Dataset Information

Direct real-time detection of the structural and biochemical events in the myosin power stroke.

ABSTRACT: A principal goal of molecular biophysics is to show how protein structural transitions explain physiology. We have developed a strategic tool, transient time-resolved FRET [(TR)(2)FRET], for this purpose and use it here to measure directly, with millisecond resolution, the structural and biochemical kinetics of muscle myosin and to determine directly how myosin's power stroke is coupled to the thermodynamic drive for force generation, actin-activated phosphate release, and the weak-to-strong actin-binding transition. We find that actin initiates the power stroke before phosphate dissociation and not after, as many models propose. This result supports a model for muscle contraction in which power output and efficiency are tuned by the distribution of myosin structural states. This technology should have wide application to other systems in which questions about the temporal coupling of allosteric structural and biochemical transitions remain unanswered.

SUBMITTER: Muretta JM

PROVIDER: S-EPMC4655543 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Direct real-time detection of the structural and biochemical events in the myosin power stroke.

Muretta Joseph M JM Rohde John A JA Johnsrud Daniel O DO Cornea Sinziana S Thomas David D DD

Proceedings of the National Academy of Sciences of the United States of America 20151102 46

A principal goal of molecular biophysics is to show how protein structural transitions explain physiology. We have developed a strategic tool, transient time-resolved FRET [(TR)(2)FRET], for this purpose and use it here to measure directly, with millisecond resolution, the structural and biochemical kinetics of muscle myosin and to determine directly how myosin's power stroke is coupled to the thermodynamic drive for force generation, actin-activated phosphate release, and the weak-to-strong act ...[more]

PMID: 26578772

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Project description:Background: Ischaemic stroke remains a significant contributor to permanent disability world-wide. Therapeutic interventions for acute ischaemic stroke (AIS) are available, but need to be administered early after symptom onset in order to be effective. Currently, one of the main factors responsible for poor clinical outcome is an unnecessary long time between symptom onset and arrival at a hospital (pre-hospital delay). In the future, technological devices with the capability of real-time detection of AIS may become available. The health economic implications of such devices have not been explored. Methods: We developed a novel probabilistic model to estimate the maximally allowable annual costs of different hypothetical real-time AIS detection devices in different populations given currently accepted willingness-to-pay thresholds. Distributions of model parameters were extracted from the literature. Effectiveness of the intervention was quantified as reduction in disability-adjusted life-years associated with faster access to thrombolysis and mechanical thrombectomy. Incremental costs were calculated from a societal perspective including acute treatment costs and long-term costs for nursing care, home help, and loss of production. The impact of individual model parameters was explored in one-way and multi-way sensitivity analyses. Results: The model yields significantly shorter prehospital delays and a higher proportion of acute ischaemic patients that fulfill the time-based eligibility criteria for thrombolysis or mechanical thrombectomy in the scenario with a real-time stroke detection device as compared to the control scenario. Depending on the sociodemographic and geographic characteristics of the study population and operating characteristics of the device, the maximally allowable annual cost for the device to operate in a cost-effective manner assuming a willingness-to-pay threshold of GBP 30.000 ranges from GBP 22.00 to GBP 9,952.00. Considering the results of multiway sensitivity analyses, the upper bound increases to GBP 29,449.10 in the subgroup of young patients with a very high annual risk of ischaemic stroke (50 years/20% annual risk). Conclusion: Data from probabilistic modeling suggest that real-time AIS detection devices can be expected to be cost-effective only for a small group of highly selected individuals.

Dataset Information

Direct real-time detection of the structural and biochemical events in the myosin power stroke.

Publications

Direct real-time detection of the structural and biochemical events in the myosin power stroke.

Similar Datasets

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