No abstract

The restriction point (R-point) marks the critical event when a mammalian cell commits to proliferation and becomes independent of growth stimulation. It is fundamental for normal differentiation and tissue homeostasis, and seems to be dysregulated in virtually all cancers. Although the R-point has been linked to various activities involved in the regulation of G1-S transition of the mammalian cell cycle, the underlying mechanism remains unclear. Using single-cell measurements, we show here that the Rb-E2F pathway functions as a bistable switch to convert graded serum inputs into all-or-none E2F responses. Once turned ON by sufficient serum stimulation, E2F can memorize and maintain this ON state independently of continuous serum stimulation. We further show that, at critical concentrations and duration of serum stimulation, bistable E2F activation correlates directly with the ability of a cell to traverse the R-point.

De novo engineering of gene circuits inside cells is extremely difficult, and efforts to realize predictable and robust performance must deal with noise in gene expression and variation in phenotypes between cells. Here we demonstrate that by coupling gene expression to cell survival and death using cell-cell communication, we can programme the dynamics of a population despite variability in the behaviour of individual cells. Specifically, we have built and characterized a 'population control' circuit that autonomously regulates the density of an Escherichia coli population. The cell density is broadcasted and detected by elements from a bacterial quorum-sensing system, which in turn regulate the death rate. As predicted by a simple mathematical model, the circuit can set a stable steady state in terms of cell density and gene expression that is easily tunable by varying the stability of the cell-cell communication signal. This circuit incorporates a mechanism for programmed death in response to changes in the environment, and allows us to probe the design principles of its more complex natural counterparts.

Background Non-pharmaceutical interventions (NPIs) were implemented by many countries to reduce the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of COVID-19. A resurgence in COVID-19 cases has been reported in some countries that lifted some of these NPIs. We aimed to understand the association of introducing and lifting NPIs with the level of transmission of SARS-CoV-2, as measured by the time-varying reproduction number ( R ), from a broad perspective across 131 countries. Methods In this modelling study, we linked data on daily country-level estimates of R from the London School of Hygiene & Tropical Medicine (London, UK) with data on country-specific policies on NPIs from the Oxford COVID-19 Government Response Tracker, available between Jan 1 and July 20, 2020. We defined a phase as a time period when all NPIs remained the same, and we divided the timeline of each country into individual phases based on the status of NPIs. We calculated the R ratio as the ratio between the daily R of each phase and the R from the last day of the previous phase (ie, before the NPI status changed) as a measure of the association between NPI status and transmission of SARS-CoV-2. We then modelled the R ratio using a log-linear regression with introduction and relaxation of each NPI as independent variables for each day of the first 28 days after the change in the corresponding NPI. In an ad-hoc analysis, we estimated the effect of reintroducing multiple NPIs with the greatest effects, and in the observed sequence, to tackle the possible resurgence of SARS-CoV-2. Findings 790 phases from 131 countries were included in the analysis. A decreasing trend over time in the R ratio was found following the introduction of school closure, workplace closure, public events ban, requirements to stay at home, and internal movement limits; the reduction in R ranged from 3% to 24% on day 28 following the introduction compared with the last day before introduction, although the reduction was significant only for public events ban ( R ratio 0·76, 95% CI 0·58–1·00); for all other NPIs, the upper bound of the 95% CI was above 1. An increasing trend over time in the R ratio was found following the relaxation of school closure, bans on public events, bans on public gatherings of more than ten people, requirements to stay at home, and internal movement limits; the increase in R ranged from 11% to 25% on day 28 following the relaxation compared with the last day before relaxation, although the increase was significant only for school reopening ( R ratio 1·24, 95% CI 1·00–1·52) and lifting bans on public gathe...

We have constructed a synthetic ecosystem consisting of two Escherichia coli populations, which communicate bi-directionally through quorum sensing and regulate each other's gene expression and survival via engineered gene circuits. Our synthetic ecosystem resembles canonical predatorprey systems in terms of logic and dynamics. The predator cells kill the prey by inducing expression of a killer protein in the prey, while the prey rescue the predators by eliciting expression of an antidote protein in the predator. Extinction, coexistence and oscillatory dynamics of the predator and prey populations are possible depending on the operating conditions as experimentally validated by long-term culturing of the system in microchemostats. A simple mathematical model is developed to capture these system dynamics. Coherent interplay between experiments and mathematical analysis enables exploration of the dynamics of interacting populations in a predictable manner.