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PubMed2005

Quantitative kinetic analysis of the bacteriophage lambda genetic network.

The lysis-lysogeny decision of bacteriophage lambda has been a paradigm for a developmental genetic network, which is composed of interlocked positive and negative feedback loops. This genetic network is capable of responding to environmental signals and to the number of infecting phages. An interplay between CI and Cro functions suggested a bistable switch model for the lysis-lysogeny decision. Here, we present a real-time picture of the execution of lytic and lysogenic pathways with unprecedented temporal resolution. We monitor, in vivo, both the level and function of the CII and Q gene regulators. These activators are cotranscribed yet control opposite developmental pathways. Conditions that favor the lysogenic response show severe delay and down-regulation of Q activity, in both CII-dependent and CII-independent ways. Whereas CII activity correlates with its protein level, Q shows a pronounced threshold before its function is observed. Our quantitative analyses suggest that by regulating CII and CIII, Cro plays a key role in the ability of the lambda genetic network to sense the difference between one and more than one phage particles infecting a cell. Thus, our results provide an improved framework to explain the longstanding puzzle of the decision process.

Bacteriophage lambda↗
PubMed2005

Intrinsically photosensitive retinal ganglion cells detect light with a vitamin A-based photopigment, melanopsin.

In mammals, intrinsically photosensitive retinal ganglion cells (ipRGCs) mediate non-image-forming visual functions such as pupillary light reflex (PLR) and circadian photoentrainment. This photosensitivity requires melanopsin, an invertebrate opsin-like protein expressed by the ipRGCs. The precise role of melanopsin remains uncertain. One suggestion has been that melanopsin may be a photoisomerase, serving to regenerate an unidentified pigment in ipRGCs. This possibility was echoed by a recent report that melanopsin is expressed also in the mouse retinal pigment epithelium (RPE), a key center for regeneration of rod and cone pigments. To address this question, we studied mice lacking RPE65, a protein essential for the regeneration of rod and cone pigments. Rpe65-/- ipRGCs were approximately 20- to 40-fold less photosensitive than normal at both single-cell and behavioral (PLR) levels but were rescued by exogenous 9-cis-retinal (an 11-cis-retinal analog), indicating the requirement of a vitamin A-based chromophore for ipRGC photosensitivity. In contrast, 9-cis-retinal was unable to restore intrinsic photosensitivity to melanopsin-ablated ipRGCs, arguing against melanopsin functioning merely in photopigment regeneration. Interestingly, exogenous all-trans-retinal was also able to rescue the low sensitivity of rpe65-/- ipRGCs, suggesting that melanopsin could be a bistable pigment. Finally, we detected no melanopsin in the RPE and no changes in rod and cone sensitivities due to melanopsin ablation. Together, these results strongly suggest that melanopsin is the photopigment in the ipRGCs.

Animals↗
PubMed2005

Noise-induced stability in dryland plant ecosystems.

Dryland plant ecosystems tend to exhibit bistable dynamics with two preferential configurations of bare and vegetated soils. Climate fluctuations are usually believed to act as a source of disturbance on these ecosystems and to reduce their stability and resilience. In contrast, this work shows that random interannual fluctuations of precipitation may lead to the emergence of an intermediate statistically stable condition between the two stable states of the deterministic dynamics of vegetation. As a result, there is an enhancement of ecosystem resilience and a decrease in the likelihood of catastrophic shifts to the desert state.

Biometry↗
PubMed2005

A reversible molecular valve.

In everyday life, a macroscopic valve is a device with a movable control element that regulates the flow of gases or liquids by blocking and opening passageways. Construction of such a device on the nanoscale level requires (i) suitably proportioned movable control elements, (ii) a method for operating them on demand, and (iii) appropriately sized passageways. These three conditions can be fulfilled by attaching organic, mechanically interlocked, linear motor molecules that can be operated under chemical, electrical, or optical stimuli to stable inorganic porous frameworks (i.e., by self-assembling organic machinery on top of an inorganic chassis). In this article, we demonstrate a reversibly operating nanovalve that can be turned on and off by redox chemistry. It traps and releases molecules from a maze of nanoscopic passageways in silica by controlling the operation of redox-activated bistable [2]rotaxane molecules tethered to the openings of nanopores leading out of a nanoscale reservoir.

Models, Chemical↗
PubMed2005

The electroosmotic droplet switch: countering capillarity with electrokinetics.

Electroosmosis, originating in the double-layer of a small liquid-filled pore (size R) and driven by a voltage V, is shown to be effective in pumping against the capillary pressure of a larger liquid droplet (size B) provided the dimensionless parameter sigmaR(2)/epsilon|zeta|VB is small enough. Here sigma is surface tension of the droplet liquid/gas interface, epsilon is the liquid dielectric constant, and zeta is the zeta potential of the solid/liquid pair. As droplet size diminishes, the voltage required to pump electroosmotically scales as V approximately R(2)/B. Accordingly, the voltage needed to pump against smaller higher-pressure droplets can actually decrease provided the pump poresize scales down with droplet size appropriately. The technological implication of this favorable scaling is that electromechanical transducers made of moving droplets, so-called "droplet transducers," become feasible. To illustrate, we demonstrate a switch whose bistable energy landscape derives from the surface energy of a droplet-droplet system and whose triggering derives from the electroosmosis effect. The switch is an electromechanical transducer characterized by individual addressability, fast switching time with low voltage, and no moving solid parts. We report experimental results for millimeter-scale droplets to verify key predictions of a mathematical model of the switch. With millimeter-size water droplets and micrometer-size pores, 5 V can yield switching times of 1 s. Switching time scales as B(3)/VR(2). Two possible "grab-and-release" applications of arrays of switches are described. One mimics the controlled adhesion of an insect, the palm beetle; the other uses wettability to move a particle along a trajectory.

Journal Article↗
PubMed2005

Demonstration of cue recruitment: change in visual appearance by means of Pavlovian conditioning.

Until half a century ago, associative learning played a fundamental role in theories of perceptual appearance [Berkeley, G. (1709) An Essay Towards a New Theory of Vision (Dublin), 1st Ed.]. But starting in 1955 [Gibson, J. J. & Gibson, E. J. (1955) Psychol. Rev. 62, 32-41], most studies of perceptual learning have not been concerned with association or appearance but rather with improvements in discrimination ability. Here we describe a "cue recruitment" experiment, which is a straightforward adaptation of Pavlov's classical conditioning experiment, that we used to measure changes in visual appearance caused by exposure to novel pairings of signals in visual stimuli. Trainees viewed movies of a rotating wire-frame (Necker) cube. This stimulus is perceptually bistable. On training trials, depth cues (stereo and occlusion) were added to force the perceived direction of rotation. Critically, an additional signal was also added, contingent on rotation direction. Stimuli on test trials contained the new signal but not the depth cues. Over 45 min, two of the three new signals that we tested acquired the ability to bias perceived rotation direction on their own. Results were consistent across the eight trainees in each experiment, and the new cue's effectiveness was long lasting. Whereas most adaptation aftereffects on appearance are opposite in direction to the training stimuli, these effects were positive. An individual new signal can be recruited by the visual system as a cue for the construction of visual appearance. Cue recruitment experiments may prove useful for reexamining of the role of experience in perception.

Conditioning, Classical↗
PubMed2005

Silent plateau potentials, rhythmic bursts, and pacemaker firing: three patterns of activity that coexist in quadristable subthalamic neurons.

Subthalamic neurons display uncommon intrinsic behaviors that are likely to contribute to the motor and cognitive functions of the basal ganglia and to many of its disorders. Here, we report silent plateau potentials in these cells. These plateau responses start with a transient burst of action potentials that quickly diminish in amplitude because of spike inactivation and current shunt. The resulting interruption of spiking reveals a stable depolarization (up state) that clamps the cell membrane potential near -40 mV for several seconds. These plateau potentials coexist in single subthalamic neurons with more familiar patterns of burst and pacemaker firing. Within a narrow range of baseline membrane potentials (-67 to -60 mV), depolarization abruptly switches single cells from bistable to rhythmic bursts or tonic firing modes, thus selecting entirely distinct algorithms for integrating cortical and pallidal synaptic inputs.

Action Potentials↗
PubMed2005

Clusters of interacting receptors can stabilize synaptic efficacies.

Synaptic weights store memories that can last a lifetime. Yet, memory depends on synaptic protein receptors that are recycled in and out of the membrane at a fast rate, possibly several times an hour. Several proposals to bridge this vast gap in time scales between memory and its molecular substrate have relied on bistable molecular switches. Here, we propose an alternative to this approach based on clusters of interacting receptors in the synaptic membrane. We show that such clusters can be metastable and that the lifetime of such clusters can be many orders of magnitude larger than the lifetime of the receptors of which they are composed. We also demonstrate how bidirectional synaptic plasticity can be implemented in this framework.

Computer Simulation↗
PubMed2005

Punishing and abstaining for public goods.

The evolution of cooperation within sizable groups of nonrelated humans offers many challenges for our understanding. Current research has highlighted two factors boosting cooperation in public goods interactions, namely, costly punishment of defectors and the option to abstain from the joint enterprise. A recent modeling approach has suggested that the autarkic option acts as a catalyzer for the ultimate fixation of altruistic punishment. We present an alternative, more microeconomically based model that yields a bistable outcome instead. Evolutionary dynamics can lead either to a Nash equilibrium of punishing and nonpunishing cooperators or to an oscillating state without punishers.

Altruism↗
PubMed2006

Evaluation of synthetic linear motor-molecule actuation energetics.

By applying atomic force microscope (AFM)-based force spectroscopy together with computational modeling in the form of molecular force-field simulations, we have determined quantitatively the actuation energetics of a synthetic motor-molecule. This multidisciplinary approach was performed on specifically designed, bistable, redox-controllable [2]rotaxanes to probe the steric and electrostatic interactions that dictate their mechanical switching at the single-molecule level. The fusion of experimental force spectroscopy and theoretical computational modeling has revealed that the repulsive electrostatic interaction, which is responsible for the molecular actuation, is as high as 65 kcal.mol(-1), a result that is supported by ab initio calculations.

Microscopy, Atomic Force↗
PubMed2003

Prediction and measurement of an autoregulatory genetic module.

The deduction of phenotypic cellular responses from the structure and behavior of complex gene regulatory networks is one of the defining challenges of systems biology. This goal will require a quantitative understanding of the modular components that constitute such networks. We pursued an integrated approach, combining theory and experiment, to analyze and describe the dynamics of an isolated genetic module, an in vivo autoregulatory gene network. As predicted by the model, temperature-induced protein destabilization led to the existence of two expression states, thus elucidating the trademark bistability of the positive feedback-network architecture. After sweeping the temperature, observed population distributions and coefficients of variation were in quantitative agreement with those predicted by a stochastic version of the model. Because model fluctuations originated from small molecule-number effects, the experimental validation underscores the importance of internal noise in gene expression. This work demonstrates that isolated gene networks, coupled with proper quantitative descriptions, can elucidate key properties of functional genetic modules. Such an approach could lead to the modular dissection of naturally occurring gene regulatory networks, the deduction of cellular processes such as differentiation, and the development of engineered cellular control.

Cell Differentiation↗
PubMed2002

GATA-3 transcriptional imprinting in Th2 lymphocytes: a mathematical model.

Immunological memory involves the fast recall of cytokine expression by T helper (Th) lymphocytes. Two distinct profiles of cytokine expression, Th1 and Th2, can be induced by antigen and polarizing signals during activation of naive Th cells and can subsequently be reexpressed on stimulation by antigen alone. The transcription factor GATA-3 induces Th2 development. GATA-3 is activated by the Th2-polarizing stimulus, IL-4, and has recently been observed to autoactivate its transcription. Based on these experimental data, we developed a mathematical model of GATA-3 expression that assumes independent activation of GATA-3 transcription by IL-4 and by GATA-3. Cooperativity of GATA-3 transcriptional activation is shown to create a threshold for autoactivation, resulting in the coexistence of two distinct GATA-3 expression states: a state of basal expression and a state of high expression sustained by autoactivation. Suprathreshold IL-4 signals induce a transition from basal to high GATA-3 expression. Thus, GATA-3 autoactivation creates a bistable system that can memorize a transient inductive signal. The model further predicts conditions under which the state of high GATA-3 expression can be abolished, which may extinguish the Th2 cytokine memory.

Animals↗
PubMed2001

Intrinsic noise in gene regulatory networks.

Cells are intrinsically noisy biochemical reactors: low reactant numbers can lead to significant statistical fluctuations in molecule numbers and reaction rates. Here we use an analytic model to investigate the emergent noise properties of genetic systems. We find for a single gene that noise is essentially determined at the translational level, and that the mean and variance of protein concentration can be independently controlled. The noise strength immediately following single gene induction is almost twice the final steady-state value. We find that fluctuations in the concentrations of a regulatory protein can propagate through a genetic cascade; translational noise control could explain the inefficient translation rates observed for genes encoding such regulatory proteins. For an autoregulatory protein, we demonstrate that negative feedback efficiently decreases system noise. The model can be used to predict the noise characteristics of networks of arbitrary connectivity. The general procedure is further illustrated for an autocatalytic protein and a bistable genetic switch. The analysis of intrinsic noise reveals biological roles of gene network structures and can lead to a deeper understanding of their evolutionary origin.

Gene Expression Regulation↗
PubMed1988

Molecular model for receptor-stimulated calcium spiking.

Many cells exhibit periodic transient increases in cytosolic calcium levels rather than a sustained rise when stimulated by a hormone or growth factor. We propose here a molecular model that accounts for periodic calcium spiking induced by a constant stimulus. Four elements give rise to repetitive calcium transients: cooperativity and positive feedback between a pair of reciprocally coupled (crosscoupled) messengers, followed by deactivation and then by reactivation. The crosscoupled messengers in our model are inositol 1,4,5-trisphosphate (InsP3) and cytosolic calcium ions. The opening of calcium channels in the endoplasmic reticulum by the binding of multiple molecules of InsP3 provides the required cooperativity. The stimulation of receptor-activated phospholipase C by released calcium ions leads to positive feedback. InsP3 is destroyed by a phosphatase, and calcium ion is pumped back into the endoplasmic reticulum. These processes generate bistability: the cytosolic calcium concentration abruptly increases from a basal level to a stimulated level at a threshold degree of activation of phospholipase C. Spiking further requires slow deactivation and subsequent reactivation. In our model, mitochondrial sequestration of calcium ion prevents the cytosolic level from increasing above several micromolar and enables the system to return to the basal state. When the endoplasmic reticulum calcium store is refilled to a critical level by the Ca2+-ATPase pump, cooperative positive feedback between the InsP3-gated channel and phospholipase C begins again to give the next calcium spike. The time required for the calcium level in the endoplasmic reticulum to reach a threshold sets the interval between spikes. The amplitude, shape, and period of calcium spikes calculated for this model are like those observed experimentally.

Calcium↗
PubMed1988

Feasibility of long-term storage of graded information by the Ca2+/calmodulin-dependent protein kinase molecules of the postsynaptic density.

The feasibility of long-term information storage by brain type II Ca2+/calmodulin-dependent protein kinase molecules is explored. Recent evidence indicates that this protein has switch-like properties. Equations are derived showing that a single kinase holoenzyme could form a bistable switch having the stability necessary to encode long-term memory, and that a group of kinase molecules, such as that contained within the postsynaptic density, could form a device capable of storing graded information.

Calcium↗
PubMed1990

Conditions that alter intracellular cAMP levels affect expression of the cAMP phosphodiesterase gene in Dictyostelium.

We examined expression of the Dictyostelium cAMP phosphodiesterase (PDE) gene under conditions that alter intracellular cAMP levels during in vitro differentiation of wild-type strain V12M2 and a sporogenous derivative, HB200. In control cultures, cellular PDE activity peaked at 6 hr and declined by 8 hr, while secreted PDE activity continued to increase through 8 hr. Lowering intracellular cAMP levels with caffeine or progesterone increased cellular and secreted PDE activities 2-fold, increased stalk cell differentiation, and inhibited spore differentiation. In contrast, exposure to 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP; a membrane-permeable cAMP analog) or ammonia (which promotes intracellular cAMP accumulation in V12M2 and HB200 cells) lowered PDE activities by as much as 45%, decreased stalk cell differentiation, and increased spore differentiation. Simultaneous exposure to 8-Br-cAMP and caffeine gave intermediate PDE activities as would be expected if 8-Br-cAMP entered the cell and bypassed the caffeine-mediated block to adenylate cyclase activation. In all cases, we observed commensurate changes in developmental PDE transcript levels. The developmental time course of expression was not significantly altered by these treatments. These results suggest that the magnitude of PDE gene expression is negatively regulated by intracellular cAMP levels and provide evidence for one of the earliest changes in gene expression that is consistent with cell-type specificity. These results are discussed in terms of a bistable switch employing intracellular cAMP as a regulator of cell fate.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1997

An endogenous calcium oscillator may control early embryonic division.

Transient elevations in the concentration of free cytosolic calcium ion ([Ca2+]i) promote cell phase transitions in early embryonic division and persist even if these transitions are blocked. These observations suggest that a [Ca2+]i oscillator is an essential timing element of the early embryonic "master clock." We explore this possibility by coupling a [Ca2+]i oscillator model to an early embryonic cell cycle model based on the protein interactions that govern the activity of the M-phase-promoting factor (MPF). We hypothesize three dynamical states of the MPF system and choose parameter sets to represent each. We then investigate how [Ca2+]i dynamics may control early embryonic division in both sea urchin and Xenopus embryos. To investigate both systems, distinct [Ca2+]i profiles matching those observed in sea urchin embryos (in which [Ca2+]i exhibits sharp transients) and Xenopus embryos (in which [Ca2+]i is elevated and oscillates sinusoidally) are imposed on each of the hypothesized dynamical states of MPF. In the first hypothesis, [Ca2+]i oscillations entrain the autonomous MPF oscillator. In the second and third hypotheses, where the MPF system rests in excitatory and bistable states, respectively, [Ca2+]i oscillations drive MPF activation cycles. Simulation results show that hypotheses two and three, in which a [Ca2+]i oscillator is a fundamental timing element of the master clock, best account for key experimental observations and the questions that they raise. Finally, we propose experiments to elucidate further [Ca2+]i regulation and the fundamental components of the early embryonic master clock.

Animals↗
PubMed1999

Continuous and lurching traveling pulses in neuronal networks with delay and spatially decaying connectivity.

Propagation of discharges in cortical and thalamic systems, which is used as a probe for examining network circuitry, is studied by constructing a one-dimensional model of integrate-and-fire neurons that are coupled by excitatory synapses with delay. Each neuron fires only one spike. The velocity and stability of propagating continuous pulses are calculated analytically. Above a certain critical value of the constant delay, these pulses lose stability. Instead, lurching pulses propagate with discontinuous and periodic spatio-temporal characteristics. The parameter regime for which lurching occurs is strongly affected by the footprint (connectivity) shape; bistability may occur with a square footprint shape but not with an exponential footprint shape. For strong synaptic coupling, the velocity of both continuous and lurching pulses increases logarithmically with the synaptic coupling strength g(syn) for an exponential footprint shape, and it is bounded for a step footprint shape. We conclude that the differences in velocity and shape between the front of thalamic spindle waves in vitro and cortical paroxysmal discharges stem from their different effective delay; in thalamic networks, large effective delay between inhibitory neurons arises from their effective interaction via the excitatory cells which display postinhibitory rebound.

Axons↗