Mechanisms of intrinsic beating variability in cardiac cell cultures and model pacemaker networks

Heart rate variability (HRV) exhibits fluctuations characterized by a power law behavior of its power spectrum. The interpretation of this nonlinear HRV behavior, resulting from interactions between extracardiac regulatory mechanisms, could be clinically useful. However, the involvement of intrinsic variations of pacemaker rate in HRV has scarcely been investigated. We examined beating variability in spontaneously active incubating cultures of neonatal rat ventricular myocytes using microelectrode arrays. In networks of mathematical model pacemaker cells, we evaluated the variability induced by the stochastic gating of transmembrane currents and of calcium release channels and by the dynamic turnover of ion channels. In the cultures, spontaneous activity originated from a mobile focus. Both the beat-to-beat movement of the focus and beat rate variability exhibited a power law behavior. In the model networks, stochastic fluctuations in transmembrane currents and stochastic gating of calcium release channels did not reproduce the spatiotemporal patterns observed in vitro. In contrast, long-term correlations produced by the turnover of ion channels induced variability patterns with a power law behavior similar to those observed experimentally. Therefore, phenomena leading to long-term correlated variations in pacemaker cellular function may, in conjunction with extracardiac regulatory mechanisms, contribute to the nonlinear characteristics of HRV.     

Beating irregularity of single pacemaker cells isolated from the rabbit sinoatrial node.

Single pacemaker heart cells discharge irregularly. Data on fluctuations in interbeat interval of single pacemaker cells isolated from the rabbit sinoatrial node are presented. The coefficient of variation of the interbeat interval is quite small, approximately 2%, even though the coefficient of variation of diastolic depolarization rate is approximately 15%. It has been hypothesized that random fluctuations in interbeat interval arise from the stochastic behavior of the membrane ionic channels. To test this hypothesis, we constructed a single channel model of a single pacemaker cell isolated from the rabbit sinoatrial node, i.e., a model into which the stochastic open-close kinetics of the individual membrane ionic channels are incorporated. Single channel conductances as well as single channel open and closed lifetimes are based on experimental data from whole cell and single channel experiments that have been published in the past decade. Fluctuations in action potential parameters of the model cell are compared with those observed experimentally. It is concluded that fluctuations in interbeat interval of single sinoatrial node pacemaker cells indeed are due to the stochastic open-close kinetics of the membrane ionic channels.     

Neutrophil influx during non-typhoidal salmonellosis: who is in the driver's seat?

A massive neutrophil influx in the intestine is the histopathological hallmark of Salmonella enterica serovar Typhimurium-induced enterocolitis in humans. Two major hypotheses on the mechanism leading to neutrophil infiltration in the intestinal mucosa have emerged. One hypothesis suggests that S. enterica serovar Typhimurium takes an active role in triggering this host response by injecting proteins, termed effectors, into the host cell cytosol which induce a proinflammatory gene expression profile in the intestinal epithelium. The second hypothesis suggests a more passive role for the pathogen by proposing that bacterial invasion stimulates the innate pathways of inflammation because the pathogen-associated molecular patterns of S. enterica serovar Typhimurium are recognized by pathogen recognition receptors on cells in the lamina propria. A review of the current literature reveals that, while pathogen recognition receptors are clearly involved in eliciting neutrophil influx during S. enterica serovar Typhimurium infection, a direct contribution of effectors in triggering proinflammatory host cell responses cannot currently be ruled out.     

Adding energy gradients and long‐distance dispersal to a neutral model improves predictions of Madagascan bird diversity

Macroecological patterns are likely the result of both stochastically neutral mechanisms and deterministic differences between species. In Madagascar, the simplest stochastically neutral hypothesis – the mid‐domain effects (MDE) hypothesis – has already been rejected. However, rejecting the MDE hypothesis does not necessarily refute the existence of all other neutral mechanisms. Here, we test whether adding complexity to a basic neutral model improves predictions of biodiversity patterns. The simplest MDE model assumes that: (1) species' ranges are continuous and unfragmented, (2) are randomly located throughout the landscape, and (3) can be stacked independently and indefinitely. We designed a simulation based on neutral theory that allowed us to weaken each of these assumptions incrementally by adjusting the habitat capacity as well as the likelihood of short‐ and long‐distance dispersal. Simulated outputs were compared to four empirical patterns of bird diversity: the frequency distributions of species richness and range size, the within‐island latitudinal diversity gradient, and the distance‐decay of species compositional similarity. Neutral models emulated empirical diversity patterns for Madagascan birds accurately. The frequency distribution of range size, latitudinal diversity gradient, and the distance‐decay of species compositional similarity could be attributed to stochastic long‐distance migration events and zero‐sum population dynamics. However, heterogenous environmental gradients improved predictions of the frequency distribution of species richness. Patterns of bird diversity in Madagascar can broadly be attributed to stochastic long‐distance migration events and zero‐sum population dynamics. This implies that rejecting simple hypotheses, such as MDE, does not serve as evidence against stochastic processes in general. However, environmental gradients were necessary to explain patterns of species richness and deterministic differences between species are probably important for explaining the distributions of narrow‐range and endemic species.     

Initiation of embryonic cardiac pacemaker activity by inositol 1,4,5-trisphosphate-dependent calcium signaling

In the adult, the heart rate is driven by spontaneous and repetitive depolarizations of pacemaker cells to generate a firing of action potentials propagating along the conduction system and spreading into the ventricles. In the early embryo before E9.5, the pacemaker ionic channel responsible for the spontaneous depolarization of cells is not yet functional. Thus the mechanisms that initiate early heart rhythm during cardiogenesis are puzzling. In the absence of a functional pacemaker ionic channel, the oscillatory nature of inositol 1,4,5-trisphosphate (InsP3)-induced intracellular Ca2+ signaling could provide an alternative pacemaking mechanism. To test this hypothesis, we have engineered pacemaker cells from embryonic stem (ES) cells, a model that faithfully recapitulates early stages of heart development. We show that InsP3-dependent shuttle of free Ca2+ in and out of the endoplasmic reticulum is essential for a proper generation of pacemaker activity during early cardiogenesis and fetal life.     

Niches versus neutrality: uncovering the drivers of diversity in a species-rich community

Ecological models suggest that high diversity can be generated by purely niche-based, purely neutral or by a mixture of niche-based and neutral ecological processes. Here, we compare the degree to which four contrasting hypotheses for coexistence, ranging from niche-based to neutral, explain species richness along a body mass niche axis. We derive predictions from these hypotheses and confront them with species body-mass patterns in a highly sampled marine phytoplankton community. We find that these patterns are consistent only with a mechanism that combines niche and neutral processes, such as the emergent neutrality mechanism. In this work, we provide the first empirical evidence that a niche-neutral model can explain niche space occupancy pattern in a natural species-rich community. We suggest this class of model may be a useful hypothesis for the generation and maintenance of species diversity in other size-structured communities.     

Repetitive activity of a branched Hodgkin-Huxley axon with multiple encoding sites

Afferent activity in a receptor afferent fiber with several encoding sites is generally believed to represent the activity of the fastest pacemaker that resets all more slowly encoding sites. Alternatively, some impulse mixing as well as some nonlinear summation of receptor current to a single encoder have been considered. In this article the repetitive firing activity of a Hodgkin-Huxley axon consisting of two branches that join into a single stem axon was investigated. The model axon was stimulated by constant-current injection into either the right or the left or both branches. It was found that the model axon generated an (infinite) train of action potentials if the input current was large enough. The discharge frequency found was constant, and on combined stimulation of both branches with different current, the site of impulse initiation was always in the branch receiving the higher input current, excluding a simple impulse mixing. On the other hand, the combined stimulation of both branches evoked repetitive firing with a higher frequency than expected by the pacemaker-resetting hypothesis. Moreover, a stimulus that is subthreshold for repetitive firing if injected into one branch yields repetitive firing when it is injected into both branches, a behavior inconsistent with impulse mixing and pacemaker resetting. On the other hand, current injection into one branch allowed repetitive activity only within a rather limited range of firing frequencies. Using distributed current injection into both branches, however, allowed many more different firing frequencies. Such behavior is inconsistent with both pacemaker resetting and (nonlinear) input current summation. Consequently, the repetitive firing behavior of a branched Hodgkin-Huxley axon with multiple encoding sites appears to be more complex than postulated in the simple hypotheses.     

Mechanistic Mathematical Modeling Tests Hypotheses of the Neurovascular Coupling in fMRI

Functional magnetic resonance imaging (fMRI) measures brain activity by detecting the blood-oxygen-level dependent (BOLD) response to neural activity. The BOLD response depends on the neurovascular coupling, which connects cerebral blood flow, cerebral blood volume, and deoxyhemoglobin level to neuronal activity. The exact mechanisms behind this neurovascular coupling are not yet fully investigated. There are at least three different ways in which these mechanisms are being discussed. Firstly, mathematical models involving the so-called Balloon model describes the relation between oxygen metabolism, cerebral blood volume, and cerebral blood flow. However, the Balloon model does not describe cellular and biochemical mechanisms. Secondly, the metabolic feedback hypothesis, which is based on experimental findings on metabolism associated with brain activation, and thirdly, the neurotransmitter feed-forward hypothesis which describes intracellular pathways leading to vasoactive substance release. Both the metabolic feedback and the neurotransmitter feed-forward hypotheses have been extensively studied, but only experimentally. These two hypotheses have never been implemented as mathematical models. Here we investigate these two hypotheses by mechanistic mathematical modeling using a systems biology approach; these methods have been used in biological research for many years but never been applied to the BOLD response in fMRI. In the current work, model structures describing the metabolic feedback and the neurotransmitter feed-forward hypotheses were applied to measured BOLD responses in the visual cortex of 12 healthy volunteers. Evaluating each hypothesis separately shows that neither hypothesis alone can describe the data in a biologically plausible way. However, by adding metabolism to the neurotransmitter feed-forward model structure, we obtained a new model structure which is able to fit the estimation data and successfully predict new, independent validation data. These results open the door to a new type of fMRI analysis that more accurately reflects the true neuronal activity.     

Stochastically Gating Ion Channels Enable Patterned Spike Firing through Activity-Dependent Modulation of Spike Probability

The transformation of synaptic input into patterns of spike output is a fundamental operation that is determined by the particular complement of ion channels that a neuron expresses. Although it is well established that individual ion channel proteins make stochastic transitions between conducting and non-conducting states, most models of synaptic integration are deterministic, and relatively little is known about the functional consequences of interactions between stochastically gating ion channels. Here, we show that a model of stellate neurons from layer II of the medial entorhinal cortex implemented with either stochastic or deterministically gating ion channels can reproduce the resting membrane properties of stellate neurons, but only the stochastic version of the model can fully account for perithreshold membrane potential fluctuations and clustered patterns of spike output that are recorded from stellate neurons during depolarized states. We demonstrate that the stochastic model implements an example of a general mechanism for patterning of neuronal output through activity-dependent changes in the probability of spike firing. Unlike deterministic mechanisms that generate spike patterns through slow changes in the state of model parameters, this general stochastic mechanism does not require retention of information beyond the duration of a single spike and its associated afterhyperpolarization. Instead, clustered patterns of spikes emerge in the stochastic model of stellate neurons as a result of a transient increase in firing probability driven by activation of HCN channels during recovery from the spike afterhyperpolarization. Using this model, we infer conditions in which stochastic ion channel gating may influence firing patterns in vivo and predict consequences of modifications of HCN channel function for in vivo firing patterns.     

The cellular basis of cell sorting kinetics

Cell sorting is a dynamical cooperative phenomenon that is fundamental for tissue morphogenesis and tissue homeostasis. According to Steinberg's differential adhesion hypothesis, the structure of sorted cell aggregates is determined by physical characteristics of the respective tissues, the tissue surface tensions. Steinberg postulated that tissue surface tensions result from quantitative differences in intercellular adhesion. Several experiments in cell cultures as well as in developing organisms support this hypothesis.The question of how tissue surface tension might result from differential adhesion was addressed in some theoretical models. These models describe the cellular interdependence structure once the temporal evolution has stabilized. In general, these models are capable of reproducing sorted patterns. However, the model dynamics at the cellular scale are defined implicitly and are not well-justified. The precise mechanism describing how differential adhesion generates the observed sorting kinetics at the tissue level is still unclear.It is necessary to formulate the concepts of cell level kinetics explicitly. Only then it is possible to understand the temporal development at the cellular and tissue scales. Here we argue that individual cell mobility is reduced the more the cells stick to their neighbors. We translate this assumption into a precise mathematical model which belongs to the class of stochastic interacting particle systems. Analyzing this model, we are able to predict the emergent sorting behavior at the population level. We describe qualitatively the geometry of cell segregation depending on the intercellular adhesion parameters. Furthermore, we derive a functional relationship between intercellular adhesion and surface tension and highlight the role of cell mobility in the process of sorting. We show that the interaction between the cells and the boundary of a confining vessel has a major impact on the sorting geometry.     

Masting,mixtures and modes: are two models better than one?

A key hypothesis in population ecology is that synchronous and intermittent seed production, known as mast seeding, is driven by the alternating allocation of carbohydrates and mineral nutrients between growth and reproduction in different years, i.e. ‘resource switching’. Such behaviour may ultimately generate bimodal distributions of long‐term flower and seed production, and evidence of these patterns has been taken to support the resource switching hypothesis. Here, we show how a widely‐used statistical test of bimodality applied by many studies in different ecological contexts may fail to reject the null hypothesis that focal probability distributions are unimodal. Using data from five tussock grass species in South Island, New Zealand, we find clear evidence of bimodality only when flowering patterns are analyzed with probabilistic mixture models. Mixture models provide a theory oriented framework for testing hypotheses of mast seeding patterns, enabling the different responses underlying medium‐ and high‐ versus non‐ and low‐flowering years to be modelled more realistically by associating these with distinct probability distributions. Coupling theoretical expectations with more rigorous statistical approaches will empower ecologists to reject null hypotheses more often.     

Morning sickness: adaptive cause or nonadaptive consequence of embryo viability?

"Morning sickness" is the common term for nausea and vomiting in early human pregnancy (NVP). Recent interest in why NVP occurs-that is, in the evolutionary costs and benefits of NVP-has spurred the development of two alternative hypotheses. The "prophylaxis," or "maternal and embryonic protection," hypothesis suggests that NVP serves a beneficial function by expelling foods that may contain harmful toxins and microorganisms and triggering aversions to such foods throughout pregnancy. The alternative "by-product" hypothesis suggests that NVP is a nonfunctional by-product of conflict--over resource allocation--between the pregnant woman and the embryo. The critical predictions of the prophylaxis hypothesis have been developed and tested, whereas the by-product hypothesis has not been subjected to similar scrutiny. To address this gap, we developed a graphical model and used it to derive predictions from the by-product hypothesis under two different assumptions, namely, that NVP is either (i) a by-product of current conflict between a pregnant woman and an embryo or (ii) a by-product of honest signals of viability produced by the embryo. Neither version of the by-product hypothesis is fully consistent with available data. By contrast, the timing of NVP, its variation among societies, and associated patterns of food cravings and aversions are consistent with the prophylaxis hypothesis.     

Conditions for the invasion of male‐haploidy in diploid populations

Male‐haploidy has independently evolved several times in different phylogenetic groups and has led to various extant lineages in the insects, Arachnida and Rotifera. Although the stability of male‐haploidy as an evolutionary strategy is not well understood, various theories address the invasion of male‐haploidy in diploid populations. Here two of these theories: (i) the maternal transmission hypothesis (MTH) and (ii) the deleterious mutation hypothesis (DMH), are re‐investigated with an agent‐based model to understand the role of genetic drift as a mechanism facilitating the spread of male‐haploidy. These two hypotheses are analysed separately and comparatively, and the results suggest dominance of the MTH. In addition, comparison of the stochastic results to deterministic results using the same model structure shows how genetic drift can enhance the parameter space where male‐haploidy can be expected to invade.     

An information-theoretical approach to phylogeography

Data analysis in phylogeographic investigations is typically conducted in either a qualitative manner, or alternatively via the testing of null hypotheses. The former, where inferences about population processes are derived from geographical patterns of genetic variation, may be subject to confirmation bias and prone to overinterpretation. Testing the predictions of null hypotheses is arguably less prone to bias than qualitative approaches, but only if the tested hypotheses are biologically meaningful. As it is difficult to know a priori if this is the case, there is the general need for additional methodological approaches in phylogeographic research. Here, we explore an alternative method for analysing phylogeographic data that utilizes information theory to quantify the probability of multiple hypotheses given the data. We accomplish this by augmenting the model‐selection procedure implemented in ima with calculations of Akaike Information Criterion scores and model probabilities. We generate a ranking of 17 models each representing a set of historical evolutionary processes that may have contributed to the evolution of Plethodon idahoensis, and then quantify the relative strength of support for each hypothesis given the data using metrics borrowed from information theory. Our results suggest that two models have high probability given the data. Each of these models includes population divergence and estimates of ancestral θ that differ from estimates of descendent θ, inferences consistent with prior work in this system. However, the models disagree in that one includes migration as a parameter and one does not, suggesting that there are two regions of parameter space that produce model likelihoods that are similar in magnitude given our data. Results of a simulation study suggest that when data are simulated with migration, most of the optimal models include migration as a parameter, and further that when all of the shared polymorphism results from incomplete lineage sorting, most of the optimal models do not. The results could also indicate a lack of precision, which may be a product of the amount of data that we have collected. In any case, the information‐theoretic metrics that we have applied to the analysis of our data are statistically rigorous, as are hypothesis‐testing approaches, but move beyond the ‘reject/fail to reject’ dichotomy of conventional hypothesis testing in a manner that provides considerably more flexibility to researchers.     

植食性哺乳动物食物选择的生态学意义及行为机制

综述了植食性哺乳动物食物选择行为机制的研究进展。植食性动物的食物选择是觅食生态学研究最为活跃的领域,动物食物选择对策主要有营养选择、植物次生化合物假设、营养平衡假设、最优觅食理论和条件性气味回避假设。动物学习食物选择的行为过程中,觅食个体能通过其认知过程和感知过程来处理食物信息、学习选择食物项目是一种可塑性行为方式,有利于动物获得适应栖息地的行为模式。幼体通过社会学习自母体学习的觅食经验,在幼体一生的食物选择中均具有重要的作用。在环境条件相对稳定条件下,幼体可模仿成体的食物选择模式;在环境剧烈变化的条件下,动物通过试错学习选择的食物项目可能较模仿成体所摄取的食物项目营养含量更丰富。     

Wagner and Dollo: a stochastic duet by composing two parsimonious solos

New contributions toward generalizing evolutionary models expand greatly our ability to analyze complex evolutionary characters and advance phylogeny reconstruction. In this article, we extend the binary stochastic Dollo model to allow for multi-state characters. In doing so, we align previously incompatible Wagner and Dollo parsimony principles under a common probabilistic framework by embedding arbitrary continuous-time Markov chains into the binary stochastic Dollo model. This approach enables us to analyze character traits that exhibit both Dollo and Wagner characteristics throughout their evolutionary histories. Utilizing Bayesian inference, we apply our novel model to analyze intron conservation patterns and the evolution of alternatively spliced exons. The generalized framework we develop demonstrates potential in distinguishing between phylogenetic hypotheses and providing robust estimates of evolutionary rates. Moreover, for the two applications analyzed here, our framework is the first to provide an adequate stochastic process for the data. We discuss possible extensions to the framework from both theoretical and applied perspectives.     

Relationship between moonlight and nightly activity patterns of the ocelot (Leopardus pardalis) and some of its prey species in Formosa,Northern Argentina

The moon can profoundly influence the activity patterns of animals. If predators are more successful under bright moonlight, prey species are likely to respond by shifting their own activity patterns (predator-avoidance hypothesis). However, the assumption that prey will necessarily avoid full-moon nights does not take into account that moonlight also allows prey to more easily detect predators, and to forage more efficiently. Thus, nightly activity patterns could depend on night vision capabilities (visual-acuity hypothesis). To consider the possible influences of moonlight and to distinguish between these hypotheses, we used camera-trapping records of a predator, the ocelot (Leopardus pardalis), and several of its night-active prey to compare activity patterns under different moonlight conditions. The ocelots' activity patterns were not strongly related to moonlight, but showed a slight tendency for higher activity during brighter nights. Tapeti rabbits (Sylvilagus brasiliensis) and brocket deer (Mazama americana) showed a clear preference for brighter nights. White-eared opossums (Didelphis albiventris) also showed a trend to be less active in new moon light. In contrast, smaller grey four-eyed opossums (Philander opossum) and the poor eye-sight nine-banded armadillo (Dasypus novemcinctus) showed similar activity patterns across all moon phases. Since activity patterns of most prey species were not shifted away from the activity of the ocelot, the differences between species are probably linked to their night vision capabilities, and emphasise the need for more information on the visual system of these taxa. Their activity patterns seem to be less strongly linked to avoidance of predation than previously thought, suggesting that foraging and predator detection benefits may play a more important role than usually acknowledged.     

Food-Entrained Feeding and Locomotor Circadian Rhythms in Rats Under Different Lighting Conditions

It has been suggested that two endogenous timekeeping systems, a light-entrainable pacemaker (LEP) and a food-entrainable pacemaker (FEP), control circadian rhythms. To understand the function and interaction between these two mechanisms better, we studied two behavioral circadian rhythmicities, feeding and locomotor activity, in rats exposed to two conflicting zeitgebers, food restriction and light-dark cycles. For this, the food approaches and wheel-running activity of rats kept under light-dark (LD) 12:12, constant darkness (DD), or constant light (LL) conditions and subjected to different scheduled feeding patterns were continuously recorded. To facilitate comparison of the results obtained under the different lighting conditions, the period of the feeding cycles was set in all three cases about Ih less than the light-entrained or free-running circadian rhythms. The results showed that, depending on the lighting conditions, some components of the feeding and wheel-running circadian rhythms could be entrained by food pulses, while others retained their free-running or light-entrained state. Under LD, food pulses had little influence on the light-entrained feeding and loco-motor rhythms. Under DD, relative coordination between free-running and food-associated rhythms may appear. In both cases, the feeding activity associated with the food pulses could be divided into a prominent phase-dependent peak of activity within the period of food availability and another afterward. Wheel-running activity mainly followed the food pulses. Under LL conditions, the food-entrained activity consisted mainly of feeding and wheel-running anticipatory activity. The results provide new evidence that lighting conditions influence the establishment and persistence of food-entrained circadian rhythms in rats. The existence of two coupled pacemakers, LEP and FEP, or a multioscillatory LEP may both explain our experimental results.