scholarly journals The mechanism of thin filament regulation: Models in conflict?

2019 ◽  
Vol 151 (11) ◽  
pp. 1265-1271 ◽  
Author(s):  
Michael A. Geeves ◽  
Sherwin S. Lehrer ◽  
William Lehman
Keyword(s):  
Rate Constant ◽  
Binding Sites ◽  
Thin Filament ◽  
State Model ◽  
Muscle Contractility ◽  
Thin Filaments ◽  
Thin Filament Regulation ◽  
Three State Model ◽  
State Models ◽  
Two State Model

In a recent JGP article, Heeley et al. (2019. J. Gen. Physiol. https://doi.org/10.1085/jgp.201812198) reopened the debate about two- versus three-state models of thin filament regulation. The authors review their work, which measures the rate constant of Pi release from myosin.ADP.Pi activated by actin or thin filaments under a variety of conditions. They conclude that their data can be described by a two-state model and raise doubts about the generally accepted three-state model as originally formulated by McKillop and Geeves (1993. Biophys. J. https://doi.org/10.1016/S0006-3495(93)81110-X). However, in the following article, we follow Plato’s dictum that “twice and thrice over, as they say, good it is to repeat and review what is good.” We have therefore reviewed the evidence for the three- and two-state models and present our view that the evidence is overwhelmingly in favor of three structural states of the thin filament, which regulate access of myosin to its binding sites on actin and, hence, muscle contractility.

Worklife and Unemployment: A New Consideration

2021 ◽  
Author(s):  
David I. Rosenbaum ◽  
Kalana Jayanetti
Keyword(s):  
Initial Data ◽  
State Model ◽  
Inactive State ◽  
Three State Model ◽  
Good Proxy ◽  
Two State Model

Abstract Do traditional two-state worklife estimates need adjustment for unemployment? To answer, an augmented three-state model classifies individuals as either 1) employed; 2) unemployed; or 3) inactive but not marginally attached. Periods of unemployment may reduce worklives; however, removal of those marginally attached or discouraged from the inactive state raises worklives. The three-state model results are compared to worklife estimates from the same initial data using the traditional two-state model. Results show that in many cases, the two-state model results are a good proxy for the three-state results that control for unemployment.

scholarly journals The structure of the native cardiac thin filament at systolic Ca2+ levels

2021 ◽  
Vol 118 (13) ◽  
pp. e2024288118
Author(s):  
Cristina M. Risi ◽  
Ian Pepper ◽  
Betty Belknap ◽  
Maicon Landim-Vieira ◽  
Howard D. White ◽  
...  
Keyword(s):  
Cardiac Muscle ◽  
Binding Sites ◽  
Short Range ◽  
Bound States ◽  
Thin Filament ◽  
Narrow Range ◽  
The Other ◽  
Thin Filaments ◽  
Troponin Complex ◽  
Myosin Binding

Every heartbeat relies on cyclical interactions between myosin thick and actin thin filaments orchestrated by rising and falling Ca2+ levels. Thin filaments are comprised of two actin strands, each harboring equally separated troponin complexes, which bind Ca2+ to move tropomyosin cables away from the myosin binding sites and, thus, activate systolic contraction. Recently, structures of thin filaments obtained at low (pCa ∼9) or high (pCa ∼3) Ca2+ levels revealed the transition between the Ca2+-free and Ca2+-bound states. However, in working cardiac muscle, Ca2+ levels fluctuate at intermediate values between pCa ∼6 and pCa ∼7. The structure of the thin filament at physiological Ca2+ levels is unknown. We used cryoelectron microscopy and statistical analysis to reveal the structure of the cardiac thin filament at systolic pCa = 5.8. We show that the two strands of the thin filament consist of a mixture of regulatory units, which are composed of Ca2+-free, Ca2+-bound, or mixed (e.g., Ca2+ free on one side and Ca2+ bound on the other side) troponin complexes. We traced troponin complex conformations along and across individual thin filaments to directly determine the structural composition of the cardiac native thin filament at systolic Ca2+ levels. We demonstrate that the two thin filament strands are activated stochastically with short-range cooperativity evident only on one of the two strands. Our findings suggest a mechanism by which cardiac muscle is regulated by narrow range Ca2+ fluctuations.

Allosteric theory

Hemoglobin ◽  
2018 ◽  
pp. 42-57
Author(s):  
Jay F. Storz
Keyword(s):  
Active Site ◽  
Binding Sites ◽  
Allosteric Regulation ◽  
Theoretical Models ◽  
State Model ◽  
Regulatory Control ◽  
Indirect Interaction ◽  
Protein Activity ◽  
Conformational States ◽  
Two State Model

Chapter 3 provides a brief overview of allostery, the modulation of protein activity that is caused by an indirect interaction between structurally remote binding sites. In this mode of intramolecular regulatory control, the binding of ligand at a protein’s active site is influenced by the binding of another ligand at a different site in the same protein. This interaction at a distance is mediated by a ligation-induced transition between alternative conformational states. Hemoglobin is regarded as the “allosteric paradigm,” and the oxygenation-linked transition between alternative quaternary conformations provides a textbook example of how allostery works. This chapter reviews different theoretical models, such as the Monod-Wyman-Changeux “two-state” model, to explain the allosteric regulation of hemoglobin function.

scholarly journals SIMULATIONS OF FINANCIAL MARKETS IN A POTTS-LIKE MODEL

2005 ◽  
Vol 16 (08) ◽  
pp. 1311-1317 ◽  
Author(s):  
TETSUYA TAKAISHI
Keyword(s):  
Financial Markets ◽  
Financial Market ◽  
Potts Model ◽  
State Model ◽  
Exponential Distributions ◽  
Stylized Facts ◽  
Time Correlations ◽  
Long Time ◽  
Three State Model ◽  
Two State Model

A three-state model based on the Potts model is proposed to simulate financial markets. The three states are assigned to "buy", "sell" and "inactive" states. The model shows the main stylized facts observed in the financial market: fat-tailed distributions of returns and long time correlations in the absolute returns. At low inactivity rate, the model effectively reduces to the two-state model of Bornholdt and shows similar results to the Bornholdt model. As the inactivity increases, we observe the exponential distributions of returns.

Three timescales in prism adaptation

2015 ◽  
Vol 113 (1) ◽  
pp. 328-338 ◽  
Author(s):  
Masato Inoue ◽  
Motoaki Uchimura ◽  
Ayaka Karibe ◽  
Jacinta O'Shea ◽  
Yves Rossetti ◽  
...  
Keyword(s):  
Visual Feedback ◽  
Learning System ◽  
Prism Adaptation ◽  
State Model ◽  
Prism Exposure ◽  
The Difference ◽  
Three State Model ◽  
Two State Model ◽  
Adaptation Task ◽  
Plos Biol

It has been proposed that motor adaptation depends on at least two learning systems, one that learns fast but with poor retention and another that learns slowly but with better retention (Smith MA, Ghazizadeh A, Shadmehr R. PLoS Biol 4: e179, 2006). This two-state model has been shown to account for a range of behavior in the force field adaptation task. In the present study, we examined whether such a two-state model could also account for behavior arising from adaptation to a prismatic displacement of the visual field. We first confirmed that an “adaptation rebound,” a critical prediction of the two-state model, occurred when visual feedback was deprived after an adaptation-extinction episode. We then examined the speed of decay of the prism aftereffect (without any visual feedback) after repetitions of 30, 150, and 500 trials of prism exposure. The speed of decay decreased with the number of exposure trials, a phenomenon that was best explained by assuming an “ultraslow” system, in addition to the fast and slow systems. Finally, we compared retention of aftereffects 24 h after 150 or 500 trials of exposure: retention was significantly greater after 500 than 150 trials. This difference in retention could not be explained by the two-state model but was well explained by the three-state model as arising from the difference in the amount of adaptation of the “ultraslow process.” These results suggest that there are not only fast and slow systems but also an ultraslow learning system in prism adaptation that is activated by prolonged prism exposure of 150–500 trials.

scholarly journals Activation and inactivation of single calcium channels in snail neurons.

1984 ◽  
Vol 83 (5) ◽  
pp. 751-769 ◽  
Author(s):  
A M Brown ◽  
H D Lux ◽  
D L Wilson
Keyword(s):  
Waiting Time ◽  
Single Channel ◽  
Waiting Times ◽  
State Model ◽  
Ca Channel ◽  
Snail Neurons ◽  
Channel Opening ◽  
Three State Model ◽  
State Models ◽  
Ca Currents

Activation and inactivation properties of Ca currents were investigated by studying the behavior of single Ca channels in snail neurons. The methods described in the previous paper were used. In addition, a zero-phase digital filter has been incorporated to improve the analysis of latencies to first opening, or waiting times. It was found that a decrease in the probability of single channel opening occurred with time. This was especially marked at 29 degrees C and paralleled the inactivation observed in macroscopic currents. The fact that a single channel was observed means that there is a significant amount of reopening from the "inactivated" state. Small depolarizations at 18 degrees C showed little inactivation. From these measurements, histograms of single channel open, closed, and waiting times were analyzed to estimate the rate constants of a three-state model of activation. Two serious discrepancies with the model were found. First, waiting time distributions at -20 mV were slower than those predicted by parameters obtained from an analysis of the single channel closed times. Second, it was shown that the time and the magnitude of the peak of the waiting time histogram were inconsistent with a three-state model. It is concluded that a minimum of four states are involved in activation. Some four-state models may be eliminated from further consideration. However, a comprehensive model of Ca channel kinetics must await further measurements.

scholarly journals Computing DNA duplex instability profiles efficiently with a two-state model: trends of promoters and binding sites

2010 ◽  
Vol 11 (1) ◽  
Author(s):  
Miriam R Kantorovitz ◽  
Zoi Rapti ◽  
Vladimir Gelev ◽  
Anny Usheva
Keyword(s):  
Binding Sites ◽  
State Model ◽  
Dna Duplex ◽  
Two State Model

scholarly journals Novel insights into sarcomere regulatory systems control of cardiac thin filament activation

2021 ◽  
Vol 153 (7) ◽  
Author(s):  
Christopher Solís ◽  
R. John Solaro
Keyword(s):  
Thin Filament ◽  
Thick Filament ◽  
Detailed Knowledge ◽  
Thin Filaments ◽  
Myosin Binding Protein ◽  
Regulatory Systems ◽  
Associated Proteins ◽  
Filament Activation ◽  
Three State Model ◽  
Pointed End

Our review focuses on sarcomere regulatory mechanisms with a discussion of cardiac-specific modifications to the three-state model of thin filament activation from a blocked to closed to open state. We discuss modulation of these thin filament transitions by Ca2+, by crossbridge interactions, and by thick filament–associated proteins, cardiac myosin–binding protein C (cMyBP-C), cardiac regulatory light chain (cRLC), and titin. Emerging evidence supports the idea that the cooperative activation of the thin filaments despite a single Ca2+ triggering regulatory site on troponin C (cTnC) cannot be considered in isolation of other functional domains of the sarcomere. We discuss long- and short-range interactions among these domains with the regulatory units of thin filaments, including proteins at the barbed end at the Z-disc and the pointed end near the M-band. Important to these discussions is the ever-increasing understanding of the role of cMyBP-C, cRLC, and titin filaments. Detailed knowledge of these control processes is critical to the understanding of mechanisms sustaining physiological cardiac state with varying hemodynamic load, to better defining genetic and acquired cardiac disorders, and to developing targets for therapies at the level of the sarcomeres.

scholarly journals A Novel Approach for Calculating Exact Forms of mRNA Distribution in Single-Cell Measurements

Mathematics ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 27
Author(s):  
Jiaxin Chen ◽  
Feng Jiao
Keyword(s):  
Steady State ◽  
Single Cell ◽  
Gene Activation ◽  
State Model ◽  
Distribution Data ◽  
Mrna Levels ◽  
Novel Approach ◽  
Kinetic Rates ◽  
Three State Model ◽  
Two State Model

Gene transcription is a stochastic process manifested by fluctuations in mRNA copy numbers in individual isogenic cells. Together with mathematical models of stochastic transcription, the massive mRNA distribution data that can be used to quantify fluctuations in mRNA levels can be fitted by Pm(t), which is the probability of producing m mRNA molecules at time t in a single cell. Tremendous efforts have been made to derive analytical forms of Pm(t), which rely on solving infinite arrays of the master equations of models. However, current approaches focus on the steady-state (t→∞) or require several parameters to be zero or infinity. Here, we present an approach for calculating Pm(t) with time, where all parameters are positive and finite. Our approach was successfully implemented for the classical two-state model and the widely used three-state model and may be further developed for different models with constant kinetic rates of transcription. Furthermore, the direct computations of Pm(t) for the two-state model and three-state model showed that the different regulations of gene activation can generate discriminated dynamical bimodal features of mRNA distribution under the same kinetic rates and similar steady-state mRNA distribution.

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