Proc Natl Acad Sci U S A
September 2016
Finding potent multidrug combinations against cancer and infections is a pressing therapeutic challenge; however, screening all combinations is difficult because the number of experiments grows exponentially with the number of drugs and doses. To address this, we present a mathematical model that predicts the effects of three or more antibiotics or anticancer drugs at all doses based only on measurements of drug pairs at a few doses, without need for mechanistic information. The model provides accurate predictions on available data for antibiotic combinations, and on experiments presented here on the response matrix of three cancer drugs at eight doses per drug.
View Article and Find Full Text PDFIn most conditions, glucose is the best carbon source for E. coli: it provides faster growth than other sugars, and is consumed first in sugar mixtures. Here we identify conditions in which E.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
March 2016
The observed intercellular heterogeneity within a clonal cell population can be mapped as dynamical states clustered around an attractor point in gene expression space, owing to a balance between homeostatic forces and stochastic fluctuations. These dynamics have led to the cancer cell attractor conceptual model, with implications for both carcinogenesis and new therapeutic concepts. Immortalized and malignant EBV-carrying B-cell lines were used to explore this model and characterize the detailed structure of cell attractors.
View Article and Find Full Text PDFBackground: Understanding how cells make decisions, and why they make the decisions they make, is of fundamental interest in systems biology. To address this, we study the decisions made by E. coli on which genes to express when presented with two different sugars.
View Article and Find Full Text PDFBacteria often face complex environments. We asked how gene expression in complex conditions relates to expression in simpler conditions. To address this, we obtained accurate promoter activity dynamical measurements on 94 genes in E.
View Article and Find Full Text PDFBackground: Lag phase is a period of time with no growth that occurs when stationary phase bacteria are transferred to a fresh medium. Bacteria in lag phase seem inert: their biomass does not increase. The low number of cells and low metabolic activity make it difficult to study this phase.
View Article and Find Full Text PDFMost genes change expression levels across conditions, but it is unclear which of these changes represents specific regulation and what determines their quantitative degree. Here, we accurately measured activities of ~900 S. cerevisiae and ~1800 E.
View Article and Find Full Text PDFEdelaar raises concerns about the way we tested our theory. Our mathematical theorem predicts that despite the high dimensionality of trait space, trade-offs between tasks leads to phenotypes in low-dimensional regions in trait space, such as lines and triangles. We address Edelaar's questions with statistical tests that eliminate pseudoreplication concerns, finding that our predictions remain convincingly supported.
View Article and Find Full Text PDFBackground: Bacterial growth as a function of nutrients has been studied for decades, but is still not fully understood. In particular, the growth laws under dynamically changing environments have been difficult to explore, because of the rapidly changing conditions. Here, we address this challenge by means of a robotic assay and measure bacterial growth rate, promoter activity and substrate level at high temporal resolution across the entire growth curve in batch culture.
View Article and Find Full Text PDFA gene can be said to be insulated from environmental variations if its expression level depends only on its cognate inducers, and not on variations in conditions. We tested the insulation of the lac promoter of E. coli and of synthetic constructs in which the transcription factor CRP acts as either an activator or a repressor, by measuring their input function-their expression as a function of inducers-in different growth conditions.
View Article and Find Full Text PDFProtein removal has a central role in numerous cellular processes. Obtaining systematic measurements of multiple protein removal rates is necessary to understand the principles that govern these processes, but it is currently a major technical challenge. To address this, we developed 'bleach-chase', a noninvasive method for measuring the half-lives of multiple proteins at high temporal resolution in living cells.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
December 2011
Joint improvisation is the creative action of two or more people without a script or designated leader. Examples include improvisational theater and music, and day-to-day activities such as conversations. In joint improvisation, novel action is created, emerging from the interaction between people.
View Article and Find Full Text PDFLatency and ongoing replication have both been proposed to explain the drug-insensitive human immunodeficiency virus (HIV) reservoir maintained during antiretroviral therapy. Here we explore a novel mechanism for ongoing HIV replication in the face of antiretroviral drugs. We propose a model whereby multiple infections per cell lead to reduced sensitivity to drugs without requiring drug-resistant mutations, and experimentally validate the model using multiple infections per cell by cell-free HIV in the presence of the drug tenofovir.
View Article and Find Full Text PDFBackground: Gene regulation networks are made of recurring regulatory patterns, called network motifs. One of the most common network motifs is negative auto-regulation, in which a transcription factor represses its own production. Negative auto-regulation has several potential functions: it can shorten the response time (time to reach halfway to steady-state), stabilize expression against noise, and linearize the gene's input-output response curve.
View Article and Find Full Text PDFCells remove proteins by two processes: degradation and dilution due to cell growth. The balance between these basic processes is poorly understood. We addressed this by developing an accurate and noninvasive method for measuring protein half-lives, called "bleach-chase," that is applicable to fluorescently tagged proteins.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
July 2010
A key circuit in the response of cells to damage is the p53-mdm2 feedback loop. This circuit shows sustained, noisy oscillations in individual human cells following DNA breaks. Here, we apply an engineering approach known as systems identification to quantify the in vivo interactions in the circuit on the basis of accurate measurements of its power spectrum.
View Article and Find Full Text PDFWhen E. coli cells express unneeded protein, they grow more slowly. Such penalty to fitness associated with making proteins is called protein cost.
View Article and Find Full Text PDFDrugs and drug combinations have complex biological effects on cells and organisms. Little is known about how drugs affect protein dynamics that determine these effects. Here, we use a dynamic proteomics approach to accurately follow 15 protein levels in human cells in response to 13 different drugs.
View Article and Find Full Text PDFCells need to allocate their limited resources to express a wide range of genes. To understand how Escherichia coli partitions its transcriptional resources between its different promoters, we employ a robotic assay using a comprehensive reporter strain library for E. coli to measure promoter activity on a genomic scale at high-temporal resolution and accuracy.
View Article and Find Full Text PDFNatural habitats of some microorganisms may fluctuate erratically, whereas others, which are more predictable, offer the opportunity to prepare in advance for the next environmental change. In analogy to classical Pavlovian conditioning, microorganisms may have evolved to anticipate environmental stimuli by adapting to their temporal order of appearance. Here we present evidence for environmental change anticipation in two model microorganisms, Escherichia coli and Saccharomyces cerevisiae.
View Article and Find Full Text PDFExtinctions of local subpopulations are common events in nature. Here, we ask whether such extinctions can affect the design of biological networks within organisms over evolutionary timescales. We study the impact of extinction events on modularity of biological systems, a common architectural principle found on multiple scales in biology.
View Article and Find Full Text PDFAntimicrob Agents Chemother
October 2008
Weak electric currents generated using conductive electrodes have been shown to increase the efficacy of antibiotics against bacterial biofilms, a phenomenon termed "the bioelectric effect." The purposes of the present study were (i) to find out whether insulated electrodes that generate electric fields without "ohmic" electric currents, and thus are not associated with the formation of metal ions and free radicals, can inhibit the growth of planktonic bacteria and (ii) to define the parameters that are most effective against bacterial growth. The results obtained indicate that electric fields generated using insulated electrodes can inhibit the growth of planktonic Staphylococcus aureus and Pseudomonas aeruginosa and that the effect is amplitude and frequency dependent, with a maximum at 10 MHz.
View Article and Find Full Text PDFMol Syst Biol
December 2008
Gene regulation networks contain recurring circuit patterns called network motifs. One of the most common network motif is the incoherent type 1 feed-forward loop (I1-FFL), in which an activator controls both gene and repressor of that gene. This motif was shown to act as a pulse generator and response accelerator of gene expression.
View Article and Find Full Text PDFOrganisms often adapt to new conditions by means of beneficial mutations that become fixed in the population. Often, full adaptation requires several different mutations in the same cell, each of which may affect a different aspect of the behavior. Can one predict order in which these mutations become fixed? To address this, we experimentally studied evolution of Escherichia coli in a growth medium in which the effects of different adaptations can be easily classified as affecting growth rate or the lag-phase duration.
View Article and Find Full Text PDFCells respond to signals by regulating gene expression. The relation between the level of input signals and the transcription rate of the gene is called the gene's input function. Because most genes are regulated by more than one signal, the input functions are usually multidimensional.
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