Biological systems that perform multiple tasks face a fundamental trade-off: A given phenotype cannot be optimal at all tasks. Here we ask how trade-offs affect the range of phenotypes found in nature. Using the Pareto front concept from economics and engineering, we find that best-trade-off phenotypes are weighted averages of archetypes--phenotypes specialized for single tasks. For two tasks, phenotypes fall on the line connecting the two archetypes, which could explain linear trait correlations, allometric relationships, as well as bacterial gene-expression patterns. For three tasks, phenotypes fall within a triangle in phenotype space, whose vertices are the archetypes, as evident in morphological studies, including on Darwin's finches. Tasks can be inferred from measured phenotypes based on the behavior of organisms nearest the archetypes.

Cell elongation and polarization are basic morphogenetic responses to extracellular matrix adhesion. We demonstrate here that human cultured fibroblasts readily polarize when plated on rigid, but not on compliant, substrates. On rigid surfaces, large and uniformly oriented focal adhesions are formed, whereas cells plated on compliant substrates form numerous small and radially oriented adhesions. Live-cell monitoring showed that focal adhesion alignment precedes the overall elongation of the cell, indicating that focal adhesion orientation may direct cell polarization. siRNA-mediated knockdown of 85 human protein tyrosine kinases (PTKs) induced distinct alterations in the cell polarization response, as well as diverse changes in cell traction force generation and focal adhesion formation. Remarkably, changes in rigidity-dependent traction force development, or focal adhesion mechanosensing, were consistently accompanied by abnormalities in the cell polarization response. We propose that the different stages of cell polarization are regulated by multiple, PTK-dependent molecular checkpoints that jointly control cell contractility and focal-adhesion-mediated mechanosensing.

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.

A primary goal of systems biology is to understand the design principles of the transcription networks that govern the timing of gene expression 1-5 . Here we measured promoter activity for ∼100 genes in parallel from living cells at a resolution of minutes and accuracy of 10%, based on GFP and Lux reporter libraries 3 . Focusing on the amino-acid biosynthesis systems of Escherichia coli 4 , we identified a previously unknown temporal expression program and expression hierarchy that matches the enzyme order in unbranched pathways. We identified two design principles: the closer the enzyme is to the beginning of the pathway, the shorter the response time of the activation of its promoter and the higher its maximal promoter activity. Mathematical analysis suggests that this 'just-in-time' (ref. 5) transcription program is optimal under constraints of rapidly reaching a production goal with minimal total enzyme production 6,7 . Our findings suggest that metabolic regulation networks are designed to generate precision promoter timing and activity programs that can be understood using the engineering principles of production pipelines.Amino-acid biosynthesis (AAB) in E. coli is carried out by well-characterized enzymatic pathways 4,6-11 . The genes encoding these enzymes are governed by a transcriptional regulatory network 12,13 , which is an excellent model system for studying the design principles of metabolic regulation. To study the dynamics of transcription of AAB genes at high temporal resolution and accuracy, we constructed a library of 52 reporter strains that represent ∼50% of known AAB genes. We designed each reporter strain by cloning one of the promoter regions of E. coli K-12 MG1655 upstream of a Lux or a fast-folding GFP reporter gene (Fig. 1a). We measured promoter activity with a high temporal resolution by measuring fluorescence, luminescence and absorbance from 96 cultures in parallel in a multiwell fluorimeter 3,14 .

Nervous system maps are of critical importance for understanding how nervous systems develop and function. We systematically map here all cholinergic neuron types in the male and hermaphrodite C. elegans nervous system. We find that acetylcholine (ACh) is the most broadly used neurotransmitter and we analyze its usage relative to other neurotransmitters within the context of the entire connectome and within specific network motifs embedded in the connectome. We reveal several dynamic aspects of cholinergic neurotransmitter identity, including a sexually dimorphic glutamatergic to cholinergic neurotransmitter switch in a sex-shared interneuron. An expression pattern analysis of ACh-gated anion channels furthermore suggests that ACh may also operate very broadly as an inhibitory neurotransmitter. As a first application of this comprehensive neurotransmitter map, we identify transcriptional regulatory mechanisms that control cholinergic neurotransmitter identity and cholinergic circuit assembly.DOI: http://dx.doi.org/10.7554/eLife.12432.001

gr-qc/9602057 We prove three theorems in general relativity which rule out classical scalar hair of static, spherically symmetric, possibly electrically charged black holes. We first generalize Bekenstein's no-hair theorem for a multiplet of minimally coupled real scalar fields with not necessarily quadratic action to the case of a charged black hole. We then use a conformal map of the geometry to convert the problem of a charged (or neutral) black hole with hair in the form of a neutral self-interacting scalar field nonminimally coupled to gravity to the preceding problem, thus establishing a no-hair theorem for the cases with nonminimal coupling parameter ξ < 0 or ξ ≥ 1 2 . The proof also makes use of a causality requirement on the field configuration. Finally, from the required behavior of the fields at the horizon and infinity we exclude hair of a charged black hole in the form of a charged self-interacting scalar field nonminimally coupled to gravity for any ξ.

Most genes are regulated by multiple transcription factors that bind specific sites in DNA regulatory regions. These cis-regulatory regions perform a computation: the rate of transcription is a function of the active concentrations of each of the input transcription factors. Here, we used accurate gene expression measurements from living cell cultures, bearing GFP reporters, to map in detail the input function of the classic lacZYA operon of Escherichia coli, as a function of about a hundred combinations of its two inducers, cAMP and isopropyl ␤-D-thiogalactoside (IPTG). We found an unexpectedly intricate function with four plateau levels and four thresholds. This result compares well with a mathematical model of the binding of the regulatory proteins cAMP receptor protein (CRP) and LacI to the lac regulatory region. The model is also used to demonstrate that with few mutations, the same region could encode much purer AND-like or even OR-like functions. This possibility means that the wild-type region is selected to perform an elaborate computation in setting the transcription rate. The present approach can be generally used to map the input functions of other genes. T ranscription factor proteins regulate genes by binding to specific sites in their DNA cis-regulatory regions (1-9). Often, multiple transcription factors regulate the same gene. The regulatory regions of a gene must therefore perform a computation: the rate of transcription is a function of the active concentrations of each of the input transcription factors (6-9, 47, 48). This point has been demonstrated, for example, for the endo-16 gene during sea-urchin development, where multiple transcription factors combine to perform an intricate logical computation (6). Cis-regulatory regions are usually studied by genetic methods, by deleting the various transcription factors or mutating sites in the regulatory region. The picture that emerges from such studies is often stated in terms of logic gates such as AND and OR gates (4, 10). However, the precise computations performed by regulatory regions may be more complex than logic gates. In general they are multidimensional functions of the active transcription factor concentrations. Knowing these functions is essential to understand the dynamics of the transcription networks that control cell responses.Here, we use accurate gene expression measurements to map in detail the input function of one of the best characterized regulatory regions, that of the lacZYA operon (lac operon) of Escherichia coli (1-3). The lac operon encodes for three genes responsible for lactose catabolism and transport. It is transcriptionally regulated by the repressor LacI and the activator cAMP receptor protein (CRP). LacI binds to three operator sites, O1, O2, and O3, located at positions ϩ9, ϩ411, and Ϫ84 with respect to the transcriptional start site of the lacZ gene (11). The strongest site, O1, overlaps the Ϫ10 region of the promoter [the RNA polymerase (RNAP) binding site] (11-13). Repression is enhanced by a DNA loop that f...

Recent studies suggest that certain cellular sensory systems display fold-change detection (FCD): a response whose entire shape, including amplitude and duration, depends only on fold changes in input and not on absolute levels. Thus, a step change in input from, for example, level 1 to 2 gives precisely the same dynamical output as a step from level 2 to 4, because the steps have the same fold change. We ask what the benefit of FCD is and show that FCD is necessary and sufficient for sensory search to be independent of multiplying the input field by a scalar. Thus, the FCD search pattern depends only on the spatial profile of the input and not on its amplitude. Such scalar symmetry occurs in a wide range of sensory inputs, such as source strength multiplying diffusing/convecting chemical fields sensed in chemotaxis, ambient light multiplying the contrast field in vision, and protein concentrations multiplying the output in cellular signaling systems. Furthermore, we show that FCD entails two features found across sensory systems, exact adaptation and Weber's law, but that these two features are not sufficient for FCD. Finally, we present a wide class of mechanisms that have FCD, including certain nonlinear feedback and feed-forward loops. We find that bacterial chemotaxis displays feedback within the present class and hence, is expected to show FCD. This can explain experiments in which chemotaxis searches are insensitive to attractant source levels. This study, thus, suggests a connection between properties of biological sensory systems and scalar symmetry stemming from physical properties of their input fields.adaptation | sensory response | spatial search O rganisms and cells sense their environment using sensory systems. Certain sensory systems have been extensively studied, and their input-output relations are well-characterized, including human senses, such as vision (1, 2), touch, and hearing, and unicellular senses, such as bacterial chemotaxis (3). Many sensory systems have common features. One such feature is exact adaptation in which the output to a change in input to a new constant level gradually returns to a level independent of the input. A second common feature, called Weber's law, states that the maximal response to a change in signal is inversely proportional to the background signal (4): Δy = kΔu/u 0 , where k is a constant, y is the output, and Δu is the signal change over the background u 0 . Weber's law in vision, chemotaxis, and other sensory systems applies over a range of several orders of magnitude of background input levels. Note that this definition stems from current practice that generalizes Weber's original measurements on psychophysical threshold sensitivity (4-7).Recent studies of the input-output properties of certain cellular signaling systems (8, 9) suggest that these systems show a feature called fold-change detection (FCD): a response whose entire shape, including its amplitude and duration, depends only on fold changes in input and not on absolute levels (10) (Fig. 1 A and...