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Life on Earth, including for microbes and cold-blooded animals, often occurs in frigid environments. At frigid temperatures, nearly all intracellular processes slow down which is colloquially said to decelerate life’s pace and, potentially, aging. But even for one cell, an outstanding conceptual challenge is rigorously explaining how the slowed-down intracellular processes collectively sustain a cell’s life and set its pace. Here, by monitoring individual yeast cells for months at near-freezing temperatures, we show how global gene-expression dynamics and Reactive Oxygen Species (ROS) act together as the primary factors that dictate and constrain the pace at which a budding yeast’s life can progresses in frigid environments. We discovered that yeast cells help each other in surviving and dividing at frigid temperatures. By investigating the underlying mechanism, involving glutathione secretion, we discovered that ROS is the primary determinant of yeast’s ability to survive and divide at near-freezing temperatures. Observing days-to-months-long cell-cycle progression in individual cells revealed that ROS inhibits S-G2-M (replicative) phase while elongating G1 (growth) phase up to a temperature-dependent threshold duration, beyond which yeast cannot divide and bursts as an unsustainably large cell. We discovered that an interplay between global gene-expression speed and ROS sets the threshold G1-duration by measuring rates of genome-wide transcription and protein synthesis at frigid temperatures and then incorporating them into a mathematical model. The same interplay yields unbeatable “speed limits” for cell cycling – shortest and longest allowed doubling times – at each temperature. These results establish quantitative principles for engineering cold-tolerant microbes and reveal how frigid temperatures can fundamentally constrain microbial life and cell cycle at the systems-level.

Computationally efficient evaluation of penalized estimators of multivariate exponential family distributions is sought. These distributions encompass among others Markov random fields with variates of mixed type (e.g., binary and continuous) as special case of interest. The model parameter is estimated by maximization of the pseudo-likelihood augmented with a convex penalty. The estimator is shown to be consistent. With a world of multi-core computers in mind, a computationally efficient parallel Newton–Raphson algorithm is presented for numerical evaluation of the estimator alongside conditions for its convergence. Parallelization comprises the division of the parameter vector into subvectors that are estimated simultaneously and subsequently aggregated to form an estimate of the original parameter. This approach may also enable efficient numerical evaluation of other high-dimensional estimators. The performance of the proposed estimator and algorithm are evaluated and compared in a simulation study. Finally, the presented methodology is applied to data of an integrative omics study.

The conventional view is that high temperatures cause microorganisms to replicate slowly or die. In this view, microorganisms autonomously combat heat-induced damages. However, microorganisms co-exist with each other, which raises the underexplored and timely question of whether microorganisms can cooperatively combat heat-induced damages at high temperatures. Here, we use the budding yeast Saccharomyces cerevisiae to show that cells can help each other and their future generations to survive and replicate at high temperatures. As a consequence, even at the same temperature, a yeast population can exponentially grow, never grow or grow after unpredictable durations (hours to days) of stasis, depending on its population density. Through the same mechanism, yeasts collectively delay and can eventually stop their approach to extinction, with higher population densities stopping faster. These features arise from yeasts secreting and extracellularly accumulating glutathione—a ubiquitous heat-damage-preventing antioxidant. We show that the secretion of glutathione, which eliminates harmful extracellular chemicals, is both necessary and sufficient for yeasts to collectively survive at high temperatures. A mathematical model, which is generally applicable to any cells that cooperatively replicate by secreting molecules, recapitulates all of these features. Our study demonstrates how organisms can cooperatively define and extend the boundaries of life-permitting temperatures. Saccharomyces cerevisiae cells work collectively to survive and replicate at high temperatures by secreting glutathione, an antioxidant that mitigates heat-mediated damage to yeast cells.

The conventional view is that high temperatures cause microorganisms to replicate slowly or die. In this view, microorganisms autonomously combat heat-induced damages. However, microorganisms co-exist with each other, which raises the underexplored and timely question of whether microorganisms can cooperatively combat heat-induced damages at high temperatures. Here, we use the budding yeast Saccharomyces cerevisiae to show that cells can help each other and their future generations to survive and replicate at high temperatures. As a consequence, even at the same temperature, a yeast population can exponentially grow, never grow or grow after unpredictable durations (hours to days) of stasis, depending on its population density. Through the same mechanism, yeasts collectively delay and can eventually stop their approach to extinction, with higher population densities stopping faster. These features arise from yeasts secreting and extracellularly accumulating glutathione-a ubiquitous heat-damage-preventing antioxidant. We show that the secretion of glutathione, which eliminates harmful extracellular chemicals, is both necessary and sufficient for yeasts to collectively survive at high temperatures. A mathematical model, which is generally applicable to any cells that cooperatively replicate by secreting molecules, recapitulates all of these features. Our study demonstrates how organisms can cooperatively define and extend the boundaries of life-permitting temperatures.

SUMMARYHow the rising global temperatures affect organisms is a timely question. The conventional view is that high temperatures cause microbes to replicate slowly or die, both autonomously. Yet, microbes co-exist as a population, raising the underexplored question of whether they can cooperatively combat rising temperatures. Here we show that, at high temperatures, budding yeasts help each other and future generations of cells replicate by secreting and extracellularly accumulating glutathione - a ubiquitous heat-damage-reducing antioxidant. Yeasts thereby collectively delay and can halt population extinctions at high temperatures. As a surprising consequence, even for the same temperature, a yeast population can either exponentially grow, never grow, or grow after unpredictable durations (hours-to-days) of stasis, depending on its population density. Despite the conventional theory stating that heat-shocked cells autonomously die and cannot stop population extinctions, we found that non-growing yeast-populations at high temperatures - due to cells cooperatively accumulating extracellular glutathione - continuously decelerate and can eventually stop their approach to extinction, with higher population-densities stopping faster. We show that exporting glutathione, but not importing, is required for yeasts to survive high temperatures. Thus, cooperatively eliminating harmful extracellular agents – not glutathione’s actions inside individual cells – is both necessary and sufficient for surviving high temperatures. We developed a mathematical model - which is generally applicable to any cells that cooperatively replicate by secreting molecules - that recapitulates all these features. These results show how cells can cooperatively extend boundaries of life-permitting temperatures.

The nuclear pore complex (NPC) is the gatekeeper for nuclear transport in eukaryotic cells. A key component of the NPC is the central shaft lined with intrinsically disordered proteins (IDPs) known as FG-Nups, which control the selective molecular traffic. Here, we present an approach to realize artificial NPC mimics that allows controlling the type and copy number of FG-Nups. We constructed 34 nm-wide 3D DNA origami rings and attached different numbers of NSP1, a model yeast FG-Nup, or NSP1-S, a hydrophilic mutant. Using (cryo) electron microscopy, we find that NSP1 forms denser cohesive networks inside the ring compared to NSP1-S. Consistent with this, the measured ionic conductance is lower for NSP1 than for NSP1-S. Molecular dynamics simulations reveal spatially varying protein densities and conductances in good agreement with the experiments. Our technique provides an experimental platform for deciphering the collective behavior of IDPs with full control of their type and position., FG-Nups are disordered proteins in the nuclear pore complex (NPC) where they selectively control nuclear transport. Here authors build NPC-mimics based on DNA origami rings which attach a certain numbers of Nups to analyse those nanopores by cryoEM and conductance measurements.

One snapshot of the peer review process for “Death Rate of E. coli during Starvation Is Set by Maintenance Cost and Biomass Recycling” (Schink et al., 2019).