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. Although central to creative processes and social interaction, joint improvisation remains largely unexplored due to the lack of experimental paradigms. Here we introduce a paradigm based on a theater practice called the mirror game. We measured the hand motions of two people mirroring each other at high temporal and spatial resolution. We focused on expert actors and musicians skilled in joint improvisation. We found that players can jointly create novel complex motion without a designated leader, synchronized to less than 40 ms. In contrast, we found that designating one player as leader deteriorated performance: The follower showed 2—3 Hz oscillation around the leader's smooth trajectory, decreasing synchrony and reducing the range of velocities reached. A mathematical model suggests a mechanism for these observations based on mutual agreement on future motion in mirrored reactive—predictive controllers. This is a step toward understanding the human ability to create novelty by improvising together.
Different proteins have different expression levels. It is unclear to what extent these expression levels are optimized to their environment. Evolutionary theories suggest that protein expression ...levels maximize fitness, but the fitness as a function of protein level has seldom been directly measured. To address this, we studied the lac system of Escherichia coli, which allows the cell to use the sugar lactose for growth. We experimentally measured the growth burden due to production and maintenance of the Lac proteins (cost), as well as the growth advantage (benefit) conferred by the Lac proteins when lactose is present. The fitness function, given by the difference between the benefit and the cost, predicts that for each lactose environment there exists an optimal Lac expression level that maximizes growth rate. We then performed serial dilution evolution experiments at different lactose concentrations. In a few hundred generations, cells evolved to reach the predicted optimal expression levels. Thus, protein expression from the lac operon seems to be a solution of a cost-benefit optimization problem, and can be rapidly tuned by evolution to function optimally in new environments.
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. This approach offers a way to search for effective multidrug combinations using a small number of experiments.
When E. coli cells express unneeded protein, they grow more slowly. Such penalty to fitness associated with making proteins is called protein cost. Protein cost is an important component in the ...cost-benefit tradeoffs that underlie the evolution of protein circuits, but its origins are still poorly understood. Here, we ask how the protein cost varies during the exponential growth phase of E. coli. We find that cells growing exponentially following an upshift from overnight culture show a large cost when producing unneeded proteins. However, after several generations, while still in exponential growth, the cells enter a phase where cost is much reduced despite vigorous unneeded protein production. We find that this reduced-cost phase depends on the ppGpp system, which adjusts the amount of ribosomes in the cell and does not occur after a downshift from rich to poor medium. These findings suggest that protein cost is a transient phenomenon that happens upon an upshift in conditions and that cost is reduced when ribosomes and other cellular systems have increased to their appropriate steady-state level in the new condition.
► Protein cost is relative reduction in growth rate of cells expressing unneeded proteins ► Cost of expressing unneeded proteins is a transient phenomenon ► Protein cost is reduced several generations after upshift in conditions ► The reduced-cost phase depends on the ppGpp system and relates to balanced growth
Latency 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. We then examine the drug sensitivity of cell-to-cell spread of HIV, a mode of HIV transmission that can lead to multiple infection events per target cell. Infections originating from cell-free virus decrease strongly in the presence of antiretrovirals tenofovir and efavirenz whereas infections involving cell-to-cell spread are markedly less sensitive to the drugs. The reduction in sensitivity is sufficient to keep multiple rounds of infection from terminating in the presence of drugs. We examine replication from cell-to-cell spread in the presence of clinical drug concentrations using a stochastic infection model and find that replication is intermittent, without substantial accumulation of mutations. If cell-to-cell spread has the same properties in vivo, it may have adverse consequences for the immune system, lead to therapy failure in individuals with risk factors, and potentially contribute to viral persistence and hence be a barrier to curing HIV infection.
Natural 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. We show that anticipation is an adaptive trait, because pre-exposure to the stimulus that typically appears early in the ecology improves the organism's fitness when encountered with a second stimulus. Additionally, we observe loss of the conditioned response in E. coli strains that were repeatedly exposed in a laboratory evolution experiment only to the first stimulus. Focusing on the molecular level reveals that the natural temporal order of stimuli is embedded in the wiring of the regulatory network-early stimuli pre-induce genes that would be needed for later ones, yet later stimuli only induce genes needed to cope with them. Our work indicates that environmental anticipation is an adaptive trait that was repeatedly selected for during evolution and thus may be ubiquitous in biology.
Proteome Half-Life Dynamics in Living Human Cells Eden, Eran; Geva-Zatorsky, Naama; Issaeva, Irina ...
Science (American Association for the Advancement of Science),
02/2011, Volume:
331, Issue:
6018
Journal Article
Peer reviewed
Cells 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. Assaying 100 proteins in living human cancer cells showed half-lives that ranged between 45 minutes and 22.5 hours. A variety of stresses that stop cell division showed the same general effect: Long-lived proteins became longer-lived, whereas short-lived proteins remained largely unaffected. This effect is due to the relative strengths of degradation and dilution and suggests a mechanism for differential killing of rapidly growing cells by growth-arresting drugs. This approach opens a way to understand proteome half-life dynamics in living cells.
In 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. coli ...strains grow slower on glucose than on other sugars, namely when a single amino acid (arginine, glutamate, or proline) is the sole nitrogen source. In sugar mixtures with these nitrogen sources, E. coli still consumes glucose first, but grows faster rather than slower after exhausting glucose, generating a reversed diauxic shift. We trace this counterintuitive behavior to a metabolic imbalance: levels of TCA-cycle metabolites including α-ketoglutarate are high, and levels of the key regulatory molecule cAMP are low. Growth rates were increased by experimentally increasing cAMP levels, either by adding external cAMP, by genetically perturbing the cAMP circuit or by inhibition of glucose uptake. Thus, the cAMP control circuitry seems to have a 'bug' that leads to slow growth under what may be an environmentally rare condition.
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. Any subpopulation selected from a population of cells repopulated the whole original basin of attraction within days to weeks. Cells at the basin edges were unstable and prone to apoptosis. Cells continuously changed states within their own attractor, thus driving the repopulation, as shown by fluorescent dye tracing. Perturbations of key regulatory genes induced a jump to a nearby attractor. Using the Fokker–Planck equation, this cell population behavior could be described as two virtual, opposing influences on the cells: one attracting toward the center and the other promoting diffusion in state space (noise). Transcriptome analysis suggests that these forces result from high-dimensional dynamics of the gene regulatory network. We propose that they can be generalized to all cancer cell populations and represent intrinsic behaviors of tumors, offering a previously unidentified characteristic for studying cancer.
Most 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. coli promoters using fluorescent reporters. We show that in both organisms 60–90% of promoters change their expression between conditions by a constant global scaling factor that depends only on the conditions and not on the promoter's identity. Quantifying such global effects allows precise characterization of specific regulation—promoters deviating from the global scale line. These are organized into few functionally related groups that also adhere to scale lines and preserve their relative activities across conditions. Thus, only several scaling factors suffice to accurately describe genome‐wide expression profiles across conditions. We present a parameter‐free passive resource allocation model that quantitatively accounts for the global scaling factors. It suggests that many changes in expression across conditions result from global effects and not specific regulation, and provides means for quantitative interpretation of expression profiles.
Libraries of S. cerevisiae and E. coli promoter reporters measured under different conditions reveal scaling relationships between expression profiles across conditions and suggest that most changes in activity are due to global effects.
Synopsis
Libraries of S. cerevisiae and E. coli promoter reporters measured under different conditions reveal scaling relationships between expression profiles across conditions and suggest that most changes in activity are due to global effects.
Between any two conditions, the activity of most promoters changes by a constant global scaling factor that depends only on the conditions and not on the promoter's identity.
The value of the global scaling factor between any two conditions corresponds to the change in growth rate and magnitude of the condition‐specific response.
When specific groups of genes are activated, they also tend to change according to scaling factors, changing the degree to which the entire group is activated, while preserving the ratios between genes within the group.
Altogether, a handful of scaling factors are sufficient for quantitatively describing genome‐wide expression profiles across conditions.
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