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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

In lieu of an abstract, here is a brief excerpt of the content:Advocates, Not Problem ParentsAnonymous TwoNothing could have prepared us for the shock of hearing that our son had a brain tumor.Rob* was 13½, an active, healthy eighth grader, when he developed a headache so bad he couldn’t get out of bed in the morning. We saw the pediatrician three times over the next ten days. On the third visit, after ruling out problems at home, stress at school, strep (...) throat and mono, he sent us for an MRI. When the radiology tech handed me the films and told us to drive back to the pediatrician’s office, I knew we were in trouble. Sure enough, after all the other patients had left, our long–time doctor called us into his tiny office, shut the door and fumbled with the films as he pointed to a white spot that he said was a brain tumor.So began the experience that would change the course of our lives. We remember the diagnosis in detail and relive it in slow motion. We recall packing suitcases, driving to the hospital, waiting to be seen in the emergency room, and walking through doors marked “Pediatric Hematology/Oncology” for the first time.We date everything “BC” (Before Cancer) or “AD” (After Diagnosis). We are grateful every day that [End Page 13] our son is alive, but we know he is forever changed. We are changed: Our nuclear family, our extended family, everyone who knew us and supported us at the time was affected. A pediatric cancer diagnosis is a bomb that shatters your world without warning. If you’re lucky, you can pick up a lot of the pieces, maybe even most of them, but the world you re–enter is never the one you inhabited before.Our doctor delivered the diagnosis to Rob and me at the same time. I’ve thought about this many times and perhaps one day will ask him: Why did he choose to do it that way? Was it a conscious decision or just happenstance? Was it kinder, in the long run—like pulling off a band–aid quickly—or terribly risky? What if I had collapsed at the news? I asked to step into the hall to use the phone. In a state of numbness, I called my husband. He knew we had had an MRI a few hours earlier. “Come quickly,” I said. “There’s a mass.”We chose to go to a top-ranked major medical center and were admitted that evening. A couple of days later, the discovery of tumor markers in Rob’s cerebrospinal fluid and blood confirmed a central nervous system mixed germ cell tumor. We were told he would require six cycles of chemotherapy, followed by six weeks of radiation, and possibly second–look surgery and high-dose chemo with stem cell rescue on top of that. We were given a consent form listing a catalogue of short–and long–term side effects, among them the likelihood of infertility. We were urged to start treatment as soon as possible.By sheer coincidence I had just completed a project for a small, nonprofit organization that existed to inform young adult cancer patients about their fertility rights and options. I knew that infertility concerns were usually pushed aside at diagnosis to make way for other priorities, namely the urgency of starting treatment. And that’s exactly the kind of pressure we were facing.But my husband and I were not ready to sign away our son’s fertility in what felt like a no–confidence vote, a capitulation. We needed to believe that he would survive and put this horror behind him, that he would look forward to marriage and starting a family. We were willing to cede nothing to the disease at this early stage of the game. Was this rational, naive or selfish on our part? I don’t know.The medical team seemed surprised when we asked for a delay in treatment in order to collect sperm samples. They warned that our son’s condition could decline suddenly—and that postponing treatment by even several days might be dangerous. However, at our insistence, they agreed to the delay... (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 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)

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)

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)

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)

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)

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)

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)

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)

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

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)

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 lack of engagement of philosophy with decisions made under conditions of risk and uncertainty has lately received increasing attention. But philosophers have devoted little thought to the development of a conceptual framework for distinguishing different types of risks. This article begins by illustrating the need for a more nuanced conceptual framework. As the normative considerations risks give rise to are highly varied, ethicists need to distinguish between different types of risks. It then offers two ideas. First, it proposes that (...) we understand ‘risk’ as a multi-dimensional concept, i.e. a concept that can always be evaluated in different dimensions, e.g. a qualitative, a quantitative and an epistemic dimension. While this understanding of risk underlies the current practice of risk analysis, making it explicit is of value, in particular for the philosophical debate. It draws attention to the diversity of risks, helps to group them sensibly and sharpens existing arguments. Second, the article introduces a novel account of the notion ‘systemic risk’. Criticising existing accounts, it proposes we understand ‘systemic risk’ as referring to a risk that endangers the functioning of a system and originates in the system or its background noise, where a system is conceived of as a set of interdependent, interacting components that form a complex, functionally defined whole. The article identifies a number of structural features shared by systemic risks and evaluates the distinctive normative considerations they give rise to. It then argues that the notion ‘systemic risk’ is particularly suited to characterise some of the most pressing risks faced in an increasingly interconnected world. While the notion ‘systemic risk’ rests on the understanding of ‘risk’ as a multi-dimensional concept, it also complements it. Its necessity shows that in addressing risks, it is sometimes helpful to move beyond a characterisation based solely on their dimensions. (shrink)

This two-volume work, first published in 1843, was John Stuart Mill's first major book. It reinvented the modern study of logic and laid the foundations for his later work in the areas of political economy, women's rights and representative government. In clear, systematic prose, Mill (1806–73) disentangles syllogistic logic from its origins in Aristotle and scholasticism and grounds it instead in processes of inductive reasoning. An important attempt at integrating empiricism within a more general theory of human knowledge, the work (...) constitutes essential reading for anyone seeking a full understanding of Mill's thought. Volume 1 contains Mill's introduction, which elaborates upon his definition of logic as 'not the science of Belief, but the science of Proof, or Evidence'. It also features discussions of the central components of logical reasoning - propositions and syllogisms - in relation to Mill's theories of inductive reasoning and experimental method. (shrink)

This paper discusses three relevant logics that obey Component Homogeneity - a principle that Goddard and Routley introduce in their project of a logic of significance. The paper establishes two main results. First, it establishes a general characterization result for two families of logic that obey Component Homogeneity - that is, we provide a set of necessary and sufficient conditions for their consequence relations. From this, we derive characterization results for S*fde, dS*fde, crossS*fde. Second, the paper establishes complete sequent calculi (...) for S*fde, dS*fde, crossS*fde. Among the other accomplishments of the paper, we generalize the semantics from Bochvar, Hallden, Deutsch and Daniels, we provide a general recipe to define containment logics, we explore the single-premise/single-conclusion fragment of S*fde, dS*fde, crossS*fdeand the connections between crossS*fde and the logic Eq of equality by Epstein. Also, we present S*fde as a relevant logic of meaninglessness that follows the main philosophical tenets of Goddard and Routley, and we briefly examine three further systems that are closely related to our main logics. Finally, we discuss Routley's criticism to containment logic in light of our results, and overview some open issues. (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)

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)

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)

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)

Two strategies used to uncover neural systems for episodic-like memory in animals are discussed: (i) an attribute of episodic memory (what? when? where?) is examined in order to reveal the neuronal interactions supporting that component of memory; and (ii) the connections of a structure thought to be central to episodic memory in humans are studied at a level of detail not feasible in humans. By focusing on spatial memory (where?) and the hippocampus, it has proved possible to bring the (...) strategies together. A review of lesion, disconnection and immediate early-gene studies in animals reveals the importance of interactions between the hippocampus and specific nuclei in the diencephalon (most notably the anterior thalamic nuclei) for spatial memory. Other parts of this extended hippocampal system include the mammillary bodies and the posterior cingulate (retrosplenial) cortex. Furthermore, by combining lesion and immediate early-gene studies it is possible to show how the loss of one component structure or tract can influence the remaining regions in this group of structures. The validity of this convergent approach is supported by new findings showing that the same set of regions is implicated in anterograde amnesia in humans. (shrink)

This study is a reading of Lonergan on "system and history," a topic central to his thought. The study begins by establishing two preliminary contexts. First, it constructs an overview of the problematic in chapter one. Second, it establishes a further context in chapter two by analyzing his writings on the topic in 1959, the year he gave a graduate seminar on "System and History." Subsequent chapters trace the emergence in the history of Lonergan's thought of historical heuristics, of historical (...) maieutics, and of the relation of both in his theory and philosophy of history. ;The study largely prescinds, however, from Lonergan's theory of the dialectic of history. Instead, it draws attention to the role of the emergence of an adequate human science in what Lonergan calls "the challenge of history," that is, the challenge of decreasing the role of mere chance and fate in history while increasing the role of conscious grasp and deliberate choice. Meeting that challenge requires, as Lonergan insists, "a human science that is concerned, to adapt a phrase from Marx, not only with knowing history but also with directing it." Lonergan considered the needed human science at once a possible project and "a vastly ambitious task." The needed human science involves "a critique of history" in the service of the "intelligent direction of history," and Lonergan holds some combination of the two central to a practical theory of history. Those two components emerge first in historical and economic manuscripts Lonergan wrote in the 1930s as examined in chapter three of the study. Chapter four examines those topics in Insight, together with Lonergan's view that emergent probability generically determines the course of human history. Chapter five examines the relation of historical scholarship to the need for an upper blade of historical heuristics in the period between Insight and Method. Finally, chapter six explores how the themes of historical heuristics and historical maieutics meet, albeit in subtle ways, in Lonergan's Method in Theology. (shrink)

This study investigates the determinants of the ratification of International Covenant on Economic, Social, and Cultural Rights (ICESCR). To do so, it proposes an explanation that postulates that states employ treaty ratification as a device to signal their resolve to implement polices required by the treaty at issue in order to appease demanding domestic constituencies, predicting that states with lower compliance capacity tend to commit faster than states with higher compliance capacity. Applying this explanation to the ICESCR leads to two (...) expectations. First, the larger government spending a proxy of high compliance capacity is hypothesized to delay the ratification process. Second, states with the unitary system are expected to ratify the ICESCR more promptly because the centralized power structure in unitary states significantly restricts the pursuit of the policy autonomy by minorities at local level that the right to self-determination entails. The Cox proportional hazard analysis lends support to both hypotheses. (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)

This paper ties together three threads of discussion about the following question: in accepting a system of axioms S, what else are we thereby warranted in accepting, on the basis of accepting S? First, certain foundational positions in the philosophy of mathematics are said to be epistemically stable, in that there exists a coherent rationale for accepting a corresponding system of axioms of arithmetic, which does not entail or otherwise rationally oblige the foundationalist to accept statements beyond the logical consequences (...) of those axioms. Second, epistemic stability is said to be incompatible with the implicit commitment thesis, according to which accepting a system of axioms implicitly commits the foundationalist to accept additional statements not immediately available in that theory. Third, epistemic stability stands in tension with the idea that in accepting a system of axioms S, one thereby also accepts soundness principles for S. We offer a framework for analysis of sets of implicit commitment which reconciles epistemic stability with the latter two notions, and argue that all three ideas are in fact compatible. (shrink)

Although Caenorhabditis and Drosophila proved invaluable in unraveling the molecular mechanisms of apoptosis, it is now clear that these animals are of limited value for understanding the evolution of apoptotic systems. Whereas data from these invertebrates led to the assumption that the extrinsic apoptotic pathway is restricted to vertebrates, recent data from cnidarians and sponges indicate that this pathway predates bilaterian origins. Here we review the phylogenetic distribution of caspase‐8, the initiator caspase of the extrinsic apoptotic pathway, its paralogs (...) and other components of the network. The ancestral caspase‐8 gave rise to four paralogs early in vertebrate evolution, and these have been maintained in many tetrapods. However, eutherians have lost caspase‐18 and myomorph rodents have lost caspase‐10, these losses suggesting functional redundancy amongst caspase‐8 paralogs. The apoptotic network of the eumetazoan ancestor appears to have been complex and vertebrate like, and is only now being revealed by studying simple animals. (shrink)

The article is devoted to the formation of linguistic, communicative and cultural competence among students bilinguals in teaching Russian language and speech culture. The authors put forward the thesis that the training of specialists in the conditions of bilingualism re quires not only a higher level of learning a second language, but also a qualitatively different level of comprehension. It is proved that the discipline ‘Russian and the culture of speech‘ assumes formation of communicative and culturological competence of the higher (...) education institutions, which are trained on two-profile offices taking into account a regional component. Relevance of research in this area is increasing each year since the treatment of the person as the center of all systems of cognition highlights in the pedagogical University the formation of the modern language personality, capable of effective professional activity. The functional approach provides detection of features of functioning of language units in different spheres of public work. The communicative principle means that acquisition of Russian as a means of communication happens in the course of speech practice most approached to process of communication in Russian. The detection of similarity and distinctions between languages, interlingual comparison promotes establishment and a lexical interference. The linguistic-cultural principle provides understanding of language as the phenomena of culture and is connected with ability to define national-cultural components of linguistic units - words, phraseological combinations, grammatical categories of the text. Involvement of regional component as a basis in practice of teaching Russian and culture of speech increases efficiency of all process of training of students of national branch. (shrink)

Whereas most branches of neuroscience are thought to provide mechanistic explanations, systems neuroscience is not. Two reasons are traditionally cited in support of this conclusion. First, systems neuroscientists rarely, if ever, rely on the dual strategies of decomposition and localization. Second, they typically emphasize organizational properties over the properties of individual components. In this paper, I argue that neither reason is conclusive: researchers might rely on alternative strategies for mechanism discovery, and focusing on organization is often appropriate and (...) consistent with the norms of mechanistic explanation. Thus, many explanations in systems neuroscience can also be viewed as mechanistic explanations. (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)

This paper presents a methodology to design and implement programs intended to decide cases, described as sets of factors, according to a theory of a particular domain based on a set of precedent cases relating to that domain. We useDialectical Frameworks, a recent development in AI knowledge representation, as the central feature of our design method. ADFs will play a role akin to that played by Entity–Relationship models in the design of database systems. First, we explain how the factor (...) hierarchy of the well-known legal reasoning system CATO can be used to instantiate an ADF for the domain of US Trade Secrets. This is intended to demonstrate the suitability of ADFs for expressing the design of legal cased based systems. The method is then applied to two other legal domains often used in the literature of AI and Law. In each domain, the design is provided by the domain analyst expressing the cases in terms of factors organised into an ADF from which an executable program can be implemented in a straightforward way by taking advantage of the closeness of the acceptance conditions of the ADF to components of an executable program. We evaluate the ease of implementation, the performance and efficacy of the resulting program, ease of refinement of the program and the transparency of the reasoning. This evaluation suggests ways in which factor based systems, which are limited by taking as their starting point the representation of cases as sets of factors and so abstracting away the particular facts, can be extended to address open issues in AI and Law by incorporating the case facts to improve the decision, and by considering justification and reasoning using portion of precedents. (shrink)

This two-volume work, first published in 1843, was John Stuart Mill's first major book. It reinvented the modern study of logic and laid the foundations for his later work in the areas of political economy, women's rights and representative government. In clear, systematic prose, Mill disentangles syllogistic logic from its origins in Aristotle and scholasticism and grounds it instead in processes of inductive reasoning. An important attempt at integrating empiricism within a more general theory of human knowledge, the work constitutes (...) essential reading for anyone seeking a full understanding of Mill's thought. Volume 1 contains Mill's introduction, which elaborates upon his definition of logic as 'not the science of Belief, but the science of Proof, or Evidence'. It also features discussions of the central components of logical reasoning - propositions and syllogisms - in relation to Mill's theories of inductive reasoning and experimental method. (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)

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)

Beginning in the 1970s and culminating in the first two decades of the 21st century, there has been a marked shift in the sciences from a predominantly reductionist and mechanistic approach to a broader and more holistic viewpoint. It goes without saying that such a shift in point of view will have significant implications, not only for the sciences but for our concepts of nature and of human beings. The present essay is an attempt to assess the significance of this (...) change in the focus of the sciences and to describe the nature of its components. Originally, it had a far more limited scope, that of comparing two of the parts of the new nonreductionist stance: brain plasticity and biological systems theory. Unfortunately, my understanding of one of these factors (systems theory) turned out to be incorrect, while the section on brain plasticity was incomplete. The result of this dual realization is an essay of far greater scope, taking in both new developments in the sciences far beyond that of plasticity, and reassessing the content and impact of systems theory, which is greater than I had thought. I will begin with a study of systems theory, dealing first with the unexpected mathematics which made its present status possible. Then I will deal with its history, which reaches back over a century. One of the confusions into which we are liable to fall is to fail to distinguish the old systems theory from the new. This is even more likely because the two versions of the theory have many features in common. (shrink)