Simulation methods with extended stability for stiff biochemical kinetics

Background: With increasing computer power, simulating the dynamics of complex systems in chemistry and biology is becoming increasingly routine. The modelling of individual reactions in (bio)chemical systems involves a large number of random events that can be simulated by the stochastic simulation algorithm (SSA). The key quantity is the step size, or waiting time, τ, whose value inversely depends on the size of the propensities of the different channel reactions and which needs to be re-evaluated after every firing event. Such a discrete event simulation may be extremely expensive, in particular for stiff systems where τ can be very short due to the fast kinetics of some of the channel reactions. Several alternative methods have been put forward to increase the integration step size. The so-called τ-leap approach takes a larger step size by allowing all the reactions to fire, from a Poisson or Binomial distribution, within that step. Although the expected value for the different species in the reactive system is maintained with respect to more precise methods, the variance at steady state can suffer from large errors as τ grows. Results: In this paper we extend Poisson τ-leap methods to a general class of Runge-Kutta (RK) τ-leap methods. We show that with the proper selection of the coefficients, the variance of the extended τ-leap can be well-behaved, leading to significantly larger step sizes.Conclusions: The benefit of adapting the extended method to the use of RK frameworks is clear in terms of speed of calculation, as the number of evaluations of the Poisson distribution is still one set per time step, as in the original τ-leap method. The approach paves the way to explore new multiscale methods to simulate (bio)chemical systems.

Globally aligned photomosaic of the Lucky Strike hydrothermal vent field (Mid-Atlantic Ridge, 37°18.5’N): Release of georeferenced data, mosaic construction, and viewing software

We present a georeferenced photomosaic of the Lucky Strike hydrothermal vent field (Mid-Atlantic Ridge, 37°18’N). The photomosaic was generated from digital photographs acquired using the ARGO II seafloor imaging system during the 1996 LUSTRE cruise, which surveyed a ~1 km2 zone and provided a coverage of ~20% of the seafloor. The photomosaic has a pixel resolution of 15 mm and encloses the areas with known active hydrothermal venting. The final mosaic is generated after an optimization that includes the automatic detection of the same benthic features across different images (feature-matching), followed by a global alignment of images based on the vehicle navigation. We also provide software to construct mosaics from large sets of images for which georeferencing information exists (location, attitude, and altitude per image), to visualize them, and to extract data. Georeferencing information can be provided by the raw navigation data (collected during the survey) or result from the optimization obtained from imatge matching. Mosaics based solely on navigation can be readily generated by any user but the optimization and global alignment of the mosaic requires a case-by-case approach for which no universally software is available. The Lucky Strike photomosaics (optimized and navigated-only) are publicly available through the Marine Geoscience Data System (MGDS, http://www.marine-geo.org). The mosaic-generating and viewing software is available through the Computer Vision and Robotics Group Web page at the University of Girona (http://eia.udg.es/_rafa/mosaicviewer.html)

Fine-Tuning Translation Kinetics Selection as the Driving Force of Codon Usage Bias in the Hepatitis A Virus Capsid

Hepatitis A virus (HAV), the prototype of genus Hepatovirus, has several unique biological characteristics that distinguish it from other members of the Picornaviridae family. Among these, the need for an intact eIF4G factor for the initiation of translation results in an inability to shut down host protein synthesis by a mechanism similar to that of other picornaviruses. Consequently, HAV must inefficiently compete for the cellular translational machinery and this may explain its poor growth in cell culture. In this context of virus/cell competition, HAV has strategically adopted a naturally highly deoptimized codon usage with respect to that of its cellular host. With the aim to optimize its codon usage the virus was adapted to propagate in cells with impaired protein synthesis, in order to make tRNA pools more available for the virus. A significant loss of fitness was the immediate response to the adaptation process that was, however, later on recovered and more associated to a re-deoptimization rather than to an optimization of the codon usage specifically in the capsid coding region. These results exclude translation selection and instead suggest fine-tuning translation kinetics selection as the underlying mechanism of the codon usage bias in this specific genome region. Additionally, the results provide clear evidence of the Red Queen dynamics of evolution since the virus has very much evolved to re-adapt its codon usage to the environmental cellular changing conditions in order to recover the original fitness.

Conditional BDNF release under pathological conditions improves Huntington's disease pathology by delaying neuronal dysfunction

Background Brain-Derived Neurotrophic Factor (BDNF) is the main candidate for neuroprotective therapy for Huntington's disease (HD), but its conditional administration is one of its most challenging problems. Results Here we used transgenic mice that over-express BDNF under the control of the Glial Fibrillary Acidic Protein (GFAP) promoter (pGFAP-BDNF mice) to test whether up-regulation and release of BDNF, dependent on astrogliosis, could be protective in HD. Thus, we cross-mated pGFAP-BDNF mice with R6/2 mice to generate a double-mutant mouse with mutant huntingtin protein and with a conditional over-expression of BDNF, only under pathological conditions. In these R6/2:pGFAP-BDNF animals, the decrease in striatal BDNF levels induced by mutant huntingtin was prevented in comparison to R6/2 animals at 12 weeks of age. The recovery of the neurotrophin levels in R6/2:pGFAP-BDNF mice correlated with an improvement in several motor coordination tasks and with a significant delay in anxiety and clasping alterations. Therefore, we next examined a possible improvement in cortico-striatal connectivity in R62:pGFAP-BDNF mice. Interestingly, we found that the over-expression of BDNF prevented the decrease of cortico-striatal presynaptic (VGLUT1) and postsynaptic (PSD-95) markers in the R6/2:pGFAP-BDNF striatum. Electrophysiological studies also showed that basal synaptic transmission and synaptic fatigue both improved in R6/2:pGAP-BDNF mice. Conclusions These results indicate that the conditional administration of BDNF under the GFAP promoter could become a therapeutic strategy for HD due to its positive effects on synaptic plasticity.

Mastoparan, a novel mitogen for Swiss 3T3 cells, stimulates pertussis toxin-sensitive arachidonic acid release without inositol phosphate accumulation

Mastoparan, a basic tetradecapeptide isolated from wasp venom, is a novel mitogen for Swiss 3T3 cells. This peptide induced DNA synthesis in synergy with insulin in a concentration-dependent manner; half-maximum and maximum responses were achieved at 14 and 17 microM, respectively. Mastoparan also stimulated DNA synthesis in the presence of other growth promoting factors including bombesin, insulin-like growth factor-1, and platelet-derived growth factor. The synergistic mitogenic stimulation by mastoparan can be dissociated from activation of phospholipase C. Mastoparan did not stimulate phosphoinositide breakdown, Ca2+ mobilization or protein kinase C-mediated phosphorylation of a major cellular substrate or transmodulation of the epidermal growth factor receptor. In contrast, mastoparan stimulated arachidonic acid release, prostaglandin E2 production, and enhanced cAMP accumulation in the presence of forskolin. These responses were inhibited by prior treatment with pertussis toxin. Hence, mastoparan stimulates arachidonic acid release via a pertussis toxin-sensitive G protein in Swiss 3T3 cells. Arachidonic acid, like mastoparan, stimulated DNA synthesis in the presence of insulin. The ability of mastoparan to stimulate mitogenesis was reduced by pertussis toxin treatment. These results demonstrate, for the first time, that mastoparan stimulates reinitiation of DNA synthesis in Swiss 3T3 cells and indicate that this peptide may be a useful probe to elucidate signal transduction mechanisms in mitogenesis.

Comment on "Kinetics of spinodal decomposition in the ising model with vacancy diffusion"

In a recent paper [Phys. Rev. B 50, 3477 (1994)], P. Fratzl and O. Penrose present the results of the Monte Carlo simulation of the spinodal decomposition problem (phase separation) using the vacancy dynamics mechanism. They observe that the t1/3 growth regime is reached faster than when using the standard Kawasaki dynamics. In this Comment we provide a simple explanation for the phenomenon based on the role of interface diffusion, which they claim is irrelevant for the observed behavior.

Kinetics of martensitic transitions in Cu-Al-Mn under thermal cycling: Analysis at multiple length scales

In this paper we study the evolution of the kinetic features of the martensitic transition in a Cu-Al-Mn single crystal under thermal cycling. The use of several experimental techniques including optical microscopy, calorimetry, and acoustic emission, has enabled us to perform an analysis at multiple scales. In particular, we have focused on the analysis of avalanche events (associated with the nucleation and growth of martensitic domains), which occur during the transition. There are significant differences between the kinetics at large and small length scales. On the one hand, at small length scales, small avalanche events tend to sum to give new larger events in subsequent loops. On the other hand, at large length scales the large domains tend to split into smaller ones on thermal cycling. We suggest that such different behavior is the necessary ingredient that leads the system to the final critical state corresponding to a power-law distribution of avalanches.

Accuracy in the experimental calorimetric study of the crystallization kinetics and predicitve transformation diagrams: Application to a Ga-Te amorphous alloy

The uncertainties inherent to experimental differential scanning calorimetric data are evaluated. A new procedure is developed to perform the kinetic analysis of continuous heating calorimetric data when the heat capacity of the sample changes during the crystallization. The accuracy of isothermal calorimetric data is analyzed in terms of the peak-to-peak noise of the calorimetric signal and base line drift typical of differential scanning calorimetry equipment. Their influence in the evaluation of the kinetic parameters is discussed. An empirical construction of the time-temperature and temperature heating rate transformation diagrams, grounded on the kinetic parameters, is presented. The method is applied to the kinetic study of the primary crystallization of Te in an amorphous alloy of nominal composition Ga20Te80, obtained by rapid solidification.

Design and construction of precision heat fluxmeters

The possibility of local elastic instabilities is considered in a first¿order structural phase transition, typically a thermoelastic martensitic transformation, with associated interfacial and volumic strain energy. They appear, for instance, as the result of shape change accommodation by simultaneous growth of different crystallographic variants. The treatment is phenomenological and deals with growth in both thermoelastic equilibrium and in nonequilibrium conditions produced by the elastic instability. Scaling of the transformed fraction curves against temperature is predicted only in the case of purely thermoelastic growth. The role of the transformation latent heat on the relaxation kinetics is also considered, and it is shown that it tends to increase the characteristic relaxation times as adiabatic conditions are approached, by keeping the system closer to a constant temperature. The analysis also reveals that the energy dissipated in the relaxation process has a double origin: release of elastic energy Wi and entropy production Si. The latter is shown to depend on both temperature rate and thermal conduction in the system.