Quantifying metastatic inefficiency:rare genotypes versus rare dynamics

abstract: We introduce and solve a ‘null model’ of stochastic metastatic colonization. The model is described by a single parameter θ: the ratio of the rate of cell division to the rate of cell death for a disseminated tumour cell in a given secondary tissue environment. We are primarily interested in the case in which colonizing cells are poorly adapted for proliferation in the local tissue environment, so that cell death is more likely than cell division, i.e. θ 1), i.e. the statistics show a duality mapping (1 − θ) → (θ − 1). We conclude our analysis with a study of heterogeneity in the fitness of colonising cells, and describe a phase diagram delineating parameter regions in which metastatic colonization is dominated either by low or high fitness cells, showing that both are plausible given our current knowledge of physiological conditions in human cancer

Buffered Qualitative Stability explains the robustness and evolvability of transcriptional networks

The gene regulatory network (GRN) is the central decision‐making module of the cell. We have developed a theory called Buffered Qualitative Stability (BQS) based on the hypothesis that GRNs are organised so that they remain robust in the face of unpredictable environmental and evolutionary changes. BQS makes strong and diverse predictions about the network features that allow stable responses under arbitrary perturbations, including the random addition of new connections. We show that the GRNs of E. coli, M. tuberculosis, P. aeruginosa, yeast, mouse, and human all verify the predictions of BQS. BQS explains many of the small- and large‐scale properties of GRNs, provides conditions for evolvable robustness, and highlights general features of transcriptional response. BQS is severely compromised in a human cancer cell line, suggesting that loss of BQS might underlie the phenotypic plasticity of cancer cells, and highlighting a possible sequence of GRN alterations concomitant with cancer initiation. DOI: http://dx.doi.org/10.7554/eLife.02863.00

Correlating Cell Behavior with Tissue Topology in Embryonic Epithelia

Measurements on embryonic epithelial tissues in a diverse range of organisms have shown that the statistics of cell neighbor numbers are universal in tissues where cell proliferation is the primary cell activity. Highly simplified non-spatial models of proliferation are claimed to accurately reproduce these statistics. Using a systematic critical analysis, we show that non-spatial models are not capable of robustly describing the universal statistics observed in proliferating epithelia, indicating strong spatial correlations between cells. Furthermore we show that spatial simulations using the Subcellular Element Model are able to robustly reproduce the universal histogram. In addition these simulations are able to unify ostensibly divergent experimental data in the literature. We also analyze cell neighbor statistics in early stages of chick embryo development in which cell behaviors other than proliferation are important. We find from experimental observation that cell neighbor statistics in the primitive streak region, where cell motility and ingression are also important, show a much broader distribution. A non-spatial Markov process model provides excellent agreement with this broader histogram indicating that cells in the primitive streak may have significantly weaker spatial correlations. These findings show that cell neighbor statistics provide a potentially useful signature of collective cell behavior.Comment: PLoS one 201

Universal attenuators and their interactions with feedback loops in gene regulatory networks

Using a combination of mathematical modelling, statistical simulation and large-scale data analysis we study the properties of linear regulatory chains (LRCs) within gene regulatory networks (GRNs). Our modelling indicates that downstream genes embedded within LRCs are highly insulated from the variation in expression of upstream genes, and thus LRCs act as attenuators. This observation implies a progressively weaker functionality of LRCs as their length increases. When analyzing the preponderance of LRCs in the GRNs of Escherichia coli K12 and several other organisms, we find that very long LRCs are essentially absent. In both E. coli and M. tuberculosis we find that four-gene LRCs are intimately linked to identical feedback loops that are involved in potentially chaotic stress response, indicating that the dynamics of these potentially destabilising motifs are strongly restrained under homeostatic conditions. The same relationship is observed in a human cancer cell line (K562), and we postulate that four-gene LRCs act as 'universal attenuators'. These findings suggest a role for long LRCs in dampening variation in gene expression, thereby protecting cell identity, and in controlling dramatic shifts in cell-wide gene expression through inhibiting chaos-generating motifs.</p

The Effect of Music as a Motivational Tool on Isokinetic Concentric Performance in College Aged Students

International Journal of Exercise Science 7(1) : 54-61, 2014. Music has been identified as a motivational tool in physical activity and associated with improved performance in aerobic and anaerobic exercise. However, the effects of music on isokinetic strength testing have not been examined. The purpose of this study was to measure the difference in lower limb isokinetic force output in males and females when exposed to a motivational environment (arousing music) and non-motivational environment (silence). A 2 x 2 analysis of variance (group x gender) was used with participants (n = 19; 12 male, 7 female) serving as their own control. Participants performed 5 isokinetic concentric repetitions of knee extension and knee flexion at a set velocity of 60°/sec in both a non-music trial and music trial. Testing order was randomized to control for learning effect. No significant interactions were found for both the flexion and extension conditions (p \u3e .05); however, there was a main effect for gender on the extension variable (p \u3c .05). The authors concluded that music had no effect on lower limb force output in either males or females. The study may have been limited by a number of confounding effects, warranting a repeated yet enhanced research design of the study. Strength coaches, athletic trainers, and injury rehabilitation specialists (e.g., physical therapists) can use knowledge of this topic when working with clients and patients who are unmotivated to continue treatment. Music may not serve as an enhancer of patient or athlete performance in isokinetic testing or maximal isokinetic performance, but it may serve to increase enjoyment of otherwise monotonous activity

Population adaptation for genetic algorithm-based cognitive radios

Abstract — Genetic algorithms are best suited for optimization problems involving large search spaces. The problem space encountered when optimizing the transmission parameters of an agile or cognitive radio for a given wireless environment and set of performance objectives can become prohibitively large due to the high number of parameters and their many possible values. Recent research has demonstrated that genetic algorithms are a viable implementation technique for cognitive radio engines. However, the time required for the genetic algorithms to come to a solution substantionally increases as the system complexity grows. In this paper, we present a population adaptation technique for genetic algorithms that takes advantage of the information from previous cognition cycles in order to reduce the time required to reach an optimal decision. Our simulation results demonstrate that the amount of information from the previous cognition cycle can be determined from the environmental variation factor (EVF), which represents the amount of change in the environment parameters since the previous cognition cycle. I

Tests of the extension and deadbolt models of integrin activation

Despite extensive evidence that integrin conformational changes between bent and extended conformations regulate affinity for ligands, an alternative hypothesis has been proposed in which a deadbolt can regulate affinity for ligand in the absence of extension. Here, we tested both the deadbolt and the extension models. According to the deadbolt model, a hairpin loop in the β3 tail domain could act as a deadbolt to restrain the displacement of the β3 I domain β6-α7 loop and maintain integrin in the low affinity state. We found that mutating or deleting the β3 tail domain loop has no effect on ligand binding by either αIIbβ3 or αVβ3 integrins. In contrast, we found that mutations that lock integrins in the bent conformation with disulfide bonds resist inside-out activation induced by cytoplasmic domain mutation. Furthermore, we demonstrated that extension is required for accessibility to fibronectin but not smaller fragments. The data demonstrate that integrin extension is required for ligand binding during integrin inside-out signaling and that the deadbolt does not regulate integrin activation. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc