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Biomedical subjects

T R Chay

Publications and source records attributed to T R Chay.

10 recordsLinked to original sources

Studies on re-entrant arrhythmias and ectopic beats in excitable tissues by bifurcation analyses.

A phase-plane bifurcation analysis is a useful way to theoretically understand how various types of arrhythmias may arise from excitable tissues. In this paper, we have performed phase-plane bifurcation analysis to characterize arrhythmogenic states in excitable tissues. To achieve this, we have first formulated a model which is simple enough to be mathematically tractable, yet captures the non-linear features of cardiac excitation and conduction. In this model, single cells are connected in a circular fashion by gap conductances. Each cell carries the following two types of currents: a passive outward current and an inward "excitable" current which contains an activation and an inactivation gate. The activation gate is responsible for the upstroke of action potential and inactivation gate is responsible for the termination of the plateau potential. With this model, we have constructed bifurcation diagrams as a function of a bifurcation parameter. The parameter chosen as the bifurcation parameter has the property of raising maximum diastolic potential while shorting the refractory period. Our analysis revealed the existence of three distinct multi-stable phases in certain ranges of the bifurcation parameter: (1) bistability between a rotor and a quiescent state, (2) bistability between rotor and ectopic beats, and (3) three stable states co-existing among quiescent state, rotor, and ectopic beats. In these three regions, external impulses exert very distinct effects: In region 1, a brief current pulse can annihilate a re-entrant arrhythmia to quiescence. To initiate re-entry from a quiescent tissue, however, it takes two pulses (a primary pulse followed by a premature pulse at a site different from the "primary" site). In region 2, a brief pulse can convert a re-entrant arrhythmia to ectopic beats. To convert the ectopic beats back to circus movement, these beats have to be suppressed by a few brief current pulses to initiate one-way propagation. Depending on the frequency and strength of impulses in region 3, the tissue can switch back and forth among quiescence, circus movement, and ectopic beats. For comparison, we have also included a more complete Beeler-Reuter cardiac cell model in our analysis and obtained essentially the same results. From the behavioral similarities of these models, we conclude that re-entrant and ectopic arrhythmias must be intrinsic properties of excitable tissues and external stimuli can convert one mode of arrhythmia to another in the multistability regions.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials

The Hodgkin-Huxley Na+ channel model versus the five-state Markovian model.

In describing the Na+ channel-gating kinetics, it is generally believed the Hodgkin-Huxley model is inadequate and other types of Markovian models are more appropriate. In this paper, we perform detailed kinetic analyses to find out whether the Hodgkin-Huxley model is really unacceptable. Specifically, we consider two models for the analyses: A five-state Markovian model that allows inactivation to take place before opening and a Hodgkin-Huxley eight-state model. The criteria used to check the goodness of the two models are (a) Akaike's information criterion; (b) chi 2 tests on the waiting-time, open-time, and closed-time distributions, and the number of openings per record; and (c) comparison between all latency distributions and the probability of the open state predicted from the two models. In order to do this, we first develop a method of constructing probability density histograms of a specified event (e.g., waiting time, closed time, open time, number of openings per patch) from the multichannel patch-clamp recordings. The goodness of our method is checked by simulating multichannel patch recordings using a multinomial random number generator. Our kinetic analysis on the single Na+ channel recordings from the cardiac cells revealed that (a) on the basis of Akaike's information criterion, the Hodgkin-Huxley model is definitely a better model than the five-state model, but (b) on the basis of chi 2 tests on the probability density functions, the latter model is slightly better than the former. We find no evidence that the Hodgkin-Huxley model is inferior to the five-state model for this cell type.

Ion Channel Gating

The effect of ATP-sensitive K+ channels on the electrical burst activity and insulin secretion in pancreatic beta-cells.

In recent years, the electrical burst activity of the insulin releasing pancreatic beta-cells has attracted many experimentalists and theoreticians, largely because of its functional importance, but also because of the nonlinear nature of the burst activity. The ATP-sensitive K+ channels are believed to play an important role in electrical activity and insulin release. In this paper, we show by computer simulation how ATP and antidiabetic drugs can lengthen the plateau fraction of bursting and how these chemicals can increase the intracellular Ca2+ level in the pancreatic beta-cell.

Adenosine Diphosphate

Theoretical methods for study of kinetics of models of the mitochondrial respiratory chain.

In earlier work, Hill and Chance obtained exact steady-state kinetic properties for partial models of the mitochondrial respiratory chain with two isopotential pools and one four-state "site enzyme" between the two pools. That work is extended here to full models of the respiratory chain with four isopotential pools and three four-state site enzymes between pairs of pools. Because of the complexity of the model, exact calculations are no longer possible. Instead, we show, by means of some examples, the feasibility of using Monte Carlo calculations on all cases and numerical solution of thousands of kinetic differential equations in many cases.

Enzymes

Rupture of base pairing in double-stranded poly(riboadenylic acid)-poly(ribouridylic acid) by formaldehyde: medium chain lenghts.

By assuming that the opening of hydrogen bonds due to thermal fluctuations is a very fast step and that the reaction of formaldehyde with the imino or amino group is a slow step, we have constructed a model for the unwinding process of poly(A-U) induced by formaldehyde. The denaturation equation derived from the model is essentially the same as that of the zipper model for moderately long chain lengths. The model predicts the following phenomena which are in agreement with our experimental findings. The rate of unwinding is approximately first order for unfractionated polynucleotides and zero order for fractionated samples. This means that formaldehyde ruptures helical residues sequentially starting from the ends and working toward the center. Our model further predicts that the denaturation rate is linearly dependent on -log[Na+] and pH at low ionic strength and is almost independent of [Na+] and pH at high ionic strength. Spectrophotometric measurements on poly(A-U) were done to confirm our theoretical findings.

Chemical Phenomena

Modelling receptor-controlled intracellular calcium oscillators.

This paper presents mathematical models for the hepatocyte calcium oscillator which follow the concepts in a class of informal models developed to account for the striking dependence on the receptor type of several features of the calcium oscillations, in particular the shape and duration of the free calcium transients. The essence of these models is that the transients should be timed by a build-up of activated GTP-binding proteins, which, combined with positive feedback processes and perhaps with cooperative effects, leads to a sudden activation of phospholipase C (PLC), followed by negative feedback processes which switch off the calcium rise and lead to a fall in free calcium back to resting levels. These models predict pulsatile oscillations in inositol (1,4,5)P3 as well as in free calcium. We show that receptor-controlled intracellular calcium oscillators involving an unknown positive feedback pathway onto PLC and negative feedback from protein kinase C (PKC) onto G-proteins and receptors, or negative feedback by stimulation of GTPase activity can simulate many of the features of observed intracellular calcium oscillations. These oscillators exhibit a dependence of frequency on agonist concentration and a dependence of transient duration on receptor and G-protein type. We also show that a PLC-dependent GTPase activating factor (GAF) could provide explanations for some otherwise puzzling features of intracellular calcium oscillations.

Animals

Kinetics of helix-coil transition in all sizes of polypeptides.

The relaxation behavior of the helix-coil transition has been investigated for all sizes of polypeptides. Unlike previously reported results, regardless of the size of polypeptides, the first-order kinetics plays a principal role in the relaxation process when a helical state is relaxed to a half-coiled state [i.e. s(f) is congruent to 1, where s(f) is the helix stability parameter at the final state]. On the other hand, when a helical state is relaxed to a coiled state [i.e., s(f) is less than 1], the zeroth-order kinetics plays a major role. In addition, the range of the validity of a kinetic version of the zipper model has been investigated. We have found that when a helical state is relaxed to a state where s(f) is less than or equal to 1, the zipper model is valid for polypeptides with chain length N satisfying the relation N is less than 1/(sigmagammaC)1/2 where sigma is the cooperativity parameter and gammaC is the coil nucleation rate parameter.

Kinetics