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Slowdown of growth controls cellular differentiation.

ABSTRACT: How can changes in growth rate affect the regulatory networks behavior and the outcomes of cellular differentiation? We address this question by focusing on starvation response in sporulating Bacillus subtilis We show that the activity of sporulation master regulator Spo0A increases with decreasing cellular growth rate. Using a mathematical model of the phosphorelay-the network controlling Spo0A-we predict that this increase in Spo0A activity can be explained by the phosphorelay protein accumulation and lengthening of the period between chromosomal replication events caused by growth slowdown. As a result, only cells growing slower than a certain rate reach threshold Spo0A activity necessary for sporulation. This growth threshold model accurately predicts cell fates and explains the distribution of sporulation deferral times. We confirm our predictions experimentally and show that the concentration rather than activity of phosphorelay proteins is affected by the growth slowdown. We conclude that sensing the growth rates enables cells to indirectly detect starvation without the need for evaluating specific stress signals.

SUBMITTER: Narula J

PROVIDER: S-EPMC5289222 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Slowdown of growth controls cellular differentiation.

Narula Jatin J Kuchina Anna A Zhang Fang F Fujita Masaya M Süel Gürol M GM Igoshin Oleg A OA

Molecular systems biology 20160523 5

How can changes in growth rate affect the regulatory networks behavior and the outcomes of cellular differentiation? We address this question by focusing on starvation response in sporulating Bacillus subtilis We show that the activity of sporulation master regulator Spo0A increases with decreasing cellular growth rate. Using a mathematical model of the phosphorelay-the network controlling Spo0A-we predict that this increase in Spo0A activity can be explained by the phosphorelay protein accumula ...[more]

PMID: 27216630

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Project description:ImportanceAfter decades of rapid increase, Medicare per-beneficiary spending growth was historically low in the period leading up to the passage of the Affordable Care Act. In the years immediately following the legislation, Medicare expenditure growth slowed even further.ObjectiveTo evaluate factors contributing to the slowdown in Medicare per-beneficiary spending growth.Design, setting, and participantsIn this cross-sectional study, expected spending growth for 2012 to 2015 and 2016 to 2018 was predicted holding payment rates and population characteristics constant. By contrasting predicted and actual spending growth during these periods, the contribution of population vs payment factors to the Medicare spending slowdown was determined. Analyses included all Medicare fee-for-service beneficiaries aged 65 years and older, ranging from 30 to 35 million beneficiaries annually between 2007 and 2018. Data analyses were conducted from January 2018 to August 2018 and updated with new data in June 2021.Main outcomes and measuresThe main outcome included annual growth in total per-beneficiary spending. The roles of payment rate changes and differences in the Medicare population over time were considered, including demographic characteristics and numbers of chronic conditions.ResultsBetween 2008 to 2011 and 2012 to 2015, the adjusted annual Medicare Parts A and B per-beneficiary spending growth rate declined from 3.3% to -0.1%. From 2016 to 2018, the mean annual Medicare spending growth rate rose relative to the previous period but remained lower than in the baseline period at 1.7% per year. This slowdown extended across all sectors within Parts A and B, except for physician-administered drugs offered under Part B. Changes in payment rates (including sequestration measures) and beneficiary characteristics explained 44% of the difference in overall per-beneficiary spending growth between 2007 to 2011 and 2012 to 2015, and 63% between 2007 to 2011 and 2016 to 2018.Conclusions and relevanceIn this cross-sectional study of trends in spending growth per Medicare beneficiary aged 65 years or older, results suggested that Medicare payment policy, including sector-specific payment rate changes and sequestration, will be a critical determinant of whether the Medicare spending growth slowdown persists.

Dataset Information

Slowdown of growth controls cellular differentiation.

Publications

Slowdown of growth controls cellular differentiation.

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