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)

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

The juvenile hormones of insects regulate an unusually large diversity of processes during postembryonic development and adult reproduction. It is a long‐standing puzzle in insect developmental biology and physiology how one hormone can have such diverse effects. The search for molecular mechanisms of juvenile hormone action has been guided by classical models for hormone–receptor interaction. Yet, despite substantial effort, the search for a juvenile hormone receptor has been frustrating and has yielded limited results. We note here (...) that a number of lipid‐soluble signaling molecules in vertebrates, invertebrates and plants show curious similarities to the properties of juvenile hormones of insects. Until now, these signaling molecules have been thought of as uniquely evolved mechanisms that perform specialized regulatory functions in the taxon where they were discovered. We show that this array of lipid signaling molecules share interesting properties and suggest that they constitute a large set of signal control and transduction mechanisms that include, but range far beyond, the classical steroid hormone signaling mechanism. Juvenile hormone is the insect representative of this widespread and diverse system of lipid signaling molecules that regulate protein activity in a variety of ways. We propose a synthetic perspective for understanding juvenile hormone action in light of other lipid signaling systems and suggest that lipid activation of proteins has evolved to modulate existing signal activation and transduction mechanisms in animals and plants. Since small lipids can be inserted into many different pathways, lipid‐activated proteins have evolved to play a great diversity of roles in physiology and development. BioEssays 25:994–1001, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

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

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

Understanding how traits are integrated at the organismal level remains a fundamental problem at the interface of developmental and evolutionary biology. Hormones, regulatory signaling molecules that coordinate multiple developmental and physiological processes, are major determinants underlying phenotypic integration. The probably best example for this is the lipid-like juvenile hormone (JH) in insects. Here we review the manifold effects of JH, the most versatile animal hormone, with an emphasis on the fruit fly Drosophila melanogaster, an organism amenable to (...) both genetics and endocrinology. JH affects a remarkable number of processes and traits in Drosophila development and life history, including metamorphosis, behavior, reproduction, diapause, stress resistance and aging. While many molecular details underlying JH signaling remain unknown, we argue that studying “hormonal pleiotropy” offers intriguing insights into phenotypic integration and the mechanisms underlying life history evolution. In particular, we illustrate the role of JH as a key mediator of life history trade-offs. BioEssays 27:999–1010, 2005. © 2005 Wiley Periodicals, Inc. (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)

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

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)

Small gaseous molecules play important roles in biological signaling in both animal and plant physiology. The hydrocarbon gas ethylene has long been known to regulate diverse aspects of plant growth and development, including fruit ripening, leaf senescence and flower abscission. Recent progress has been made toward identifying components involved in ethylene signal transduction in the plant Arabidopsis thaliana. Ethylene is perceived by five receptors that have similarity to two‐component signaling proteins. The hydrophobic amino‐terminus of the receptors binds ethylene, (...) and mutations in this domain both prevent ethylene binding and confer ethylene insensitivity to the plant; the carboxyl‐terminal portion of the receptors has similarity to bacterial his tidine protein kinases. Genetic data suggest a model in which ethylene binding inhibits receptor signaling, yet precisely how these receptors function is unclear. Two of the receptors have been found to associate with a negative regulator of ethylene responses called CTR1, which appears to be a mitogen‐activated protein kinase (MAPK) kinase kinase. BioEssays 23:619–627, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

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

Systems thinking is an increasingly recognized paradigm in education in both natural and social sciences, a particular focus being, naturally, in biology. This article argues that plant biology, and in particular, plant hormonal signaling, provides highly illustrative models for learning and teaching in a systems paradigm, because it offers examples of highly complex networks, ranging from the molecular‐ to ecosystem‐scale, and in addition lends itself to the use of real‐life biological objects.

Because of its elegant simplicity, the Arabidopsis root has become a model for studying plant organogenesis. In this review we focus on recent results indicating the importance of signaling in root development. A role for positional information in root cell specification has been demonstrated by ablation analyses. Through mutational analysis, genes have been identified that play a role in radial pattern formation. The embryonic phenotypes of these mutants raised the possibility that division patterns in post‐embryonic roots are dependent on (...) signaling that originates during embryonic development. Analysis of expression of the SCARECROW gene indicates that it may play a role in this ‘top‐down’ signaling process. Characterization of root epidermis development has led to the identification of negative regulators of root‐hair formation. These appear to set up a prepattern which is reinforced by signaling by plant hormones. (shrink)

Intercellular signaling by growth factors, hormones and neurotransmitters produces second messenger molecules such as cyclic adenosine monophosphate (cAMP) and diacylglycerol (DAG). Protein Kinase A and Protein Kinase C are the principal effector proteins of these prototypical second messengers in certain cell types. Recently, novel receptors for cAMP and DAG have been identified. These proteins, designated EPAC (Exchange Protein directly Activated by cAMP) or cAMP‐GEF (cAMP regulated Guanine nucleotide Exchange Factor) and CalDAG‐GEF (Calcium and Diacylglycerol regulated Guanine nucleotide Exchange Factor) (...) or RasGRP (Ras Guanine nucleotide Releasing Protein) are able to mediate some of the physiologic effects of the second messengers in a protein‐kinase‐independent fashion. These proteins are exchange factors for Ras family GTPases that operate in pathways that run parallel to the classic kinase‐dependent pathways. The rapidly emerging recognition of the functions of these “non‐kinase” effectors in diverse processes such as insulin secretion, thymocyte development, asthma and malignant transformation creates new opportunities for discovery and identifies potential new therapeutic targets. BioEssays 26:730–738, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Recent years have witnessed tremendous growth in the epidermal growth factor (EGF) family of peptide growth factors and the ErbB family of tyrosine kinases, the receptors for these factors. Accompanying this growth has been an increased appreciation for the roles these molecules play in tumorigenesis and in regulating cell proliferation and differentiation during development. Consequently, a significant question has been how diverse biological responses are specified by these hormones and receptors. Here we discuss several characteristics of hormone-receptor interactions and (...) receptor coupling that contribute to specificity: 1) a single EGF family hormone can bind multiple receptors; 2) a single ErbB family receptor can bind multiple hormones; 3) there are three distinct functional groups of EGF family hormones; 4) EGF family hormones can activate receptors in trans, and this heterodimerization diversifies biological responses; 5) ErbB3 requires a receptor partner for signaling; and 6) ErbB family receptors differentially couple to signaling pathways and biological responses. BioEssays 20:41–48, 1998. © 1998 John Wiley & Sons, Inc. (shrink)

Philosophers of science diverge on the question what drives the growth of scientific knowledge. Most of the twentieth century was dominated by the notion that theories propel that growth whereas experiments play secondary roles of operating within the theoretical framework or testing theoretical predictions. New experimentalism, a school of thought pioneered by Ian Hacking in the early 1980s, challenged this view by arguing that theory-free exploratory experimentation may in many cases effectively probe nature and potentially spawn higher evidence-based theories. Because (...) theories are often powerless to envisage workings of complex biological systems, theory-independent experimentation is common in the life sciences. Some such experiments are triggered by compelling observation, others are prompted by innovative techniques or instruments, whereas different investigations query big data to identify regularities and underlying organizing principles. A distinct fourth type of experiments is motivated by a major question. Here I describe two question-guided experimental discoveries in biochemistry: the cyclic adenosine monophosphate mediator of hormone action and the ubiquitin-mediated system of protein degradation. Lacking underlying theories, antecedent data bases, or new techniques, the sole guides of the two discoveries were respective substantial questions. Both research projects were similarly instigated by theory-free exploratory experimentation and continued in alternating phases of results-based interim working hypotheses, their examination by experiment, provisional hypotheses again, and so on. These two cases designate theory-free, question-guided, stepwise biochemical investigations as a distinct subtype of the new experimentalism mode of scientific enquiry. (shrink)

The discovery of the first intracellular substrate for insulin, IRS‐1, redirected the field of diabetes research and has led to many important advances in our understanding of insulin action. Detailed analysis of IRS‐1 demonstrates structure/function relationships for this modular docking molecule, including mechanisms of substrate recognition and signal propagation. Recent work has also identified other structurally similar molecules, including IRS‐2, the Drosophila protein, DOS, and the Grb2‐binding protein, Gab1, suggesting that this intracellular signalling strategy is conserved evolutionarily and is utilized (...) by an expanding number of receptor systems. In fact, IRS‐1 itself has been shown to be important in other growth factor and cytokine signalling systems, including growth hormone and several interleukins. Analysis of mice lacking IRS‐1 confirms an important physiological role for this protein in glucose metabolism and general cell growth in the intact animal. Disregulation of the signalling pathways integrated by the IRS proteins may contribute to the pathophysiology of non‐insulin‐dependent diabetes mellitus or other diseases. (shrink)

Various explanations have been proposed to account for complex differentiation and development in humans, despite the human genome containing only two to three times the number of genes in invertebrates. Ignored are the actions of adrenal and sex steroids—androgens, estrogens, glucocorticoids, mineralocorticoids, and progestins—which act through receptors that arose from an ancestral nuclear receptor in a protochordate. This ligand‐based mechanism is unique to vertebrates and was integrated into the already robust network of transcription factors in invertebrates. Adrenal and sex steroids (...) influence almost all aspects of vertebrate differentiation and development. I propose that evolution of this ligand‐based mechanism in a primitive vertebrate was an important contribution to vertebrate complexity. Sequencing of genomes from a cephalochordate, such as amphioxus, and from hagfish and lamprey will establish early events in the evolution of steroid hormone signaling, and also allow genetic studies to elucidate how vertebrate complexity depends on steroid hormones. BioEssays 25:396–400, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Unraveling the molecular detail of insulin receptor activation has proved challenging, but a major advance is the recent determination of crystallographic structures of insulin in complex with its primary binding site on the receptor. The current model for insulin receptor activation is that two distinct surfaces of insulin monomer engage sequentially with two distinct binding sites on the extracellular surface of the insulin receptor, which is itself a disulfide‐linked (αβ)2 homodimer. In the process, conformational changes occur both within the (...) class='Hi'>hormone and the receptor, the latter resulting in the disruption of the intracellular interactions that hold the kinase domains in their basal state and in the initiation of the phosphorylation events that drive insulin signaling. The purpose of this paper is to summarize the extant structural data relating to hormone binding and how it effects receptor activation, as well as to discuss the issues that remain unresolved. (shrink)

The recent literature on causality has seen the introduction of several distinctions within causality, which are thought to be important for understanding the widespread scientific practice of focusing causal explanations on a subset of the factors that are causally relevant for a phenomenon. Concepts used to draw such distinctions include, among others, stability, specificity, proportionality, or actual-difference making. In this contribution, I propose a new distinction that picks out an explanatorily salient class of causes in biological systems. Some select causes (...) in complex biological systems, I argue, have the property of enabling coherent causal control of these systems. Examples of such control variables include hormones and other signaling molecules, e.g., TOR (target of rapamycin), morphogens or the products of homeotic selector genes in embryonic pattern formation. I propose an analysis of this notion based on concepts borrowed from causal graph theory. (shrink)

The hypothesis that foreseeable developments in interventions directed to forestall and to treat the disabilities of aging might result in the extension of the human lifespan may be further supported by the “evolutionary theory of aging.” Besides caloric restriction, several hormone supply or replacement strategies are considered to contrast the functional decline associated with aging. Hormone treatments may include growth hormone (GH), insulin‐like growth factor I (IGF‐I) signaling, dehydroepiandrosterone (DHEA), melatonin, testosterone, progesterone, and estrogen. In the (...) 1990s, DHEA was exalted as a possible candidate for the “fountain of youth.” Several experiments on animals have shown that DHEA is a multifunctional adrenal steroid with immune function enhancement, anti‐diabetic, anti‐cancer, and anti‐aging effects. The ethical questions concerning the extension of the lifespan belong to two distinct areas: the area of individual morality and the area of social morality. (shrink)

Melatonin is a hormone with complex roles in the pathogenesis of autoimmune disorders. Over the years, it has become clear that melatonin may exacerbate some autoimmune conditions, whereas it alleviates others such as multiple sclerosis. Multiple sclerosis is an autoimmune disorder characterized by a dysregulated immune response directed against the central nervous system. Indeed, the balance between pathogenic CD4+ T cells secreting IFN‐γ (TH1) or IL‐17 (TH17); and FoxP3+ regulatory T cells and IL‐10+ type 1 regulatory T cells (Tr1 (...) cells) is thought to play an important role in disease activity. Recent evidence suggests that melatonin ameliorates multiple sclerosis by controlling the balance between effector and regulatory cells, suggesting that melatonin‐triggered signaling pathways are potential targets for therapeutic intervention. Here, we review the available data on the effects of melatonin on immune processes relevant for MS and discuss its therapeutic potential. (shrink)

Genes induced by the plant hormone auxin are probably involved in the execution of vital cellular functions and developmental processes. Experimental approaches designed to elucidate the molecular mechanisms of auxin action have focused on auxin perception, genetic dissection of the signaling apparatus and specific gene activation. Auxin‐responsive promoter elements of early genes provide molecular tools for probing auxin signaling in reverse. Functional analysis of several auxin‐specific promoters of unrelated early genes suggests combinatorial utilization of both conserved and (...) variable elements. These elements are arranged into autonomous domains and the combination of such modules generates uniquely composed promoters. Modular promoters allow for auxin‐mediated transcriptional responses to be revealed in a tissue‐ and development‐specific manner. (shrink)

Reactive oxygen species (ROS) are known as toxic metabolic products in plants and other aerobic organisms. An elaborate and highly redundant plant ROS network, composed of antioxidant enzymes, antioxidants and ROS-producing enzymes, is responsible for maintaining ROS levels under tight control. This allows ROS to serve as signaling molecules that coordinate an astonishing range of diverse plant processes. The specificity of the biological response to ROS depends on the chemical identity of ROS, intensity of the signal, sites of production, (...) plant developmental stage, previous stresses encountered and interactions with other signaling molecules such as nitric oxide, lipid messengers and plant hormones. Although many components of the ROS signaling network have recently been identified, the challenge remains to understand how ROS-derived signals are integrated to eventually regulate such biological processes as plant growth, development, stress adaptation and programmed cell death. (shrink)

Interleukin 5 (IL‐5) is a kind of peptide hormone released from T lymphocytes of mammals infected with microorganisms or parasites. It is an acidic glycoprotein with a molecular mass of 40 to 50 kDa that consists of a homodimer of polypeptides. It controls hematopoiesis so that it increases natural immunity. In the mouse, IL‐5 acts on committed B cells to induce differentiation into Ig‐producing cells and on common progenitors for CD5+ pre‐B cells and CD5+ macrophages to support their survival. (...) The antibodies secreted by CD5+ B cells seem to be responsible for the primary protection against the infection with microorganisms or parasites. It also supports the growth and/or differentiation of eosinophil precursor and mature eosinophils, which can be effective for the removal of parasites in combination with the antibodies against them. Murine IL‐5 receptor (IL‐5R) consists of two different polypeptide chains; αL chain and β chain. The IL‐5R α chain is 60 kDa protein that binds IL‐5 with low affinity. The IL‐5R β chain is a 130 kDa protein which does not bind IL‐5 by itself but is necessary to form the high affinity IL‐5R. The β chain was identified by using one of the anti‐IL‐5R mAb and anti‐IL‐3R mAb as the IL‐3R homologue. This β chain is also used as the β chain of GM‐CSF receptor. This fact suggests that there is a common signaling mechanism among these cytokines and efficient cooperation among them. At the same time, these findings may explain the overlapping role of these cytokines in the development of granulocytes. (shrink)

Phospholipase C is a family of cellular proteins believed to play a significant role in the intracellular signaling mechanisms utilized by diverse hormones. One class of hormones, polypeptide growth factors, elicits its influence on cellular function through stimulation of cell surface receptor tyrosine kinase activity. Certain growth factors appear to stimulate cellular phospholipase C activity by selective, receptor‐mediated tyrosine phosphorylation of the phospholipase C‐γ1 isozyme. While the role of phospholipase C activity in growth factor regulation of cell proliferation remains (...) to be clarified, the selective growth factor‐stimulated tyrosine phosphorylation and activation of phospholipase C‐γ1 is an interesting example of enzyme–substrate interaction at the crossroads of two important intracellular signaling pathways. (shrink)

Fully grown Xenopus oocytes can remain in their immature state essentially indefinitely, or, in response to the steroid hormone progesterone, can be induced to develop into fertilizable eggs. This process is termed oocyte maturation. Oocyte maturation is initiated by a novel plasma membrane steroid hormone receptor. Progesterone brings about inhibition of adenylate cyclase and activation of the Mos/MEK1/p42 MAP kinase cascade, which ultimately brings about the activation of the universal M phase trigger Cdc2/cyclin B. Oocyte maturation provides an (...) interesting example of how signaling cascades entrain the cell cycle clock to environmental changes. BioEssays 21:833–842, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

The negative co‐variation of life‐history traits such as fecundity and lifespan across species suggests the existence of ubiquitous trade‐offs. Mechanistically, trade‐offs result from the need to differentially allocate limited resources to traits like reproduction versus self‐maintenance, with selection favoring the evolution of optimal allocation mechanism. Here I discuss the physiological (endocrine) mechanisms that underlie optimal allocation rules and how such rules evolve. The hormone testosterone may mediate life‐history trade‐offs due to its pleiotropic actions in male vertebrates. Conservation in the (...) actions of testosterone in vertebrates has prompted the ‘evolutionary constraint hypothesis,’ which assumes that testosterone signaling mechanisms and male traits evolve as a unit. This hypothesis implies that the actions of testosterone are similar across sexes and species, and only the levels of circulating testosterone concentrations change during evolution. In contrast, the ‘evolutionary potential hypothesis’ proposes that testosterone signaling mechanisms and male traits evolve independently. In the latter scenario, the linkage between hormone and traits itself can be shaped by selection, leading to variation in trade‐off functions. I will review recent case studies supporting the evolutionary potential hypothesis and suggest micro‐evolutionary experiments to unravel the mechanistic basis of life‐history evolution. BioEssays 29: 133–144, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Angiogenesis, the generation of new blood vessels from pre‐existing vessels, is an integral component of wound healing, responses to inflammation and other physiologic processes. It is also an essential part of tumor growth; in the absence of new vessel formation, tumors cannot expand beyond a small volume. Although much is known about angiogenesis and its regulation, there is no overall theory that describes or explains this process. It is here suggested that the intracrine hypothesis, which ascribes to certain extracellular (...) class='Hi'>signaling peptides (whether hormones, growth factors, DNA‐binding proteins or enzymes) a role in both intracellular biology and extracellular signaling, can contribute to a more general understanding of angiogenesis. Intracrine factors participate in angiogenesis in the following ways: (1) they can act within the cells that synthesized them (type I intracrine action), (2) they can be secreted and then taken up by their cell of synthesis to act intracellularly (type II intracrine action ), or (3) they can be secreted and internalized by a distant target cell (type III intracrine action). The parallels between the intracrine growth factor mechanisms cancer cells employ in stimulating their own growth and the mechanisms operative in endothelial cell proliferation during angiogenesis (“intracrine reciprocity”) are discussed. Collectively, these explorations lead to testable hypotheses regarding the regulation of normal and pathological angiogenesis, and point to similarities between tumor‐induced angiogenesis and tissue differentiation. BioEssays 28: 943–953, 2006. © 2006 Wiley periodicals, Inc. (shrink)

Insulin resistance is thought to be the primary defect in the pathophysiology of type 2 diabetes. Thus, understanding the cellular mechanisms of insulin action may contribute significantly to developing new treatments for this disease. Although the effects of insulin on glucose and lipid metabolism are well documented, gaps remain in our understanding of the precise molecular mechanisms of signal transduction for the hormone. One potential clue to understanding the unique cellular effects of insulin may lie in the compartmentalization of (...) signaling molecules and metabolic enzymes. We review this evidence, and speculate on how PI-3 kinase-independent and -dependent signaling pathways both diverge from the insulin receptor and converge at discrete targets to insure the specificity of insulin action. BioEssays 23:215–222, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Published in 1981, “The Maximin Strategy in Modern Obstetrics” offered two claims—first, that obstetrical interventions ought to be assessed not singly, but rather as packages of interconnected measures that could cumulatively increase risks of harm; and second, that many of these interventions, considered either singly or as a package, lacked a sound evidence base. The first claim has been well supported by later literature, although the term “cascade effect” has proven a more felicitous descriptor for the phenomenon of interventions that (...) trigger the use of other interventions to monitor, prevent, or treat possible side-effects. The second claim was initially supported in a very inadequate way, since the “Maximin” article appeared before an understanding of the methods of systematic reviews of medical evidence had been widely promulgated. Despite these defects, subsequent, rigorously conducted systematic reviews have tended to confirm the impression first offered in 1981, that practices that support physiologic childbearing and the innate, hormonally driven capacities of childbearing women and their fetuses/newborns are much more in keeping with the available evidence than practices involving common or routine high-technology interference with physiologic processes. Harm may occur either directly, through high-technology interventions, or when such procedures distract attention and resources from safe, effective biological processes and lower-technology measures. Surveys indicate a lack of knowledge of this evidence among childbearing women, signaling a serious ethical deficiency in shared decision-making processes and perhaps the skills and knowledge of maternity care clinicians. (shrink)

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

Osteoporosis is characterized by reduced bone density and strength. Bone mass peaks between age 30 and 40 and then declines. This can be accelerated by factors including menopause and insufficient dietary calcium. Hormone replacement therapy (HRT) is currently the standard treatment for osteoporosis. However, growing concern over potential side effects of HRT has driven a search for alternative therapies. A recent report1 reveals a potential alternative to HRT: a gender‐neutral synthetic steroid that increases bone mass and strength without affecting (...) reproductive organs. This compound acts via a novel extranuclear sex steroid receptor signaling mechanism that has important implications for nuclear receptor biology and human health. BioEssays 25:195–199, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Secretion is a fundamental cellular process involving the regulated release of intracellular products from cells. Physiological functions such as neurotransmission, or the release of hormones and digestive enzymes, are all governed by cell secretion. Anomalies in the processes involved in secretion contribute to the development and progression of diseases such as diabetes and other hormonal disorders. To unravel the mechanisms that govern such diseases, it is essential to understand how hormones, growth factors and neurotransmitters are synthesized and processed, and how (...) their signals are recognized, amplified and transmitted by intracellular signaling pathways in the target cells. Here, we discuss diverse aspects of the detailed mechanisms involved in secretion based on mathematical models. The models range from stochastic ones describing the trafficking of secretory vesicles to deterministic ones investigating the regulation of cellular processes that underlie hormonal secretion. In all cases, the models are closely related to experimental results and suggest theoretical predictions for the secretion mechanisms. (shrink)

We consider Walker's thorough review in the context of thinking about future research on the relation between sleep and memory. We first address methodological issues including type of memory and sleep-stage dependency. We suggest a broader investigation of potential signaling molecules that may be critical to sleep-related consolidation. A brief review of the importance of the stress hormone cortisol illustrates this point.

In human languages, a palindrome reads the same forward as backward (e.g., ‘madam’). In regulatory DNA, a palindrome is an inverted sequence repeat that allows a transcription factor to bind as a homodimer or as a heterodimer with another type of transcription factor. Regulatory palindromes are typically imperfect, that is, the repeated sequences differ in at least one base pair, but the functional significance of this asymmetry remains poorly understood. Here, we review the use of imperfect palindromes in Drosophila photoreceptor (...) differentiation and mammalian steroid receptor signaling. Moreover, we discuss mechanistic explanations for the predominance of imperfect palindromes over perfect palindromes in these two gene regulatory contexts. Lastly, we propose to elucidate whether specific imperfectly palindromic variants have specific regulatory functions in steroid receptor signaling and whether such variants can help predict transcriptional outcomes as well as the response of individual patients to drug treatments. (shrink)

‘Virtue signaling’ is the practice of using moral talk in order to enhance one’s moral reputation. Many find this kind of behavior irritating. However, some philosophers have gone further, arguing that virtue signaling actively undermines the proper functioning of public moral discourse and impedes moral progress. Against this view, I argue that widespread virtue signaling is not a social ill, and that it can actually serve as an invaluable instrument for moral change, especially in cases where moral (...) argument alone does not suffice. Specifically, virtue signaling can change the broader public’s social expectations, which can in turn motivate the adoption of new, positive social norms. I also argue that the reputation-seeking motives underlying virtue signaling impose important constraints on virtue signalers’ behavior, which serve to keep the worst excesses of virtue signaling in check. (shrink)

There is an urgent need for novel protection strategies to sustainably secure crop production under changing climates. Studying microbial effectors, defined as microbe‐derived proteins that alter signalling inside plant cells, has advanced our understanding of plant immunity and microbial plant colonisation strategies. Our understanding of effectors in the establishment and beneficial outcome of plant symbioses is less well known. Combining functional and comparative interaction assays uncovered specific symbiont effector targets in highly interconnected plant signalling networks and revealed the potential of (...) effectors in beneficially modulating plant traits. The diverse functionality of symbiont effectors differs from the paradigmatic immuno‐suppressive function of pathogen effectors. These effectors provide solutions for improving crop resilience against climate stress by their evolution‐driven specification in host protein targeting and modulation. Symbiont effectors represent stringent tools not only to identify genetic targets for crop breeding, but to serve as applicable agents in crop management strategies under changing environments. (shrink)

Shannon information is commonly assumed to be the wrong way in which to conceive of information in most biological contexts. Since the theory deals only in correlations between systems, the argument goes, it can apply to any and all causal interactions that affect a biological outcome. Since informational language is generally confined to only certain kinds of biological process, such as gene expression and hormone signalling, Shannon information is thought to be unable to account for this restriction. It is (...) often concluded that a richer, teleosemantic sense of information is needed. I argue against this view, and show that a coherent and sufficiently restrictive theory of biological information can be constructed with Shannon information at its core. This can be done by paying due attention some crucial distinctions: between information quantity and its fitness value, and between carrying information and having the function of doing so. From this I construct an account of how informational functions arise, and show that the “subject matter” of these functions can easily be seen as the natural information dealt with by Shannon’s theory. (shrink)

Virtue signaling—using public moral discourse to enhance one’s moral reputation—is a familiar concept. But, what about profile pictures framed by “Vaccines work!”? Or memes posted to anti-vaccine groups echoing the group’s view that “Only sheep believe Big Pharma!”? These actions don’t express moral views—both claims are empirical (if imprecise). Nevertheless, they serve a similar purpose: to influence the judgments of their audience. But, where rainbow profiles guide their audience to view the agent as morally good, these acts guide their (...) audience to view the agent as epistemically good. They are instances of epistemic virtue signaling. The first goal of this paper is to offer an account of epistemic virtue signaling. I argue that epistemic virtue signaling occurs through both behavioral and propositional signals, and serves purposes similar to those of moral virtue signaling across a wide variety of discourses. The second is to show that there is much work for this concept to do. In particular, this concept illuminates a double bind faced by those who suffer from and seek to overcome testimonial injustice. I close by demonstrating how this double bind arises in the dissolution of medical autonomy, focusing on the care gap faced by pregnant women of color in the United States today, as compared with their white counterparts. (shrink)

The signaling theory of religion has many claimed virtues, but these are not necessarily all realizable at the same time. Modeling choices involve trade-offs, and the available options here have not traditionally been well understood. This paper offers an overview of signaling theory relevant to the signaling theory of religion, arguing for a narrow, “core” reading of it. I outline a broad taxonomy of the choices on offer for signaling models, and examples of how previous and (...) potential approaches to modeling religious signaling meet or fail to meet the initial promise of the theory. A pluralist approach to religious signaling seems possible, but this would require a high level of detail and specificity with respect to both formal models and target systems. (shrink)

Coalitions and alliances are core aspects of human behavior. All societies recognize alliances among communities, usually based in part on kinship and marriage. Aggression between groups is ubiquitous, often deadly, fueled by revenge, and can have devastating effects on general human welfare. Given its significance, it is surprising how little we know about the neurobiological and hormonal mechanisms that underpin human coalitionary behavior. Here we first briefly review a model of human coalitionary behavior based on a process of runaway social (...) selection. We then present several exploratory analyses of neuroendocrine responses to coalitionary social events in a rural Dominican community, with the objective of understanding differences between in-group and out-group competition in adult and adolescent males. Our analyses indicate: (1) adult and adolescent males do not elevate testosterone when they defeat their friends, but they do elevate testosterone when they defeat outsiders; (2) pre-competition testosterone and cortisol levels are negatively associated with strength of coalitionary ties; and (3) adult males usually elevate testosterone when interacting with adult women who are potential mates, but in a striking reversal, they have lower testosterone if the woman is a conjugal partner of a close friend. These naturalistic studies hint that reciprocity, dampening of aggression, and competition among friends and allies may be biologically embedded in unique ways among humans. (shrink)

The paper offers a model of Kant's claim that unity of consciousness entails objectivity of experience. This claim has nothing especially to do with thought, language or the categories but is a general truth about arbitrary signaling systems of the sort modeled in the paper. In conclusion I draw some consequences for various forms of idealism.

Costly signaling theories of religion contend that religious belief and behaviors function as costly signals of cooperative intent. Such signals are evolvable because they allow likely cooperators to find one another, while excluding potential cheats or free riders that would be unwilling to pay the price associated with sending the signal. As a result, under the right conditions, religious costly signaling can emerge as an evolutionary stable strategy. However, reliability certifying costly signaling can evolve and stabilize only (...) when certain necessary conditions are satisfied. In this paper we argue that current versions of the theory do not adequately demonstrate that these conditions are met. (shrink)

Why do people share or publicly engage with fake stories? Two possible answers come to mind: (a) people are deeply irrational and believe these stories to be true; or (b) they intend to deceive their audience. Both answers presuppose the idea that people put the stories forward as true. But I argue that in some cases, these outlandish (yet also very popular) stories function as signals of one's group membership. This signaling function can make better sense of why, despite (...) their unusual nature or lack of a factual basis, some of these stories are so widespread. (shrink)

Tosi and Warmke discuss cases where the speaker intends for the audience to take their expressions as evidence of good moral character. However, another possibility exists that similarly exploits the social communicative architecture. A contribution to public moral discourse may also attempt to strut by demonstrating evidence of bad moral character, by purposely failing to meet the evaluative standards of its audience—or, paradigmatically for my purposes, a particular section of its actual or notional audience. I call this kind of communication (...) vice signaling. On their face, virtue signaling and vice signaling may seem to be opposites, since the labels imply that they are signaling opposite things. But certain cases of vice signaling are in fact also cases of virtue signaling. These are the cases where someone flaunts the standards of an out-group in order to demonstrate solidarity, seriousness, or some other virtue to their in-group. In this paper I attempt to describe these cases and point out the moral risks and opportunities they present. (shrink)

Although informed consent models for prescribing hormone replacement therapy are becoming increasingly prevalent, many physicians continue to require an assessment and referral letter from a mental health professional prior to prescription. Drawing on personal and communal experience, the author argues that assessment and referral requirements are dehumanising and unethical, foregrounding the ways in which these requirements evidence a mistrust of trans people, suppress the diversity of their experiences and sustain an unjustified double standard in contrast to other forms of (...) clinical care. Physicians should abandon this unethical requirement in favour of an informed consent approach to transgender care. (shrink)

In the context of transgender health, most people are not comfortable with allowing a twelve‐year‐old child with gender dysphoria to elect to undergo gender reassignment surgery. The likelihood is too high that the child would be unable to fully comprehend the scope of a decision that carries significant, permanent consequences, particularly because the decision to surgically change gender is based upon a conception of gender that can fluctuate during adolescent years. Conversely, however, most people would not contend that this fluidity (...) is reason to wholly deny certain medical care such as hormonal treatments to transgender youth, a demographic with extremely high rates of violent behavior, self‐harm, and suicide. This paper will explore ethical considerations to this emerging debate of what therapeutic options should be offered to transgender children and adolescents.Pediatric endocrinologists have been treating gender dysphoric adolescents with puberty‐suppressing drugs and, to a lesser extent, with cross‐sex hormone therapies for more than twenty years. Clinicians and thought leaders have mentioned ethical components of this emerging practice in the few cohort studies and clinical review articles about the subject. However, ethics have generally been a secondary consideration in the medical academic literature. In this paper, I will provide a brief overview of the practice, summarize the current research on hormone treatment for transgender minors, and provide an ethical analysis of the practice. (shrink)

Collins provides a grand theory that unifies all forms of human violence occurring in face-to-face situations, ranging from spousal abuse to medieval warfare. Laitin appreciates Collins's microscopic analysis of diverse data but points to important shortcomings in the theory, especially Collins's metaphoric explanations that are not testable. Here Collins's theory is merged with an existing biosocial model of dominance, replacing the metaphors with tangible, measurable hormonal mechanisms.