Cells are exposed to changes in extracellular stimulus concentration that vary as a function of rate. However, how cells integrate information conveyed from stimulation rate along with concentration remains poorly understood. Here, we examined how varying the rate of stress application alters budding yeast mitogen-activated protein kinase (MAPK) signaling and cell behavior at the single-cell level. We show that signaling depends on a rate threshold that operates in conjunction with stimulus concentration to determine the timing of MAPK signaling during rate-varying stimulus treatments. We also discovered that the stimulation rate threshold and stimulation rate-dependent cell survival are sensitive to changes in the expression levels of the Ptp2 phosphatase, but not of another phosphatase that similarly regulates osmostress signaling during switch-like treatments. Our results demonstrate that stimulation rate is a regulated determinant of cell behavior and provide a paradigm to guide the dissection of major stimulation rate dependent mechanisms in other systems.

A hallmark of cellular stress response pathways is to protect cells from different environmental insults. While much is known about how cells are protected against acute stresses of different types, the mechanisms underpinning how cells are protected against gradually changing stresses are poorly understood. Here we demonstrate that a linear stress gradient but not a step, pulse or a quadratic gradient of the same stressor and intensity causes a severe cell growth phenotype. We determined that this phenotype is caused by the failure of cells to activate the stress-activated protein kinase signaling pathway due to a threshold in the rate of stress application. This lack of response occurs despite cells physically detecting the relatively slow changes in stress signal.These findings have fundamental implications for understanding mechanisms of how temporally changing environments impact biological phenotype.

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The paper provides an overview of three common virtualization threats that have been observed in log files in the authors' network and suggests solutions to mitigate those security vulnerabilities. The solutions offered have been implemented on a network with over 200 hosts 40 of which are virtualized.