Transfer of information between senders and receivers, of one kind or another, is essential to all life. David Lewis introduced a game theoretic model of the simplest case, where one sender and one receiver have pure common interest. How hard or easy is it for evolution to achieve information transfer in Lewis signaling?. The answers involve surprising subtleties. We discuss some if these in terms of evolutionary dynamics in both finite and infinite populations, with and without mutation.

Sender–receiver games, first introduced by David Lewis ([1969]), have received increased attention in recent years as a formal model for the emergence of communication. Skyrms ([2010]) showed that simple models of reinforcement learning often succeed in forming efficient, albeit not necessarily minimal, signalling systems for a large family of games. Later, Alexander et al. ([2012]) showed that reinforcement learning, combined with forgetting, frequently produced both efficient and minimal signalling systems. In this article, I define a ‘dynamic’ sender–receiver game in (...) which the state–action pairs are not held constant over time and show that neither of these two models of learning learn to signal in this environment. However, a model of reinforcement learning with discounting of the past does learn to signal; it also gives rise to the phenomenon of linguistic drift. 1 Introduction2 Dynamic Signalling Games with Reinforcement Learning2.1 Introducing new states2.2 Swapping state–action pairs3 Discounting the Past3.1 Learning to signal in a dynamic world3.2 An unexpected outcome: linguistic drift4 ConclusionAppendix: A Markov Chain Analysis. (shrink)

Signalling games are popular models for studying the evolution of meaning, but typical approaches do not incorporate vagueness as a feature of successful signalling. Complementing recent like-minded models, we describe an aggregate population-level dynamic that describes a process of imitation of successful behaviour under imprecise perception and realization of similar stimuli. Applying this new dynamic to a generalization of Lewis’s signalling games, we show that stochastic imprecision leads to vague, yet by-and-large efficient signal use, and, moreover, that it (...) unifies evolutionary outcomes and helps avoid sub-optimal categorization. The upshot of this is that we see ‘as-if’-generalization at an aggregate level, without agents actually generalizing. _1_ Introduction _2_ Background _2.1_ Sim-max games and conceptual spaces _2.2_ Vagueness in sim-max games and conceptual spaces _2.3_ Vagueness, functional pressure, and transmission biases _3_ Imprecise Imitation _3.1_ Replicator dynamic in behavioural strategies _3.2_ Noise-perturbed conditional imitation _4_ Exploring Imprecise Imitation _4.1_ Setting the stage _4.2_ Simulation set-up _4.3_ Measures of interest _4.4_ Results _5_ Discussion _5.1_ Levels of vagueness _5.2_ Evolutionary benefits of imprecision _5.3_ Related work _6_ Conclusion Appendix. (shrink)

Adaptors are proteins of multi‐modular structure without enzymatic activity. Their capacity to organise large, temporary protein complexes by linking proteins together in a regulated and selective fashion makes them of outstanding importance in the establishment and maintenance of specificity and efficiency in all known signal transduction pathways. This review focuses on the structural and functional characterisation of adaptors involved in tyrosine kinase (TK) signalling. TK‐linked adaptors can be distinguished by their domain composition and binding specificities. However, such structural classifications have (...) proven inadequate as indicators of functional roles. A better way to understand the logic of signalling networks might be to look at functional aspects of adaptor proteins such as signalling specificity, negative versus positive contribution to signal propagation, or their position in the signalling hierarchy. All of these functions are dynamic, suggesting that adaptors have important regulatory roles rather than acting only as stable linkers in signal transduction. BioEssays 28: 465–479, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Volatile compounds, such as nitric oxide and ethylene gas, play a vital role as signaling molecules in organisms. Ethylene is a plant hormone that regulates a wide range of plant growth, development, and responses to stress and is perceived by a family of ethylene receptors that localize in the endoplasmic reticulum. Constitutive Triple Response 1 (CTR1), a Raf‐like protein kinase and a key negative regulator for ethylene responses, tethers to the ethylene receptors, but undergoes nuclear translocation upon activation of (...) ethylene signaling. This ER‐to‐nucleus trafficking transforms CTR1 into a positive regulator for ethylene responses, significantly enhancing stress resilience to drought and salinity. The nuclear trafficking of CTR1 demonstrates that the spatiotemporal control of ethylene signaling is essential for stress adaptation. Understanding the mechanisms governing the spatiotemporal control of ethylene signaling elements is crucial for unraveling the system‐level regulatory mechanisms that collectively fine‐tune ethylene responses to optimize plant growth, development, and stress adaptation. (shrink)

We present a dynamic model of the evolution of communication in a Lewis signaling game while systematically varying the degree of common interest between sender and receiver. We show that the level of common interest between sender and receiver is strongly predictive of the amount of information transferred between them. We also discuss a set of rare but interesting cases in which common interest is almost entirely absent, yet substantial information transfer persists in a *cheap talk* regime, and (...) offer a diagnosis of how this may arise. -/- . (shrink)

The transcription factor NF‐κB (p65/p50) plays a central role in the coordination of cellular responses by activating the transcription of numerous target genes. The precise role of the dynamics of NF‐κB signalling in regulating gene expression is still an open question. Here, we show that besides external stimulation intracellular parameters can influence the dynamics of NF‐κB. By applying mathematical modelling and bifurcation analyses, we show that NF‐κB is capable of exhibiting different types of dynamics in response to the same stimulus. (...) We identified the total NF‐κB concentration and the IκBα transcription rate constant as two critical parameters that modulate the dynamics and the fold change of NF‐κB. Both parameters might vary as a result of cell‐to‐cell variability. The regulation of the IκBα transcription rate constant, e.g. by co‐factors, provides the possibility of regulating the NF‐κB dynamics by crosstalk. (shrink)

In addition to the infant cry being a signal for attention, it may also be a critical component of the early formation of attachments with caregivers. We consider the complex development of that attachment, which involves reciprocal interactive signaling and a host of evolutionarily conserved caregiver factors.

A modified version of Spence’s signaling model is analyzed to explore the relationships among the type composition, career concerns, and signal effort levels chosen by agents. We show that an increase in the proportion of high-type agents does not change an agent’s effort levels monotonically. High signaling efforts are induced when the proportion of the high type is in the middle range. Moreover, when the proportion of the high type is small, career concerns increase the signaling effort (...) levels and have a more positive influence on the effort level of a high-type agent. However, when the proportion of the high type is large, career concerns might instead decrease the effort levels. (shrink)

This paper examines biology-inspired costly signaling explanations when applied to human conduct. Such explanations are part of a trend in the human behavioral sciences to investigate elements of human behavior as outcomes of quasi-Darwinian processes. The paper addresses four methodological concerns. The first worry is that quite often the requisite empirical support, in terms of population dynamics, appears to be missing. Second, fairly plausible alternative explanations are not considered or too easily disregarded. Third, the mechanism that is supposed to (...) cause reproduction and spread in a population is insufficiently spelled out. Fourth, and more specifically, it is often unclear how exactly false signaling (cheating) would be selected against. (shrink)

We consider how human subjects establish signaling conventions in the context of Lewis-Skyrms signaling games. These experiments involve games where there are precisely the right number of signal types to represent the states of nature, games where there are more signal types than states, and games where there are fewer signal types than states. The aim is to determine the conditions under which subjects are able to establish signaling conventions in such games and to identify a learning (...) dynamics that approximates how they succeed when they do. Our results suggest that human agents tend to use a win-stay/lose-shift with inertia dynamics to establish conventions in such games. We briefly consider the virtues and vices of this low-rationality dynamics. (shrink)

I introduce an extension of the Lewis-Skyrms signaling game, analysed from a dynamical perspective via simple reinforcement learning. In Lewis’ (Convention, Blackwell, Oxford, 1969) conception of a signaling game, salience is offered as an explanation for how individuals may come to agree upon a linguistic convention. Skyrms (Signals: evolution, learning & information, Oxford University Press, Oxford, 2010a) offers a dynamic explanation of how signaling conventions might arise presupposing no salience whatsoever. The extension of the atomic (...) class='Hi'>signaling game examined here—which I will refer to as a salience game—introduces a variable parameter into the atomic signaling game which allows for degrees of salience, thus filling in the continuum between Skyrms’ and Lewis’ models. The model does not presuppose any salience at the outset, but illustrates a process by which accidentally evolved salience is amplified, to the benefit of the players. It is shown that increasing degrees of salience allow populations to avoid sub-optimal pooling equilibria and to coordinate upon conventions more quickly. (shrink)

We propose a signaling pathway in which cell‐extracellular matrix (ECM) adhesion components PINCH‐1 and kindlin‐2 sense mechanical signals from ECM and link them to proline biosynthesis, a vital metabolic pathway for macromolecule synthesis, redox balance, and ECM remodeling. ECM stiffening promotes PINCH‐1 expression via integrin signaling, which suppresses dynamin‐related protein 1 (DRP1) expression and mitochondrial fission, resulting in increased kindlin‐2 translocation into mitochondria and interaction with Δ1‐pyrroline‐5‐carboxylate (P5C) reductase 1 (PYCR1). Kindlin‐2 interaction with PYCR1 protects the latter from (...) proteolytic degradation, leading to elevated PYCR1 level. Additionally, PINCH‐1 promotes P5C synthase (P5CS) expression and P5C synthesis, which, together with increased PYCR1 level, support augmented proline biosynthesis. This signaling pathway is frequently activated in fibrosis and cancer, resulting in increased proline biosynthesis and excessive collagen matrix production, which in turn further promotes ECM stiffening. Targeting this signaling pathway, therefore, may provide an effective strategy for alleviating fibrosis and cancer progression. (shrink)

Long‐term potentiation and long‐term depression are thought to be cellular mechanisms contributing to learning and memory. Although the physiological phenomena have been well characterized, little consensus of their underlying molecular mechanisms has emerged. One reason for this may be the under‐appreciated complexity of the signaling pathways that can arise if key signaling molecules are discretely localized within the synapse. Recent findings suggest an unanticipated degree of structural organization at the synapse, and improved methods in cellular imaging of living (...) tissue have provided much‐needed information about the intracellular dynamics of Ca2+, thought to be critical for both LTP and LTD. In this review, we briefly summarize some of these developments, and show that a more complete understanding of cellular signaling depends on the successful integration of traditional biochemistry and molecular biology with the spatial and temporal details of synaptic ultrastructure. Biophysically realistic computer simulations can have an important role in bridging these disciplines. BioEssays 24:1130–1144, 2002. © 2002 Wiley‐Periodicals, Inc. (shrink)

The insulin/insulin‐like growth factor‐1 (IGF‐1) signaling (IIS) pathway is a pivotal genetic program regulating cell growth, tissue development, metabolic physiology, and longevity of multicellular organisms. IIS integrates a fine‐tuned cascade of signaling events induced by insulin/IGF‐1, which is precisely controlled by post‐translational modifications. The ubiquitin/proteasome‐system (UPS) influences the functionality of IIS through inducible ubiquitylation pathways that regulate internalization of the insulin/IGF‐1 receptor, the stability of downstream insulin/IGF‐1 signaling targets, and activity of nuclear receptors for control of gene (...) expression. An age‐related decline in UPS activity is often associated with an impairment of IIS, contributing to pathologies such as cancer, diabetes, cardiovascular, and neurodegenerative disorders. Recent findings identified a key role of diverse ubiquitin modifications in insulin signaling decisions, which governs dynamic adaption upon environmental and physiological changes. In this review, we discuss the mutual crosstalk between ubiquitin and insulin signaling pathways in the context of cellular and organismal homeostasis. (shrink)

The spontaneous emergence of signaling has already been studied in terms of standard evolutionary dynamics of signaling games. Standard evolutionary dynamics is given by the replicator equations. Thus, it is not clear whether the results for standard evolutionary dynamics depend crucially on the functional form of the replicator equations. In this paper I show that the basic results for the replicator dynamics of signaling games carry over to a number of other evolutionary dynamics. ‡This research was supported (...) by the Konrad Lorenz Institute for Evolution and Cognition Research. †To contact the author, please write to: Konrad Lorenz Institute for Evolution and Cognition Research, Adolf Lorenz Gasse 2, A-3422 Altenberg, Austria; e-mail: [email protected]. (shrink)

Brian Skyrms applies adaptive dynamics (of cultural evolution and individual learning) to social theory, investigating altruism, spite, fairness, trust, division of labor, and signaling. Correlation is seen to be fundamental. Spontaneous emergence of social structure and of signaling systems are examined in the context of learning dynamics.

In this chapter, we explore a tension between the mindshaping hypothesis and commonsense Western ideas about moral agency and its relation to the social world. To illustrate this tension, we focus on the phenomenon of virtue signaling. We argue that moral intuitions about the perniciousness of virtue signaling reflect an individualistic conception of agency that we call the inside-out ideal. We argue that this ideal fits poorly with the deeply social, interactive, and regulative portrait of human nature revealed (...) by the mindshaping hypothesis. As an alternative to the inside-out ideal, we advocate for a more outside-in conception of agency. We argue that recent work on self control fits with such a conception, and show how it provides the virtue signaler with a path towards genuine moral growth that is scaffolded by mindshaping dynamics connected to reputational incentives and communal support, and should be accepted as perfectly morally legitimate. (shrink)

Both the quantity of information and the informational content of a signal are defined in the context of signaling games. Informational content is a generalization of standard philosophical notions of propositional content. It is shown how signals that initially carry no information may spontaneously acquire informational content by evolutionary or learning dynamics. It is shown how information can flow through signaling chains or signaling networks.

. In this essay I point toward the difficulties inherent in ontological objectivity and seek to restore our truth claims to validity through a relational ontology and the dynamic of coimplication in signals and noise. Theological examination of art and science points toward similarities between art, religion, and science. All three have often focused upon a “metaphysics of presence,” the desire for absolute presence of the object . If we accept a relational ontology, however, we must accept that the (...) revelation of presence is always simultaneously a concealment. This helps explain technoscientific achievement without recourse to a philosophically flawed objectivity. Twentieth‐century information theory shows the impossibility of a “pure signal.” By accepting that signal and noise are permanently interconnected, we begin to see how noise makes signal possible and even how noise becomes signal . Information theory thus underscores important similarities and leads toward new approaches in aesthetics, Christian theology, and scientific research. By comparing art, religion, and science, I argue that rejecting a metaphysics of presence without rejecting presence itself allows human beings to know the world. Although religion, science, and art often seek the absolute presence of their objects, they function better without. (shrink)

David Lewis (1969) introduced sender-receiver games as a way of investigating how meaningful language might evolve from initially random signals. In this report I investigate the conditions under which Lewis signaling games evolve to perfect signaling systems under various learning dynamics. While the 2-state/2- term Lewis signaling game with basic urn learning always approaches a signaling system, I will show that with more than two states suboptimal pooling equilibria can evolve. Inhomogeneous state distributions increase the likelihood (...) of pooling equilibria, but learning strategies with negative reinforcement or certain sorts of mutation can decrease the likelihood of, and even eliminate, pooling equilibria. Both Moran and APR learning strategies (Bereby-Meyer and Erev 1998) are shown to promote successful convergence to signaling systems. A model is presented that illustrates how a language that codes state-act pairs in an order-based grammar might evolve in the context of a Lewis signaling game. The terms, grammar, and the corresponding partitions of the state space co-evolve to generate a language whose structure appears to reflect canonical natural kinds. The evolution of these apparent natural kinds, however, is entirely in service of the rewards that accompany successful distinctions between the sender and receiver. Any metaphysics grounded on the structure of a natural language that evolved in this way would track arbitrary, but pragmatically useful distinctions. (shrink)

The cGAS‐STING signaling pathway plays a pivotal role in sensing cytosolic DNA and initiating innate immune responses against various threats, with disruptions in this pathway being associated with numerous immune‐related disorders. Therefore, precise regulation of the cGAS‐STING signaling is crucial to ensure appropriate immune responses. Recent research, including ours, underscores the importance of protein condensation in driving the activation and maintenance of innate immune signaling within the cGAS‐STING pathway. Consequently, targeting condensation processes in this pathway presents a (...) promising approach for modulating the cGAS‐STING signaling and potentially managing associated disorders. In this review, we provide an overview of recent studies elucidating the role and regulatory mechanism of protein condensation in the cGAS‐STING signaling pathway while emphasizing its pathological implications. Additionally, we explore the potential of understanding and manipulating condensation dynamics to develop novel strategies for mitigating cGAS‐STING‐related disorders in the future. (shrink)

The complexity of the Hedgehog (Hh) signaling cascade has increased over the course of evolution; however, it does not suffice to accommodate the dynamic yet robust requirements of differential Hh signaling activity needed for embryonic development and adult homeostatic maintenance. One solution to solve this dilemma is to apply multiple forms of post‐translational modifications (PTMs) to the core Hh signaling components, modulating their abundance, localization, and signaling activity. This review summarizes various forms of protein modifications (...) utilized to regulate Hh signaling, with a special emphasis on crosstalk between different forms of PTMs and their feedback regulation by Hh signaling. (shrink)

In Lewisean signaling games with common interests, perfect signaling strategies have been shown to be optimal in terms of communicative success and evolutionary fitness. However, in signaling game models that involve contextual cues, ambiguous signaling strategies can match up to or even outperform perfect signaling. For a minimalist example of such a context signaling game, I will show that three strategy types are expected to emerge under evolutionary dynamics: perfect signaling, partial ambiguity and (...) full ambiguity. Moreover, I will show that partial ambiguity strategies are the most expected outcome and have the greatest basin of attraction among these three types when sender and receiver costs are arbitrarily small or similar. I will demonstrate that the evolutionary success of partial ambiguity is due to being risk dominant, which points to a better compatibility with other strategy types. (shrink)

The etiology of Tauopathies, a diverse class of neurodegenerative diseases associated with the Microtubule Associated Protein (MAP) Tau, is usually described by a common mechanism in which Tau dysfunction results in the loss of axonal microtubule stability. Here, we reexamine and build upon the canonical disease model to encompass other Tau functions. In addition to regulating microtubule dynamics, Tau acts as a modulator of motor proteins, a signaling hub, and a scaffolding protein. This diverse array of functions is related (...) to the dynamic nature of Tau isoform expression, post‐translational modification (PTM), and conformational flexibility. Thus, there is no single mechanism that can describe Tau dysfunction. The effects of specific pathogenic mutations or aberrant PTMs need to be examined on all of the various functions of Tau in order to understand the unique etiology of each disease state. (shrink)

It is a received view that superluminal signaling is prohibited in collapse theories of quantum mechanics. In this paper, I argue that this may be not the case. I propose two possible mechanisms of superluminal signaling in collapse theories. The first one is based on the well-accepted solution to the tails problem, and the second one is based on certain assumptions about the minds of observers. Finally, I also discuss how collapse theories can avoid such superluminal signaling.

Site‐specific phosphorylation of intermediate filament (IF) proteins on serine and threonine residues leads to alteration of the filament structure, in vitro and in vivo. Protein kinases involved in cell signaling and those activated in mitosis dynamically control spatial and temporal organization of intracellular IF phosphorylation. Thus, IF phosphorylation appears to be one of the most predominant strategies in coordinating intracellular organization of the IF network.

Over two decades ago, Davids et al. (1994) and Handford et al. (1997) raised theoretical concerns associated with traditional, reductionist, and mechanistic perspectives of movement coordination and skill acquisition for sport scientists interested in practical applications for training designs. These seminal papers advocated an emerging consciousness grounded in an ecological approach, signaling the need for sports practitioners to appreciate the constraints-led, deeply entangled, and non-linear reciprocity between the organism (performer), task, and environment subsystems. Over two decades later, the areas (...) of skill acquisition, practice and training design, performance analysis and preparation, and talent development in sport science have never been so vibrant in terms of theoretical modeling, knowledge generation and innovation, and technological deployment. Viewed at an ecological level of analysis, the work of sports practitioners has progressively transitioned toward the facilitation of an evolving relationship between an organism (athlete and team) and its environment (sports competition). This commentary sets out to explore how these original ideas from Davids et al. (1994) and Handford et al. (1997) have been advanced through the theoretical lens of ecological dynamics. Concurrently, we provide case study exemplars, from applied practice in high-performance sports organizations, to illustrate how these contemporary perspectives are shaping the work of sports practitioners (sport ecology designers) in practice and in performance preparation. (shrink)

The study of intrinsic phosphorylation dynamics and kinetics in the context of complex protein architecture in vivo has been challenging: Method limitations have prevented significant advances in the understanding of the highly variable turnover of phosphate groups, synergy, and cooperativity between P‐sites. However, over the last decade, powerful analytical technologies have been developed to determine the full catalog of the phosphoproteome for many species. The curated databases of phospho sites found by mass spectrometry analysis and the computationally predicted sites based (...) on the linear sequence of kinase motifs are valuable tools. They allow investigation of the complexity of phosphorylation in vivo, albeit with strong discrepancies between different methods. A series of hypothetical scenarios on combinatorial processive phosphorylation is proposed that are likely unverifiable with current methodologies. These proposed a priori postulates could be considered as possible extensions of the known schemes of the activation/inhibition signaling process in vivo. (shrink)

Somatic complementation by fusion of two mutant cells and mixing of their cytoplasms occurs when the genetic defect of one fusion partner is cured by the functional gene product provided by the other. We have found that complementation of mutational defects in the network mediating stimulus‐induced commitment and sporulation of Physarum polycephalum may reflect time‐dependent changes in the signaling state of its molecular building blocks. Network perturbation by fusion of mutant plasmodial cells in different states of activation, and the (...) time‐resolved analysis of somatic complementation effects can be used to systematically probe network structure and dynamics. Time‐resolved somatic complementation quantitatively detects regulatory interactions between the functional modules of a network, independent of their biochemical composition or subcellular localization, and without being limited to direct physical interactions. BioEssays 25:950–960, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Transcription factor (TF) signaling regulates gene transcription and requires a complex network of proteins. This network includes co‐activators, co‐repressors, multiple TFs, histone‐modifying complexes, and the basal transcription machinery. It has been widely appreciated that pioneer factors, such as FoxA1 and GATA1, play an important role in opening closed chromatin regions, thereby allowing binding of a secondary factor. In this review we will focus on a newly proposed model wherein multiple TFs, such as steroid receptors (SRs), can function in a (...) pioneering role. This model, termed dynamic assisted loading, integrates data from widely divergent methodologies, including genome wide ChIP‐Seq, digital genomic footprinting, DHS‐Seq, live cell protein dynamics, and biochemical studies of ATP‐dependent remodeling complexes, to present a real time view of TF chromatin interactions. Under this view, many TFs can act as initiating factors for chromatin landscape programming. Furthermore, enhancer and promoter states are more accurately described as energy‐dependent, non‐equilibrium steady states. (shrink)

You are what you eat – this well‐known phrase properly describes the phenomenon of the effects of diet on acute and chronic inflammation. Several lipids and lipophilic compounds that are delivered with food or are produced in situ in pathological conditions exert immunomodulatory activity due to their interactions with the plasma membrane. This group of compounds includes cholesterol and its oxidized derivatives, fatty acids, α‐tocopherol, and polyphenols. Despite their structural heterogeneity, all these compounds ultimately induce changes in plasma membrane architecture (...) and fluidity. By doing this, they modulate the dynamics of plasma membrane receptors, such as TLR4. This receptor is activated by lipopolysaccharide, triggering acute inflammation during bacterial infection, which often leads to sepsis and is linked with diverse chronic inflammatory diseases. In this review, we discuss how the impact on plasma membrane properties contributes to the immunomodulatory activity of dietary compounds, pointing to the therapeutic potential of some of them.Also watch the Video Abstract. (shrink)

Reproduction and immunity are energy intensive, intimately linked processes in most organisms. In women, pregnancy is associated with widespread immunological adaptations that alter immunity to many diseases, whereas, immune dysfunction has emerged as a major cause for infertility in both men and women. Deciphering the molecular bases of this dynamic association is inherently challenging in mammals. This relationship has been traditionally studied in fast‐living, invertebrate species, often in the context of resource allocation between life history traits. More recently, these (...) studies have advanced our understanding of the mechanistic underpinnings of the immunity‐fertility dialogue. Here, we review the molecular connections between reproduction and immunity from the perspective of human pregnancy to mechanistic discoveries in laboratory organisms. We focus particularly on recent invertebrate studies identifying conserved signaling pathways and transcription factors that regulate resource allocation and shape the balance between reproductive status and immune health. (shrink)

Pickering & Garrod (P&G) explain dialogue dynamics in terms of forward modeling and prediction-by-simulation mechanisms. Their theory dissolves a strict segregation between production and comprehension processes, and it links dialogue to action-based theories of joint action. We propose that the theory can also incorporate intentional strategies that increase communicative success: for example, signaling strategies that help remaining predictable and forming common ground.

This chapter discusses Mina Bissell's pathbreaking research on cancer. Along with her colleagues and students, Bissell focused her attention on how the causal pathways regulating cell behavior were a two way street. Healthy cells’ and cancer cells’ behavior are both highly context-dependent. The pathway to this insight was not direct. Bissell’s work began with research into cellular metabolism. As a result of this early research, she found that cells can “change their fate” – revert to, or activate, functions not typical (...) of cells in the differentiated state. This had important implications for our understanding of cancer's etiology and treatment. Bissell - among others - emphasized in her research that it was not simply cell intrinsic properties – such as mutations to “oncogenes” and “tumor suppressor” genes – that determine the typical behaviors of cancer cells, but also a variety of extrinsic properties in the surrounding environment: metabolic and other signaling molecules, the extracellular matrix, and tissue architecture. (shrink)

The exploration of plant behavior on a cellular scale in a minimal invasive manner is key to understanding plant adaptations to their environment. Plant hormones regulate multiple aspects of growth and development and mediate environmental responses to ensure a successful life cycle. To monitor the dynamics of plant hormone actions in intact tissue, we need qualitative and quantitative tools with high temporal and spatial resolution. Here, we describe a set of biological instruments (reporters) for the analysis of the distribution and (...) signaling of various plant hormones. Furthermore, we provide examples of their utility for gaining novel insights into plant hormone action with a deeper focus on the drought hormone abscisic acid. (shrink)

A tight control of intracellular [Ca2+\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^{2+}$$\end{document}] is essential for the survival and normal function of cells. In this study we investigate key mechanistic steps by which calcium is regulated and calcium oscillations could occur using in silico modeling of membrane transporters. To do so we give a deterministic description of intracellular Ca2+\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^{2+}$$\end{document} dynamics using nonlinear dynamics in order to understand Ca2+\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} (...) \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^{2+}$$\end{document} signaling. We first present the ordinary differential equations system for cell calcium kinetics and make a preliminary work on Sobol indices. We then describe and analyze complex transporters action. Besides, we analyze the whole system. We finally perform numerical simulations and compare our results to real data. (shrink)

Cancer is a complex disease, necessitating research on many different levels; at the subcellular level to identify genes, proteins and signaling pathways associated with the disease; at the cellular level to identify, for example, cell-cell adhesion and communication mechanisms; at the tissue level to investigate disruption of homeostasis and interaction with the tissue of origin or settlement of metastasis; and finally at the systems level to explore its global impact, e.g. through the mechanism of cachexia. Mathematical models have been (...) proposed to identify key mechanisms that underlie dynamics and events at every scale of interest, and increasing effort is now being paid to multi-scale models that bridge the different scales. With more biological data becoming available and with increased interdisciplinary efforts, theoretical models are rendering suitable tools to predict the origin and course of the disease. The ultimate aims of cancer models, however, are to enlighten our concept of the carcinogenesis process and to assist in the designing of treatment protocols that can reduce mortality and improve patient quality of life. Conventional treatment of cancer is surgery combined with radiotherapy or chemotherapy for localized tumors or systemic treatment of advanced cancers, respectively. Although radiation is widely used as treatment, most scheduling is based on empirical knowledge and less on the predictions of sophisticated growth dynamical models of treatment response. Part of the failure to translate modeling research to the clinic may stem from language barriers, exacerbated by often esoteric model renderings with inaccessible parameterization. Here we discuss some ideas for combining tractable dynamical tumor growth models with radiation response models using biologically accessible parameters to provide a more intuitive and exploitable framework for understanding the complexity of radiotherapy treatment and failure. (shrink)

Phosphatidylinositol 5‐phosphate (PtdIns5P), the least characterized among the three phosphatidylinositol monophosphates, is emerging as a bioactive lipid involved in the control of several cellular functions. Similar to PtdIns3P, it is present in low amounts in mammalian cells, and can be detected at the plasma membrane and endomembranes as well as in the nucleus. Changes in PtdIns5P levels are observed in mammalian cells following specific stimuli or stresses, and in human diseases. Recently, the contribution of several enzymes such as PIKfyve, myotubularins, (...) and type II PtdInsP‐kinases to PtdIns5P metabolism has gained a strong experimental support. Here, we provide a picture emerging from recent studies showing how this lipid can be generated and act as a regulator of membrane and cytoskeleton dynamics, and as a modulator of gene expression. We briefly summarize the current methods and tools for studying PtdIns5P, and discuss how PtdIns5P can integrate and coordinate different functions in a spatiotemporal manner. (shrink)

The calcium signals regulate the production and secretion of many signaling molecules like inositol trisphosphate ( $$IP_{3}$$ ) and adenosine triphosphate (ATP) in various cells including pancreatic $$\beta$$ -cells. The calcium signaling mechanisms regulating $$IP_{3}$$, ATP and insulin responsible for various functions of $$\beta$$ -cells are still not well understood. Any disturbance in these mechanisms can alter the functions of $$\beta$$ -cells leading to diabetes and metabolic disorders. Therefore, a mathematical model is proposed by incorporating the reaction-diffusion equation (...) for calcium dynamics and a system of first-order differential equations for $$IP_{3}$$, ATP-production and insulin secretion with initial and boundary conditions. The model incorporates the temporal dependence of $$IP_{3}$$ -production and degradation, ATP production and insulin secretion on calcium dynamics in a $$\beta$$ -cell. The piecewise linear finite element method has been used for the spatial dimension and the Crank-Nicolson scheme for the temporal dimension to obtain numerical results. The effect of changes in source influxes and buffers on calcium dynamics and production of $$IP_{3}$$, ATP and insulin levels in a $$\beta$$ -cell has been analyzed. It is concluded that the dysfunction of source influx and buffers can cause significant variations in calcium levels and dysregulation of $$IP_{3}$$, ATP and insulin production, which can lead to various metabolic disorders, diabetes, obesity, etc. The proposed model provides crucial information about the changes in mechanisms of calcium dynamics causing proportionate disturbances in $$IP_3$$, ATP and insulin levels in pancreatic cells, which can be helpful for devising protocols for diagnosis and treatment of various metabolic diseases. (shrink)

This paper examines and contrasts two closely related evolutionary explanations in human behaviour: signalling theory, and the theory of Credibility Enhancing Displays. Both have been proposed to explain costly, dangerous, or otherwise ‘extravagant’ social behaviours, especially in the context of religious belief and practice, and each have spawned significant lines of empirical research. However, the relationship between these two theoretical frameworks is unclear, and research which engages both of them is largely absent. In this paper we seek to address this (...) gap at the theoretical level, examining the core differences between the two approaches and prospects and conditions for future empirical testing. We clarify the dynamical and mechanistic bases of signalling and CREDs as explanatory models and contrast the previous uses to which they have been put in the human sciences. Because of idiosyncrasies regarding those uses, several commonly supposed differences and comparative advantages are actually misleading and not in fact generalisable. We also show that signalling and CREDs theories as explanatory models are not interchangeable, because of deep structural differences. As we illustrate, the proposed causal networks of each theory are distinct, with important differences in the endogeneity of various phenomena within each model and their explanatory targets. As a result, they can be seen as complementary rather than in competition. We conclude by surveying the current state of the literature and identifying the differential predictions which could underpin more comprehensive empirical comparison in future research. (shrink)

As a result of the time‐ and context‐dependency of gene expression, gene regulatory and signaling pathways undergo dynamic changes during development. Creating a model of the dynamics of molecular interaction networks offers enormous potential for understanding how a genome orchestrates the developmental processes of an organism. The dynamic nature of pathway topology calls for new modeling strategies that can capture transient molecular links at the runtime. The aim of this paper is to present a brief and informative, (...) but not all‐inclusive, viewpoint on the computational aspects of modeling and simulation of a non‐static molecular network. BioEssays 26:68–72, 2004. © 2003 Wiley Periodicals, Inc. (shrink)

Cyclic adenosine monophosphate (cAMP) and cAMP‐dependent protein kinase A (PKA) are evolutionary conserved molecules with a well‐established position in the complex network of signal transduction pathways. cAMP/PKA‐mediated signaling pathways are implicated in many biological processes that cooperate in organ development including the motility, survival, proliferation and differentiation of epithelial cells. Cell surface polarity, here defined as the anisotropic organisation of cellular membranes, is a critical parameter for most of these processes. Changes in the activity of cAMP/PKA elicit a variety (...) of effects on intracellular membrane dynamics, including membrane sorting and trafficking. One of the most intriguing aspects of cAMP/PKA signaling is its evolutionary conserved abundance on the one hand and its precise spatial–temporal actions on the other. Here, we review recent developments with regard to the role of cAMP/PKA in the regulation of intracellular membrane trafficking in relation to the dynamics of epithelial surface domains. BioEssays 30:146–155, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Cellular mechanisms whereby quiescent stem cells sense tissue injury and transition to an activated state are largely unknown. Quiescent skeletal muscle stem cells (MuSCs, also called satellite cells) have elaborate, heterogeneous projections that rapidly retract in response to muscle injury. They may therefore act as direct sensors of their niche environment. Retraction is driven by a Rac‐to‐Rho GTPase activity switch that promotes downstream MuSC activation events. These and other observations lead to several hypotheses: (1) projections are morphologically dynamic at (...) quiescence, providing a surveillance function for muscle damage; (2) quiescent projection dynamics are regulated by the relative balance of Rac and Rho activities promoted by niche‐derived cues; (3) projections, particularly their associated filopodia, sense tissue damage via changes to the biomechanical properties of the niche and/or detection of signaling cues released by damaged myofibers; and (4) the dynamic nature of projections results in a population of MuSCs with heterogeneous functional properties. These concepts may extend to other types of quiescent stem cells, as well as prove useful in translational research settings. (shrink)

Since its introduction in the 1980s, futility as a concept has held contested meaning and applications throughout medicine. There has been little discussion within the psychiatric literature about the use of futility in the care of individuals experiencing severe and persistent mental illness (SPMI), despite some tacit acceptance that futility may apply in certain cases of psychiatric illness. In this paper, we explore the literature surrounding futility and argue that its connotation within medicine is to describe situations where patients (or (...) their substitute decision-makers) believe that interventions will almost certainly provide no meaningful benefit. We then provide two arguments in support of the use of futility within the care of individuals experiencing SPMI: that some SPMI can be considered a terminal illness, and that the risk-benefit ratio is a dynamic entity such that futility can help describe what Gillett calls the ‘risk of unacceptable badness’ when it comes to considering how an intervention might impact a patient’s quality of life. We posit that capacity should not pose an obstacle to declaring futility when caring for individuals experiencing SPMI and explain how futility is not antithetical to recovery in mental health. Finally, we describe how using futility within psychiatric practice can allow for a reorientation of care by signalling the need to shift to a palliative approach. (shrink)

Game theory has a prominent role in evolutionary biology, in particular in the ecological study of various phenomena ranging from conflict behaviour to altruism to signalling and beyond. The two central methodological tools in biological game theory are the concepts of Nash equilibrium and evolutionarily stable strategy. While both were inspired by a dynamic conception of evolution, these concepts are essentially static—they only show that a population is uninvadable, but not that a population is likely to evolve. In this (...) article, we argue that a static methodology can lead to misleading views about dynamic evolutionary processes. We advocate, instead, a more pluralistic methodology, which includes both static and dynamic game theoretic tools. Such an approach provides a more complete picture of the evolution of strategic behaviour. 1 Introduction2 The Equilibrium Methodology3 Common Interest Signalling3.1 Lewis’s signalling game3.2 Static analysis3.3 Dynamic analysis4 The Sir Philip Sidney Game4.1 Static analysis4.2 Other equilibria4.3 Dynamic analysis5 Related Literature6 Static and Dynamic Approaches. (shrink)

Common wisdom holds that communication is impossible when messages are costless and communicators have totally opposed interests. This article demonstrates that such wisdom is false. Non-convergent dynamics can sustain partial information transfer even in a zero-sum signalling game. In particular, I investigate a signalling game in which messages are free, the state-act payoffs resemble rock–paper–scissors, and senders and receivers adjust their strategies according to the replicator dynamic. This system exhibits Hamiltonian chaos and trajectories do not converge to equilibria. This (...) persistent out-of-equilibrium behaviour results in messages that do not perfectly reveal the sender's private information, but do transfer information as quantified by the Kullback–Leibler divergence. This finding shows that adaptive dynamics can enable information transmission even though messages at equilibria are meaningless. This suggests a new explanation for the evolution or spontaneous emergence of meaning: non-convergent adaptive dynamics. (shrink)

There is increasing evidence that dynamic changes to chromatin, chromosomes and nuclear architecture are regulated by RNA signalling. Although the precise molecular mechanisms are not well understood, they appear to involve the differential recruitment of a hierarchy of generic chromatin modifying complexes and DNA methyltransferases to specific loci by RNAs during differentiation and development. A significant fraction of the genome-wide transcription of non-protein coding RNAs may be involved in this process, comprising a previously hidden layer of intermediary genetic information (...) that underpins developmental ontogeny and the differences between species, ecotypes and individuals. It is also evident that RNA editing is a primary means by which hardwired genetic information in animals can be altered by environmental signals, especially in the brain, indicating a dynamic RNA-mediated interplay between the transcriptome, the environment and the epigenome. Moreover, RNA-directed regulatory processes may also transfer epigenetic information not only within cells but also between cells and organ systems, as well as across generations. (shrink)

As endosymbionts, the mitochondria are unique among organelles. This review provides insights into mitochondrial behavior and introduces the idea of a unified collective, an interconnected reticulum reminiscent of the Borg, a fictional humanoid species from the Star Trek television series whereby decisions are made within their network (or “hive”), linked to signaling cascades that coordinate the cross‐talk between mitochondrial and cellular processes (“subspace domain”). Similarly, mitochondrial dynamics are determined by two distinct processes, namely the local regulation of fission/fusion and (...) the global control of their behavior through cellular signaling pathways. Indeed, decisions within the hive provide each mitochondrial unit with autonomous control of their own degradation, whereby mitochondrial fusion is inactivated and they become substrates for autophagy. Decisions within the subspace domain couple signaling pathways involved in the functional integration of mitochondria with complex cellular transitions, including developmental cues, mitosis, and apoptosis. (shrink)