Both RalA and RalB interact with the ubiquitous calcium sensor, calmodulin (CaM). New structural and biophysical characterisation of these interactions strongly suggests that, in the native membrane‐associated state, only RalA can be extracted from the membrane by CaM and this non‐canonical interaction could underpin the divergent signalling roles of these closely related GTPases. The isoform specificity for RalA exhibited by CaM is hypothesised to contribute to the disparate signalling roles of RalA and RalB in mitochondrial dynamics. This would lead to (...) CaM shuttling RalA to the mitochondrial membrane but leaving RalB localisation unperturbed, and in doing so triggering mitochondrial fission pathways rather than mitophagy. (shrink)

The tricarboxylic acid (TCA) or Krebs cycle, which takes place in prokaryotic cells and in the mitochondria of eukaryotic cells, is central to life on Earth and participates in key events such as energy production and anabolic processes. Despite its relevance, it is not perceived as tightly regulated compared to other key metabolisms such as glycolysis/gluconeogenesis. A better understanding of the functioning of the TCA cycle is crucial due to mitochondrial function impairment in several diseases, especially those that occur (...) with neurodegeneration. This article revisits what is known about the regulation of the Krebs cycle and hypothesizes the need for large‐scale, rapid regulation of TCA cycle enzyme activity. Evidence of mitochondrial enzyme activity regulation by activation/deactivation of protein kinases and phosphatases exists in the literature. Apart from indirect regulation via G protein‐coupled receptors (GPCRs) at the cell surface, signaling upon activation of GPCRs in mitochondrial membranes may lead to a direct regulation of the enzymes of the Krebs cycle. Hormonal‐like regulation by posttranscriptional events mediated by activable kinases and phosphatases deserve proper assessment using isolated mitochondria. Also see the video abstract here: https://youtu.be/aBpDSWiMQyI. (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)

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)

Ion channels mediate ion flux across biological membranes and regulate important organellar and cellular tasks. A recent study revealed the presence of four new proteins, the MIM complex (composed by Mim1 and Mim2), Ayr1, OMC7, and OMC8, that are able to form ion‐conducting channels in the outer mitochondria membrane (OMM). These findings strongly indicate that the OMM is endowed with many solute‐specific channels, in addition to porins and known channels mediating protein import into mitochondria. These solute‐specific channels provide (...) essential pathways for the controlled transport of ions and metabolites and may thus add a further layer of specificity to the regulation of mitochondrial function at the organelle‐cytosol and/or inter‐organellar interface. Future studies will be required to fully understand the way(s) of regulation of these new channels and to integrate them into signaling pathways within the cells. (shrink)

MPZL3 is a nuclear‐encoded, mitochondrially localized, immunoglobulin‐like V‐type protein that functions as a key regulator of epithelial cell differentiation, lipid metabolism, ROS production, glycemic control, and energy expenditure. Recently, MPZL3 has surfaced as an important modulator of sebaceous gland function and of hair follicle cycling, an organ transformation process that is also governed by peripheral clock gene activity and PPARγ. Given the phenotype similarities and differences between Mpzl3 and Pparγ knockout mice, we propose that MPZL3 serves as a signaling (...) hub that is regulated by core clock gene products and/or PPARγ to translate signals from these nuclear transcription factors to the mitochondria to modulate circadian and metabolic regulation. Conservation between murine and human MPZL3 suggests that human MPZL3 may have similarly complex functions in health and disease. We summarize current knowledge and discuss future directions to elucidate the full spectrum of MPZL3 functions in mammalian physiology. (shrink)

The importance of electrical signalling in bacteria is an emerging paradigm. Bacillus subtilis biofilms exhibit electrical communication that regulates metabolic activity and biofilm growth. Starving cells initiate oscillatory extracellular potassium signals that help even the distribution of nutrients within the biofilm and thus help regulate biofilm development. Quorum sensing also regulates biofilm growth and crucially there is convergence between electrical and quorum sensing signalling axes. This makes B. subtilis an interesting model for cell signalling research. SpoOF is predicted to act (...) as a logic gate for signalling pathway convergence, raising interesting questions about the functional nature of this gate and the relative importance of these disparate signals on biofilm behaviour. How is an oscillating signal integrated with a quorum signal? The model presented offers rich opportunities for future experimental and theoretical modelling research. The importance of direct cell‐to‐cell electrical signalling in prokaryotes, so characteristic of multicellular eukaryotes, is also discussed. (shrink)

This paper discusses the evidence for the role of CREB in neural stem/progenitor cell (NSPC) function and oncogenesis and how these functions may be important for the development and growth of brain tumours. The cyclic‐AMP response element binding (CREB) protein has many roles in neurons, ranging from neuronal survival to higher order brain functions such as memory and drug addiction behaviours. Recent studies have revealed that CREB also has a role in NSPC survival, differentiation and proliferation. Recent work has shown (...) that over‐expression of CREB in transgenic animals can impart oncogenic properties on cells in various tissues and that aberrant CREB expression is associated with tumours in patients. It is the central position of CREB, downstream of key developmental and growth signalling pathways, which give CREB the ability to influence a spectrum of cell activities, such as cell survival, growth and differentiation in both normal and cancer cells. (shrink)

Bone morphogenetic proteins (BMPs) are typically members of the transforming growth factor β (TGF-β) family with diverse roles in embryonic development. At least five genes with homology to BMPs are expressed during Xenopus development, along with their receptors and intracellular signalling pathways. The evidence suggests that BMPs have roles to play in both mesoderm induction and dorsoventral patterning. Studies in Xenopus have also identified a number of inhibitory binding proteins for the classical BMPs, encoded by genes such as chordin and (...) noggin. These proteins appear to be responsible for establishing a morphogen gradient of BMP4 activity, which specifies different dorsoventral fates in early gastrulae. An emerging theme is that inhibition of BMP signalling is an important mechanism regulating cell fate decisions in early development. BioEssays 21:751–760, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

This paper is a short survey of different languageswith imperfect information introduced in (Hintikka and Sandu 1989).The imperfect information concerns both quantifiers and connectives.At the end, I will sketch a connection between these languages and linearlogic.

Aerobic mitochondria serve as the power sources of eukaryotes by producing ATP through oxidative phosphorylation (OXPHOS). The enzymes involved in OXPHOS are multisubunit complexes encoded by both nuclear and mitochondrial DNA. Thus, regulation of respiration is necessarily a highly coordinated process that must organize production, assembly and function of mitochondria to meet an organism's energetic needs. Here I review the role of OXPHOS in metabolic adaptation and diversification of higher animals. On a physiological timescale, endocrine‐initiated signaling pathways (...) allow organisms to modulate respiratory enzyme concentration and function under changing environmental conditions. On an evolutionary timescale, mitochondrial enzymes are targets of natural selection, balancing cytonuclear coevolutionary constraints against physiological innovation. By synthesizing our knowledge of biochemistry, physiology and evolution of respiratory regulation, I propose that we can now explore questions at the interface of these fields, from molecular translation of environmental cues to selection on mitochondrial haplotype variation. BioEssays 28: 890–901, 2006. © 2006 Wiley periodicals, Inc. (shrink)

According to the causal interpretation of quantum mechanics, one can precisely define the state of an individual particle in a many-body system by its position, momentum, and spin. It is shown in the EPR spin experiment that the quantum torque brings about an instantaneous change in the state of one of the particles when the other undergoes a local interaction, but that such a transfer of “information” cannot be extracted by any experiment subject to the laws of quantum mechanics.

Movement and positional control of mitochondria and other organelles are coordinated with cell cycle progression in the budding yeast, Saccharomyces cerevisiae. Recent studies have revealed a checkpoint that inhibits cytokinesis when there are severe defects in mitochondrial inheritance. An established checkpoint signaling pathway, the mitotic exit network (MEN), participates in this process. Here, we describe mitochondrial motility during inheritance in budding yeast, emerging evidence for mitochondrial quality control during inheritance, and organelle inheritance checkpoints for mitochondria and other (...) organelles. (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 endoplasmic reticulum (ER) organelle is the key intracellular site of both protein and lipid biosynthesis. ER dysfunction, termed ER stress, can result in protein accretion within the ER and cell death; a pathophysiological process contributing to a range of metabolic diseases and cancers. ER stress leads to the activation of a protective signalling cascade termed the Unfolded Protein Response (UPR). However, chronic UPR activation can ultimately result in cellular apoptosis. Emerging evidence suggests that cells undergoing ER stress and UPR (...) activation can release extracellular signals that can propagate UPR activation to target tissues in a cell non‐autonomous signalling mechanism. Separately, studies have determined that the UPR plays a key regulatory role in the biosynthesis of bioactive signalling lipids including sphingolipids and ceramides. Here we weigh the evidence to combine these concepts and propose that during ER stress, UPR activation drives the biosynthesis of ceramide lipids, which are exported and function as cell non‐autonomous signals to propagate UPR activation in target cells and tissues. (shrink)

Paraspeckles are nuclear condensates, or membranelees organelles, that are built on the long noncoding RNA, NEAT1, and have been linked to many diseases. Although originally described as constitutive structures, here, in reviewing this field, we develop the hypothesis that cells increase paraspeckle abundance as part of a general stress response, to aid pro‐survival pathways. Paraspeckles increase in many scenarios: when cells transform from one state to another, become infected with viruses and bacteria, begin to degenerate, under inflammation, in aging, and (...) in cancer. Cells increase paraspeckles by increasing transcription of NEAT1 and adjusting its RNA processing. These increases in NEAT1 are driven by numerous stress‐sensing signaling pathways, including signaling to mitochondria and stress granules, revealing crosstalk between the cytoplasm and nucleoplasm in the stress response. Thus, paraspeckles are an important piece of the puzzle in cellular homeostasis, and could be considered RNA‐scaffolded nuclear equivalents of dynamic stress‐induced structures that form in the cytoplasm. We speculate that, in general, cells rely on phase‐separated paraspeckles to transiently tweak gene regulation in times of cellular flux. (shrink)

Depletion of mitochondrial endo/exonuclease G‐like (EXOG) in cultured neonatal cardiomyocytes stimulates mitochondrial oxygen consumption rate (OCR) and induces hypertrophy via reactive oxygen species (ROS). Here, we show that neurohormonal stress triggers cell death in endo/exonuclease G‐like‐depleted cells, and this is marked by a decrease in mitochondrial reserve capacity. Neurohormonal stimulation with phenylephrine (PE) did not have an additive effect on the hypertrophic response induced by endo/exonuclease G‐like depletion. Interestingly, PE‐induced atrial natriuretic peptide (ANP) gene expression was completely abolished in endo/exonuclease (...) G‐like‐depleted cells, suggesting a reverse signaling function of endo/exonuclease G‐like. Endo/exonuclease G‐like depletion initially resulted in increased mitochondrial OCR, but this declined upon PE stimulation. In particular, the reserve capacity of the mitochondrial respiratory chain and maximal respiration were the first indicators of perturbations in mitochondrial respiration, and these marked the subsequent decline in mitochondrial function. Although pathological stimulation accelerated these processes, prolonged EXOG depletion also resulted in a decline in mitochondrial function. At early stages of endo/exonuclease G‐like depletion, mitochondrial ROS production was increased, but this did not affect mitochondrial DNA (mtDNA) integrity. After prolonged depletion, ROS levels returned to control values, despite hyperpolarization of the mitochondrial membrane. The mitochondrial dysfunction finally resulted in cell death, which appears to be mainly a form of necrosis. In conclusion, endo/exonuclease G‐like plays an essential role in cardiomyocyte physiology. Loss of endo/exonuclease G‐like results in diminished adaptation to pathological stress. The decline in maximal respiration and reserve capacity is the first sign of mitochondrial dysfunction that determines subsequent cell death. (shrink)

Neuronal signalling involves multiple neuropeptides that are diverse in structure and function. Complex patterns of tissue‐specific expression arise from alternate RNA splicing of neuropeptide‐encoding gene transcripts. The pattern of expression and its role in cell signalling is diffecult to study at the level of single neurons in the complex vertebrate brain. However, in the model molluscan system, Lymnaea, it is possible to show that alternate mRNA expression of the FMRFamide gene is specific to single identified neurons. Two different transcripts are (...) expressed in a mutually exclusive manner in different neurons. Post‐translational processing of the two precursor proteins leads to completely distinct sets of neuropeptide transmitters. The function of these transmitter cocktails, resulting from alternate mRNA splicing, was studied physiologically in identified neurons forming part of a behaviourally important network regulating heartbeat. (shrink)

Many mammals use scent marks to advertise territory ownership, but only recently have we started to understand the complexity of these scent signals and the types of information that they convey. Whilst attention has generally focused on volatile odorants as the main information molecules in scents, studies of the house mouse have now defined a role for a family of proteins termed major urinary proteins (MUPs) which are, of course, involatile. MUPs bind male signalling volatiles and control their release from (...) scent marks. These proteins are also highly polymorphic and the pattern of polymorphic variants provides a stable ownership signal that communicates genome‐derived information on the individual identity of the scent owner. Here we review the interaction between the chemical basis of mouse scents and the dynamics of their competitive scent marking behaviour, demonstrating how it is possible to provide reliable signals of the competitive ability and identity of individual males. BioEssays 26:1288–1298, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Natural languages are compositional in that the meaning of complex expressions depends on those of the parts and how they are put together. Here, I ask the following question: why are languages compositional? I answer this question by extending Lewis–Skyrms signaling games with a rudimentary form of compositional signaling and exploring simple reinforcement learning therein. As it turns out: in complex worlds, having compositional signaling helps simple agents learn to communicate. I am also able to show that (...) learning the meaning of a function word, once meanings of atomic words are known, presents no difficulty. (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)

Starting from logical structures of classical and quantum mechanics we reconstruct the logic of so-called no-signaling theories, where the correlations among subsystems of a composite system are restricted only by a simplest form of causality forbidding an instantaneous communication. Although such theories are, as it seems, irrelevant for the description of physical reality, they are helpful in understanding the relevance of quantum mechanics. The logical structure of each theory has an epistemological flavor, as it is based on analysis of (...) possible results of experiments. In this note we emphasize that not only logical structures of classical, quantum and no-signaling theory may be treated on the same ground but it is also possible to give to all of them a common ontological basis by constructing a “phase space” in all cases. In non-classical cases the phase space is not a set, as in classical theory, but a more general object obtained by means of category theory, but conceptually it plays the same role as the phase space in classical physics. (shrink)

What are the functional units of the brain? If the function of the brain is to process information-carrying signals, then the functional units will be the senders and receivers of those signals. Neurons have been the default candidate, with action potentials as the signals. But there are alternatives: synapses fit the action potential picture more cleanly, and glial activities (e.g., in astrocytes) might also be characterized as signaling. Are synapses or nonneuronal cells better candidates to play the role of (...) functional units? Will informational signaling still be the best model for brain function if we move beyond the neuron doctrine? (shrink)

Mitochondria hold diverse and pivotal roles in fundamental processes that govern cell survival, differentiation, and death, in addition to organismal growth, maintenance, and aging. The mitochondrial protein import system is a major contributor to mitochondrial biogenesis and lies at the crossroads between mitochondrial and cellular homeostasis. Recent findings highlight the mitochondrial protein import system as a signaling hub, receiving inputs from other cellular compartments and adjusting its function accordingly. Impairment of protein import, in a physiological, or disease context, (...) elicits adaptive responses inside and outside mitochondria. In this review, we discuss recent developments, relevant to the mechanisms of mitochondrial protein import regulation, with a particular focus on quality control, proteostatic and metabolic cellular responses, triggered upon impairment of mitochondrial protein import. (shrink)

In recent years, the research field of the evolution of art has witnessed contributions from a wide range of disciplines across the "three cultures". In this thesis, I make both a critical review of existing explanations, and try to do elucidate the evolution of art by employing insights, methods and concepts from different disciplines. First, I critically evaluate the evidentiary criteria from standard evolutionary psychology some accounts employ to demonstrate that art qualifies as a human biological adaptation. I argue that (...) these criteria do not suffice to make that claim. Furthermore, I make the case for a cultural evolutionary approach to the arts. One commonly used evidentiary criterion for art as adaptation is the “tight fit” between artnbsp;human cognition, which is interpreted as suggesting that cognition has undergone selection to produce and appreciate art. However, disentangling cultural and genetic evolution allows formulating thenbsp;hypothesis that art has evolved culturally to match human cognition. Second, I observe that in ancient and modern hunter gatherer societies, artistic activities are virtually alwaysnbsp;with ritual. I discuss what this implies for the adaptive significance of art. Specifically, if the arts have culturally evolved in function of ritualistic purposes, their adaptive value has depended on the adaptiveness of ritual. Third, because architecture is characterized by the combination of utilitarian and aesthetic aspects, it is particularly interesting from an evolutionary perspective and therefore I devote special attention to it. Employing the cross-species comparative approach, I investigate two main purposes human architecture has in common with nonhuman animal constructions: protection andnbsp;Based on the phylogenetic approach I establish that protection may have been the primary function of building aptitudes in humannbsp;and that building was later co-opted for signaling purposes. Subsequently, I comparatively evaluate thenbsp;of signaling models in the cultural evolution of architectural aesthetics. Furthermore I combine insights from environmental psychology, niche construction and cultural evolution theory to develop the hypothesis that a function of religious monumental architecture may have been to support nbsp;or even to galvanize nbsp;social learning. Finally, I connect the account I developed to the cognitive science of religion. I complement the frequently held view that religious monumental architecture is a costly signal with the mechanism of sensory exploitation. I attempt to demonstrate that by exploiting thenbsp;response of awe in religious followers, religious monumental architecture promotes and regulates prosocial behavior and creates in them an openness to adopt supernatural beliefs. Fourth, I dealnbsp;the evolution of visual art, paying again special attention to cultural evolution andnbsp;explanatory value of sensory exploitation. I assert that the relatively late appearance of figurative art in the course of human evolution may be attributed to an increase in the number of social learning opportunities within and between human populations at that time. I support this assertion with archaeological data that indicate overall population growth and increased population densities at that time. These demographic changes, I argue, have allowed the retention and accumulation of innovations required for figurative art making. Contrary to previous accounts, I furthermore aim to show that this process doesnbsp;require figurative art to have served adaptive purposes. Employing sensory exploitation, I establish that figurative art could have evolved by exploiting pre-existing biases of evolved psychology. The dominant themes of upper Paleolithic and late stone age figurative art, animals and humans, seem to support this contention. Fifth, I present a number of experimental studies I conducted to verify whether contemporary art experts would have socially learned to resist exploitation of evolved psychology. One aspect ofrsquo;s exploitative power may be that it elicits aesthetic pleasure by pushing “pleasure buttons” that evolved for other purposes. Consequently, spectators may trade-off rewards from indulging in art and biological activities, resulting in less effort being allocated to reproduction. I contend that, while the generalnbsp; may indeed be exploited, experts, who are typically being exposed to high doses of art, may have socially learned to resist exploitation by selectively preferring art from prestigious art contexts. The latter would be in line with the claim that prestige bias may trump content biases of evolved psychology. The results of three experimental studies supportnbsp;contention. I find that laypeople's art appreciation is positively affected by a content bias for attractive faces, mediated by aesthetic pleasure, whereas experts' appreciation is positively affected by prestige and mediated by admiration for the artist. Moreover, experts confer lower appreciation to attractive compared to moderately attractive content, which is consistentnbsp;the contention that expertise and the use of prestige are associatednbsp;resistance against beautiful content that exploits evolved preferences. This research thus suggests that expertise moderates content and context biases, which may be of relevance to an ongoing debate about their relative importance as drivers of cultural evolution. In addition, this study provides a tentative but novel explanation for the fact, famously established by philosopher Arthur Danto, that beauty lost its central position in Western art during the 20th century. However my findings cannot exclude alternative explanations for the fact that art expert appreciation deviates from evolved aesthetic preferences. Further research may experimentally assess the role of prestige bias and resistance as drivers of this deviation versus other, previously suggested, potential processes. For example, preferences of experts may deviate on account of the fact that art serves as a badge of elite group membership and thus expert art appreciation as a means to distinguish oneself from the masses. Alternatively, art experts may seek intellectual challenges instead of pushing pleasure buttons. Future research may experimentally verify the respective roles of these different hypothesized mechanisms. In addition, it may be investigated how insights from sexual selection research may help elucidating the different processes at play in cultural evolution and particularly in the cultural evolution of art appreciation, given the commonalities between sexual selection and cultural selection models. (shrink)

Intercellular signaling plays a major role in the development of vertebrate and invertebrate embryos. In several cases, including the induction of mesoderm and neural ectoderm induction in Xenopus and the induction of the vulva in C. elegans, multiple intercellular signals are utilized. This review examines a number of examples of signaling in development wherein two signals combine to affect the fate of a cell. The examples are placed in distinct categories, based on whether the signals synergize with or (...) antagonize one another, and on the inductive potential of the individual signals. These types of combinatorial signaling events are suggested to be a general feature of embryonic development. (shrink)

Early in the 20th century, Charles Manning Child attributed organismal gradients in metabolism to interactions among groups of cells. Metabolic gradients are now firmly grounded in redox chemistry, yet modern work on metabolic signaling has consistently focused on the cellular level. Multicellular redox regulation, however, may occur when redox state is determined by the behavior of a group of cells. For instance, typically an abundance of substrate will shift the redox state of mitochondria in the direction of reduction, (...) leading to increased reactive oxygen species (ROS). These ROS, in turn, may modify the conformation and activity of proteins involved in signaling pathways, resulting in phenotypic changes. In contrast, if substrate triggers the contractions of a muscular structure comprising mitochondrion‐rich cells, the resulting metabolic demand may shift the redox state in the direction of oxidation, with a corresponding decrease of ROS and different phenotypic effects. Indeed, colonial hydroids exemplify this process. Parallel examples may occur whenever mitochondria are concentrated in cells of structures that can respond to environmental perturbations with increased metabolic demand. In these circumstances, predicting the direction of metabolic signaling may require an understanding of events at the organismal level. BioEssays 28:72–77, 2006. © 2005 Wiley Periodicals, Inc. (shrink)

The evolutionarily conserved Notch signaling pathway regulates a broad spectrum of cell fate decisions and differentiation processes during fetal and postnatal life. It is involved in embryonic organogenesis as well as in the maintenance of homeostasis of self‐renewing systems. In this article, we review the role of Notch signaling in the hematopoietic system with particular emphasis on lymphocyte development and highlight the similarities in Notch function between Drosophila and mammalian differentiation processes. Recent studies indicating that aberrant NOTCH (...) class='Hi'>signaling is frequently linked to the induction of T leukemia in humans will also be discussed. BioEssays 27:1117–1128, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Cooption and modularity are informative concepts in evolutionary developmental biology. Genes function within complex networks that act as modules in development. These modules can then be coopted in various functional and evolutionary contexts. Hormonal signaling, the main focus of this review, has a modular character. By regulating the activities of genes, proteins and other cellular molecules, a hormonal signal can have major effects on physiological and ontogenetic processes within and across tissues over a wide spatial and temporal scale. Because (...) of this property, we argue that hormones are frequently involved in the coordination of life history transitions (LHTs) and their evolution (LHE). Finally, we promote the usefulness of a comparative, non-model system approach towards understanding how hormones function and guide development and evolution, highlighting thyroid hormone function in echinoids as an example. BioEssays 27:64–75, 2005. © 2004 Wiley Periodicals, Inc. (shrink)

Identification of the molecular mechanisms underlying axonal branching in vivo has begun in several neuronal systems, notably the projections formed by dorsal root ganglion (DRG) neurons or retinal ganglion cells (RGC). cGMP signalling is essential for sensory axon bifurcation at the spinal cord, whereas brain‐derived neurotrophic factor (BDNF) and ephrinA signalling establish position‐dependent branching of RGC axons. In the latter system, the degradation of specific signalling components, via the ubiquitin‐proteasome system, may provide an additional mechanism involved in axon branching of (...) RGC. The process of arborisation is essential for neurons to innervate multiple targets and to build topographic maps. The various forms of branching found in different types of neurons are regulated by distinct signalling pathways activated by multiple extracellular cues in addition to axonal guidance factors. These signalling cascades, together with transcriptional programs, most likely interact and trigger the polymerisation or depolymerisation of the actin and tubulin cytoskeleton to regulate branching. (shrink)

The Evolution of Animal Communication is a detailed examination of a wide variety of animal signalling systems. The main focus of the book is explaining how such signalling systems remain reliable when there is apparent evolutionary pressure to deceive. The principle strategy is to appeal to signal costs: signals remain reliable because the potential benefits of deceit are outweighed by the costs of producing the deceptive signal. In this review I show just how difficult this idea is to test, even (...) in the simplest cases. (shrink)

Steroid hormones are signaling molecules important for normal growth, development and differentiation of multicellular organisms. Brassinosteroids (BRs) are a class of polyhydroxylated steroids that are necessary for plant development. Molecular genetic studies in Arabidopsis thaliana have led to the cloning and characterization of the BR receptor, BRI1, which is a transmembrane receptor serine/threonine kinase. The extracellular domain of BRI1, which is composed mainly of leucine‐rich repeats, can confer BR responsivity to heterologous cells and is required for BR binding. Although (...) downstream components of BR action are mostly unknown, multiple genes whose expression are regulated by BRs have been identified and suggest mechanisms by which BRs affect cell elongation and division. BioEssays 23:1028–1036, 2001. © 2001 John Wiley & Sons, Inc. (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)

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 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)

I propose that a dishonest signaling system can be evolutionarily stable in eusocial animal societies if the amount of dishonesty is balanced by the chance of non-reproductive workers to advance to the reproductive caste in the future. I express this trade-off in a modified form of Hamilton’s rule, where I distinguish between the real and perceived cost of an altruistic act, and between the real and perceived genetic relatedness between colony members. Furthermore, I elaborate how the vertebrate neuromodulator oxytocin (...) could serve as an internal representation of the perceived cost of an altruistic act and of perceived relatedness. Behavioral and receptor localization data support this hypothesis. The encoding of cost and relatedness by oxytocin is likely integrated with a number of other functions related to social bonding. I conclude with a discussion of honesty in signaling, an outline of testable consequences of this hypothesis, and a comparison between vertebrate and insect eusociality. (shrink)

Lewis signalling games are often used to explain how it is possible for simple agents to develop systems of conventional semantic meaning. In these games, all players obtain identical payoffs in every outcome. This is an unrealistic payoff structure, but it is often employed because it is thought that semantic meaning will not emerge if interests conflict. Here it is shown that not only is conventional meaning possible when interests conflict, but it is the most likely outcome in a finite (...) population model of learning known as the Moran process. On the basis of this result it is suggested that evolutionary game theory’s standard models may yield results that are systematically distorted for a class of signalling games that have the abstract structure of social dilemmas. 1 Introduction2 The Seduction Game3 Imitation Dynamics with Small Mutations4 Dynamics with Unverifiable Message5 Analysis of a Related Three-Strategy Game6 Conclusion. (shrink)

One might think that if the majority of virtue signallers judge that a proposition is true, then there is significant evidence for the truth of that proposition. Given the Condorcet Jury Theorem, individual virtue signallers need not be very reliable for the majority judgment to be very likely to be correct. Thus, even people who are skeptical of the judgments of individual virtue signallers should think that if a majority of them judge that a proposition is true, then that provides (...) significant evidence that the proposition is true. We argue that this is mistaken. Various empirical studies converge on the following point: humans are very conformist in the contexts in which virtue signalling occurs. And stereotypical virtue signallers are even more conformist in such contexts. So we should be skeptical of the claim that virtue signallers are sufficiently independent for the Condorcet Jury Theorem to apply. We do not seek to decisively rule out the relevant application of the Condorcet Jury Theorem. But we do show that careful consideration of the available evidence should make us very skeptical of that application. Consequently, a defense of virtue signalling would need to engage with these findings and show that despite our strong tendencies for conformism, our judgements are sufficiently independent for the Condorcet Jury Theorem to apply. This suggests new directions for the debate about the epistemology of virtue signalling. (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)

This paper proposes a sender-receiver model to explain two large-scale patterns observed in natural languages: Zipf’s inverse power law relating the frequency of word use and word rank, and the negative correlation between the frequency of word use and rate of lexical change. Computer simulations show that the model recreates Zipf’s inverse power law and the negative correlation between signal frequency and rate of change, provided that agents balance the rates with which they invent new signals and forget old ones. (...) Results are robust across a wide range of parameter values and structural assumptions, such as different forgetting rules and forgetting rates. Analysis of the model further suggests that Zipf’s law relating word frequency and rank arises because of language-external factors and that frequent signals change less because frequent signals are less subject to drift than rare ones. The paper concludes with some brief considerations on model-based and data-driven approaches in philosophy. (shrink)

It has long been asserted that the evolutionary path to spoken language was paved by manual–gestural behaviors, a claim that has been revitalized in response to recent research on mirror neurons. Renewed interest in the relationship between manual and vocal behavior draws attention to its development. Here, the pointing and vocalization of 16.5-month-old infants are reported as a function of the context in which they occurred. When infants operated in a referential mode, the frequency of simultaneous vocalization and pointing exceeded (...) the frequency of vocalization-only and pointing-only responses by a wide margin. In a non-communicative context, combinatorial effects persisted, but in weaker form. Manual–vocal signals thus appear to express the operation of an integrated system, arguably adaptive in the young from evolutionary times to the present. It was speculated, based on reported evidence, that manual behavior increases the frequency and complexity of vocal behaviors in modern infants. There may be merit in the claim that manual behavior facilitated the evolution of language because it helped make available, early in development, behaviors that under selection pressures in later ontogenetic stages elaborated into speech. (shrink)

This paper proposes a sender-receiver model to explain two large-scale patterns observed in natural languages: Zipf’s inverse power law relating the frequency of word use and word rank, and the negative correlation between the frequency of word use and rate of lexical change. Computer simulations show that the model recreates Zipf’s inverse power law and the negative correlation between signal frequency and rate of change, provided that agents balance the rates with which they invent new signals and forget old ones. (...) Results are robust across a wide range of parameter values and structural assumptions, such as different forgetting rules and forgetting rates. Analysis of the model further suggests that Zipf’s law relating word frequency and rank arises because of language-external factors and that frequent signals change less because frequent signals are less subject to drift than rare ones. The paper concludes with some brief considerations on model-based and data-driven approaches in philosophy. (shrink)

The neural crest is a transient population of multipotent progenitors arising at the lateral edge of the neural plate in vertebrate embryos. After delamination and migration from the neuroepithelium, these cells contribute to a diverse array of tissues including neurons, smooth muscle, craniofacial cartilage, bone cells, endocrine cells and pigment cells. Considerable progress in recent years has furthered our understanding at a molecular level of how this important group of cells is generated and how they are assigned to specific lineages. (...) Here we review a number of recent studies supporting a role for Wnt signaling in neural crest induction, differentiation, and apoptosis. We also summarize the timing of expression of a number of Wnt ligands and receptors with respect to neural crest induction. BioEssays 25:317–325, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

The accusation of virtue signalling is typically understood as a serious charge. Those accused usually respond by attempting to show that they are doing no such thing. In this paper, I argue that we ought to embrace the charge, rather than angrily reject it. I argue that this response can draw support from cognitive science, on the one hand, and from social epistemology on the other. I claim that we may appropriately concede that what we are doing is virtue signalling, (...) because virtue signalling is morally appropriate. It neither expresses vices, nor is hypocritical, nor does it degrade the quality of public moral discourse. Signalling our commitment to norms is a central and justifiable function of moral discourse, and the same signals provide evidence that is appropriately taken into account in forming moral beliefs. (shrink)

Pancreatic β‐cells in the islet of Langerhans produce the hormone insulin, which maintains blood glucose homeostasis. Perturbations in β‐cell function may lead to impairment of insulin production and secretion and the onset of diabetes mellitus. Several essential β‐cell factors have been identified that are required for normal β‐cell function, including six genes that when mutated give rise to inherited forms of diabetes known as Maturity Onset Diabetes of the Young (MODY). However, the intracellular signaling pathways that control expression of (...) MODY and other factors continue to be revealed. Post‐transplant diabetes mellitus in patients taking the calcineurin inhibitors tacrolimus (FK506) or cyclosporin A indicates that calcineurin and its substrate the Nuclear Factor of Activated T‐cells (NFAT) may be required for β‐cell function. Here recent advances in our understanding of calcineurin and NFAT signaling in the β‐cell are reviewed. Novel therapeutic approaches for the treatment of diabetes are also discussed. BioEssays 29:1011–1021, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Planar cell polarity (PCP) refers to the polarization of a field of cells within the plane of a cell sheet. This form of polarization is required for diverse cellular processes in vertebrates, including convergent extension (CE), the establishment of PCP in epithelial tissues and ciliogenesis. Perhaps the most distinct example of vertebrate PCP is the uniform orientation of stereociliary bundles at the apices of sensory hair cells in the mammalian auditory sensory organ. The establishment of PCP in the mammalian cochlea (...) occurs concurrently with CE in this ciliated epithelium, therefore linking three cellular processes regulated by the vertebrate PCP pathway in the same tissue and emerging as a model system for dissecting PCP signaling. This review summarizes the morphogenesis of this model system to assist the interpretation of the emerging data and proposes molecular mechanisms underlying PCP signaling in vertebrates. BioEssays 29: 120–132, 2007. © 2007 Wiley Periodicals, Inc. (shrink)