Diffusive spatio-temporal noise in a first-passage time model for intracellular calcium release

The intracellular release of calcium from the endoplasmic reticulum is controlled by ion channels. The resulting calcium signals exhibit a rich spatio-temporal signature, which originates at least partly from microscopic fluctuations. While stochasticity in the gating transition of ion channels has been incorporated into many models, the distribution of calcium is usually described by deterministic reaction-diffusion equations. Here we test the validity of the latter modeling approach by using two different models to calculate the frequency of localized calcium signals (calcium puffs) from clustered IP3 receptor channels. The complexity of the full calcium system is here limited to the basic opening mechanism of the ion channels and, in the mathematical reduction simplifies to the calculation of a first passage time. Two models are then studied: (i) a hybrid model, where channel gating is treated stochastically, while calcium concentration is deterministic and (ii) a fully stochastic model with noisy channel gating and Brownian calcium ion motion. The second model utilises the recently developed two-regime method [M. B. Flegg, S. J. Chapman, and R. Erban, “The two-regime method for optimizing stochastic reaction-diffusion simulations,” J. R. Soc., Interface9, 859–868 (Year: 2012)]10.1098/rsif.2011.0574 in order to simulate a large domain with precision required only near the Ca2+ absorbing channels. The expected time for a first channel opening that results in a calcium puff event is calculated. It is found that for a large diffusion constant, predictions of the interpuff time are significantly overestimated using the model (i) with a deterministic non-spatial calcium variable. It is thus demonstrated that the presence of diffusive noise in local concentrations of intracellular Ca2+ ions can substantially influence the occurrence of calcium signals. The presented approach and results may also be relevant for other cell-physiological first-passage time problems with small ligand concentration and high cooperativity

PHYCOBILISOMES AND ISOLATED PHYCOBILIPROTEINS. EFFECT OF GLUTARDIALDEHYDE AND BENZOQUINONE ON FLUORESCENCE

The fluorescence of the biliproteins C-phycocyanin from Spirulina platensis, B-phycoerythrin from Porphyridium cruentum and of isolated whole P. cruentum phycobilisomes is quenched in the presence of glutardialdehyde (GA) or benzoquinone (BQ). The kinetics of fluorescence decrease thus induced is biphasic. If GA is used as a quencher, the fluorescence can be recovered at 77 K. Contrary to the GA-effect, only a minor recovery takes place with BQ at 77K, thus demonstrating a different mechanism of action of GA and BQ on biliprotein

Experience with daptomycin daily dosing in ICU patients undergoing continuous renal replacement therapy

Purpose: For critically ill patients undergoing continuous renal replacement therapy (CRRT), daptomycin dosing recommendations are scarce. We, therefore, retrospectively assessed routinely measured daptomycin plasma concentrations, daptomycin dose administered and microbiological data in 11 critically ill patients with Gram-positive infections that had received daptomycin once daily. Methods: The retrospective analysis included critically ill patients treated at the intensive care unit (ICU) who had daptomycin plasma concentrations measured. Results: Daptomycin dose ranged from 3 to 8mg/kg/q24h in patients undergoing CRRT (n=7) and 6 to 10mg/kg/q24h in patients without CRRT (n=4). Peak and trough concentrations showed a high intra- and inter-patient variability in both groups, independent of the dosage per kg body weight. No drug accumulation was detected in CRRT patients with once-daily daptomycin dosing. Causative pathogens were Enterococcus faecium (n=6), coagulase-negative Staphylococcus (n=2), Staphylococcus aureus (n=2) and unknown in one patient. Microbiological eradication was successful in 8 of 11 patients. Two of three patients with unsuccessful microbiological eradication and fatal outcome had an Enterococcus faecium infection. Conclusion: In critically ill patients undergoing CRRT, daptomycin exposure with once-daily dosing was similar to ICU patients with normal renal function, but lower compared to healthy volunteers. Our data suggest that daptomycin once-daily dosing is appropriate in patients undergoing CRR

The inverse cascade and nonlinear alpha-effect in simulations of isotropic helical hydromagnetic turbulence

A numerical model of isotropic homogeneous turbulence with helical forcing is investigated. The resulting flow, which is essentially the prototype of the alpha^2 dynamo of mean-field dynamo theory, produces strong dynamo action with an additional large scale field on the scale of the box (at wavenumber k=1; forcing is at k=5). This large scale field is nearly force-free and exceeds the equipartition value. As the magnetic Reynolds number R_m increases, the saturation field strength and the growth rate of the dynamo increase. However, the time it takes to built up the large scale field from equipartition to its final super-equipartition value increases with magnetic Reynolds number. The large scale field generation can be identified as being due to nonlocal interactions originating from the forcing scale, which is characteristic of the alpha-effect. Both alpha and turbulent magnetic diffusivity eta_t are determined simultaneously using numerical experiments where the mean-field is modified artificially. Both quantities are quenched in a R_m-dependent fashion. The evolution of the energy of the mean field matches that predicted by an alpha^2 dynamo model with similar alpha and eta_t quenchings. For this model an analytic solution is given which matches the results of the simulations. The simulations are numerically robust in that the shape of the spectrum at large scales is unchanged when changing the resolution from 30^3 to 120^3 meshpoints, or when increasing the magnetic Prandtl number (viscosity/magnetic diffusivity) from 1 to 100. Increasing the forcing wavenumber to 30 (i.e. increasing the scale separation) makes the inverse cascade effect more pronounced, although it remains otherwise qualitatively unchanged.Comment: 21 pages, 26 figures, ApJ (accepted

Accurate Prediction of DnaK-Peptide Binding via Homology Modelling and Experimental Data

Molecular chaperones are essential elements of the protein quality control machinery that governs translocation and folding of nascent polypeptides, refolding and degradation of misfolded proteins, and activation of a wide range of client proteins. The prokaryotic heat-shock protein DnaK is the E. coli representative of the ubiquitous Hsp70 family, which specializes in the binding of exposed hydrophobic regions in unfolded polypeptides. Accurate prediction of DnaK binding sites in E. coli proteins is an essential prerequisite to understand the precise function of this chaperone and the properties of its substrate proteins. In order to map DnaK binding sites in protein sequences, we have developed an algorithm that combines sequence information from peptide binding experiments and structural parameters from homology modelling. We show that this combination significantly outperforms either single approach. The final predictor had a Matthews correlation coefficient (MCC) of 0.819 when assessed over the 144 tested peptide sequences to detect true positives and true negatives. To test the robustness of the learning set, we have conducted a simulated cross-validation, where we omit sequences from the learning sets and calculate the rate of repredicting them. This resulted in a surprisingly good MCC of 0.703. The algorithm was also able to perform equally well on a blind test set of binders and non-binders, of which there was no prior knowledge in the learning sets. The algorithm is freely available at http://limbo.vib.be

An hydrodynamic shear instability in stratified disks

We discuss the possibility that astrophysical accretion disks are dynamically unstable to non-axisymmetric disturbances with characteristic scales much smaller than the vertical scale height. The instability is studied using three methods: one based on the energy integral, which allows the determination of a sufficient condition of stability, one using a WKB approach, which allows the determination of the necessary and sufficient condition for instability and a last one by numerical solution. This linear instability occurs in any inviscid stably stratified differential rotating fluid for rigid, stress-free or periodic boundary conditions, provided the angular velocity $\Omega$ decreases outwards with radius $r$. At not too small stratification, its growth rate is a fraction of $\Omega$. The influence of viscous dissipation and thermal diffusivity on the instability is studied numerically, with emphasis on the case when $d \ln \Omega / d \ln r =-3/2$ (Keplerian case). Strong stratification and large diffusivity are found to have a stabilizing effect. The corresponding critical stratification and Reynolds number for the onset of the instability in a typical disk are derived. We propose that the spontaneous generation of these linear modes is the source of turbulence in disks, especially in weakly ionized disks.Comment: 19 pages, 13 figures, to appear in A&

Preoperative and perioperative use of levosimendan in cardiac surgery: European expert opinion

In cardiac surgery, postoperative low cardiac output has been shown to correlate with increased rates of organ failure and mortality. Catecholamines have been the standard therapy for many years, although they carry substantial risk for adverse cardiac and systemic effects, and have been reported to be associated with increased mortality. On the other hand, the calcium sensitiser and potassium channel opener levosimendan has been shown to improve cardiac function with no imbalance in oxygen consumption, and to have protective effects in other organs. Numerous clinical trials have indicated favourable cardiac and non-cardiac effects of preoperative and perioperative administration of levosimendan. A panel of 27 experts from 18 countries has now reviewed the literature on the use of levosimendan in on-pump and off-pump coronary artery bypass grafting and in heart valve surgery. This panel discussed the published evidence in these various settings, and agreed to vote on a set of questions related to the cardioprotective effects of levosimendan when administered preoperatively, with the purpose of reaching a consensus on which patients could benefit from the preoperative use of levosimendan and in which kind of procedures, and at which doses and timing should levosimendan be administered. Here, we present a systematic review of the literature to report on the completed and ongoing studies on levosimendan, including the newly commenced LEVO-CTS phase III study (NCT02025621), and on the consensus reached on the recommendations proposed for the use of preoperative levosimendan

Resistance of a domain wall in the quasiclassical approach

Starting from a simple microscopic model, we have derived a kinetic equation for the matrix distribution function. We employed this equation to calculate the conductance $G$ in a mesoscopic F'/F/F' structure with a domain wall (DW). In the limit of a small exchange energy $J$ and an abrupt DW, the conductance of the structure is equal to $G_{2d}=4\sigma_{\uparrow}\sigma_{\downarrow }/(\sigma_{\uparrow}+\sigma_{\downarrow})L$. Assuming that the scattering times for electrons with up and down spins are close to each other we show that the account for a finite width of the DW leads to an increase in this conductance. We have also calculated the spatial distribution of the electric field in the F wire. In the opposite limit of large $J$ (adiabatic variation of the magnetization in the DW) the conductance coincides in the main approximation with the conductance of a single domain structure $G_{1d}=(\sigma_{\uparrow}+\sigma_{\downarrow})/L$. The account for rotation of the magnetization in the DW leads to a negative correction to this conductance. Our results differ from the results in papers published earlier.Comment: 11 pages; replaced with revised versio

Negative Domain Wall Resistance in Ferromagnets

The electrical resistance of a diffusive ferromagnet with magnetic domain walls is studied theoretically, taking into account the spatial dependence of the magnetization. The semiclassical domain wall resistance is found to be either negative or positive depending on the difference between the spin-dependent scattering life-times. The predictions can be tested experimentally by transport studies in doped ferromagnets.Comment: 4 pages, 2 figures, accepted Phys. Rev. Let