Cellular signaling is potentially regulated by cell density in receptor trafficking networks

Previous work has shown that receptor trafficking is a potential site for the control of signaling pathways. In most biological experiments, the ligand concentration and cell density vary within a wide range among different systems. However, there is less attention to systematically analyze how much cellular signal response is affected by cell densities. Here, we use a quantitative mathematical model to investigate signal responses in different receptor trafficking networks by simultaneous variations of ligand concentration and cell density. Computational analysis of the model revealed that receptor trafficking networks have potential sigmoid responses to ratio between ligand and surface receptor number per cell, which is a key factor to control the signaling responses in receptor trafficking networks. Furthermore, cell density also affects the robustness of dose-response curve upon the variation of binding affinity.     

A theoretical model linking interspecific variation in density dependence to species abundances

Understanding the factors that govern the commonness and rarity of individual species is a central challenge in community ecology. Empirical studies have often found that abundance is related to traits associated with competitive ability and suitability to the local environment and, more recently, also to negative conspecific density dependence. Here, we construct a theoretical framework to show how a species’ abundance is, in general, expected to be dependent on its per-capita growth rate when rare and the rate at which its growth rate declines with increasing abundance (strength of stabilization). We argue that per-capita growth rate when rare can be interpreted as competitive ability and that strength of stabilization largely reflects negative conspecific inhibition. We then analyze a simple spatially implicit model in which each species is defined by three parameters that affect its juvenile survival: its generalized competitive effect on others, its generalized response to competition, and an additional negative effect on conspecifics. This model facilitates the stable coexistence of an arbitrarily large number of species and qualitatively reproduces empirical relationships between abundance, competitive ability, and negative conspecific density dependence. Our results provide theoretical support for the combined roles of competitive ability and negative density dependence in the determination of species abundances in real ecosystems, and suggest new avenues of research for understanding abundance in models and in real communities.     

Time dependence of recruitment and derecruitment in the lung: a theoretical model.

Recruitment and derecruitment (R/D) of air spaces within the lung is greatly enhanced in lung injury and is thought to be responsible for exacerbating injury during mechanical ventilation. There is evidence to suggest that R/D is a time-dependent phenomenon. We have developed a computer model of the lung consisting of a parallel arrangement of airways and alveolar units. Each airway has a critical pressure (Pcrit) above which it tends to open and below which it tends to close but at a rate determined by how far pressure is from Pcrit. With an appropriate distribution of Pcrit and R/D velocity characteristics, the model able to produce realistic first and second pressure-volume curves of a lung inflated from an initially degassed state. The model also predicts that lung elastance will increase transiently after a deep inflation to a degree that increases as lung volume decreases and as the lung becomes injured. We conclude that our model captures the time-dependent mechanical behavior of the lung due to gradual R/D of lung units.     

Subcellular localization of beta-catenin is regulated by cell density

It is generally accepted that subcellular distribution of beta-catenin regulates its function. Membrane-bound beta-catenin mediates cell-cell adhesion, whereas elevation of the cytoplasmic and nuclear pool of the protein is associated with an oncogenic function. Although the role of beta-catenin in transformed cells is relatively well characterized, little is known about its importance in proliferation and cell-cycle control of nontransformed epithelial cells. Using different approaches we show that in human keratinocytes (HaCaT) beta-catenin is distributed throughout the cells in subconfluent, proliferating cultures. In contrast, beta-catenin is nearly exclusively located at the plasma membrane in confluent, contact-inhibited cells. Hence, we demonstrate for the first time that beta-catenin is translocated from the cytoplasm to the plasma membrane in response to high cell density. We conclude that beta-catenin plays an important role in proliferation and mediating contact-inhibition by changing intracellular localization.     

Turing instabilities in a mathematical model for signaling networks

GTPase molecules are important regulators in cells that continuously run through an activation/deactivation and membrane-attachment/membrane-detachment cycle. Activated GTPase is able to localize in parts of the membranes and to induce cell polarity. As feedback loops contribute to the GTPase cycle and as the coupling between membrane-bound and cytoplasmic processes introduces different diffusion coefficients a Turing mechanism is a natural candidate for this symmetry breaking. We formulate a mathematical model that couples a reaction–diffusion system in the inner volume to a reaction–diffusion system on the membrane via a flux condition and an attachment/detachment law at the membrane. We present a reduction to a simpler non-local reaction–diffusion model and perform a stability analysis and numerical simulations for this reduction. Our model in principle does support Turing instabilities but only if the lateral diffusion of inactivated GTPase is much faster than the diffusion of activated GTPase.     

Parameter estimation in a generalized discrete-time model of density dependence

Flexible discrete-time per-capita-growth-rate models accommodating a variety of density-dependent relationships offer parsimonious explanations for the variation of population abundance through time. However, the accuracy of standard approaches to parameter estimation and confidence interval construction for such models has not been explored in a generalized setting or with consideration of limited sample sizes typical for ecology. Here, we use simulated data to quantify the relative effects of sample size, population perturbations, and environmental stochasticity on statistical inference. We focus on the key parameters that inform population dynamic predictions in a generalized Beverton–Holt model. We find that reliable parameter estimation requires data spanning ranges where both low and high density dependence act. However, the asymptotic distribution of the likelihood ratio test statistic can be fairly accurate for constructing confidence regions even when point estimation is poor. Consideration of the joint profile likelihood surface is shown to be useful for assessing reliability of point estimates and dynamical population predictions. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Evolution of dispersal in density regulated populations: A haploid model

The evolution of dispersal is explored in a density-dependent framework. Attention is restricted to haploid populations in which the genotypic fitnesses at a single diallelic locus are decreasing functions of the changing number of individuals in the population. It is shown that migration between two populations in which the genotypic response to density is reversed can maintain both alleles when the intermigration rates are constant or nondecreasing functions of the population densities. There is always a unique symmetric interior equilibrium with equal numbers but opposite gene frequencies in the two populations, provided the system is not degenerate. Numerical examples with exponential and hyperbolic fitnesses suggest that this is the only stable equilibrium state under constant positive migration rates (m) less than . Practically speaking, however, there is only convergence after a reasonable number of generations for relatively small migration rates ( ). A migration-modifying mutant at a second, neutral locus, can successfully enter two populations at a stable migration-selection balance if and only if it reduces the intermigration rates of its carriers at the original equilibrium population size. Moreover, migration modification will always result in a higher equilibrium population size, provided the system approaches another symmetric interior equilibrium. The new equilibrium migration rate will be lower than that at the original equilibrium, even when the modified migration rate is a nondecreasing function of the population sizes. Therefore, as in constant viability models, evolution will lead to reduced dispersal.     

B cell signaling is regulated by induced palmitoylation of CD81

Signaling through the B cell antigen receptor (BCR) is amplified and prolonged by coligation of the BCR to the CD19/CD21/CD81 coreceptor complex. Coligation is induced during immune responses by the simultaneous binding of complement-tagged antigens to the complement receptor, CD21, and to the BCR. Enhanced signaling is due in part to the ability of the CD19/CD21/CD81 complex to stabilize the BCR in sphingolipid- and cholesterol-rich membrane microdomains termed lipid rafts. The tetraspanin CD81 is essential for the raft-stabilizing function of the coreceptor. Here we show that coligation of the BCR and the CD19/CD21/CD81 complex leads to selective, rapid, and reversible palmitoylation of CD81 and that palmitoylation is necessary for the raft stabilizing function of the CD19/CD21/CD81 complex. Inducible palmitoylation may represent a novel mechanism by which tetraspanins function to facilitate lipid raft-dependent receptor signaling.     

Intracellular trafficking of guanylate-binding proteins is regulated by heterodimerization in a hierarchical manner

Guanylate-binding proteins (GBPs) belong to the dynamin family of large GTPases and represent the major IFN-γ-induced proteins. Here we systematically investigated the mechanisms regulating the subcellular localization of GBPs. Three GBPs (GBP-1, GBP-2 and GBP-5) carry a C-terminal CaaX-prenylation signal, which is typical for small GTPases of the Ras family, and increases the membrane affinity of proteins. In this study, we demonstrated that GBP-1, GBP-2 and GBP-5 are prenylated in vivo and that prenylation is required for the membrane association of GBP-1, GBP-2 and GBP-5. Using co-immunoprecipitation, yeast-two-hybrid analysis and fluorescence complementation assays, we showed for the first time that GBPs are able to homodimerize in vivo and that the membrane association of GBPs is regulated by dimerization similarly to dynamin. Interestingly, GBPs could also heterodimerize. This resulted in hierarchical positioning effects on the intracellular localization of the proteins. Specifically, GBP-1 recruited GBP-5 and GBP-2 into its own cellular compartment and GBP-5 repositioned GBP-2. In addition, GBP-1, GBP-2 and GBP-5 were able to redirect non-prenylated GBPs to their compartment in a prenylation-dependent manner. Overall, these findings prove in vivo the ability of GBPs to dimerize, indicate that heterodimerization regulates sub-cellular localization of GBPs and underscore putative membrane-associated functions of this family of proteins.     

The graph theoretical analysis of the SSVEP harmonic response networks

Steady-state visually evoked potentials (SSVEP) have been widely used in the neural engineering and cognitive neuroscience researches. Previous studies have indicated that the SSVEP fundamental frequency responses are correlated with the topological properties of the functional networks entrained by the periodic stimuli. Given the different spatial and functional roles of the fundamental frequency and harmonic responses, in this study we further investigated the relation between the harmonic responses and the corresponding functional networks, using the graph theoretical analysis. We found that the second harmonic responses were positively correlated to the mean functional connectivity, clustering coefficient, and global and local efficiencies, while negatively correlated with the characteristic path lengths of the corresponding networks. In addition, similar pattern occurred with the lowest stimulus frequency (6.25 Hz) at the third harmonic responses. These findings demonstrate that more efficient brain networks are related to larger SSVEP responses. Furthermore, we showed that the main connection pattern of the SSVEP harmonic response networks originates from the interactions between the frontal and parietal–occipital regions. Overall, this study may bring new insights into the understanding of the brain mechanisms underlying SSVEP.     

Spatio-temporal patterns of fish assemblages in a large regulated alluvial river

1. The River Durance, the last alpine tributary of the River Rhône, is a large, braided alluvial hydrosystem. Following large-scale regulation, flow downstream of the Serre-Ponçon dam has been maintained at 1/40th of previous annual mean discharge. To assess the effects of historical disturbances, fish assemblages and habitat use were analysed during five summers in a representative reach of the middle Durance.
2. Habitat availability and use were assessed with a multi-scale approach including the variables water depth, current velocity, roughness height of substratum, amount of woody debris and lateral/longitudinal location. Eighteen fish species were sampled by electrofishing in 289 habitat sample units.
3. Partial least square (PLS) regression showed that taxa were mainly distributed according to relationships between their total length and water depth/velocity variables. Fish assemblage composition was also related to roughness height as well as distance from the bank or to the nearest large woody debris. However, PLS regression revealed no significant differences in habitat selection between two periods of varying hydromorphological stability.
4. Fish distribution patterns and density were related to proximity to the bank and cover, indicating that local scale variables need to be considered in conservation and restoration programmes.     

Individual variability and population regulation: a model of the significance of within-generation density dependence

Most models of theoretical population ecology consider population density as a state variable and thus ignore the fact that populations are composed not of identical average individuals but of individuals which are usually different. However, this individual variability may be important for population regulation. We therefore analysed an individual-based population model which explicitly describes within-generation processes, i.e. individual growth, starvation, and resource dynamics. The results show that if population dynamics are dominated by slow changes in resource level, the population size in the model undergoes wide oscillation, often leading to extinction. If, on the other hand, fast within-generation processes predominate, such as starvation and sudden drops in resource levels, the population fluctuates to a limited extent around an average. Within-generation density dependence may thus be an important mechanism which is largely ignored in classic time-discrete state-variable models. We conclude that the individual-based approach provides important insights into the hierarchical organization of population dynamics, i.e. the relationship between fast processes at the individual level and slower processes at the population level.     

An age-structured model of dendritic cell trafficking in the lung

As the sentinels of the immune system, dendritic cells (DC) play a critical role in initiating and maintaining appropriate T cell responses through capture and presentation of antigen, costimulation, and mediator release. Although much is known about certain aspects of DC function, the exact relationship between lung epithelial DC precursor populations in the blood and their functional role in antigen presentation are not clearly understood. I created an age-structured mathematical model for DC trafficking into the lung to address this question. While capturing experimentally observed system dynamics, I found that blood DC are preferentially recruited over blood monocytes. For short-lived antigens, the model results suggest that lung epithelial DC derived from blood DC exhibit a 625% increase in antigen density compared with those derived from blood monocytes. Finally, these results motivate future experimental studies to clarify aspects of DC trafficking in the lung.     

Spatio-temporal variation in the structure of pollination networks

Pollination networks are representations of all interactions between co-existing plants and their flower visiting animals at a given site. Although the study of networks has become a distinct sub-discipline in pollination biology, few studies have attempted to quantify spatio-temporal variation in species composition and structure of networks. We here investigate patterns of year-to-year change in pollination networks from six different sites spanning a large latitudinal gradient. We quantified level of species persistence and interactions among years, and examined year-to-year variation of network structural parameters in relation to latitude and sampling effort. In addition, we tested for correlations between annual variation in network parameters and short and long-term climate change variables. Numbers of plant and animal species and interactions were roughly constant from one year to another at all sites. However, composition of species and interactions changed from one year to another. Turnover was particularly high for flower visitors and interactions. On the other hand, network structural parameters (connectance, nestedness, modularity and centralization) remained remarkably constant between years, regardless of network size and latitude. Inter-annual variation of network parameters was not related to short or long term variation in climate variables (mean annual temperature and annual precipitation). We thus conclude that pollination networks are highly dynamic and variable in composition of species and interactions among years. However, general patterns of network structure remain constant, indicating that species may be replaced by topologically similar species. These results suggest that pollination networks are to some extent robust against factors affecting species occurrences.     

Coherent coupling of feedback loops: a design principle of cell signaling networks

MOTIVATION: It is widely accepted that cell signaling networks have been evolved to be robust against perturbations. To investigate the topological characteristics resulting in such robustness, we have examined large-scale signaling networks and found that a number of feedback loops are present mostly in coupled structures. In particular, the coupling was made in a coherent way implying that same types of feedback loops are interlinked together. RESULTS: We have investigated the role of such coherently coupled feedback loops through extensive Boolean network simulations and found that a high proportion of coherent couplings can enhance the robustness of a network against its state perturbations. Moreover, we found that the robustness achieved by coherently coupled feedback loops can be kept evolutionarily stable. All these results imply that the coherent coupling of feedback loops might be a design principle of cell signaling networks devised to achieve the robustness.     

Localization of AMP kinase is regulated by stress, cell density, and signaling through the MEK-->ERK1/2 pathway

5'-AMP-activated protein kinase (AMPK) serves as an energy sensor and is at the center of control for a large number of metabolic reactions, thereby playing a crucial role in Type 2 diabetes and other human diseases. AMPK is present in the nucleus and cytoplasm; however, the mechanisms that regulate the intracellular localization of AMPK are poorly understood. We have now identified several factors that control the distribution of AMPK. Environmental stress regulates the intracellular localization of AMPK, and upon recovery from heat shock or oxidant exposure AMPK accumulates in the nuclei. We show that under normal growth conditions AMPK shuttles between the nucleus and the cytoplasm, a process that depends on the nuclear exporter Crm1. However, nucleocytoplasmic shuttling does not take place in high-density cell cultures, for which AMPK is confined to the cytoplasm. Furthermore, we demonstrate that signaling through the mitogen-activated protein kinase kinase (MEK)-->extracellular signal-regulated kinase 1/2 (ERK1/2) cascade plays a crucial role in controlling the proper localization of AMPK. As such, pharmacological inhibitors that interfere with this pathway alter AMPK distribution under nonstress conditions. Taken together, our studies identify novel links between the physiological state of the cell, the activation of MEK-->ERK1/2 signaling, and the nucleocytoplasmic distribution of AMPK. This sets the stage to develop new strategies to regulate the intracellular localization of AMPK and thereby the modification of targets that are relevant to human disease.     

Compositional response of Phaseolus vulgaris rhizomicrobiome to a changing soil environment is regulated by long-distance plant signaling

Plant and Soil - Global climate change may greatly alter the structure and stability of drylands, creating an urgent need to recover their functions and services. Biological soil crust (biocrust),...