yet be fully appreciated.

A classical particle in heat bath under the influence of external noise

A very simple model of a classical particle in a heat bath under the influence of external noise is studied. By means of a suitable hypothesis, the heat bath is reduced to an internal colored noise (OrnsteinUhlenbeck noise). In a second step, an external noise is coupled to the bath. The steady state probability distributions are obtained.

Mismatch of arterial and central venous blood gas analysis during haemorrhage.

BACKGROUND AND OBJECTIVE: Arterial base excess and lactate levels are key parameters in the assessment of critically ill patients. The use of venous blood gas analysis may be of clinical interest when no arterial blood is available initially. METHODS: Twenty-four pigs underwent progressive normovolaemic haemodilution and subsequent progressive haemorrhage until the death of the animal. Base excess and lactate levels were determined from arterial and central venous blood after each step. In addition, base excess was calculated by the Van Slyke equation modified by Zander (BE(z)). Continuous variables were summarized as mean +/- SD and represent all measurements (n = 195). RESULTS: Base excess according to National Committee for Clinical Laboratory Standards for arterial blood was 2.27 +/- 4.12 versus 2.48 +/- 4.33 mmol(-l) for central venous blood (P = 0.099) with a strong correlation (r(2) = 0.960, P < 0.001). Standard deviation of the differences between these parameters (SD-DIFBE) did not increase (P = 0.355) during haemorrhage as compared with haemodilution. Arterial lactate was 2.66 +/- 3.23 versus 2.71 +/- 2.80 mmol(-l) in central venous blood (P = 0.330) with a strong correlation (r(2) = 0.983, P < 0.001). SD-DIFLAC increased (P < 0.001) during haemorrhage. BE(z) for central venous blood was 2.22 +/- 4.62 mmol(-l) (P = 0.006 versus arterial base excess according to National Committee for Clinical Laboratory Standards) with strong correlation (r(2) = 0.942, P < 0.001). SD-DIFBE(z)/base excess increased (P < 0.024) during haemorrhage. CONCLUSION: Central venous blood gas analysis is a good predictor for base excess and lactate in arterial blood in steady-state conditions. However, the variation between arterial and central venous lactate increases during haemorrhage. The modification of the Van Slyke equation by Zander did not improve the agreement between central venous and arterial base excess.

Prediction of Infant Drug Exposure Through Breastfeeding: Population PK Modeling and Simulation of Fluoxetine Exposure.

The likelihood of significant exposure to drugs in infants through breast milk is poorly defined, given the difficulties of conducting pharmacokinetics (PK) studies. Using fluoxetine (FX) as an example, we conducted a proof-of-principle study applying population PK (popPK) modeling and simulation to estimate drug exposure in infants through breast milk. We simulated data for 1,000 mother-infant pairs, assuming conservatively that the FX clearance in an infant is 20% of the allometrically adjusted value in adults. The model-generated estimate of the milk-to-plasma ratio for FX (mean: 0.59) was consistent with those reported in other studies. The median infant-to-mother ratio of FX steady-state plasma concentrations predicted by the simulation was 8.5%. Although the disposition of the active metabolite, norfluoxetine, could not be modeled, popPK-informed simulation may be valid for other drugs, particularly those without active metabolites, thereby providing a practical alternative to conventional PK studies for exposure risk assessment in this population.

Three-dimensional aspects of fluid flows in channels. II. Effects of meniscus and thin film regimes on viscous fingers

We perform a three-dimensional study of steady state viscous fingers that develop in linear channels. By means of a three-dimensional lattice-Boltzmann scheme that mimics the full macroscopic equations of motion of the fluid momentum and order parameter, we study the effect of the thickness of the channel in two cases. First, for total displacement of the fluids in the channel thickness direction, we find that the steady state finger is effectively two-dimensional and that previous two-dimensional results can be recovered by taking into account the effect of a curved meniscus across the channel thickness as a contribution to surface stresses. Second, when a thin film develops in the channel thickness direction, the finger narrows with increasing channel aspect ratio in agreement with experimental results. The effect of the thin film renders the problem three-dimensional and results deviate from the two-dimensional prediction.