751 research outputs found
Chemotactic response and adaptation dynamics in Escherichia coli
Adaptation of the chemotaxis sensory pathway of the bacterium Escherichia
coli is integral for detecting chemicals over a wide range of background
concentrations, ultimately allowing cells to swim towards sources of attractant
and away from repellents. Its biochemical mechanism based on methylation and
demethylation of chemoreceptors has long been known. Despite the importance of
adaptation for cell memory and behavior, the dynamics of adaptation are
difficult to reconcile with current models of precise adaptation. Here, we
follow time courses of signaling in response to concentration step changes of
attractant using in vivo fluorescence resonance energy transfer measurements.
Specifically, we use a condensed representation of adaptation time courses for
efficient evaluation of different adaptation models. To quantitatively explain
the data, we finally develop a dynamic model for signaling and adaptation based
on the attractant flow in the experiment, signaling by cooperative receptor
complexes, and multiple layers of feedback regulation for adaptation. We
experimentally confirm the predicted effects of changing the enzyme-expression
level and bypassing the negative feedback for demethylation. Our data analysis
suggests significant imprecision in adaptation for large additions.
Furthermore, our model predicts highly regulated, ultrafast adaptation in
response to removal of attractant, which may be useful for fast reorientation
of the cell and noise reduction in adaptation.Comment: accepted for publication in PLoS Computational Biology; manuscript
(19 pages, 5 figures) and supplementary information; added additional
clarification on alternative adaptation models in supplementary informatio
Modeling a bacterial ecosystem through chemotaxis simulation of a single cell
International audienceWe present in this paper an artificial life ecosystem in which bacteria are evolved to perform chemotaxis. In this system, surviving bacteria have to overcome the problems of detecting resources (or sensing the environment), modulating their motion to generate a foraging behavior, and communicating with their kin to produce more sophisticated behaviors. A cell’s chemotactic pathway is modulated by a hybrid approach that uses an algebraic model for the receptor clusters activity, an ordinary differential equation for the adaptation dynamics, and a metabolic model that converts nutrients into biomass. The results show some analysis of the motion obtained from some bacteria and their effects on the evolved population behavior. The evolutionary process improves the bacteria’s ability to react to their environment, enhancing their growth and allowing them to better survive. As future work, we propose to investigate the effect of emergent bacterial communication as new species arise, and to explore the dynamics of colonies
Quantitative Modeling of Escherichia coli Chemotactic Motion in Environments Varying in Space and Time
Escherichia coli chemotactic motion in spatiotemporally varying environments is studied by using a computational model based on a coarse-grained description of the intracellular signaling pathway dynamics. We find that the cell's chemotaxis drift velocity vd is a constant in an exponential attractant concentration gradient [L]∝exp(Gx). vd depends linearly on the exponential gradient G before it saturates when G is larger than a critical value GC. We find that GC is determined by the intracellular adaptation rate kR with a simple scaling law: . The linear dependence of vd on G = d(ln[L])/dx directly demonstrates E. coli's ability in sensing the derivative of the logarithmic attractant concentration. The existence of the limiting gradient GC and its scaling with kR are explained by the underlying intracellular adaptation dynamics and the flagellar motor response characteristics. For individual cells, we find that the overall average run length in an exponential gradient is longer than that in a homogeneous environment, which is caused by the constant kinase activity shift (decrease). The forward runs (up the gradient) are longer than the backward runs, as expected; and depending on the exact gradient, the (shorter) backward runs can be comparable to runs in a spatially homogeneous environment, consistent with previous experiments. In (spatial) ligand gradients that also vary in time, the chemotaxis motion is damped as the frequency ω of the time-varying spatial gradient becomes faster than a critical value ωc, which is controlled by the cell's chemotaxis adaptation rate kR. Finally, our model, with no adjustable parameters, agrees quantitatively with the classical capillary assay experiments where the attractant concentration changes both in space and time. Our model can thus be used to study E. coli chemotaxis behavior in arbitrary spatiotemporally varying environments. Further experiments are suggested to test some of the model predictions
A Small Conductance Calcium-Activated K<sup>+</sup> Channel in C. elegans, KCNL-2, Plays a Role in the Regulation of the Rate of Egg-Laying
In the nervous system of mice, small conductance calcium-activated potassium (SK) channels function to regulate neuronal excitability through the generation of a component of the medium afterhyperpolarization that follows action potentials. In humans, irregular action potential firing frequency underlies diseases such as ataxia, epilepsy, schizophrenia and Parkinson's disease. Due to the complexity of studying protein function in the mammalian nervous system, we sought to characterize an SK channel homologue, KCNL-2, in C. elegans, a genetically tractable system in which the lineage of individual neurons was mapped from their early developmental stages. Sequence analysis of the KCNL-2 protein reveals that the six transmembrane domains, the potassium-selective pore and the calmodulin binding domain are highly conserved with the mammalian homologues. We used widefield and confocal fluorescent imaging to show that a fusion construct of KCNL-2 with GFP in transgenic lines is expressed in the nervous system of C. elegans. We also show that a KCNL-2 null strain, kcnl-2(tm1885), demonstrates a mild egg-laying defective phenotype, a phenotype that is rescued in a KCNL-2-dependent manner. Conversely, we show that transgenic lines that overexpress KCNL-2 demonstrate a hyperactive egg-laying phenotype. In this study, we show that the vulva of transgenic hermaphrodites is highly innervated by neuronal processes and by the VC4 and VC5 neurons that express GFP-tagged KCNL-2. We propose that KCNL-2 functions in the nervous system of C. elegans to regulate the rate of egg-laying. © 2013 Chotoo et al
Predicted Auxiliary Navigation Mechanism of Peritrichously Flagellated Chemotactic Bacteria
Chemotactic movement of Escherichia coli is one of the most thoroughly studied paradigms of simple behavior. Due to significant competitive advantage conferred by chemotaxis and to high evolution rates in bacteria, the chemotaxis system is expected to be strongly optimized. Bacteria follow gradients by performing temporal comparisons of chemoeffector concentrations along their runs, a strategy which is most efficient given their size and swimming speed. Concentration differences are detected by a sensory system and transmitted to modulate rotation of flagellar motors, decreasing the probability of a tumble and reorientation if the perceived concentration change during a run is positive. Such regulation of tumble probability is of itself sufficient to explain chemotactic drift of a population up the gradient, and is commonly assumed to be the only navigation mechanism of chemotactic E. coli. Here we use computer simulations to predict existence of an additional mechanism of gradient navigation in E. coli. Based on the experimentally observed dependence of cell tumbling angle on the number of switching motors, we suggest that not only the tumbling probability but also the degree of reorientation during a tumble depend on the swimming direction along the gradient. Although the difference in mean tumbling angles up and down the gradient predicted by our model is small, it results in a dramatic enhancement of the cellular drift velocity along the gradient. We thus demonstrate a new level of optimization in E. coli chemotaxis, which arises from the switching of several flagellar motors and a resulting fine tuning of tumbling angle. Similar strategy is likely to be used by other peritrichously flagellated bacteria, and indicates yet another level of evolutionary development of bacterial chemotaxis
Strategies and Practices in Off-Label Marketing of Pharmaceuticals: A Retrospective Analysis of Whistleblower Complaints
Aaron Kesselheim and colleagues analyzed unsealed whistleblower complaints
against pharmaceutical companies filed in US federal fraud cases that contained
allegations of off-label marketing, and develop a taxonomy of the various
off-label practices
Differential Affinity and Catalytic Activity of CheZ in E. coli Chemotaxis
Push–pull networks, in which two antagonistic enzymes control the
activity of a messenger protein, are ubiquitous in signal transduction pathways.
A classical example is the chemotaxis system of the bacterium
Escherichia coli, in which the kinase CheA and the
phosphatase CheZ regulate the phosphorylation level of the messenger protein
CheY. Recent experiments suggest that both the kinase and the phosphatase are
localized at the receptor cluster, and Vaknin and Berg recently demonstrated
that the spatial distribution of the phosphatase can markedly affect the
dose–response curves. We argue, using mathematical modeling, that the
canonical model of the chemotaxis network cannot explain the experimental
observations of Vaknin and Berg. We present a new model, in which a small
fraction of the phosphatase is localized at the receptor cluster, while the
remainder freely diffuses in the cytoplasm; moreover, the phosphatase at the
cluster has a higher binding affinity for the messenger protein and a higher
catalytic activity than the phosphatase in the cytoplasm. This model is
consistent with a large body of experimental data and can explain many of the
experimental observations of Vaknin and Berg. More generally, the combination of
differential affinity and catalytic activity provides a generic mechanism for
amplifying signals that could be exploited in other two-component signaling
systems. If this model is correct, then a number of recent modeling studies,
which aim to explain the chemotactic gain in terms of the activity of the
receptor cluster, should be reconsidered
Protective role of DNJ-27/ERdj5 in Caenorhabditis elegans models of human neurodegenerative diseases
Aims: Cells have developed quality control systems for protection against proteotoxicity. Misfolded and aggregation-prone proteins, which are behind the initiation and progression of many neurodegenerative diseases (ND), are known to challenge the proteostasis network of the cells. We aimed to explore the role of DNJ-27/ERdj5, an endoplasmic reticulum (ER)-resident thioredoxin protein required as a disulfide reductase for the degradation of misfolded proteins, in well-established Caenorhabditis elegans models of Alzheimer, Parkinson and Huntington diseases. Results: We demonstrate that DNJ-27 is an ER luminal protein and that its expression is induced upon ER stress via IRE-1/XBP-1. When dnj-27 expression is downregulated by RNA interference we find an increase in the aggregation and associated pathological phenotypes (paralysis and motility impairment) caused by human β-amyloid peptide (Aβ), α-synuclein (α-syn) and polyglutamine (polyQ) proteins. In turn, DNJ-27 overexpression ameliorates these deleterious phenotypes. Surprisingly, despite being an ER-resident protein, we show that dnj-27 downregulation alters cytoplasmic protein homeostasis and causes mitochondrial fragmentation. We further demonstrate that DNJ-27 overexpression substantially protects against the mitochondrial fragmentation caused by human Aβ and α-syn peptides in these worm models. Innovation: We identify C. elegans dnj-27 as a novel protective gene for the toxicity associated with the expression of human Aβ, α-syn and polyQ proteins, implying a protective role of ERdj5 in Alzheimer, Parkinson and Huntington diseases. Conclusion: Our data support a scenario where the levels of DNJ-27/ERdj5 in the ER impact cytoplasmic protein homeostasis and the integrity of the mitochondrial network which might underlie its protective effects in models of proteotoxicity associated to human ND
Population dynamics and feeding behavior of Triatoma brasiliensis and Triatoma pseudomaculata, main vectors of Chagas disease in Northeastern Brazil
Accretion of Planetary Material onto Host Stars
Accretion of planetary material onto host stars may occur throughout a star's
life. Especially prone to accretion, extrasolar planets in short-period orbits,
while relatively rare, constitute a significant fraction of the known
population, and these planets are subject to dynamical and atmospheric
influences that can drive significant mass loss. Theoretical models frame
expectations regarding the rates and extent of this planetary accretion. For
instance, tidal interactions between planets and stars may drive complete
orbital decay during the main sequence. Many planets that survive their stars'
main sequence lifetime will still be engulfed when the host stars become red
giant stars. There is some observational evidence supporting these predictions,
such as a dearth of close-in planets around fast stellar rotators, which is
consistent with tidal spin-up and planet accretion. There remains no clear
chemical evidence for pollution of the atmospheres of main sequence or red
giant stars by planetary materials, but a wealth of evidence points to active
accretion by white dwarfs. In this article, we review the current understanding
of accretion of planetary material, from the pre- to the post-main sequence and
beyond. The review begins with the astrophysical framework for that process and
then considers accretion during various phases of a host star's life, during
which the details of accretion vary, and the observational evidence for
accretion during these phases.Comment: 18 pages, 5 figures (with some redacted), invited revie
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