RESUMEN

BACKGROUND: To control and manipulate cellular signaling, we need to understand cellular strategies for information transfer, integration, and decision-making. A key feature of signal transduction is the generation of only a few intracellular messengers by many extracellular stimuli. METHODOLOGY/PRINCIPAL FINDINGS: Here we model molecular cross-talk between two classic second messengers, cyclic AMP (cAMP) and calcium, and show that the dynamical complexity of the response of both messengers increases substantially through their interaction. In our model of a non-excitable cell, both cAMP and calcium concentrations can oscillate. If mutually inhibitory, cross-talk between the two second messengers can increase the range of agonist concentrations for which oscillations occur. If mutually activating, cross-talk decreases the oscillation range, but can generate 'bursting' oscillations of calcium and may enable better filtering of noise. CONCLUSION: We postulate that this increased dynamical complexity allows the cell to encode more information, particularly if both second messengers encode signals. In their native environments, it is unlikely that cells are exposed to one stimulus at a time, and cross-talk may help generate sufficiently complex responses to allow the cell to discriminate between different combinations and concentrations of extracellular agonists.

Asunto(s)

RESUMEN

Determining the effect of a compound on I (Kr) is a standard screen for drug safety. Often the effect is described using a single IC(50) value, which is unable to capture complex effects of a drug. Using verapamil as an example, we present a method for using recordings from native myocytes at several drug doses along with qualitative features of I (Kr) from published studies of HERG current to estimate parameters in a mathematical model of the drug effect on I (Kr). I (Kr) was recorded from canine left ventricular myocytes using ruptured patch techniques. A voltage command protocol was used to record tail currents at voltages from -70 to -20 mV, following activating pulses over a wide range of voltages and pulse durations. Model equations were taken from a published I (Kr) Markov model and the drug was modeled as binding to the open state. Parameters were estimated using a combined global and local optimization algorithm based on collected data with two additional constraints on I (Kr) I-V relation and I (Kr) inactivation. The method produced models that quantitatively reproduce both the control I (Kr) kinetics and dose dependent changes in the current. In addition, the model exhibited use and rate dependence. The results suggest that: (1) the technique proposed here has the practical potential to develop data-driven models that quantitatively reproduce channel behavior in native myocytes; (2) the method can capture important drug effects that cannot be reproduced by the IC(50) method. Although the method was developed for I (Kr), the same strategy can be applied to other ion channels, once appropriate channel-specific voltage protocols and qualitative features are identified.

Asunto(s)

RESUMEN

Heterogeneity of cardiac electrical properties can lead to heart rhythm disorders. Numerical studies have shown that stimuli chosen to maximize dynamic heterogeneity terminate wave propagation. However, experimental investigations suggest that similar sequences induce fragmentation of the wave fronts, rather than complete wave block. In this paper we show that an insulating boundary in an otherwise homogeneous medium can disrupt dynamically induced wave block by breaking a symmetry in the spatial pattern of action potential duration, leading to unidirectional block and reentrant activation.

Asunto(s)

Asunto(s)

RESUMEN

BACKGROUND: A goal of systems biology is the quantitative modelling of biochemical networks. Yet for many biochemical systems, parameter values and even the existence of interactions between some chemical species are unknown. It is therefore important to be able to easily investigate the effects of adding or removing reactions and to easily perform a bifurcation analysis, which shows the qualitative dynamics of a model for a range of parameter values. RESULTS: We present Facile, a Perl command-line tool for analysing the dynamics of a systems biology model. Facile implements the law of mass action to automatically compile a biochemical network (written as, for example, E + S <-> C) into scripts for analytical analysis (Mathematica and Maple), for simulation (XPP and Matlab), and for bifurcation analysis (AUTO). Facile automatically identifies mass conservations and generates the reduced form of a model with the minimum number of independent variables. This form is essential for bifurcation analysis, and Facile produces a C version of the reduced model for AUTO. CONCLUSION: Facile is a simple, yet powerful, tool that greatly accelerates analysis of the dynamics of a biochemical network. By acting at the command-line and because of its intuitive, text-based input, Facile is quick to learn and can be incorporated into larger programs or into automated tasks.

Asunto(s)

RESUMEN

PURPOSE: To compare the initial mechanical characteristics of 4 systems used to fix tendons to the femur during anterior cruciate ligament reconstruction. METHODS: A total of 32 porcine femurs were used to study the following fixation systems: Bioabsorbable interference screw (Stryker, Kalamazoo, MI), Bio-Transfix Cross-pin (Arthrex, Naples, FL), Biosteon Cross-pin (Stryker), and a fixation technique based on wrapping the graft around the femoral condyle itself, thus allowing it to be fixed in place without the use of any hardware. The mechanical characteristics of each system were obtained by a preconditioned failure tensile test. RESULTS: The yield load values (990.9 +/- 242.6 N for Bio-Transfix, 905.1 +/- 158.8 N for Biosteon Cross-pin, 684.4 +/- 119.7 N for the without-hardware system (WHS), and 369.4 +/- 120.1 N for the interference screw) revealed significant differences between the techniques that used cross-pins and the other 2 techniques (P < .006) on the one hand, and between the without hardware technique and the interference screw (P < .004) on the other. The stiffness of the 2 cross-pin fixation systems (117.6 +/- 22.5 N for Bio-Transfix and 112.6 +/- 22.5 N for Biosteon) was greater (P < .01) than those of the other systems (79.4 +/- 15.2 N for the WHS and 68.5 +/- 13 N for the interference screw). CONCLUSIONS: The initial biomechanical properties of the 2 cross-pin fixation systems proved to be superior to those of the other 2 systems studied. The WHS fixation system exhibited better mechanical properties than its interference screw counterpart. CLINICAL RELEVANCE: The better initial mechanical characteristics encountered using the Bio-Transfix and Biosteon Cross-pin systems indicate that these systems are better equipped to bear the loads generated by aggressive rehabilitation. The WHS fixation system provides an alternative to interference screw fixation.

Asunto(s)