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PubMed2026

The value of a prophage-borne defense system in phage-phage competition.

Temperate phages that incorporate into their bacterial hosts' genomes often encode defense systems that protect their hosts from superinfection by unrelated phages. Yet the evolutionary value of such defenses to the phage remains unclear. We present a minimal theoretical framework to quantify the selective advantage of a prophage-borne defense system in competition between temperate phages infecting the same bacterial host. The model reveals regimes in which a "defensive phage" can invade and persist despite growth costs, regimes of bistability, and others in which all phage types coexist due to a rock-paper-scissors-like dynamic between defensive, non-defensive, and defense-loss variants. Because defense systems can be non-transitive, true rock-paper-scissors relations can lead to persistent oscillations. These results identify simple conditions under which phage-encoded defense systems are evolutionarily stable, providing testable predictions for the prevalence and maintenance of these systems in natural microbial communities.

Prophages↗

PubMed2006

Adaptive response of a gene network to environmental changes by fitness-induced attractor selection.

Cells switch between various stable genetic programs (attractors) to accommodate environmental conditions. Signal transduction machineries efficiently convey environmental changes to the gene regulation apparatus in order to express the appropriate genetic program. However, since the number of environmental conditions is much larger than that of available genetic programs so that the cell may utilize the same genetic program for a large set of conditions, it may not have evolved a signaling pathway for every environmental condition, notably those that are rarely encountered. Here we show that in the absence of signal transduction, switching to the appropriate attractor state expressing the genes that afford adaptation to the external condition can occur. In a synthetic bistable gene switch in Escherichia coli in which mutually inhibitory operons govern the expression of two genes required in two alternative nutritional environments, cells reliably selected the "adaptive attractor" driven by gene expression noise. A mathematical model suggests that the "non-adaptive attractor" is avoided because in unfavorable conditions, cellular activity is lower, which suppresses mRNA metabolism, leading to larger fluctuations in gene expression. This, in turn, renders the non-adaptive state less stable. Although attractor selection is not as efficient as signal transduction via a dedicated cascade, it is simple and robust, and may represent a primordial mechanism for adaptive responses that preceded the evolution of signaling cascades for the frequently encountered environmental changes.

Adaptation, Biological↗

PubMed2005

Neuromagnetic correlates of streaming in human auditory cortex.

The brain is constantly faced with the challenge of organizing acoustic input from multiple sound sources into meaningful auditory objects or perceptual streams. The present study examines the neural bases of auditory stream formation using neuromagnetic and behavioral measures. The stimuli were sequences of alternating pure tones, which can be perceived as either one or two streams. In the first experiment, physical stimulus parameters were varied between values that promoted the perceptual grouping of the tone sequence into one coherent stream and values that promoted its segregation into two streams. In the second experiment, an ambiguous tone sequence produced a bistable percept that switched spontaneously between one- and two-stream percepts. The first experiment demonstrated a strong correlation between listeners' perception and long-latency (>60 ms) activity that likely arises in nonprimary auditory cortex. The second demonstrated a covariation between this activity and listeners' perception in the absence of physical stimulus changes. Overall, the results indicate a tight coupling between auditory cortical activity and streaming perception, suggesting that an explicit representation of auditory streams may be maintained within nonprimary auditory areas.

Acoustic Stimulation↗

PubMed2005

NMDA/AMPA ratio impacts state transitions and entrainment to oscillations in a computational model of the nucleus accumbens medium spiny projection neuron.

We describe a computational model of the principal cell in the nucleus accumbens (NAcb), the medium spiny projection (MSP) neuron. The model neuron, constructed in NEURON, includes all of the known ionic currents in these cells and receives synaptic input from simulated spike trains via NMDA, AMPA, and GABAA receptors. After tuning the model by adjusting maximal current conductances in each compartment, the model cell closely matched whole-cell recordings from an adult rat NAcb slice preparation. Synaptic inputs in the range of 1000-1300 Hz are required to maintain an "up" state in the model. Cell firing in the model required concurrent depolarization of several dendritic branches, which responded independently to afferent input. Depolarization from action potentials traveled to the tips of the dendritic branches and increased Ca2+ influx through voltage-gated Ca2+ channels. As NMDA/AMPA current ratios were increased, the membrane showed an increase in hysteresis of "up" and "down" state dwell times, but intrinsic bistability was not observed. The number of oscillatory inputs required to entrain the model cell was determined to be approximately 20% of the "up" state inputs. Altering the NMDA/AMPA ratio had a profound effect on processing of afferent input, including the ability to entrain to oscillations in afferent input in the theta range (4-12 Hz). These results suggest that afferent information integration by the NAcb MSP cell may be compromised by pathology in which the NMDA current is altered or modulated, as has been proposed in both schizophrenia and addiction.

Animals↗

PubMed2006

The continuous wagon wheel illusion is associated with changes in electroencephalogram power at approximately 13 Hz.

Continuously moving objects sometimes appear to spontaneously reverse their motion direction. The mechanisms underlying this bistable phenomenon (the "continuous wagon wheel illusion") are heavily debated, but one interpretation suggests that motion information is perceived in discrete episodes at a rate between 10 and 15 Hz. Here, we asked observers to report the perceived direction of a continuously rotating wheel while 32-channel electroencephalogram (EEG) was recorded. We then separated periods of perceived true from illusory (reversed) motion and compared the EEG power spectrum under these two perceptually distinct yet physically identical conditions. The only reliable difference was observed approximately 13 Hz over centroparietal electrodes, independent of the temporal frequency of the wheel. Thus, it is likely to reflect internal processes rather than purely stimulus-driven activity. EEG power (13 Hz) decreased before the onset of illusory motion and increased before transitions back to real motion. Using this relationship, it was possible to predict above chance, on a trial-by-trial basis, the direction of the upcoming perceptual transition. These data are compatible with the idea that motion perception occurs in snapshots <100 ms in duration.

Adult↗

PubMed2004

Long-residency hydration, cation binding, and dynamics of loop E/helix IV rRNA-L25 protein complex.

Molecular dynamics simulations of RNA-protein complex between Escherichia coli loop E/helix IV (LE/HeIV) rRNA and L25 protein reveal a qualitative agreement between the experimental and simulated structures. The major groove of LE is a prominent rRNA cation-binding site. Divalent cations rigidify the LE major groove geometry whereas in the absence of divalent cations LE extensively interacts with monovalent cations via inner-shell binding. The HeIV region shows bistability of its major groove explaining the observed differences between x-ray and NMR structures. In agreement with the experiments, the simulations suggest that helix-alpha1 of L25 is the least stable part of the protein. Inclusion of Mg2+ cations into the simulations causes perturbation of basepairing at the LE/HeIV junction, which does not, however, affect the protein binding. The rRNA-protein complex is mediated by a number of highly specific hydration sites with long-residing water molecules and two of them are bound throughout the entire 24-ns simulation. Long-residing water molecules are seen also outside the RNA-protein contact areas with water-binding times substantially enhanced compared to simulations of free RNA. Long-residency hydration sites thus represent important elements of the three-dimensional structure of rRNA.

Binding Sites↗

PubMed2004

Calcium and glycolysis mediate multiple bursting modes in pancreatic islets.

Pancreatic islets of Langerhans produce bursts of electrical activity when exposed to stimulatory glucose levels. These bursts often have a regular repeating pattern, with a period of 10-60 s. In some cases, however, the bursts are episodic, clustered into bursts of bursts, which we call compound bursting. Consistent with this are recordings of free Ca2+ concentration, oxygen consumption, mitochondrial membrane potential, and intraislet glucose levels that exhibit very slow oscillations, with faster oscillations superimposed. We describe a new mathematical model of the pancreatic beta-cell that can account for these multimodal patterns. The model includes the feedback of cytosolic Ca2+ onto ion channels that can account for bursting, and a metabolic subsystem that is capable of producing slow oscillations driven by oscillations in glycolysis. This slow rhythm is responsible for the slow mode of compound bursting in the model. We also show that it is possible for glycolytic oscillations alone to drive a very slow form of bursting, which we call "glycolytic bursting." Finally, the model predicts that there is bistability between stationary and oscillatory glycolysis for a range of parameter values. We provide experimental support for this model prediction. Overall, the model can account for a diversity of islet behaviors described in the literature over the past 20 years.

Animals↗

PubMed2005

Sensitivity analysis of discrete stochastic systems.

Sensitivity analysis quantifies the dependence of system behavior on the parameters that affect the process dynamics. Classical sensitivity analysis, however, does not directly apply to discrete stochastic dynamical systems, which have recently gained popularity because of its relevance in the simulation of biological processes. In this work, sensitivity analysis for discrete stochastic processes is developed based on density function (distribution) sensitivity, using an analog of the classical sensitivity and the Fisher Information Matrix. There exist many circumstances, such as in systems with multistability, in which the stochastic effects become nontrivial and classical sensitivity analysis on the deterministic representation of a system cannot adequately capture the true system behavior. The proposed analysis is applied to a bistable chemical system--the Schlögl model, and to a synthetic genetic toggle-switch model. Comparisons between the stochastic and deterministic analyses show the significance of explicit consideration of the probabilistic nature in the sensitivity analysis for this class of processes.

Algorithms↗

PubMed2006

Bifurcation and singularity analysis of a molecular network for the induction of long-term memory.

Withdrawal reflexes of the mollusk Aplysia exhibit sensitization, a simple form of long-term memory (LTM). Sensitization is due, in part, to long-term facilitation (LTF) of sensorimotor neuron synapses. LTF is induced by the modulatory actions of serotonin (5-HT). Pettigrew et al. developed a computational model of the nonlinear intracellular signaling and gene network that underlies the induction of 5-HT-induced LTF. The model simulated empirical observations that repeated applications of 5-HT induce persistent activation of protein kinase A (PKA) and that this persistent activation requires a suprathreshold exposure of 5-HT. This study extends the analysis of the Pettigrew model by applying bifurcation analysis, singularity theory, and numerical simulation. Using singularity theory, classification diagrams of parameter space were constructed, identifying regions with qualitatively different steady-state behaviors. The graphical representation of these regions illustrates the robustness of these regions to changes in model parameters. Because persistent protein kinase A (PKA) activity correlates with Aplysia LTM, the analysis focuses on a positive feedback loop in the model that tends to maintain PKA activity. In this loop, PKA phosphorylates a transcription factor (TF-1), thereby increasing the expression of an ubiquitin hydrolase (Ap-Uch). Ap-Uch then acts to increase PKA activity, closing the loop. This positive feedback loop manifests multiple, coexisting steady states, or multiplicity, which provides a mechanism for a bistable switch in PKA activity. After the removal of 5-HT, the PKA activity either returns to its basal level (reversible switch) or remains at a high level (irreversible switch). Such an irreversible switch might be a mechanism that contributes to the persistence of LTM. The classification diagrams also identify parameters and processes that might be manipulated, perhaps pharmacologically, to enhance the induction of memory. Rational drug design, to affect complex processes such as memory formation, can benefit from this type of analysis.

Algorithms↗

PubMed2006

Mechanical unfolding of RNA: from hairpins to structures with internal multiloops.

Mechanical unfolding of RNA structures, ranging from hairpins to ribozymes, using laser optical tweezer experiments have begun to reveal the features of the energy landscape that cannot be easily explored using conventional experiments. Upon application of constant force (f), RNA hairpins undergo cooperative transitions from folded to unfolded states whereas subdomains of ribozymes unravel one at a time. Here, we use a self-organized polymer model and Brownian dynamics simulations to probe mechanical unfolding at constant force and constant-loading rate of four RNA structures of varying complexity. For simple hairpins, such as P5GA, application of constant force or constant loading rate results in bistable cooperative transitions between folded and unfolded states without populating any intermediates. The transition state location (DeltaxFTS) changes dramatically as the loading rate is varied. At loading rates comparable to those used in laser optical tweezer experiments, the hairpin is plastic, with DeltaxFTS being midway between folded and unfolded states; whereas at high loading rates, DeltaxFTS moves close to the folded state, i.e., RNA is brittle. For the 29-nucleotide TAR RNA with the three-nucleotide bulge, unfolding occurs in a nearly two-state manner with an occasional pause in a high free energy metastable state. Forced unfolding of the 55 nucleotides of the Hepatitis IRES domain IIa, which has a distorted L-shaped structure, results in well-populated stable intermediates. The most stable force-stabilized intermediate represents straightening of the L-shaped structure. For these structures, the unfolding pathways can be predicted using the contact map of the native structures. Unfolding of a RNA motif with internal multiloop, namely, the 109-nucleotide prohead RNA that is part of the 29 DNA packaging motor, at constant value of rf occurs with three distinct rips that represent unraveling of the paired helices. The rips represent kinetic barriers to unfolding. Our work shows 1), the response of RNA to force is largely determined by the native structure; and 2), only by probing mechanical unfolding over a wide range of forces can the underlying energy landscape be fully explored.

Computer Simulation↗

PubMed1980

Gray scale ultrasound of the parotid gland.

Gray scale ultrasonography permits markedly improved visualization of the parotid gland compared with bistable methods. The normal parotid is echogenic, similar in echo generation to thyroid tissue, but flatter anatomically. Ultrasound can detect a mass lesion in the area of the parotid gland and define whether it is intrinsic or extrinsic, but as yet has limited usefulness in determining the specificity of an abnormality.

Adenolymphoma↗

PubMed1983

Low-cost digital teleradiology systems.

The proliferation of digital imaging methods creates a need for systems that facilitate storage and retrieval of these images. Several low-cost systems with the capability to store, retrieve, and transmit digital images from the medical center to distant general-purpose desktop microcomputers over standard telephone lines were investigated. Using error checking and nonlinear gray scales, both bistable and gray scale display systems were able to transmit and reproduce diagnostic quality images. The major limitations are the lack of low-cost digital mass-storage devices and relatively slow transmission times.

Information Systems↗

PubMed1982

Perception of eye scans with the Müller-Lyer stimuli: evidence for filter theory.

Ginsburg's filter theory successfully accounts for the perceptual distortions perceived in a wide range of illusions and bistable phenomena. Essentially, the theory proposes that illusory distortions are the natural consequence of low-pass spatial filtering (based upon the human modulation transfer function) of the physical stimulus. With regard to the Müller-Lyer illusion, predictions based upon filter theory and human scan-path data are in accord. However, data linking filter theory's predictions regarding perceptual experiences associated with the illusion to the eye-scan results have been missing. In the present experiment subjects provided subjective estimations of their own eye scans while viewing each of the following stimuli: the fins-out member of the Müller-Lyer illusion, the fins-in member of the Müller-Lyer illusion, and a finless horizontal line (variations of each stimulus consisted of one, two, and three line segments). The analysis of these data supported three predictions that were derived from filter theory. Potential problems facing filter theory are also addressed.

Adolescent↗

PubMed1995

Temporal factors in visual perception: a differential approach.

The tradition in sensory and perceptual psychology is not to pay much attention to individual differences but to focus almost exclusively on normative or generic processes. Nevertheless, consistent individual differences may exist in sensory and perceptual processes, just as they do in all other areas of human behavior where their existence has been investigated. A preliminary study was made of flicker fusion frequency, apparent movement, and three other perceptual tasks as differential measures. With one exception, Letter Search, all of the tests were psychophysical rather than cognitive. All had to do with time; that is, perceptual speed mattered in all of them. The analysis focused on reliability, in the sense of consistency from trial to trial. Four of the five tests showed good reliabilities in this sense, while the fifth was borderline. In one test, Bistable Stroboscopic Motion, the dependent measure, interstimulus interval, showed a consistent though shallow tendency to lengthen with practice. In the remaining four tests practice effects were largely confined to the first two administrations.

Adult↗

PubMed1998

Effects of alcohol on perceptual speed.

In moderate to heavy doses, alcohol adversely affects performance on many tasks, and perceptual speed is a component in most performance tasks. Nevertheless, studies of alcohol's effects on perceptual speed have been largely limited to critical flicker frequency and backward masking. The present study extends these limits. 16 men and 12 women were administered four temporal-factors tests before and after the ingestion of alcohol. The four tests were Simultaneity, Apparent Movement, Bistable Stroboscopic Motion, and Backward Masking. At the first postalcohol testing (mean BAC = 0.111), all four tests showed pre-posttest changes indicating slowed perceptual speed. Perceptual speed was still slowed when BAC decreased to .096. When mean BAC decreased to .076, however, only Simultaneity and Backward Masking were still significantly slowed. At moderate BACs and possibly at lower ones, the effects of alcohol on task performance appear to be mediated in part by slowed perceptual speed.

Adult↗

PubMed1999

Background spatial frequency influences perception of luminance-based apparent movement.

Apparent movement occurs when stimulus figures are presented at different spatial locations at different times. In the present studies, the periodicity of the background upon which stimuli were presented was manipulated. Subjects viewed a bistable movement display presented on a background consisting of a variable-frequency grating. The type of movement perceived varied systematically with the spatial frequency of the background, suggesting that more than the target stimuli are processed in the generation of apparent movement.

Adolescent↗

PubMed1980

The Teorell membrane oscillator--a complete nerve model.

The membrane oscillator discovered by T. Teorell in 1954 (10) is one of the most remarkable kinetic systems exhibiting spontaneous periodic behaviour under constant environmental conditions. It can be shown and demonstrated experimentally that the intrinsic reason for the occurrence of oscillations in the Teorell oscillator, like in other physicochemical and biological oscillatory systems, is an appropriate antagonistic action of a labilizing positive and a recovering stabilizing negative feedback. Each kind of feedback causes a group of characteristic temporal phenomena, which are observed in all oscillatory systems including the living excitable nerve such as: instability, bistability, excitability, propagation of exitation and recovery, refractoriness, abolition, accommodation etc..

Cell Membrane Permeability↗

PubMed2006

Linking dynamical perceptual decisions at different levels of description in motion pattern formation: computational simulations.

A two-level dynamical model of motion pattern formation is developed in which local motion/ nonmotion perceptual decisions are based on inhibitory competition between area V1 detectors responsive to motion-specifying versus motion-independent stimulus information, and pattern-level perceptual decisions are based on inhibitory competition between area MT motion detectors with orthogonal directional selectivity. The model accounts for the effects of luminance perturbations on the relative size of the pattern-level hysteresis effects reported by Hock and Ploeger (2006) and also accounts for related experimental results reported by Hock, Kelso, and Schöner (1993). Single-trial simulations demonstrated the crucial role of local motion/nonmotion bistability and activation-dependent future-shaping interactions in stabilizing perceived global motion patterns. Such interactions maintain currently perceived motion patterns by inhibiting the soon-to-be-stimulated motion detectors that otherwise would be the basis for the perception of an alternative pattern.

Computer Simulation↗