In the bacterium Escherichia coli, the AraC protein positively and negatively regulates expression of the proteins required for the uptake and catabolism of the sugar L‐arabinose. This essay describes how work from my laboratory on this system spanning more than thirty years has aided our understanding of positive regulation, revealed DNA looping (a mechanism that explains many action‐at‐a‐distance phenomena) and, more recently, has uncovered the mechanism by which arabinose shifts AraC from a state where it prefers to bind to two (...) well‐separated DNA half‐sites and form a DNA loop to a state where it binds to two adjacent half‐sites and activates transcription. This work required learning how to assay, purify, and work with a protein possessing highly uncooperative biochemical properties. Present work is focussed on understanding arabinose‐responsive mechanism in atomic detail and is also directed towards understanding protein structure and function well enough to be able to engineer the allosteric mechanism seen in AraC onto other proteins. BioEssays 25:274–282, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

We marvel at the social complexity of insects, marked by anatomically and behaviorally distinguishable castes, division of labor and specialization—but how do such systems evolve? Insect societies are composed of individuals, each undergoing its own developmental process and each containing its own genetic information and experiencing its own developmental and experiential environment. Yet societies appear to function as if the colonies themselves are individuals with novel “social genes” and novel social developmental processes. We propose an alternative hypothesis. The origins of (...) complex social behavior, from which insect societies emerge, are derived from ancestral developmental programs. These programs originated in ancient solitary insects and required little evolutionary remodeling. We present evidence from behavioral assays, selective breeding, genetic mapping, functional genomics and endocrinology, and comparative anatomy and physiology. These insights explain how complex social behavior can evolve from heterochronic changes in reproductive signaling systems that govern ubiquitous and ancient relationships between behavior and ovarian development. BioEssays 29:334–343, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Plants have evolved systems analogous to animal innate immunity that recognise pathogen‐associated molecular patterns (PAMPs). PAMP detection is an important component of non‐host resistance in plants and serves as an early warning system for the presence of potential pathogens. Binding of a PAMP to the appropriate pattern recognition receptor leads to downstream signalling events and, ultimately, to the induction of basal defence systems. To overcome non‐host resistance, pathogens have evolved effectors that target specific regulatory components of the basal defence system. (...) In turn, this has led to the evolution in plants of cultivar‐specific resistance mediated by R proteins, which guard the targets of effectors against pathogen manipulation; the arms race continues. BioEssays 28: 880–889, 2006. © 2006 Wiley periodicals, Inc. (shrink)

Behaviors are quantitative traits determined through actions of multiple genes and subject to genome–environment interactions. Early studies concentrated on analyzing the effects of single genes on behaviors, often generating views of simplified linear genetic pathways. The genome era has generated a profound paradigm shift enabling us to identify all the genes that contribute to expression of a behavioral phenotype, to investigate how they are organized as functional ensembles and to begin to identify polymorphisms that contribute to phenotypic variation and are (...) targets for natural selection. Recent studies show that the genetic architecture of behavior is determined by dynamic and plastic modular networks of pleiotropic genes and that the behavioral phenotype manifests itself as an emergent property of such networks. Such networks are exquisitely sensitive to genetic background and sex effects. This review describes how Drosophila can serve as a model for uncovering fundamental principles of the genetic architecture of behavior. BioEssays 26:1299–1306, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Retroviruses are unusual amongst animal viruses in their capacity to integrate into host genomes and be transmitted vertically to host progeny. Vertebrate genomes contain numerous and diverse retrovirus‐derived sequences reflecting a long co‐evolutionary history during which genome invasion has occurred repeatedly, with wide‐ranging evolutionary consequences. Over the past 10 years, a detailed picture of retroviral diversity throughout vertebrate genomes has emerged, revealing striking and informative patterns that differ markedly across species. The power of these data to deliver far‐reaching insights into (...) the biology and evolution of retroviruses has been significantly advanced by recent studies identifying ongoing genome invasion in wild populations,(1) and by the characterisation of conserved mechanisms of innate antiretroviral defence.(2,3) BioEssays 28: 1153–1156, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

The ATM protein kinase is centrally involved in the cellular response to ionizing radiation (IR) and other DNA double‐strand‐break‐inducing insults. Although it has been well established that IR exposure activates the ATM kinase domain, the actual mechanism by which ATM responds to damaged DNA has remained enigmatic. Now, a landmark paper provides strong evidence that DNA‐strand breaks trigger widespread activation of ATM through changes in chromatin structure.1 This review discusses a checkpoint activation model in which chromatin perturbations lead to the (...) conversion of inactive ATM domains to phosphorylated, active ATM monomers. The new findings underscore the critical importance of epigenetic events in genome function and surveillance in mammalian cells. BioEssays 25:627–630, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

ROBERT A. COOKE, CPA, has owned or co-owned three successful small businesses and is the author of six books, including Doing Business Tax-Free and How to Start Your Own S Corporation, Second Edition, both from Wiley.

Competence is an active state that defines the way in which cells respond to an inductive signal. A challenge of developmental biology is to explain not just the nature of the signalling molecules that promote cell specification or differentiation, but also how cells acquire competence to respond to these signals and what that reflects in molecular terms. A recent paper by Carmena et al.(1) has revealed how several signalling mechanisms are used sequentially and in specific combinations to specify two mesodermal (...) lineages in Drosophila. BioEssays 21:455–458, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

Stem cell scientists and ethicists have focused intently on questions relevant to the developmental stage and developmental capacities of stem cells. Comparably less attention has been paid to an equally important set of questions about the nature of stem cells, their common characteristics, their non‐negligible differences and their possible developmental species specificity. Answers to these questions are essential to the project of justly inferring anything about human stem cell biology from studies in non‐human model systems—and so to the possibility of (...) eventually developing human therapies based on stem cell biology. After introducing and discussing these questions, I conclude with a brief discussion of the creation of novel model systems in stem cell biology: human‐to‐animal embryonic chimeras. Such novel model systems may help to overcome obstacles to extrapolation, but they are also scientifically and ethically contentious. BioEssays 26:1005‐1012, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

For both vertebrate developmental and evolutionary biologists, and also for clinicians, the neural crest (NC) is a fundamental cell population. An understanding of Sox10 function in NC development is of particular significance since Sox10 mutations underlie several neurocristopathies. Surprisingly, experiments in different model organisms aimed at identifying Sox10's role(s) have suggested at least four distinct functions. Sox10 may be critical for formation of neural crest cells (NCCs), maintaining multipotency of crest cells, specification of derivative cell fates from these cells and (...) their differentiation. Here, I discuss this controversy and argue that these functions are, in part, molecularly interrelated. BioEssays 28: 788–798, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

The International Encyclopedia of Communication Theory and Philosophy is the definitive single-source reference work on the subject, with state-of-the-art and in-depth scholarly reflection on key issues from leading international experts. It is available both online and in print. A state-of-the-art and in-depth scholarly reflection on the key issues raised by communication, covering the history, systematics, and practical potential of communication theory Articles by leading experts offer an unprecedented level of accuracy and balance Provides comprehensive, clear entries which are both cross-national (...) and cross-disciplinary in nature The Encyclopedia presents a truly international perspective with authors and positions representing not just Europe and North America, but also Latin America and Asia Published both online and in print Part of The Wiley Blackwell-ICA International Encyclopedias of Communication series, published in conjunction with the International Communication Association. (shrink)

Engineered microbes are of great potential utility in biotechnology and basic research. In principle, a cell can be built from scratch by assembling small molecule sets with auto‐catalytic properties. Alternatively, DNA can be isolated or directly synthesized and molded into a synthetic genome using existing genomic blueprints and molecular biology tools. Activating such a synthetic genome will yield a synthetic cell. Here we examine obstacles associated with this latter approach using a model system whereby a donor genome from H. influenzae (...) is fragmented, and the pieces are then modified and reassembled stepwise in an E. coli host cell. There are obstacles associated with this strategy related to DNA transfer, DNA replication, cross‐talk in gene regulation and compatibility of gene products between donor and host. Encouragingly, analysis of gene expression indicates widespread transcription of H. influenzae genes in E. coli, and analysis of gap locations in H. influenzae and other microbial genome assemblies reveals few genes routinely incompatible with E. coli. In conclusion, rebuilding and booting a genome remains a feasible and pragmatic approach to creating a synthetic microbial cell. BioEssays 29:580–590, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Eugenics is commonly thought of as having endured as science and social movement only until 1945. With the advance of both reproductive and enhancement technologies, however, concern has arisen that eugenics has resurfaced in new forms. In particular, the eugenic potential of the Human Genome Project led to talk of the rise of ‘newgenics’ and of a backdoor to eugenics. This article focuses on such concerns deriving from the practice of prenatal screening and technologies that increase our ability to generate (...) information about the kinds of children we are likely to have. Given individual preferences and social norms concerning what traits are intergenerationally desirable, how should we act and what practices and policies should we endorse or scrutinise? This article will concentrate on key components of eugenic thinking present today and emphasise continuities between the eugenic past and new- genic present in the subhumanisation of people with cognitive or intellectual disabilities. (shrink)

One facet of the control of gene expression is long‐range promoter regulation by distant enhancers. It is an important component of the regulation of genes that control metazoan development and has been appreciated for some time but the molecular mechanisms underlying this regulation have remained poorly understood. A recent study by Cleard and colleagues1 reports the first in vivo evidence of chromatin looping and boundary element promoter interaction. Specifically, they studied the function of a boundary element within the cis‐regulatory region (...) of the Abdominal‐B (Abd‐B) gene of Drosophila melanogaster. BioEssays 29: 7–10, 2007. © 2006 Wiley Periodicals, Inc. (shrink)

Recent controversy about the use of the vertebrate fossil record for external calibration of molecular clocks centers on two issues, the number of dates used for calibration and the reliability of the fossil calibration date. Viewing matters from a palaeontological perspective, we propose three qualitative, phylogenetic criteria that can be used within a comparative framework for the selection of well-constrained calibration dates from the vertebrate fossil record. On the basis of these criteria, we identify three highly suitable new fossil calibration (...) dates for molecular clock estimates: the lungfish–tetrapod split (between 419 and 408 Ma), the bird–crocodile split (between 251 and 243 Ma), and the alligator–caiman split (between 71 and 66 Ma). Together with our previously suggested bird–lizard split (between 252 and 257 Ma), these four fossil dates span a range of very different ages. They are, in our opinion, more suitable for molecular clock calibration than the traditionally used mammal–bird split, which is less well constrained. We plea for closer interactions between paleontologists and molecular biologists in studying the timescale of vertebrate evolution. BioEssays 27:1069–1075, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Title: Discipline and PunishPublisher: Pantheon booksISBN: 978-0394499420Author: Michel FoucaultTitle: Language, Counter-Memory, PracticePublisher: Wiley-BlackwellISBN: 978-0631182405Author: Michel FoucaultTitle: La Volonte de SavoirPublisher: GallimardAuthor: Michel FoucaultTitle: Oublier FoucaultPublisher: Editions GalileeISBN: 978-2718600604Author: Jean Baudrillard.

Stephen Hetherington has defended the tripartite analysis of knowledge (Hetherington in Philos Q 48:453–469, 1998; J Philos 96:565–587, 1999; J Philos Res 26:307–324, 2001a; Good knowledge, bad knowledge, Oxford University Press, Oxford, 2001b). His defence has recently come under attack (Madison in Australas J Philos 89(1):47–58, 2011; Turri in Synthese 183(3):247–259, 2012). I critically evaluate those attacks as well as Hetherington’s newest formulation of his defence (Hetherington in Philosophia 40(3):539–547, 2012b; How to know: A practicalist conception of knowledge, Wiley, (...) Oxford, 2011a; Ratio 24:176–191, 2011b; Synthese 188:217–230, 2012a). I argue that his newest formulation is vulnerable to a modified version of Madison’s and Turri’s objection. However, I argue that Hetherington’s considerations lend support to a different, though also radical, thesis which can meet the objection. This thesis is what I call the Divorce thesis: the theory of epistemic justification is importantly independent of the theory of knowledge. (shrink)

Variations in human skin pigmentation are obvious, but how have skin colour differences evolved? Although clearly a polymorphic trait, the number and identity of key variants has remained unclear. Investigation of pigmentation phenotypes in model organisms provides a route to identify these genes and showed MC1R to be one key locus. Now, cloning of a classic zebrafish mutant, golden, identifies slc24a5 as a gene involved in fish skin pigmentation.1 Strikingly this study identifies the human orthologue, SLC24A5, as likely to make (...) a major contribution to the pale skin colouration of Western Europeans. BioEssays 28: 578–582, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

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

In eukaryotes, folate metabolism is compartmentalized between the cytoplasm and organelles. The folate pathways of mitochondria are adapted to serve the metabolism of the organism. In yeast, mitochondria support cytoplasmic purine synthesis through the generation of formate. This pathway is important but not essential for survival, consistent with the flexibility of yeast metabolism. In plants, the mitochondrial pathways support photorespiration by generating serine from glycine. This pathway is essential under photosynthetic conditions and the enzyme expression varies with photosynthetic activity. In (...) mammals, the expression of the mitochondrial enzymes varies in tissues and during development. In embryos, mitochondria supply formate and glycine for purine synthesis, a process essential for survival; in adult tissues, flux through mitochondria can favor serine production. The differences in the folate pathways of mitochondria depending on species, tissues and developmental stages, profoundly alter the nature of their metabolic contribution. BioEssays 28: 595–605, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

The origin of homochirality in molecules characterizing living systems has remained a mystery since Pasteur's recognition of the problem some 150 years ago.2-5 Most theories also assume that homochirality emerged in one class of molecules (e.g. ribose) from which it was enriched in other molecules (e.g. amino acids) as well.2-5 I propose a novel, experimentally testable hypothesis describing a process by which selective chirality in amino acids and ribonucleotides emerged simultaneously and hand-in-hand with the origin and directionality of the genetic (...) code within a system of interactions involving amino acids, peptides, nucleotide bases, their sugars and polynucleotides. BioEssays 29:689–698, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Neurotrophins (NTs) are {?AUTHOR} a family of structurally related, secreted proteins that regulate the survival, differentiation and maintenance of function of different populations of peripheral and central neurons.1,2 Among these, BDNF (brain‐derived neurotrophic factor) has drawn considerable interest because both its synthesis and secretion are increased by physiological levels of activity, indicating a unique role of this neurotrophin in coupling neuronal activity to structural and functional properties of neuronal circuits. In addition to its classical neurotrophic effects, which are evident within (...) hours or days and which usually result from changes in cellular gene expression, BDNF exerts acute effects on synaptic transmission and is involved in the induction of long‐term potentiation. Many of these rapid effects of BDNF are mediated by its modulation of ion channel properties following TrkB‐mediated activation of intracellular second messenger cascades and protein phosphorylation. However, recent reports have shown that BDNF not only acts as a modulator of ion channels, but can also directly and rapidly gate a Na+ channel, thereby assigning BDNF the properties of a classical excitatory transmitter. Thus, BDNF, in addition its role as a potent neuromodulator, emerges as an excitatory transmitter‐like substance which acutely controls resting membrane potential, neuronal excitability, synaptic transmission and participates in the induction of synaptic plasticity. BioEssays 26:1185–1194, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

In vertebrates it is often found that if one considers a group of genes clustered on a certain chromosome, then the homologues of those genes often form another cluster on a different chromosome. There are four explanations, not necessarily mutually exclusive, to explain how such homologous clusters appeared. Homologous clusters are expected at a low probability even if genes are distributed at random. The duplication of a subset of the genome might create homologous clusters, as would a duplication of the (...) entire genome. Alternatively, it may be adaptive for certain combinations of genes to cluster, although clearly the genes must have duplicated prior to rearrangement into clusters. Molecular phylogenetics provides a means to examine the origins of homologous clusters, although it is difficult to discriminate between the different explanations using current data. However, with more extensive sequencing and mapping of vertebrate genomes, especially those of the early diverging chordates, it should soon become possible to resolve the origins of homologous clusters. BioEssays 21:697–703, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

Many of the features that distinguish the vertebrates from other chordates are derived from the neural crest, and it has long been argued that the emergence of this multipotent embryonic population was a key innovation underpinning vertebrate evolution. More recently, however, a number of studies have suggested that the evolution of the neural crest was less sudden than previously believed. This has exposed the fact that neural crest, as evidenced by its repertoire of derivative cell types, has evolved through vertebrate (...) evolution. In this light, attempts to derive a typological definition of neural crest, in terms of molecular signatures or networks, are unfounded. We propose a less restrictive, embryological definition of this cell type that facilitates, rather than precludes, investigating the evolution of neural crest. While the evolutionary origin of neural crest has attracted much attention, its subsequent evolution has received almost no attention and yet it is more readily open to experimental investigation and has greater relevance to understanding vertebrate evolution. Finally, we provide a brief outline of how the evolutionary emergence of neural crest potentiality may have proceeded, and how it may be investigated. BioEssays 30:530–541, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

The mechanisms by which most receptor protein‐tyrosine kinases (RTKs) transmit signals are now well established. Binding of ligand results in the dimerization of receptor monomers followed by transphosphorylation of tyrosine residues within the cytoplasmic domains of the receptors. This tidy picture has, however, some strange characters lurking around the edges. Cases have now been identified in which RTKs lack kinase activity, but, despite being “dead” appear to have roles in signal transduction. Even stranger are the cases in which genes encoding (...) RTKs produce protein products consisting of only a portion of the kinase domain. At least one such “fractured” RTK appears to be involved in signal transduction. Here we describe how these strange molecules might function and discuss the questions associated with their evolution. BioEssays 23:69–76, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

We hypothesize that life began not with the first self‐reproducing molecule or metabolic network, but as a prebiotic ecology of co‐evolving populations of macromolecular aggregates (composomes). Each composome species had a particular molecular composition resulting from molecular complementarity among environmentally available prebiotic compounds. Natural selection acted on composomal species that varied in properties and functions such as stability, catalysis, fission, fusion and selective accumulation of molecules from solution. Fission permitted molecular replication based on composition rather than linear structure, while fusion (...) created composomal variability. Catalytic functions provided additional chemical novelty resulting eventually in autocatalytic and mutually catalytic networks within composomal species. Composomal autocatalysis and interdependence allowed the Darwinian co‐evolution of content and control (metabolism). The existence of chemical interfaces within complex composomes created linear templates upon which self‐reproducing molecules (such as RNA) could be synthesized, permitting the evolution of informational replication by molecular templating. Mathematical and experimental tests are proposed. BioEssays 28: 399–412, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Directed cell migration is a fundamental component of numerous biological systems and is critical to the pathology of many diseases. Although the importance of secreted chemoattractant factors in providing navigational cues to migrating cells bearing specific chemoattractant receptors is now well‐established, how the function of these factors is regulated is not so well understood and may be of key importance to the design of new therapeutics for numerous human diseases. While regulation of migration clearly takes place on a number of (...) different levels, it is becoming clear that so‐called ‘atypical’ receptors play a role in scavenging, or altering the localisation of, chemoattractant molecules such as chemokines and complement components. These receptors do this through binding and/or internalising their chemoattractant ligands without activating signal transduction cascades leading to cell migration. The atypical chemokine receptor family currently comprises the receptors D6, DARC and CCX‐CKR. In this review, we discuss the evidence from in vitro and in vivo studies that these receptors play a role in regulating cell migration, and speculate that other orphan receptors may also belong to this family. Furthermore, with the advent of gene therapy on the horizon, the therapeutic potential of these receptors in human disease is also considered. BioEssays 29: 237–247, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Human chromosome 11p15 comprises two imprinted domains important in the control of fetal and postnatal growth. Novel studies1-3 establish that imprinting at one of these, the IGF2-H19 domain, is epigenetically deregulated (with loss of DNA methylation) in Silver-Russell Syndrome (SRS), a congenital disease of growth retardation and asymmetry. Previously, the exact opposite epigenetic alteration (gain of DNA methylation) had been detected at the domain's ‘imprinting control region’ (ICR) in patients with Beckwith-Wiedemann Syndrome (BWS), a complex disorder of fetal overgrowth. However, (...) more frequently, BWS is caused by loss of DNA methylation at the ICR that regulates the second imprinted domain at 11p15. Interestingly, a similar epigenetic alteration (with loss of methylation) at a putative ICR on human chromosome 6q24, is involved in transient neonatal diabetes mellitus (TNDM), a congenital disease with intrauterine growth retardation and a transient lack of insulin. Thus, fetal and postnatal growth is epigenetically controlled by different ICRs, at 11p15 and other chromosomal regions. BioEssays 28: 453–459, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Although interactions of proteins with glycosaminoglycans (GAGs), such as heparin and heparan sulphate, are of great biological importance, structural requirements for protein‐GAG binding have not been well‐characterised. Ionic interactions are important in promoting protein‐GAG binding. Polyelectrolyte theory suggests that much of the free energy of binding comes from entropically favourable release of cations from GAG chains. Despite their identical charges, arginine residues bind more tightly to GAGs than lysine residues. The spacing of these residues may determine protein‐GAG affinity and specificity. (...) Consensus sequences such as XBBBXXBX, XBBXBX and a critical 20 Å spacing of basic residues are found in some protein sites that bind GAG. A new consensus sequence TXXBXXTBXXXTBB is described, where turns bring basic interacting amino acid residues into proximity. Clearly, protein‐GAG interactions play a prominent role in cell‐cell interaction and cell growth. Pathogens including virus particles might target GAG‐binding sites in envelope proteins leading to infection. BioEssays 20:156–167, 1998. © 1998 John Wiley & Sons, Inc. (shrink)