In vivo kinetics of murine hemopoietic stem cells.
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We used stochastic modeling and computer simulation to study the replication, apoptosis, and differentiation of murine hemopoietic stem cells (HSCs) in vivo. This approach allows description of the behavior of an unobserved population (ie, HSCs) on the basis of the behavior of observed progeny cells (ie, granulocytes and lymphocytes). The results of previous limiting-dilution, competitive-repopulation studies in 44 mice were compared with the results of simulated transplantation studies to identify parameters that led to comparable outcomes. Using this approach, we estimated that murine HSCs replicate (on average) once every 2.5 weeks and that the frequency of murine HSCs is 8 per 10(5) nucleated marrow cells. If it is assumed that short-term repopulating cells are distinct from HSCs, that they contribute to hemopoiesis early after transplantation, and that they are independently regulated, a frequency of 4 HSCs per 10(5) nucleated marrow cells also allows simulations that best approximate the observed data. When stochastic modeling and computer simulation were applied to limiting-dilution, autologous-transplantation studies in cats heterozygous for glucose-6-phosphate-dehydrogenase, different estimates of HSC replication rate (1 per 8.3-10 weeks) and frequency (6 per 10(7) cells) were derived. Therefore, it appears that these parameters vary inversely with increased longevity, size, or both. An implication of these data is that human HSCs may be less frequent and replicate more slowly. These findings on cell kinetics have several implications. (+info)
The evolutionary fate and consequences of duplicate genes.
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Gene duplication has generally been viewed as a necessary source of material for the origin of evolutionary novelties, but it is unclear how often gene duplicates arise and how frequently they evolve new functions. Observations from the genomic databases for several eukaryotic species suggest that duplicate genes arise at a very high rate, on average 0.01 per gene per million years. Most duplicated genes experience a brief period of relaxed selection early in their history, with a moderate fraction of them evolving in an effectively neutral manner during this period. However, the vast majority of gene duplicates are silenced within a few million years, with the few survivors subsequently experiencing strong purifying selection. Although duplicate genes may only rarely evolve new functions, the stochastic silencing of such genes may play a significant role in the passive origin of new species. (+info)
A moment closure model for sexually transmitted disease transmission through a concurrent partnership network.
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A moment closure model of sexually transmitted disease spread through a concurrent partnership network is developed. The model employs pair approximations of higher-order correlations to derive equations of motion in terms of numbers of pairs and singletons. The model is derived from an underlying stochastic process of partnership network formation and disease transmission. The model is analysed numerically; and the final size and time evolution are considered for various levels of concurrency, as measured by the concurrency index kappa3 of Kretzschmar and Morris. Additionally, a new way of calculating R0 for spatial network models is developed. It is found that concurrency significantly increases R0 and the final size of a sexually transmitted disease, with some interesting exceptions. (+info)
Dyssynchronous Ca(2+) sparks in myocytes from infarcted hearts.
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The kinetics of contractions and Ca(2+) transients are slowed in myocytes from failing hearts. The mechanisms accounting for these abnormalities remain unclear. Myocardial infarction (MI) was produced by ligation of the circumflex artery in rabbits. We used confocal microscopy to record spatially resolved Ca(2+) transients during field stimulation in left ventricular (LV) myocytes from control and infarcted hearts (3 weeks). Compared with controls, Ca(2+) transients in myocytes adjacent to the infarct had lower peak amplitudes and prolonged time courses. Control myocytes showed relatively uniform changes in [Ca(2+)] throughout the cell after electrical stimulation. In contrast, in MI myocytes [Ca(2+)] increased inhomogeneously and localized increases in [Ca(2+)] occurred throughout the rising and falling phases of the Ca(2+) transient. Ca(2+) content of the sarcoplasmic reticulum did not differ between MI and control myocytes. Peak L-type Ca(2+) current density was reduced in MI myocytes. The macroscopic gain function was not different in control and MI myocytes when calculated as the amplitude of the Ca(2+) transient/peak I:(Ca). However, when calculated as the peak rate of rise of the Ca(2+) transient/peak I:(Ca), the gain function was modestly decreased in the MI myocytes. Application of isoproterenol (100 nmol/L) improved the synchronization of Ca(2+) release in MI myocytes at both 0.5 and 1 Hz. The poorly coordinated production of Ca(2+) sparks in myocytes from infarcted rabbit hearts likely contributes to the diminished and slowed macroscopic Ca(2+) transient. These abnormalities can be largely overcome when phosphorylation of Ca(2+) cycling proteins is enhanced by ss-adrenergic stimulation. (+info)
Reinterpreting space, time lags, and functional responses in ecological models.
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Natural enemy-victim interactions are of major applied importance and of fundamental interest to ecologists. A key question is what stabilizes these interactions, allowing the long-term coexistence of the two species. Three main theoretical explanations have been proposed: behavioral responses, time-dependent factors such as delayed density dependence, and spatial heterogeneity. Here, using the powerful moment-closure technique, we show a fundamental equivalence between these three elements. Limited movement by organisms is a ubiquitous feature of ecological systems, allowing spatial structure to develop; we show that the effects of this can be naturally described in terms of time lags or within-generation functional responses. (+info)
Stable Hebbian learning from spike timing-dependent plasticity.
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We explore a synaptic plasticity model that incorporates recent findings that potentiation and depression can be induced by precisely timed pairs of synaptic events and postsynaptic spikes. In addition we include the observation that strong synapses undergo relatively less potentiation than weak synapses, whereas depression is independent of synaptic strength. After random stimulation, the synaptic weights reach an equilibrium distribution which is stable, unimodal, and has positive skew. This weight distribution compares favorably to the distributions of quantal amplitudes and of receptor number observed experimentally in central neurons and contrasts to the distribution found in plasticity models without size-dependent potentiation. Also in contrast to those models, which show strong competition between the synapses, stable plasticity is achieved with little competition. Instead, competition can be introduced by including a separate mechanism that scales synaptic strengths multiplicatively as a function of postsynaptic activity. In this model, synaptic weights change in proportion to how correlated they are with other inputs onto the same postsynaptic neuron. These results indicate that stable correlation-based plasticity can be achieved without introducing competition, suggesting that plasticity and competition need not coexist in all circuits or at all developmental stages. (+info)
Reliability of a fly motion-sensitive neuron depends on stimulus parameters.
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The variability of responses of sensory neurons constrains how reliably animals can respond to stimuli in the outside world. We show for a motion-sensitive visual interneuron of the fly that the variability of spike trains depends on the properties of the motion stimulus, although differently for different stimulus parameters. (1) The spike count variances of responses to constant and to dynamic stimuli lie in the same range. (2) With increasing stimulus size, the variance may slightly decrease. (3) Increasing pattern contrast reduces the variance considerably. For all stimulus conditions, the spike count variance is much smaller than the mean spike count and does not depend much on the mean activity apart from very low activities. Using a model of spike generation, we analyzed how the spike count variance depends on the membrane potential noise and the deterministic membrane potential fluctuations at the spike initiation zone of the neuron. In a physiologically plausible range, the variance is affected only weakly by changes in the dynamics or the amplitude of the deterministic membrane potential fluctuations. In contrast, the amplitude and dynamics of the membrane potential noise strongly influence the spike count variance. The membrane potential noise underlying the variability of the spike responses in the motion-sensitive neuron is concluded to be affected considerably by the contrast of the stimulus but by neither its dynamics nor its size. (+info)
Fluctuations in repressor control: thermodynamic constraints on stochastic focusing.
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The influence of fluctuations in molecule numbers on genetic control circuits has received considerable attention. The consensus has been that such fluctuations will make regulation less precise. In contrast, it has more recently been shown that signal fluctuations can sharpen the response in a regulated process by the principle of stochastic focusing (SF) (, Proc. Natl. Acad. Sci. USA. 97:7148-7153). In many cases, the larger the fluctuations are, the sharper is the response. Here we investigate how fluctuations in repressor or corepressor numbers can improve the control of gene expression. Because SF is found to be constrained by detailed balance, this requires that the control loops contain driven processes out of equilibrium. Some simple and realistic out-of-equilibrium steps that will break detailed balance and make room for SF in such systems are discussed. We conclude that when the active repressors are controlled by corepressor molecules that display large ("coherent") number fluctuations or when corepressors can be irreversibly removed directly from promoter-bound repressors, the response in gene activity can become significantly sharper than without intrinsic noise. A simple experimental design to establish the possibility of SF for repressor control is suggested. (+info)