Allosteric and transmembrane signaling are among the major questions of structural biology. Here, we review and discuss signal transduction in four-helical TM bundles, focusing on histidine kinases and chemoreceptors found in two-component systems. Previously, piston, scissors, and helical rotation have been proposed as the mechanisms of TM signaling. We discuss theoretically possible conformational changes and examine the available experimental data, including the recent crystallographic structures of nitrate/nitrite sensor histidine kinase NarQ and phototaxis system NpSRII:NpHtrII. We show that (...) TM helices can flex at multiple points and argue that the various conformational changes are not mutually exclusive, and often are observed concomitantly, throughout the TM domain or in its part. The piston and scissoring motions are the most prominent motions in the structures, but more research is needed for definitive conclusions. Models of allosteric transmembrane signaling in microbial sensor histidine kinases and chemoreceptors are discussed in light of recent crystallographic structures. It is shown that the TM α-helices are flexible and various conformational changes are often observed concomitantly. The piston and scissoring motions are the most prominent in the structures. (shrink)

Our understanding of communication and its evolution has advanced significantly through the study of simple models involving interacting senders and receivers of signals. Many theorists have thought that the resources of mathematical information theory are all that are needed to capture the meaning or content that is being communicated in these systems. However, the way theorists routinely talk about the models implicitly draws on a conception of content that is richer than bare informational content, especially in contexts where false (...) content is important. This article shows that this concept can be made precise by defining a notion of functional content that captures the degree to which different states of the world are involved in stabilizing senders’ and receivers’ use of a signal at equilibrium. A series of case studies is used to contrast functional content with informational content, and to illustrate the explanatory role and limitations of this definition of functional content. _1_ Introduction _2_ Modelling Framework _3_ Two Kinds of Content _3.1_ Informational content _3.2_ Functional content _4_ Cases _4.1_ Case 1: Simplest case _4.2_ Case 2: Partial pooling _4.3_ Case 3: Bottleneck _4.4_ Case 4: Partial common interest _4.5_ Case 5: Deception _4.6_ Case 6: A further problem arising from divergent interests _5_ Discussion Appendix. (shrink)

In the yeast Saccharomyces cerevisiae three positive transcriptional control elements are activated by stress conditions: heat shock elements (HSEs), stress response elements (STREs) and AP‐1 responsive elements (AREs). HSEs bind heat shock transcription factor (HSF), which is activated by stress conditions causing accumulation of abnormal proteins. STREs mediate transcriptional activation by multiple stress conditions. They are controlled by high osmolarity via the HOG signal pathway, which comprises a MAP kinase module and a two‐component system homologous to prokaryotic signal transducers. (...) AREs bind the transcription factor Yap1p. The three types of control elements seem to have overlapping, but distinct functions. Some stress proteins encoded by HSE‐regulated genes are necessary for growth of yeast under moderate stress, products of STRE‐activated genes appear to be important for survival under severe stress and ARE‐controlled genes may mainly function during oxidative stress and in the response to toxic conditions, such as caused by heavy metal ions. (shrink)

The biochemical mechanism by which the phytochrome family of plant sensory photoreceptors transmit perceived informational light signals downstream to transduction pathway components is undetermined. The recent sequencing of the entire genome of the cyanobacterium Synechocystis, however, has revealed a protein that has an NH2‐terminal domain with striking sequence similarity to the photosensory NH2‐terminal domain of the phytochromes, and a COOH‐terminal domain strongly related to the transmitter histidine kinase module of bacterial two‐component sensors. The Synechocystis protein is capable of autocatalytic (...) chromophore ligation and exhibits photoreversible light‐absorption changes analogous to the phytochromes, indicating its capacity to function as an informational photoreceptor. Together with earlier observations that the COOH‐terminal domains of the plant phytochromes also have sequence similarity to the histidine kinases, these data suggest that the cyanobacteria utilize photoregulated histidine kinases as a sensory system and that the plant phytochromes may be evolutionary descendants of these photoreceptors. (shrink)

Systems biology is largely tributary to genomics and other “omic” disciplines that generate vast amounts of structural data. “Omics”, however, lack a theoretical framework that would allow using these data sets as such (rather than just tiny bits that are extracted by advanced data-mining techniques) to build explanatory models that help understand physiological processes. Systems biology provides such a framework by adding a dynamic dimension to merely structural “omics”. It makes use of bottom-up and top-down models. The former (...) are based on data about systems components, the latter on systems-level data. We trace back both modeling strategies (which are often used to delineate two branches of the field) to the modeling of metabolic and signaling pathways in the bottom-up case, and to biological cybernetics and systems theory in the top-down case. We then argue that three roots of systems biology must be discerned to account adequately for the structure of the field: pathway modeling, biological cybernetics, and “omics”. We regard systems biology as merging modeling strategies (supplemented by new mathematical procedures) from data-poor fields with data supply from a field that is quite deficient in explanatory modeling. After characterizing the structure of the field, we address some epistemological and ontological issues regarding concepts on which the top-down approach relies and that seem to us to require clarification. This includes the consequences of identifying modules in large networks without relying on functional considerations, the question of the “holism” of systems biology, and the epistemic value of the “systeome” project that aspires to become the cutting edge of the field. (shrink)

Functional information means an encoded network of functions in living organisms from molecular signaling pathways to an organism’s behavior. It is represented by two components: code and an interpretation system, which together form a self-sustaining semantic closure. Semantic closure allows some freedom between components because small variations of the code are still interpretable. The interpretation system consists of inference rules that control the correspondence between the code and the function (phenotype) and determines the shape of the fitness landscape. The (...) utility factor operates at multiple time scales: short-term selection drives evolution towards higher survival and reproduction rate within a given fitness landscape, and long-term selection favors those fitness landscapes that support adaptability and lead to evolutionary expansion of certain lineages. Inference rules make short-term selection possible by shaping the fitness landscape and defining possible directions of evolution, but they are under control of the long-term selection of lineages. Communication normally occurs within a set of agents with compatible interpretation systems, which I call communication system. Functional information cannot be directly transferred between communication systems with incompatible inference rules. Each biological species is a genetic communication system that carries unique functional information together with inference rules that determine evolutionary directions and constraints. This view of the relation between utility and inference can resolve the conflict between realism/positivism and pragmatism. Realism overemphasizes the role of inference in evolution of human knowledge because it assumes that logic is embedded in reality. Pragmatism substitutes usefulness for truth and therefore ignores the advantage of inference. The proposed concept of evolutionary pragmatism rejects the idea that logic is embedded in reality; instead, inference rules are constructed within each communication system to represent reality, and they evolve towards higher adaptability on a long time scale. (shrink)

The neuregulin gene encodes a series of polypeptide growth factors that can influence the growth state of target vertebrate cells in culture. Recently, three studies have explored the in vivo function of the neuregulin signaling system in mice by disrupting the genes encoding the neuregulin ligand(1) and two of its receptors, ErbB2(2) and ErbB4(3). Each of the genes is essential for development, and aberrations in cardiac and neural development are particularly prominent in mutant embryos. The observed defects, together with (...) the localization of expression of the neuregulin signaling components within these tissues, highlight a paracrine mechanism for neuregulin‐mediated intercellular communication. (shrink)

There is considerable evidence that the hippocampal system contributes both to (1) the temporary maintenance of memories and to (2) the processing of a particular type of memory representation. The findings on amnesia suggest that these two distinguishing features of hippocampal memory processing are orthogonal. Together with anatomical and physiological data, the neuropsychological findings support a model of cortico-hippocampal interactions in which the temporal and representational properties of hippocampal memory processing are mediated separately. We propose that neocortical association areas maintain (...) shortterm memories for specific items and events prior to hippocampal processing as well as providing the final repositories of long-term memory. The parahippocampal region supports intermediate-term storage of individual items, and the hippocampal formation itself mediates an organization of memories according to relevant relationships among items. Hippocampal-cortical interactions produce (i) strong and persistent memories for events, including their constituent elements and the relationships among them, and (ii) a capacity to express memories flexibly across a wide range of circumstances. (shrink)

The non-random mixing of biomembrane components, especially saturated phospholipids, exhibits important consequences in molecular biology. Particularly, the distribution of lipids within natural and model membranes is strongly determined by the selective association processes. These processes of phospholipids take place due to the cooperative modes in multiparticle systems as well as the specific lipid-lipid interactions both in the hydrophobic core and in the region of the polar headgroups. We demonstrated that the investigation of the selective association processes of saturated phospholipids (...) might contribute to the insight of the lipid domains appearance inside the bilayer membranes. The association probabilities of like- pairs and cross- pairs from a binary mixture of saturated phospholipids were tested for both parallel and anti-parallel alignments of the polar headgroups. The present model confirms the experimental evidence for saturated phospholipids to have a high tendency for association in parallel configuration of the electric dipole moments of the polar headgroups whether the cross-sectional area of the polar headgroup is in an usual range of 25-55 2. There are three major lipid domains in a binary mixture of saturated phospholipids: lipid domains in non-mixed phase of the first mixture component, in parallel alignment of the polar headgroups; lipid domains in non-mixed phase of the second mixture component, in anti-parallel alignment of the polar headgroups; lipid domains in mixed phase. We think that the selective association processes of phospholipids are neither exclusively, nor only involved in promoting the lipid domains appearance through bilayer phospholipid membranes. (shrink)

Various writers have attempted to use the sender-receiver formalism to account for the representational capacities of biological systems. This paper has two goals. First, I argue that the sender-receiver approach to representation cannot be complete. The mammalian circadian system represents the time of day, yet it does not control circadian behaviours by producing signals with time of day content. Informative signalling need not be the basis of our most basic representational capacities. Second, I argue that representational capacities are primarily (...) about control, and only when specific conditions obtain does this control require informative signalling. (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)

It is commonly the case that a problem concerning a mathematical or physical system can be solved in two quite different ways--by an internal or an external approach. For example, the area of a triangle can be found by integration or by showing it to be half that of a certain rectangle. In general, the first approach is, to analyse the given system into component parts, and the second approach is to deal with the system as a whole. It seems (...) that even in cases where solutions to physical problems obtained according to these two approaches are equally valid, and are equally good as explanations, scientists prefer the solution obtained by the internal approach. The reasons for this preference are examined. And it is suggested that whatever the reasons, this preference may have been partly responsible for the 19th century preference for the Kinetic Theory rather than Thermodynamics. (shrink)

In game-theoretic signaling models, evolution tends to favor perfectly precise signaling systems, but in the natural world communication is almost always imprecise. I argue that standard explanations for this discrepancy are only partially sufficient, and I show that communication is often ambiguous because signal senders take advantage of context sensitivity. As evidence, I make two additions to the signaling model: a cost for more complex signaling strategies and the ability to combine information in signals with (...) independent information. Analysis and simulation of the altered model shows that it leads to the predicted outcome of evolution favoring ambiguous signaling. (shrink)

Inappropriate saccades are prevented by fixation and by voluntary attention. The fixation system inhibits the saccade system. Like monkeys without a fixation system, humans with a weak fixation system produce many express saccades and cannot suppress prosaccades in an antisaccade task. With permanent attention to a peripheral location only a few express saccades to a stimulus at this location can be elicited: the sustained component of attention acts like fixation. When attention is captured by a precue, more express saccades are (...) obtained: the stimulus-driven component of attention facilitates saccade generation. If the cue correctly indicates the direction for an antisaccade error rate and latencies are increased. (shrink)

Although estrogens are widely considered circulating “sex steroid hormones” typically associated with female reproduction, recent evidence suggests that estrogens can act as local modulators of brain circuits in both males and females. The functional implications of this newly characterized estrogen signaling system have begun to emerge. This essay summarizes evidence in support of the hypothesis that the rapid production of estrogens in brain circuits can drive acute changes in both the production and perception of acoustic communication behaviors. These studies (...) have revealed two fundamental neurobiological concepts: (1) estrogens can be locally produced in brain circuits, independent of levels in nearby circuits and in the circulation and (2) estrogens can have very rapid effects within these brain circuits to modulate social vocalizations, acoustic processing, and sensorimotor integration. This vertebrate‐wide span of research, including vocalizing fishes, amphibians, and birds, emphasizes the importance of comparative model systems in understanding principles of neurobiology. (shrink)

The defense of plants against herbivores and pathogens involves the participation of an enormous range of different metabolites, some of which act directly as defensive weapons against enemies (toxins or deterrents) and some of which act as components of the complex internal signaling network that insures that defense is timed to enemy attack. Recent work reveals a surprising trend: The same compounds may act as both weapons and signals of defense. For example, two groups of well‐studied defensive weapons, glucosinolates (...) and benzoxazinoids, trigger the accumulation of the protective polysaccharide callose as a barrier against aphids and pathogens. In the other direction, several hormones acting in defense signaling (and their precursors and products) exhibit activity as weapons against pathogens. Knowing which compounds are defensive weapons, which are defensive signals and which are both is vital for understanding the functioning of plant defense systems. (shrink)

The aging process involves changes in immune regulation, i.e. adaptive immunity declines whereas innate immunity becomes activated. NF‐κB signaling is the master regulator of the both immune systems. Two recent articles highlight the role of the NF‐κB system in aging and immune responses. Adler et al1 showed that the NF‐κB binding domain is the genetic regulatory motif which is most strongly associated with the aging process. Kwon et al2 studying HIV‐1 infection and subsequent immune deficiency process demonstrated that (...) HIV‐1 Tat protein binds to SIRT1 protein, a well‐known longevity factor, and inhibits the SIRT1‐mediated deacetylation of the p65 component of the NF‐κB complex. As a consequence, the transactivation efficiency of the NF‐κB factor was greatly potentiated, leading to the activation of immune system and later to the decline of adaptive immunity. These observations support the scenario where immune responses and aging process can be enforced by the potentiation of NF‐κB transactivation efficiency. Longevity factors, such as SIRT1 and its activators, might regulate the efficiency of the NF‐κB signaling, the major outcome of which is inflamm‐aging via proinflammatory responses. BioEssays 30:939–942, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Mycobacterium tuberculosis is the causative agent of pulmonary tuberculosis which has infected one third of the mankind and causes 2–3 million deaths worldwide each year. The persistence of the infection ensues from the ability of M. tuberculosis to subvert host immune responses in favor of survival and growth of mycobacteria in macrophages. The mechanisms by which M. tuberculosis manipulates the host immune system have only recently come to light. These activities are attributed to lipoarabinomannans (LAM) and their precursors lipomannans (LM), (...) two predominant glycolipids of M. tuberculosis cell wall. LM are able to skew anti‐mycobacterial immune responses into un‐protective ones, while LAM evoke immunosupression upon binding to macrophage and dendritic cell receptors specialized in binding to “self” host components. A newly emerging idea implicates plasma membrane rafts in LM and LAM signaling. Depending on acylation patterns, the glycolipids may either directly incorporate into the raft membrane via mannosylphosphatidylinositol anchors or interact with raft‐associated proteins to affect the assembly of receptor signaling complexes. BioEssays 30:943–954, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Chloroplasts and other plastids are plant cell organelles that account for major biochemical functions. They contain their own gene expression system but are integrated into the signaling network of the entire cell. Both nuclear and plastid genes are involved in chloroplast biogenesis, and the gene expression pathways both inside and outside the organelle are subject to developmental and environmental control. The plastid transcription apparatus reflects this general scheme, with a basic organelle‐encoded enzymatic machinery surrounded by factors that may be (...) encoded by nuclear genes. Among the transcription regulatory mechanisms thought to play a role during plastid development are: (1) differential usage of promoter elements; (2) phosphorylation of transcription factors by a protein kinase, which is itself subject to phosphorylation and redox control; (3) dynamic changes in the composition of the transcription apparatus. In etioplasts, the dominating polymerase ‘B’ is a bacterial‐type enzyme, whereas the major chloroplast polymerase ‘A’ is a much larger enzyme reminiscent of those in the nucleus. These two enzyme forms may share common components and recruit others during development. (shrink)

Neurons of organisms with complex and flexible behavior, especially humans, must precisely control protein localization and activity to support higher brain functions such as learning and memory. In contrast, simpler organisms generally have simpler individual neurons, less complex nervous systems and display more limited behaviors. Strikingly, however, many key neuronal proteins are conserved between organisms that have very different degrees of behavioral complexity. Here we discuss a possible mechanism by which conserved neuronal proteins acquired new attributes that were crucial (...) in the evolution of complexity of nervous system structure and function. Specifically, we hypothesize that vertebrate‐specific post‐translational palmitoylation sites and PDZ‐binding protein‐protein interaction motifs act as gain‐of‐function mutations, increasing the regulatory potential of conserved proteins without affecting their core functions. We further hypothesize that the additional regulation of neurotransmitter receptors and other membrane proteins made possible by these sites and motifs is critical for the function of complex nervous systems. (shrink)

To ensure their survival in natural habitats, plants must recognize and respond to a wide variety of insect herbivores. Aphids and other Hemiptera pose a particular challenge, because they cause relatively little direct tissue damage when inserting their slender stylets intercellularly to feed from the phloem sieve elements. Plant responses to this unusual feeding strategy almost certainly include recognition of aphid salivary components and the induction of phloem‐specific defenses. Due to the excellent genetic and genomic resources that are available for (...) Arabidopsis thaliana (Arabidopsis), this plant was chosen as a model system to study the metabolic and transcriptional responses to infestation by two aphids, Myzus persicae (green peach aphid, a broad generalist) and Brevicoryne brassicae (cabbage aphid, a crucifer‐feeding specialist). Future research on Arabidopsis–aphid interactions will lead to the identification of aphid‐specific elicitors, components of the defense‐signaling pathway, and additional metabolic responses that are induced by aphid infestation. BioEssays 29:871–883, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Cytokinins are plant hormones that have, among many other functions, senescence‐modulatory effects in plant tissue. This is evident not only from biochemical data, but is vividly illustrated in the “green island” phenotype in plant leaves caused by cytokinins released for example by leaf mining insects or microbial pathogens. It is beyond doubt that, in addition to their roles in plants, cytokinins also provoke physiological and developmental effects in animals. It is hypothesized that the recently much discussed modification of plant metabolism (...) by insects and associated microbes via cytokinin signals has a counterpart in direct cytokinin signalling that interferes with the animals’ hormonal systems and impacts their population dynamics. (shrink)

The fate of eukaryotic proteins, from their synthesis to destruction, is supervised by the ubiquitin–proteasome system (UPS). The UPS is the primary pathway responsible for selective proteolysis of intracellular proteins, which is guided by covalent attachment of ubiquitin to target proteins by E1 (activating), E2 (conjugating), and E3 (ligating) enzymes in a process known as ubiquitylation. The UPS can also regulate protein synthesis by influencing multiple steps of RNA (ribonucleic acid) metabolism. Here, recent publications concerning the interplay between the UPS (...) and different types of RNA are reviewed. This interplay mainly involves specific RNA‐binding E3 ligases that link RNA‐dependent processes with protein ubiquitylation. The emerging understanding of their modes of RNA binding, their RNA targets, and their molecular and cellular functions are primarily focused on. It is discussed how the UPS adapted to interact with different types of RNA and how RNA molecules influence the ubiquitin signaling components. (shrink)

Parkinson's disease (PD) is generally sporadic but a number of genetic diseases have parkinsonism as a clinical feature. Two dominant genes, α‐synuclein (SNCA) and leucine‐rich repeat kinase 2 (LRRK2), are important for understanding inherited and sporadic PD. SNCA is a major component of pathologic inclusions termed Lewy bodies found in PD. LRRK2 is found in a significant proportion of PD cases. These two proteins may be linked as most LRRK2 PD cases have SNCA‐positive Lewy bodies. Mutations in both proteins are (...) associated with toxic effects in model systems although mechanisms are unclear. LRRK2 is an intracellular signaling protein possessing both GTPase and kinase activities that may contribute to pathogenicity. A third protein, tau, is implicated as a risk factor for PD. We discuss the potential relationship between these genes and suggest a model for PD pathogenesis where LRRK2 is upstream of pathogenic effects through SNCA, tau, or both proteins. (shrink)

Music comprises a diverse category of cognitive phenomena that likely represent both the effects of psychological adaptations that are specific to music (e.g., rhythmic entrainment) and the effects of adaptations for non-musical functions (e.g., auditory scene analysis). How did music evolve? Here, we show that prevailing views on the evolution of music – that music is a byproduct of other evolved faculties, evolved for social bonding, or evolved to signal mate quality – are incomplete or wrong. We argue instead that (...) music evolved as a credible signal in at least two contexts: coalitional interactions and infant care. Specifically, we propose that (1) the production and reception of coordinated, entrained rhythmic displays is a co-evolved system for credibly signaling coalition strength, size, and coordination ability; and (2) the production and reception of infant-directed song is a co-evolved system for credibly signaling parental attention to secondarily altricial infants. These proposals, supported by interdisciplinary evidence, suggest that basic features of music, such as melody and rhythm, result from adaptations in the proper domain of human music. The adaptations provide a foundation for the cultural evolution of music in its actual domain, yielding the diversity of musical forms and musical behaviors found worldwide. (shrink)

Stimulation of mitogenesis by the epidermal growth factor (EGF) operates through a pathway involving the receptor, the small G‐protein Ras and protein kinases of the MAP kinase cascade. It is proposed that two of the critical steps of that pathway utilize localization of components to the plasma membrane where Ras is located: recruitment of the nucleotide exchange protein Sos to the phosphorylated EGF receptor via a complex with the SH2/SH3‐containing protein Grb2 and recruitment of the protein kinase Raf to activated (...) Ras. Moreover, it is then proposed that Raf associates with the cytoskeleton at the membrane as it is being activated. Other signaling elements, including class I receptor kinases, nonreceptor tyrosine kinases and tyrosine phosphatases, are known to function at specific cellular sites. These observations have led us to propose that localization of signaling components, and particularly sites at membrane‐microfilament interfaces, play critical roles in cellular regulation. (shrink)

MUC1 and MUC4 are the two membrane mucins that have been best characterized. Although they have superficially similar structures and have both been shown to provide steric protection of epithelial surfaces, recent studies have also implicated them in cellular signaling. They act by substantially different mechanisms, MUC4 as a receptor ligand and MUC1 as a docking protein for signaling molecules. MUC4 is a novel intramembrane ligand for the receptor tyrosine kinase ErbB2/HER2/Neu, triggering a specific phosphorylation of the ErbB2 (...) in the absence of other ErbB ligands and potentiating phosphorylation and signaling through the ErbB2/ErbB3 heterodimeric receptor complex formed in the presence of neuregulin. In contrast, MUC1 has a highly conserved cytoplasmic tail, which binds β‐catenin, a key component of adherens junctions and a regulator of transcription, in a process that is tightly regulated by MUC1 phosphorylation. The specific localization of these membrane mucins to the apical surfaces of epithelial cells suggests that their signaling functions may be important as sensor mechanisms in response to invasion or damage of epithelia. BioEssays 25:66–71, 2003. © 2002 Wiley Periodicals, Inc. (shrink)

The dialogue develops arguments for and against a broad new world system - info-computationalist naturalism - that is supposed to overcome the traditional mechanistic view. It would make the older mechanistic view into a special case of the new general info-computationalist framework (rather like Euclidian geometry remains valid inside a broader notion of geometry). We primarily discuss what the info-computational paradigm would mean, especially its pancomputationalist component. This includes the requirements for a the new generalized notion of computing that would (...) include sub-symbolic information processing. We investigate whether pancomputationalism can provide the basic causal structure to the world and whether the overall research program of info-computationalist naturalism appears productive, especially when it comes to new approaches to the living world, including computationalism in the philosophy of mind. (shrink)

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)

Seven features which in practice seem to differentiate belief systems from knowledge systems are discussed. These are: nonconsensuality, “existence beliefs,” alternative worlds, evaluative components, episodic material, unboundedness, and variable credences. Each of these features gives rise to challenging representation problems. Progress on any of these problems within artificial intelligence would be helpful in the study of knowledge systems as well as belief systems, inasmuch as the distinction between the two types of systems is not absolute.

Biochemical networks, including those containing signaling pathways, display a wide range of regulatory properties. These include the ability to propagate information across different time scales and to function as switches and oscillators. The mechanisms underlying these complex behaviors involve many interacting components and cannot be understood by experiments alone. The development of computational models and the integration of these models with experiments provide valuable insight into these complex systems‐level behaviors. Here we review current approaches to the development of (...) computational models of biochemical networks and describe the insights gained from models that integrate experimental data, using three examples that deal with ultrasensitivity, flexible bistability and oscillatory behavior. These types of complex behavior from relatively simple networks highlight the necessity of using theoretical approaches in understanding higher order biological functions. BioEssays 24:1110–1117, 2002. © 2002 Wiley‐Periodicals, Inc. (shrink)

Notch signaling plays an essential role in the processes of embryogenesis and cellular differentiation, and it is believed that the oncogenic effects of dysregulated Notch signaling are an anomalous reflection of the normal functions of this cascade. Nonetheless, the cellular events associated with oncogenic Notch signaling have thus far remained elusive. In a recent report, Ferres‐Marco et al.1 described how they used the Drosphila eye as a model system and found that elevated Notch signaling in combination (...) with activation of components of the Polycomb complex of transcriptional repressors led to metastatic growth of tumors through epigenetic silencing of the Rbf gene. Rbf is the Drosophila homologue of the retinoblastoma tumor‐suppressor gene (Rb), thus it represents a novel link between Notch signaling, tumor growth and metastasis. BioEssays 28: 692–695, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Recommender Systems (RecSys) have been around since the early days of the Internet, helping users navigate the vast ocean of information and the increasingly available options that have been available for us ever since. The range of tasks for which one could use a RecSys is expanding as the technical capabilities grow, with the disruption of Machine Learning representing a tipping point in this domain, as in many others. However, the increase of the technical capabilities of AI-powered RecSys did (...) not come with a thorough consideration of their ethical implications and, despite being a well-established technical domain, the potential impacts of RecSys on their users are still under-assessed. This paper aims at filling this gap in regards to one of the main impacts of RecSys: personal autonomy. We first describe how technology can affect human values and a suitable methodology to identify these effects and mitigate potential harms: Value Sensitive Design (VSD). We use VSD to carry out a conceptual investigation of personal autonomy in the context of a generic RecSys and draw on a nuanced account of procedural autonomy to focus on two components: competence and authenticity. We provide the results of our inquiry as a value hierarchy and apply it to the design of a speculative RecSys as an example. (shrink)

Vulval development in the Caenorhabditis elegans hermaphrodite represents a simple, genetically tractable system for studying how cell signaling events control cell fata decisions. Current models suggest that proper specification of vulval cell fates relies on the integration of multiple signaling systems, including one that involves a receptor tyrosine kinase (RTK)→Ras→mitogen activated protein kinase (MAPK) cascade and one that involves a LIN‐12/Notch family receptor. In this review, we first discuss how genetic strategies are being used to identify and (...) analyze components that control vulval cell fate decisions. We then describe the different signaling systems that have been elucidated and how they relate to one another. Finally, we highlight several recently characterized genes that encode positive regulators, negative regulators or potential targets of the RTK→Ras→MAPK cascade involved in vulval induction. (shrink)

In response to the unsettled state of modern intellectual history, a model is offered for categorizing its subject matter. Two challenges to intellectual history are first examined: the relation of intellectual to social history and the relation of intellectual history to other disciplines which purport to deal with thought. The model proposed breaks down the "ideas" of intellectual historians into two sorts: 1) systems, complex bodies of thought related in a coherent fashion; and 2) embodiments, a way of fixating (...) or condensing a complex of meanings into a single expression. Each entails a distinct mode of communication, the former by processes of education or socialization, the latter by single symbols or slogans. The distinction between systems and embodiments is clarified by comparison to the abstract-concrete and the discursive-mythical thought distinctions. The "ideas" of intellectual history should ideally include both systems and embodiments as their components, as in the case of the Lutheran Reformation and the French Revolution. By showing their relation to other disciplines, these distinctions can be seen to demarcate the space in which intellectual history can operate. (shrink)

The Liver kinase B1 with its downstream target AMP activated protein kinase (LKB1‐AMPK), and the key nutrient sensor mammalian target of rapamycin complex 1 (mTORC1) form two signaling systems that coordinate metabolic and cellular activity with changes in the environment in order to preserve homeostasis. For example, nutritional fluctuations rapidly feed back on these signaling systems and thereby affect cell‐specific functions. Recent studies have started to reveal important roles of these strategic metabolic regulators in Schwann cells (...) for the trophic support and myelination of axons. Because aberrant intermediate metabolism along with mitochondrial dysfunction in Schwann cells is mechanistically linked to nerve abnormalities found in acquired and inherited peripheral neuropathies, manipulation of the LKB1‐AMPK, and mTORC1 signaling hubs may be a worthwhile therapeutic target to mitigate nerve damage in disease. Here, recent advances in our understanding of LKB1‐AMPK and mTORC1 functions in Schwann cells are covered, and future research areas for this key metabolic signaling network are proposed. (shrink)

Sceptics of informational terminology argue that by attributing content to signals, we fail to address nonhuman animal communication on its own terms. Primarily, we ignore that communication is sender driven: i.e. driven by the intrinsic physical properties of signals, themselves the result of selection pressures acting on signals to influence receivers in ways beneficial for senders. In contrast, information proponents argue that this ignores the degree to which communication is, in fact, receiver driven. The latter argue that an exclusive focus (...) on the intrinsic mechanical properties of signals cannot explain why receivers respond as they do. This is because receivers are not prisoners of sender influence. They possess response flexibility, and so we can only explain why receivers respond to signals as they do by positing that receivers ‘derive information’ from signals. I argue that, while basically true, this response flexibility can take one of two forms depending on the causal-explanatory role of information in understanding the response of the receiver: diachronic, on the one hand; and synchronic, on the other. In species with diachronic response flexibility only, information is derived by receivers from signals in a minimal sense. In such cases, information is an ultimate explanatory construct: one underpinned by historical facts at the population level. Alternatively, in species with synchronic response flexibility, information is derived by receivers from signals in a richer sense. Here, information is a proximate explanatory construct: one underpinned by cognitive-mechanistic facts at the level of the individual organism. Without recognising the different ways information can be derived from signals, and the different causal-explanatory roles information can play in understanding alternate kinds of receiver flexibility, proponents of information leave themselves open to the charge of anthropomorphising some signalling systems. (shrink)

Skyrms, building on the work of Dretske, has recently developed a novel information-theoretic account of propositional content in simple signalling systems. Information-theoretic accounts of content traditionally struggle to accommodate the possibility of misrepresentation, and I show that Skyrms’s account is no exception. I proceed to argue, however, that a modified version of Skyrms’s account can overcome this problem. On my proposed account, the propositional content of a signal is determined not by the information that it actually carries, but by (...) the information that it would carry at the nearest separating equilibrium of the underlying evolutionary dynamics. I show that this amended account yields reasonable ascriptions of false propositional content in a well-known formal model of the evolution of communication , and close with a discussion of the serious but perhaps not insuperable difficulties we face in applying the account to examples of signalling in the real world. (shrink)

The main aspects of interdisciplinary ICT technology of educational process based on the concept of functional asymmetry of the cerebral hemispheres, which reflect space-time asymmetry of the Universe and constitute a certain psychophysiological focus of human organism, are presented in the article. Its urgency stems from the tendencies of contemporary world, evolving towards the information society and influencing the development of modern education, becoming increasingly multimedia-rich and psychologised. The authors consider the major peculiarities of cognitive strategies of brain’s hemispheres, which (...) should be taken into account in modern educational systems that apply versatile multimedia means in teaching different academic disciplines. It is shown that training information offered to the students can be differentiated by the right and left video sequences, which corresponds to hemispheric information processing strategies and promotes the synergetic state of synchronization of the hemispheres functions. And the encephalographic studies show that such functional synchronization, revealing the medication state of human brain, presupposes the integration of two information processing strategies, leading to harmonization of the processes of the first and second signalling systems. The algorithms of the most effective influence of multimedia presentations of teaching materials on a student based on the concept of functional asymmetry of human brain are substantiated. These algorithms presuppose combining the "left" and "right" information in such a way that the volumes of two types of information would form a harmonious proportion. (shrink)

The precise orchestration of two opposing protein complexes – one in the cytoplasm (β‐catenin destruction complex) and the other at the plasma membrane (LRP6 signaling complex) – is critical for controlling levels of the transcriptional co‐factor β‐catenin, and subsequent activation of the Wnt/β‐catenin signal transduction pathway. The Wnt pathway component Axin acts as an essential scaffold for the assembly of both complexes. How the β‐catenin destruction and LRP6 signaling complexes are modulated following Wnt stimulation remains controversial. A recent (...) study in Science by He and coworkers reveals an underlying logic for Wnt pathway control in which Axin phosphorylation toggles a switch between the active and inactive states. This mini‐review focuses on this and two other recent studies that provide insight into the initial signaling events triggered by Wnt exposure. We emphasize regulation of the β‐catenin destruction and LRP6 signaling complexes and propose a framework for future work in this area. (shrink)

The study considers the development of methods for detecting anomalous network connections based on hybridization of computational intelligence methods. An analysis of approaches to detecting anomalies and abuses in computer networks. In the framework of this analysis, a classification of methods for detecting network attacks is proposed. The main results are reduced to the construction of multi-class models that increase the efficiency of the attack detection system, and can be used to build systems for classifying network parameters during the (...) attack. A model of an artificial immune system based on an evolutionary approach, an algorithm for genetic-competitive learning of the Kohonen network and a method of hierarchical hybridization of binary classifiers with the addition to the detection of anomalous network connections have been developed. The architecture of the network distributed attack detection system has been developed. The architecture of the attack detection system is two-tier: the first level provides the primary analysis of individual packets and network connections using signature analysis, the second level processes the processing of aggregate network data streams using adaptive classifiers. A signature analysis was performed to study network performance based on the Aho-Korasik and Boyer-Moore algorithms and their improved analogues were implemented using OpenMP and CUDA technologies. The architecture is presented and the main points of operation of the network attack generator are shown. A system for generating network attacks has been developed. This system consists of two components: an asynchronous transparent proxy server for TCP sessions and a frontend interface for a network attack generator. The results of the experiments confirmed that the functional and non-functional requirements, as well as the requirements for computing intelligent systems, are met for the developed attack detection system. (shrink)

In the past two decades, reinforcement learning has become a popular framework for understanding brain function. A key component of RL models, prediction error, has been associated with neural signals throughout the brain, including subcortical nuclei, primary sensory cortices, and prefrontal cortex. Depending on the location in which activity is observed, the functional interpretation of prediction error may change: Prediction errors may reflect a discrepancy in the anticipated and actual value of reward, a signal indicating the salience or novelty of (...) a stimulus, and many other interpretations. Anterior cingulate cortex has long been recognized as a region involved in processing behavioral error, and recent computational models of the region have expanded this interpretation to include a more general role for the region in predicting likely events, broadly construed, and signaling deviations between expected and observed events. Ongoing modeling work investigating the interaction between ACC and additional regions involved in cognitive control suggests an even broader role for cingulate in computing a hierarchically structured surprise signal critical for learning models of the environment. The result is a predictive coding model of the frontal lobes, suggesting that predictive coding may be a unifying computational principle across the neocortex. (shrink)

The deductive system in Boole's Laws of Thought (LT) involves both an algebra, which we call proto-Boolean, and a "general method in Logic" making use of that algebra. Our object is to elucidate these two components of Boole's system, to prove his principal results, and to draw some conclusions not explicit in LT. We also discuss some examples of incoherence in LT; these mask the genius of Boole's design and account for much of the puzzled and disparaging commentary LT has (...) received. Our evaluation of Boole's logical system does not differ substantially from that advanced in Hailperin's exhaustive study, Boole's Logic and Probability. Unlike the latter work, however, we make direct use of the polynomials native to LT rather than appealing to formalisms such as multisets and rings. (shrink)

Identification of Pygopus in Drosophila as a dedicated component of the Wg (fly homolog of mammalian Wnt) signaling cascade initiated many inquiries into the mechanism of its function. Surprisingly, the nearly exclusive role for Pygopus in Wg signal transduction in flies is not seen in mice, where Pygopus appears to have both Wnt‐related and Wnt‐independent functions. This review addresses the initial findings of Pygopus as a Wg/Wnt co‐activator in light of recent data from both fly and mammalian studies. We (...) compare and contrast the developmental phenotypes of pygopus mutants to those characterized for known Wg/Wnt transducers and explore the data regarding a role for mammalian Pygopus 2 in tumorigenesis. We further analyze the roles of the two conserved domains of Pygopus proteins in transcription, and propose a model for the molecular mechanism of Pygopus function in both Wg/Wnt signaling and Wnt‐independent transcriptional regulation. BioEssays 30:448–456, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

There are two ways to approach political representation. We can view each type of representation or each site of representation – namely a representative actor or institution – on an individual basis and study its internal dynamics. Alternatively, we can look at how different forms of representation and representative actors and institutions interact in a system of representation. In this article, I develop the second view. I make three contributions to the theory of representation from systemic thinking. Methodologically, I explain (...) the contours of a systemic approach to political representation. Descriptively, I propose a definition of a system of representation that captures representative pluralism, distribution of representative work and different levels of representation. Normatively, I set criteria for judging the system of representation and its individual components with systemic criteria. (shrink)

We develop here the general treatment arising from the Bethe-Salpeter equation for a two-particle bound system in which at least one of the particles is spinless. It is shown that a natural two-component formalism can be formulated for describing the propagators of scalar particles. This leads to a formulation of the Bethe-Salpeter equation in a form very reminiscent of the fermion-fermion case. It is also shown, that using this two-component formulation for spinless particles, the perturbation theory can be systematically developed (...) in a manner similar to that of fermions. Quantum electrodynamics for scalar particles is then developed in the two component formalism, and the problem of bound states, in which one of the constituent particles is spinless, is examined by means of the means of the Bethe-Salpeter equation. For this case, the Bethe-Salpeter equation is cast into a form which is convenient to perform a Foldy-Woutyhuysen transformation which we carry out, keeping the lowest-order relativistic corrections to the nonrelativistic equation. The results are compared with the corresponding fermion-fermion case. It is shown, as might have been expected, that the only spin-independent terms that occur for the fermion-fermion system which do not occur for bound scalar particle cases, is the zitterbewegung contribution. The relevance of the above considerations for systems that are essentially bound by electromagnetic interactions, such as kaonic hydrogen, is discussed. (shrink)

Effective robots and autonomous systems must be trustworthy. This chapter examines models of trustworthiness from a philosophical and empirical perspective to inform the design and adoption of autonomous systems. Trustworthiness is a property of trusted agents or organisations that engenders trust in other agent or organisations. Trust is a complex phenomena defined differently depending on the discipline. This chapter aims to bring different approaches under a single framework for investigation with three sorts of questions: Who or what is (...) trustworthy?–metaphysics. How do we know who or what is trustworthy?–epistemology. What factors influence what or who should we trust?–normativity. A two-component model of trust is used that incorporates competence (skills, reliability and experience) and integrity (motives, honesty and character). It is supposed that human levels of competence yield the highest trust whereas trust is reduced at sub-human and super-human levels. The threshold for trustworthiness of an agent or organisation in a particular context is a function of their relationship with the truster and potential impacts of decisions. Building trustworthy autonomous systems requires obeying the norms of logic, rationality and ethics under pragmatic constraints–even though there is disagreement on these principles by experts. Autonomous systems may need sophisticated social identities including empathy and reputational concerns to build human-like trust relationships. Ultimately transdisciplinary research drawing on metaphysical, epistemological and normative human and machine theories of trust are needed to design trustworthy autonomous systems for adoption. (shrink)

The article investigates the possibility of formation of creative competencies of students within the framework of scientific personnel training. It is noted that the available training courses within the framework of general training of scientific personnel allow to prepare a specialist who is able to use existing knowledge, but such a specialist is not trained in creativity. For the formation of creative competences it is necessary to take a training course of the general theory of systems, the purpose of (...) which is to create a universal methodology of reliable representation of models of objects, based on the similarity (isomorphism) of the forms and laws of the universe. A detailed argumentation of the connection between creativity and holistic representation of being, the empirical manifestation of which is isomorphism, is given. The mechanism of knowledge translation within the framework of the mechanism of multisystem integration of human being, the mechanism of knowledge borrowing by human being from sensually comprehended forms of reality is investigated. It is stated that in order to meet the set tasks of cognition, a version of the general theory of systems, extended by the metaphysical component, is required. Further, starting from the metaphysical description of the foundations of the phenomenon of isomorphism observed in the practice of cognition, it is possible to form complete collections of patterns – typical forms, templates of objects and their relations. At present, the work on such a version of the general theory of systems is being finalized. The article concludes with a discussion of the problematics of teaching general systems theory. It emphasizes two components: the issue of positioning the training course "General Theory of Systems" in relation to other courses, as well as taking into account the specifics of the subject area of students in different specialties (directions). (shrink)

I consider two threats to the idea that on-line intelligent behaviour (the production of fluid and adaptable responses to ongoing sensory input) must or should be explained by appeal to neurally located representations. The first of these threats occurs when extra-neural factors account for the kind of behavioural richness and flexibility normally associated with representation-based control. I show how this anti-representational challenge can be met, if we apply the thought that, to be a representational system, an action-oriented neural system must (...) not only be the source of at least some of the observed behavioural richness and flexibility, it must also feature two architectural traits, namely arbitrariness and homuncularity. Unfortunately, however, this solution opens the door to our second threat to representation. The homuncularity condition will not be met by any system in which the causal contribution of each component is massively context-sensitive and variable over time. I end by discussing the empirical bet that biological nervous systems will not exhibit this style of causation. (shrink)