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)

Wnt proteins form a family of secreted signaling proteins that play a key role in various developmental events such as cell differentiation, cell migration, cell polarity and cell proliferation. It is currently thought that Wnt proteins activate at least three different signaling pathways by binding to seven transmembrane receptors of the Frizzled family and the co-receptor LRP6. Despite our growing knowledge of intracellular components that mediate a Wnt signal, the molecular events at the membrane have remained rather (...) unclear. Now several publications1-4 indicate that Frizzled receptors are G-protein coupled and kinases were identified that phosphorylate the co-receptor LRP6. These data deepen our understanding of Wnt-mediated signal transduction and provide more insight into how specificity may be achieved. BioEssays 28: 339–343, 2006. © 2006 Wiley Periodicals, Inc. (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)

Cadherins are a large family of single‐pass transmembrane proteins principally involved in Ca2+‐dependent homotypic cell adhesion. The cadherin molecules comprise three domains, the intracellular domain, the transmembrane domain and the extracellular domain, and form large complexes with a vast array of binding partners (including cadherin molecules of the same type in homophilic interactions and cellular protein catenins), orchestrating biologically essential extracellular and intracellular signalling processes. While current, contrasting models for classic cadherin homophilic interaction involve varying numbers of specific repeats found (...) in the extracellular domain, the structure of the domain itself clearly remains the main determinant of cell stability and binding specificity. Through intracellular interactions, cadherin enhances its adhesive properties binding the cytoskeleton via cytoplasmic associated factors α‐ catenin, β‐catenin and p120ctn. Recent structural studies on classic cadherins and these catenin molecules have provided new insight into the essential mechanisms underlying cadherin‐mediated cell interaction and catenin‐mediated cellular signalling. Remarkable structural diversity has been observed in β‐catenin recognition of other cellular factors including APC, Tcf and ICAT, proteins that contribute to or compete with cadherin/catenin functioning. BioEssays 26:497–511, 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)

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

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)

Wnt proteins can activate different intracellular signaling cascades in various organisms by interacting with receptors of the Frizzled family. The first identified Wnt signaling pathway, the Wnt/β‐catenin pathway, has been studied in much detail and is highly conserved among species. As to non‐canonical Wnt pathways, the current situation is more nebulous partly because the intracellular mediators of this pathway are not yet fully understood and, in some cases, even identified. However, there are increasing data that prove the existence (...) of non‐canonical Wnt signaling and demonstrate its involvement in different developmental processes. In vertebrates, Wnt‐11 and Wnt‐5A can activate the Wnt/JNK pathway, which resembles the planar cell polarity pathway in Drosophila. The Wnt/Ca2+‐pathway has only been described in Xenopus and zebrafish so far and it is unclear whether it also exists in other organisms. Two recent papers provide us with new insight into non‐canonical Wnt signaling by (1) presenting a new intracellular mediator of non‐canonical signaling in Xenopus1 and (2) implicating the existence of an additional non‐canonical Wnt signaling pathway in flies.2 BioEssays 24:881–884, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

The problem of cooperation for rational actors comprises two sub problems: the problem of the intentional object (under what description does each actor perceive the situation?) and the problem of common knowledge for finite minds (how much belief iteration is required?). I will argue that subdoxastic signalling can solve the problem of the intentional object as long as this is confined to a simple coordination problem. In a more complex environment like an assurance game signals may become unreliable. Mutual (...) beliefs can then bolster the earlier attained equilibrium. I will first address these two problems by means of an example, in order to draw some more general lessons about combining evolutionary theory and rationality later on. (shrink)

Hedgehog (Hh) signaling is a widely studied signaling pathway because of its critical roles during development and in cell homeostasis. Vertebrate canonical and non‐canonical Hh signaling are typically assumed to be distinct and occur in different cellular compartments. While research has primarily focused on the canonical form of Hh signaling and its dependency on primary cilia – microtubule‐based signaling hubs – an extensive list of crucial functions mediated by non‐canonical Hh signaling has emerged. Moreover, (...) amounting evidence indicates that canonical and non‐canonical modes of Hh signaling are interlinked, and that they can overlap spatially, and in many cases interact functionally. Here, we discuss some of the many cellular effects of non‐canonical signaling and discuss new evidence indicating inter‐relationships with canonical signaling. We discuss how Smoothened (Smo), a key component of the Hh pathway, might coordinate such diverse downstream effects. Collectively, pursuit of questions such as those proposed here will aid in elucidating the full extent of Smo function in development and advance its use as a target for cancer therapeutics. (shrink)

This paper analyses the complexity of family life, which includes both its charismatic and institutional aspects. Deepening the understanding of this basic social group can be useful in explaining how human beings in their decisions and actions, as well as organizations, unceasingly transcend different oppositions and dimensions. Undertaking this topic is not only important in the context of understanding the fundamental and complex experience of family life in the process of preparing and introducing new members to society, but also (...) from the organizational perspective. It means that exploring the role of both dimensions – charismatic and institutional – which are somehow complementary, is crucial for understanding and harmonizing the different relationships and interactions within organizations, including business ones. In this way the article shows the connection between the functioning of the family and society (including organizations within it). (shrink)

The Protein Ontology provides terms for and supports annotation of species-specific protein complexes in an ontology framework that relates them both to their components and to species-independent families of complexes. Comprehensive curation of experimentally known forms and annotations thereof is expected to expose discrepancies, differences, and gaps in our knowledge. We have annotated the early events of innate immune signaling mediated by Toll-Like Receptor 3 and 4 complexes in human, mouse, and chicken. The resulting ontology and annotation data set (...) has allowed us to identify species-specific gaps in experimental data and possible functional differences between species, and to employ inferred structural and functional relationships to suggest plausible resolutions of these discrepancies and gaps. (shrink)

When cells are starved of their substrate, many nutrient transporters are induced. These undergo rapid endocytosis and redirection of their intracellular trafficking when their substrate becomes available again. The discovery that some of these transporters also act as receptors, or transceptors, suggests that at least part of the sophisticated controls governing the trafficking of these proteins has to do with their signaling function rather than with control of transport. In yeast, the general amino acid permease Gap1 mediates signaling (...) to the protein kinase A pathway. Its endocytic internalization and intracellular trafficking are subject to amino acid control. Other nutrient transceptors controlling this signal transduction pathway appear to be subject to similar trafficking regulation. Transporters with complex regulatory control have also been suggested to function as transceptors in other organisms. Hence, precise regulation of intracellular trafficking in nutrient transporters may be related to the need for tight control of nutrient‐induced signaling. (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)

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)

In signaling games, a sender has private access to a state of affairs and uses a signal to inform a receiver about that state. If no common association of signals and states is initially available, sender and receiver must coordinate to develop one. How do players divide coordination labor? We show experimentally that, if players switch roles at each communication round, coordination labor is shared. However, in games with fixed roles, coordination labor is divided: Receivers adjust their mappings more (...) frequently, whereas senders maintain the initial code, which is transmitted to receivers and becomes the common code. In a series of computer simulations, player and role asymmetry as observed experimentally were accounted for by a model in which the receiver in the first signaling round has a higher chance of adjusting its code than its partner. From this basic division of labor among players, certain properties of role asymmetry, in particular correlations with game complexity, are seen to follow. (shrink)

Evolving signaling systems can be said to induce partitions on the space of world states as they approach equilibrium. Formalizing this claim provides a general framework for understanding what it means for language to “cut nature at its seams”. In order to avoid taking our current best science as providing the adaptive target for all evolving systems, the state space of the world must be characterized exclusively in terms of the coincidence of stimuli and payoffs that drives the evolution (...) of cognitive complexity. Cognition exploits the reliable clustering of events in this space. Using this framework to analyze our ordinary concepts of truth and justification, it appears that while justification can be a simple matter of conforming to historically entrenched strategies, truth cannot be fully specified on the basis of the system’s causal history, but requires a robust clustering in the larger world state space. (shrink)

The identification of molecules controlling embryonic patterning and their functional analysis has revolutionized the fields of Developmental and Cell Biology. The use of new sequence information and modern bioinformatics tools has enriched the list of proteins that could potentially play a role in regulating cell behavior and function during early development. The recent application of efficient methods for gene knockout in zebrafish has accelerated the functional analysis of many proteins, some of which have been overlooked due to their small size. (...) Two recent publications report on the identification of one such protein and its role in zebrafish embryogenesis. The protein, currently designated Apela, was shown to act as a secreted protein whose absence adversely affected various early developmental processes. Additional signaling proteins that have been identified in one of the studies are likely to open the way to unraveling hitherto unknown developmental pathways and have the potential to provide a more comprehensive understanding of known developmental processes. (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)

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

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)

Focal adhesion kinase (FAK) is a nonreceptor protein‐tyrosine kinase implicated in controlling cellular responses to the engagement of cell‐surface integrins, including cell spreading and migration, survival and proliferation. Aberrant FAK signaling may contribute to the process of cell transformation by certain oncoproteins, including v‐Src. Progress toward elucidating the events leading to FAK activation following integrin‐mediated cell adhesion, as well as events downstream of FAK, has come through the identification of FAK phosphorylation sites and interacting proteins. A signaling partnership (...) is formed between FAK and Src‐family kinases, leading to tyrosine phosphorylation of FAK and associated ‘docking’ proteins Cas and paxillin. Subsequent recruitment of proteins containing Src homology 2 domains, including Grb2 and c‐Crk, to the complex is likely to trigger adhesion‐induced cellular responses, including changes to the actin cytoskeleton and activation of the Ras‐MAP kinase pathway. (shrink)

Prostate cancer is the most frequently diagnosed non‐skin cancer and the third leading cause of cancer mortality in men. In the initial stages, prostate cancer is dependent on androgens for growth, which is the basis for androgen ablation therapy. However, in most cases, prostate cancer progresses to a hormone refractory phenotype for which there is no effective therapy available at present. The androgen receptor (AR) is required for prostate cancer growth in all stages, including the relapsed, “androgen‐independent” tumors in the (...) presence of very low levels of androgens. This review focuses on AR function and AR‐target genes and summarizes the major signaling pathways implicated in prostate cancer progression, their crosstalk with each other and with AR signaling. This complex network of interactions is providing a deeper insight into prostate carcinogenesis and may form the basis for novel diagnostic and therapeutic strategies. BioEssays 29:1227–1238, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Notch is a mechanosensitive receptor that requires direct cell–cell contact for its activation. Both the strength and the range of notch signaling depend on the size and geometry of the contact sites between cells. These properties of cell–cell contacts in turn depend on cell shape and polarity. At the molecular level, the E3 ubiquitin ligase Neuralized links receptor activation with epithelial cell remodeling. Neur regulates the endocytosis of the Notch ligand Delta, hence Notch activation. It also targets the apical (...) polarity protein Stardust to promote the endocytosis of the Crumbs complex, thereby contributing to epithelium remodeling. Here, we review the interplay between Notch signaling and cell polarity and discuss the possible significance of linking Notch signaling with epithelial cell polarity via a common regulator. Notch receptor activation depends on direct cell–cell contacts that in turn depends on cell shape and cellular polarity. The size and geometry of cell–cell contacts have an impact on the strength and range of signaling. The E3 ubiquitin ligase Neuralized regulates the endocytosis and signaling activity of Delta. The activity of Neuralized is tightly regulated during development. Neuralized also modulates epithelial cell polarity by targeting the apical polarity protein Stardust and by promoting the endocytosis of Crumbs. Thus, the cell-specific expression of Neuralized couples Notch receptor activation with cell polarity regulation in epithelia. (shrink)

In our article, “Syntactic complexity effects in sentence production”, we reported two elicited production experiments and argued that there is a cost associated with planning and uttering syntactically complex, object-extracted structures that contain a non-local syntactic dependency. MacDonald et al. () have argued that the results of our investigation provide little new information on the topic. We disagree. Examining the production of subject versus object extractions in two constructions across two experimental paradigms—relative clauses in Experiment 1 and wh-questions in (...) Experiment 2—we found a strikingly similar pattern: reliable differences in latency and word durations, as well as in rates of disfluencies, signaling a greater cost associated with planning and uttering the syntactically more complex object extractions. MacDonald et al. reject that interpretation, namely that the differences we observed in the production of subject versus object extractions demonstrate asymmetric production difficulties. Here we address the concerns they raise by clarifying confusion and presenting novel experimental evidence in support of our original claims. (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)

Language is a complex intentional, syntactical and referential system involving a left-hemispheric specialization of the brain in which some cerebral regions such as Broca’s and Wernicke’s areas play a key-role. Because nonhuman primates are phylogenetically close to humans, research on our primate cousins might help providing clues for reconstructing the features of our ancestral communicative systems. In the present paper, after emphasising the tight relation between gestures and language in humans, we underlie the specific significance of communicative gestures and (...) of the progressive control of the oro-facial system and the vocal tract in the course of the language evolution. For this purpose, we will then review the findings related to the features, the lateralization and brain correlates of both vocal and gestural systems in nonhuman primates. (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)

Compositionality is a key design feature of human language: the meaning of complex expressions is, for the most part, systematically constructed from the meanings of its parts and their manner of composition. This paper demonstrates that rudimentary forms of compositional communicative behavior can emerge from a variant of reinforcement learning applied to signaling games. This helps explain how compositionality could have emerged gradually: if unsophisticated agents can evolve prevalent dispositions to communicate compositional-like, there is a direct evolutionary benefit (...) for adaptations that exploit the systematicity in form-meaning mappings more rigorously. (shrink)

In light of the complexity of some important matters, the best epistemic strategy for laypersons is often to rely heavily on the judgments of subject matter experts. However, given the contentiousness of some issues and the existence of fake experts, determining who to trust from the lay perspective is no simple matter. One proposed approach is for laypersons to attend to displays of intellectual virtue as indicators of expertise. I argue that this strategy is likely to fail, as non-experts often (...) display apparent intellectual virtues while legitimate experts often display apparent intellectual vices. Then, I argue that this challenge is difficult to overcome, as experts who attempt to better exhibit apparent intellectual virtues would likely compromise their own reliability in the process. Finally, I discuss two conclusions—one more optimistic and one more pessimistic—that one might draw concerning the role of intellectual virtue in the identification of experts. (shrink)

Abstractβ‐Catenin/CTNNB1 is critical for leukemia initiation or the stem cell capacity of several hematological malignancies. This review focuses on a general evaluation of β‐catenin function in normal T‐cell development and T‐cell acute lymphoblastic leukemia (T‐ALL). The integration of the existing literature offers a state‐of‐the‐art dissection of the complexity of β‐catenin function in leukemia initiation and maintenance in both Notch‐dependent and independent contexts. In addition, β‐catenin mutations are screened for in T‐ALL primary samples, and it is found that they are rare (...) and with little clinical relevance. Transcriptional analysis of Wnt family members (Ctnnb1, Axin2, Tcf7, and Lef1) and Myc in different publicly available T‐ALL cohorts indicates that the expression of these genes may correlate with T‐ALL subtypes and/or therapy outcomes. (shrink)

A categorical, higher dimensional algebra and generalized topos framework for Łukasiewicz–Moisil Algebraic–Logic models of non-linear dynamics in complex functional genomes and cell interactomes is proposed. Łukasiewicz–Moisil Algebraic–Logic models of neural, genetic and neoplastic cell networks, as well as signaling pathways in cells are formulated in terms of non-linear dynamic systems with n-state components that allow for the generalization of previous logical models of both genetic activities and neural networks. An algebraic formulation of variable ‘next-state functions’ is extended to (...) a Łukasiewicz–Moisil Topos with an n-valued Łukasiewicz–Moisil Algebraic Logic subobject classifier description that represents non-random and non-linear network activities as well as their transformations in developmental processes and carcinogenesis. The unification of the theories of organismic sets, molecular sets and Robert Rosen’s (M,R)-systems is also considered here in terms of natural transformations of organismal structures which generate higher dimensional algebras based on consistent axioms, thus avoiding well known logical paradoxes occurring with sets. Quantum bionetworks, such as quantum neural nets and quantum genetic networks, are also discussed and their underlying, non-commutative quantum logics are considered in the context of an emerging Quantum Relational Biology. (shrink)

Major histocompatibility complex (MHC)‐associated mate choice is thought to give offspring a fitness advantage through disease resistance. Primates offer a unique opportunity to understand MHC‐associated mate choice within our own zoological order, while their social diversity provides an exceptional setting to examine the genetic determinants and consequences of mate choice in animal societies. Although mate choice is constrained by social context, increasing evidence shows that MHC‐dependent mate choice occurs across the order in a variety of socio‐sexual systems and favours (...) mates with dissimilar, diverse or specific genotypes non‐exclusively. Recent research has also identified phenotypic indicators of MHC quality. Moreover, novel findings rehabilitate the importance of olfactory cues in signalling MHC genes and influencing primate mating decisions. These findings underline the importance to females of selecting a sexual partner of high genetic quality, as well as the generality of the role of MHC genes in sexual selection. (shrink)

Hutto and Myin famously argue that basic minds are not contentful and content exists only as far as it is scaffolded with social and linguistic practices. This view, however, rests on a troublesome distinction between basic and scaffolded minds. Since Hutto and Myin have to account for language purely in terms of joint action guidance, there is no reason why simpler communication systems, such as cellular signaling pathways, should not give rise to scaffolded content as well. This conclusion remains (...) valid even if one rejects the view of language as mediated through public symbols and embraces global antirepresentationalism. Content evolves spontaneously in complex regulatory systems, such as human, animal, and cellular communication. (shrink)

Fibroblast growth factors (FGFs) comprise a large family of developmental and physiological signaling molecules. All FGFs have a high affinity for the glycosaminoglycan heparin and for cell surface heparan sulfate proteoglycans. A large body of biochemical and cellular evidence points to a direct role for heparin/heparan sulfate in the formation of an active FGF/FGF receptor signaling complex. However, until recently there has been no direct demonstration that heparan is required for the biological activity of FGF in a (...) developmental system in vivo. A recent paper by Lin et al.(1) has broken through this barrier to demonstrate that heparan sulfate is essential for FGF function during Drosophila development. The establishment of a role for heparan sulfate in FGFR activation in vivo suggests that tissue-specific differences in the structure of heparan may modulate the activity of FGF. BioEssays 22:108–112, 2000. ©2000 John Wiley & Sons, Inc. (shrink)

The intracellular multiprotein complex β‐catenin destruction complex plays a key role in Wnt/β‐catenin signaling. Wnt stimulation induces the assembly of the receptor‐associated signalosome and the inactivation of the destruction complex, leading to β‐catenin accumulation and transcriptional activation of the target genes. The core components of the destruction complex include Axin, APC, GSK3β, CK1α and other proteins. Recent studies demonstrated that Axin and APC undergo liquid–liquid phase separation (LLPS), which is critical for their function to regulate (...) Wnt/β‐catenin signaling. Here, we discuss the possible roles of LLPS in Wnt/β‐catenin signaling and regulation of Axin LLPS by post‐translational modifications. (shrink)

The role of membrane receptors is regarded as being to transduce the signal represented by ligand binding from the external cell surface across the membrane into the cell. Signals are subsequently conveyed from the cytoplasm to the nucleus through a combination of second-messenger molecules, kinase/phosphorylation cascades, and transcription factor (TF) translocation to effect changes in gene expression. Mounting evidence suggests that through direct targeting to the nucleus, polypeptide ligands and their receptors may have an important additional signaling role. Ligands (...) such as those of the platelet-derived and fibroblast growth factor classes, as well as cytokines such as interferon-γ and interleukins-1 and -5, have been found to localize in the nucleus through the action of nuclear localization sequences (NLSs). Where tested, these NLSs appear to be essential for full signaling activity and may be responsible for cotranslocating receptors to the nucleus in complexes with their ligands. The implication is that, subsequent to endocytosis at the membrane, particular polypeptide ligands or their receptors, or both, may translocate to the nucleus to participate directly in gene regulation. BioEssays 20:400–411, 1998.© 1998 John Wiley & Sons Inc. (shrink)

The paper is devoted to a conceptual model of cell patterning, based on a generalized notion of the epigenetic code of a cell determining its state. We introduce the concept of signaling depending both upon the spatial distance between cells and the distance between their cell states (s-distance); signaling can repel cells in the space of cell states (s-space) or attract them. The influence of different types of repelling signaling on the evolution of cells is considered. Stabilizing (...) signaling, namely a signaling monotonically decreasing with s-distance, causes the restoring of cell states after perturbations; destabilizing signaling, i.e., the one in which the signaling monotonically increases with s-distance, causes the appearance of pairs of cells with alternating cell states (one close to the state conventionally called “head”, and another close to the “tail” state). Non-monotonic (in s-space) signaling splits the cells into groups. The model shows that different types of signaling may provide different types of cellular patterns. General principles for applying this model to complex cellular structures are discussed. (shrink)

A dichotomy result of Sevenster (2014) [29] completely classified the quantifier prefixes of regular Independence-Friendly (IF) logic according to the patterns of quantifier dependence they contain. On one hand, prefixes that contain “Henkin” or “signalling” patterns were shown to characterize fragments of IF logic that capture NP-complete problems; all the remaining prefixes were shown instead to be essentially first-order. In the present paper we develop the machinery which is needed in order to extend the results of Sevenster to non-prenex, regular (...) IF sentences. This involves shifting attention from quantifier prefixes to a (rather general) class of syntactical tree prefixes. We partially classify the fragments of regular IF logic that are thus determined by syntactical trees; in particular, a) we identify four classes of tree prefixes that are neither signaling nor Henkin, and yet express NP-complete problems and other second-order concepts; and b) we give more general criteria for checking the first-orderness of an IF sentence. (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)

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

The autophagy initiation complex is brought about via a highly ordered and stepwise assembly process. Two crucial signaling molecules, mTORC1 and AMPK, orchestrate this assembly by phosphorylating/dephosphorylating autophagy‐related proteins. Activation of Atg1 followed by recruitment of both Atg9 vesicles and the PI3K complex I to the PAS (phagophore assembly site) are particularly crucial steps in its formation. Ypt1, a small Rab GTPase in yeast cells, also plays an essential role in the formation of the autophagy initiation (...) class='Hi'>complex through multiple regulatory pathways. In this review, our primary focus is to discuss how signaling molecules initiate the assembly of the autophagy initiation complex, and highlight the significant roles of Ypt1 in this process. We end by addressing issues that need future clarification. (shrink)

The role of membrane receptors is regarded as being to transduce the signal represented by ligand binding from the external cell surface across the membrane into the cell. Signals are subsequently conveyed from the cytoplasm to the nucleus through a combination of second-messenger molecules, kinase/phosphorylation cascades, and transcription factor (TF) translocation to effect changes in gene expression. Mounting evidence suggests that through direct targeting to the nucleus, polypeptide ligands and their receptors may have an important additional signaling role. Ligands (...) such as those of the platelet-derived and fibroblast growth factor classes, as well as cytokines such as interferon-γ and interleukins-1 and -5, have been found to localize in the nucleus through the action of nuclear localization sequences (NLSs). Where tested, these NLSs appear to be essential for full signaling activity and may be responsible for cotranslocating receptors to the nucleus in complexes with their ligands. The implication is that, subsequent to endocytosis at the membrane, particular polypeptide ligands or their receptors, or both, may translocate to the nucleus to participate directly in gene regulation. BioEssays 20:400–411, 1998.© 1998 John Wiley & Sons 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)

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 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)

Fibroblast growth factors (FGFs) comprise a large family of developmental and physiological signaling molecules. All FGFs have a high affinity for the glycosaminoglycan heparin and for cell surface heparan sulfate proteoglycans. A large body of biochemical and cellular evidence points to a direct role for heparin/heparan sulfate in the formation of an active FGF/FGF receptor signaling complex. However, until recently there has been no direct demonstration that heparan is required for the biological activity of FGF in a (...) developmental system in vivo. A recent paper by Lin et al.(1) has broken through this barrier to demonstrate that heparan sulfate is essential for FGF function during Drosophila development. The establishment of a role for heparan sulfate in FGFR activation in vivo suggests that tissue-specific differences in the structure of heparan may modulate the activity of FGF. BioEssays 22:108–112, 2000. ©2000 John Wiley & Sons, Inc. (shrink)

Mutations in growth factor receptor signaling pathways are common in cancer cells, including the highly lethal brain tumor glioblastoma (GBM) where they drive tumor growth through mechanisms including altering the uptake and utilization of nutrients. However, the impact of changes in micro‐environmental nutrient levels on oncogenic signaling, tumor growth, and drug resistance is not well understood. We recently tested the hypothesis that external nutrients promote GBM growth and treatment resistance by maintaining the activity of mechanistic target of rapamycin (...) complex 2 (mTORC2), a critical intermediate of growth factor receptor signaling, suggesting that altered cellular metabolism is not only a consequence of oncogenic signaling, but also potentially an important determinant of its activity. Here, we describe the studies that corroborate the hypothesis and propose others that derive from them. Notably, this line of reasoning raises the possibility that systemic metabolism may contribute to responsiveness to targeted cancer therapies. (shrink)