The ethical foundation of the medical profession, which values service above reward and holds the doctor-patient relationship as inviolable, continues to be challenged by the commercialization of health care. This article contends that a realigned leadership framework - one that distinguishes being a leader as the ontological basis for what leaders know, have, and do - is central to safeguarding medicine's ethical foundation. Four ontological pillars of leadership - awareness, commitment, integrity, and authenticity - are proposed as fundamental elements that (...) anchor this foundation and the basic tenets of professionalism. Ontological leadership is shaped by and accessible through language; what health care leaders create in language "uses" them by providing a point of view (a context) within and from which they orient their conversations, decisions, and conduct such that they are ethically aligned and grounded. This contextual leadership framework exposes for us the limitations imposed by our mental maps, creating new opportunity sets for being and action (previously unavailable) that embody medicine's charter on professionalism. While this leadership methodology contrasts with the conventional results-oriented model where leading is generally equated with a successful clinical practice, a distinguished research program, or a promotion, it is not a replacement for it; indeed, results are essential for performance. Rather, being and action are interrelated and their correlated nature equips leaders with a framework for tackling health care's most complex problems in a manner that preserves medicine's venerable ethical heritage. (shrink)

Restructured health care reimbursement systems and new requirements for nonprofit hospitals are transforming the U.S. health system, creating opportunities for enhanced integration of public health and health care goals. This article explores the role of public health practitioners and lawyers in this moment of transformation. We argue that the population perspective and structural strategies that characterize public health can add value to the health care system but could get lost in translation as changes to tax requirements and payment systems are (...) rapidly implemented. We urge public health leaders to take a more active role in hospital assessments of community health needs and evaluation of the patient outcomes for which providers are accountable. (shrink)

Gap junction intercellular communication channels permit the exchange of small regulatory molecules and ions between neighbouring cells and coordinate cellular activity in diverse tissue and organ systems. These channels have short half‐lives and complex assembly and degradation pathways. Much of the recent work elucidating gap junction biogenesis has featured the use of connexins (Cx), the constituent proteins of gap junctions, tagged with reporter proteins such as Green Fluorescent Protein (GFP) and has illuminated the dynamics of channel assembly in live cells (...) by high‐resolution time‐lapse microscopy. With some studies, however, there are potential short‐comings associated with the GFP chimeric protein technologies. A recent report by Gaietta et al., has highlighted the use of recombinant proteins with tetracysteine tags attached to the carboxyl terminus of Cx43, which differentially labels ‘old’ and ‘new’ connexins thus opening up new avenues for studying temporal and spatial localisation of proteins and in situ trafficking events.1 BioEssays 24:876–880, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

The generation of asymmetric cell shapes is a recurring theme in biology. In budding yeast, one form of cell asymmetry occurs for division and is generated by anisotropic growth of the mother cell to form a daughter cell bud. Previous genetic studies uncovered key roles for the small GTPase Cdc42 in organizing the actin cytoskeleton and vesicle delivery to the site of bud growth,1,2 but a recent paper has also raised questions about how control of Cdc42 activity is integrated into (...) a proposed hierarchical regulatory pathway that specifies a unique site of bud formation.3 BioEssays 25:833–836, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

The Necessary Maximality Principle for c. c. c. forcing with real parameters is equiconsistent with the existence of a weakly compact cardinal. (© 2005 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim).

N- and O-linked glycan structures of cell surface and secreted glycoproteins serve a variety of functions related to cell–cell communication in systems affecting development and disease. The more sophisticated N-glycan biosynthesis pathway of metazoans diverges from that of yeast with the appearance of the medial-Golgi β-N-acetylglucosaminyltransferases (GlcNAc-Ts). Tissue-specific regulation of medial- and trans-Golgi glycosyltransferases contribute structural diversity to glycoproteins in metazoans, and this can affect their molecular properties including localization, half-life, and biological activity. Null mutations in glycosyltransferase genes positioned later (...) in the biosynthetic pathway disrupt expression of smaller subsets of glycan structures and are progressively milder in phenotype. In this review, we examine data on targeted mutations affecting glycosylation in mice and congenital mutations in man, with a view to understanding the molecular functions of glycan structures as modulators of glycoprotein activity. Finally, pathology associated with the expression of GlcNAc-Ts in cancer and diabetes-induced cardiac hypertrophy suggest that inhibitors of these enzymes may have therapeutic value. BioEssays 21:412–421, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

It has been suggested that metallothioneins, discovered about 45 years ago, play a central role in heavy metal metabolism and detoxification, and in the management of various forms of stress. The metal‐regulatory transcription factor‐1 (MTF‐1) was shown to be essential for basal and heavy metal‐induced transcription of the stress‐responsive metallothionein‐I and metallothionein‐II. Recently it has become obvious that MTF‐1 has further roles in the transcriptional regulation of genes induced by various stressors and might even contribute to some aspects of malignant (...) cell growth. Furthermore, MTF‐1 is an essential gene, as mice null‐mutant for MTF‐1 die in utero due to liver degeneration. We describe here the state of knowledge on the complex activation of MTF‐1, and propose a model with MTF‐1 as an interconnected cellular stress‐sensor protein involved in heavy metal metabolism, hepatocyte differentiation and detoxification of toxic agents. BioEssays 23:1010–1017, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Glial cells play a central role in the development and function of complex nervous systems. Drosophila is an excellent model organism for the study of mechanisms underlying neural development, and recent attention has been focused on the differentiation and function of glial cells. We now have a nearly complete description of glial cell organization in the embryo, which enables a systematic genetic analysis of glial cell development. Most glia arise from neural stem cells that originate in the neurogenic ectoderm. The (...) bifurcation of glial and neuronal fates is under the control of the glial promoting factor glial cells missing. Differentiation is propagated through the regulation of several transcription factors. Genes have been discovered affecting the terminal differentiation of glia, including the promotion glial–neuronal interactions and the formation of the blood–nerve barrier. Other roles of glia are being explored, including their requirement for axon guidance, neuronal survival, and signaling. BioEssays 23:877–887, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

The mechanisms by which sex is genetically determined are bewilderingly diverse and appear to change rapidly during evolution.(1) What makes the sex‐determining process so prone to perturbations? Two recent articles(2,3) explore theoretically the role of genetic conflict in sex determination evolution. Both studies use the idea that selection on sex‐determining genes may act differently in parents and in offspring and they suggest that the resulting conflict can drive changes in sex‐determining mechanisms. BioEssays 23:477–480, 2001. © 2001 John Wiley & (...) Sons, Inc. (shrink)

The primary transcripts, pre‐mRNAs, of almost all protein‐coding genes in higher eukaryotes contain multiple non‐coding intervening sequences, introns, which must be precisely removed to yield translatable mRNAs. The process of intron excision, splicing, takes place in a massive ribonucleoprotein complex known as the spliceosome. Extensive studies, both genetic and biochemical, in a variety of systems have revealed that essential components of the spliceosome include five small RNAs–U1, U2, U4, U5 and U6, each of which functions as a RNA, protein complex (...) called an snRNP (small nuclear ribonucleoprotein). In addition to snRNPs, splicing requires many non‐snRNP protein factors, the exact nature and number of which has been unclear. Technical advances, including new affinity purification methods and improved mass spectrometry techniques, coupled with the completion of many genome sequences, have now permitted a number of proteomic analyses of purified spliceosomes. These studies, recently reviewed by Jurica and Moore,1 reveal that the spliceosome is composed of as many as 300 distinct proteins and five RNAs, making it among the most complex macromolecular machines known. BioEssays 25:1147–1149, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

The inner ear of mammals uses neurosensory cells derived from the embryonic ear for mechanoelectric transduction of vestibular and auditory stimuli (the hair cells) and conducts this information to the brain via sensory neurons. As with most other neurons of mammals, lost hair cells and sensory neurons are not spontaneously replaced and result instead in age‐dependent progressive hearing loss. We review the molecular basis of neurosensory development in the mouse ear to provide a blueprint for possible enhancement of therapeutically useful (...) transformation of stem cells into lost neurosensory cells. We identify several readily available adult sources of stem cells that express, like the ectoderm‐derived ear, genes known to be essential for ear development. Use of these stem cells combined with molecular insights into neurosensory cell specification and proliferation regulation of the ear, might allow for neurosensory regeneration of mammalian ears in the near future. BioEssays 28: 1181–1193, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Let φ1 stand for the statement V = HOD and φ2 stand for the Ground Axiom. Suppose Ti for i = 1, …, 4 are the theories “ZFC + φ1 + φ2,” “ZFC + ¬φ1 + φ2,” “ZFC + φ1 + ¬φ2,” and “ZFC + ¬φ1 + ¬φ2” respectively. We show that if κ is indestructibly supercompact and λ > κ is inaccessible, then for i = 1, …, 4, Ai = df{δ κ is inaccessible. We show it is also (...) the case that if κ is indestructibly supercompact, then Vκ⊨T1, so by reflection, B1 = df{δ κ is inaccessible, we demonstrate that it is possible to construct a model in which κ is indestructibly supercompact and for every inaccessible cardinal δ < κ, Vδ⊨T1. It is thus not possible to prove in ZFC that Bi = df{δ < κ∣δ is an inaccessible limit of inaccessible cardinals and Vδ⊨Ti} for i = 2, …, 4 is unbounded in κ if κ is indestructibly supercompact. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (shrink)

Simple epithelial keratins K8 and K18 are components of the intracellular cytoskeleton in the cells of the single‐layered sheet tissues inside the body. As members of the intermediate filament family of proteins, their function has been a matter for debate since they were first discovered. Whilst there is an indisputable case for a structural cell‐reinforcing function for keratins in the mutilayered squamous epithelia of external barrier tissues, some very different stress‐protective features now seem to be emerging for the simple epithelial (...) keratins. Even the emerging evidence of pathological mutations in K8/K18 looks very different from mutations in stratified epithelial keratins. K8/K18‐like keratins were probably the first to evolve and, whilst stratified epithelial (keratinocyte) keratins have diversified into a large group of keratins highly specialised for providing mechanical stability, the simple epithelial keratins have retained early features that may protect the internal epithelia from a broader range of stresses, including osmotic stress and chemical toxicity. BioEssays 25:748–758, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Two recent studies by Parisi et al.1 and Ranz et al.,2 catalogue sex differences in gene expression across the whole genome of the fruit fly Drosophila melanogaster. Both report striking associations of sex‐biased gene expression with the X chromosome. Genes with male‐biased expression are depauperate on the X chromosome, whereas genes with female‐biased expression show weaker evidence of being in excess. A number of evolutionary hypotheses for the expulsion or exclusion of male‐biased genes from the X chromosome have been suggested. (...) None is entirely consistent with the available evidence. BioEssays 25:739–741, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

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

Somites are transient structures which represent the most overt segmental feature of the vertebrate embryo. The strict temporal regulation of somitogenesis is of critical developmental importance since many segmental structures adopt a periodicity based on that of the somites. Until recently, the mechanisms underlying the periodicity of somitogenesis were largely unknown. Based on the oscillations of c-hairy1 and lunatic fringe RNA, we now have evidence for an intrinsic segmentation clock in presomitic cells. Translation of this temporal periodicity into a spatial (...) periodicity, through somite formation, requires Notch signaling. While the Hox genes are certainly involved, it remains unknown how the metameric vertebrate axis becomes regionalized along the antero–posterior (AP) dimension into the occipital, cervical, thoracic, lumbar, and sacral domains. We discuss the implications of cell division as a clock mechanism underlying the regionalization of somites and their derivatives along the AP axis. Possible links between the segmentation clock and axial regionalization are also discussed. BioEssays 22:72–83, 2000. ©2000 John Wiley & Sons, Inc. (shrink)

Carbon monoxide (CO), a product of organic oxidation processes, arises in vivo during cellular metabolism, most notably heme degradation. CO binds to the heme iron of most hemoproteins. Tissue hypoxia following hemoglobin saturation represents a principle cause of CO‐induced mortality in higher organisms, though cellular targets cannot be excluded. Despite extreme toxicity at high concentrations, low concentrations of CO can confer cytoprotection during ischemia/reperfusion or inflammation‐induced tissue injury. Likewise, heme oxygenase, an enzyme that produces CO, biliverdin and iron, as well (...) as a secondary increase in ferritin synthesis, from the oxidation of heme, can confer protection in vivo and in vitro. CO has been shown to affect several intracellular signaling pathways, including guanylate cyclase, which generates guanosine 3′:5′ cyclic monophosphate and the mitogen‐activated protein kinases (MAPK). Such pathways mediate, in part, the known vasoregulatory, anti‐inflammatory, anti‐apoptotic and anti‐proliferative effects of this gas. Exogenous CO delivered at low concentrations is showing therapeutic potential as an anti‐inflammatory agent and as such can modulate numerous pathophysiological states. This review will delve into the biological significance and medical applications of this gas molecule. BioEssays 26:270–280, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Gene expression is an inherently complex process and errors often occur during the transcription and processing of mRNAs. Several surveillance mechanisms have evolved to check the fidelity at each step of mRNA manufacture. Two recent reports describe the identification of a novel pathway in eukaryotes that recognizes and degrades mRNAs that lack a stop codon.1,2 The non‐stop decay mechanism releases ribosomes stalled at the 3′ end of a mRNA and stimulates the exosome to rapidly degrade the transcript. BioEssays 24:785–788, 2002. (...) © 2002 Wiley Periodicals, Inc. (shrink)

In this entry, we survey key discussions on the role of narrative in theology and philosophy of religion. We begin with epistemological questions about whether and how narrative offers genuine understanding of reality. We explore how narrative intersects with the problems of evil and divine hiddenness. We discuss narrative's role in theological reflection and practice in general, and in black and feminist theologies specifically. We close by briefly exploring the role of narrative in theorization about life's meaning.

We develop a new method for coding sets while preserving GCH in the presence of large cardinals, particularly supercompact cardinals. We will use the number of normal measures carried by a measurable cardinal as an oracle, and therefore, in order to code a subset A of κ, we require that our model contain κ many measurable cardinals above κ. Additionally we will describe some of the applications of this result. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The metabolic organization of both normal and malignant prostate cellular phenotypes involves some unusual and surprising features. In particular, both conditions exhibit ratios of NADH/NAD+ and NADPH/NADP+ charactersitic of high oxidative states despite a chronic shortage of O2 in both conditions. In this paper, we observe that, in prostate cancer cells, the oxidizing power of the fatty acid synthesis (FAS) pathway is so large that redox is stabilized more favorably (more oxidized) than in normal prostate cells. This FAS‐facilitated redox improvement (...) occurs despite the fact that malignant cells are more O2 limited and therefore express more hypoxia inducible factor 1 (HIF1) and express hypoxia‐regulated genes more robustly. This unusual metabolic situation clearly separates direct regulatory effects of redox balance from secondary effects of hypoxia per se. The physiological significance of the FAS pathway is thus the harnessing of its oxidizing power for improving redox balance despite conditions of more extreme hypoxia. Similar hypoxia defense strategies are found in animal species that are unusually tolerant to oxygen lack. Our hypothesis is that the metabolic organization in the “low zinc, low citrate” phenotype reflects an hypoxia‐defense adaptation geared toward redox balance, with prostate cancer cells being relatively more oxidized, even if more hypoxic, than normal prostate cells. Recognition and understanding of these redox balancing and hypoxia defense functions may lead to new intervention strategies by developing new intracellular targets for prostate cancer therapy. BioEssays 24:749–757, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

In birds and frogs, species pairs retain the capacity to produce viable hybrids for tens of millions of years, an order of magnitude longer than mammals. What accounts for these differences in relative rates of pre- and postzygotic isolation? We propose that reproductive mode is a critically important but previously overlooked factor in the speciation process. Viviparity creates a post-fertilization arena for genomic conflicts absent in egg-laying species. With viviparity, conflict can arise between: mothers and embryos; sibling embryos in the (...) womb, and maternal and paternal genomes within individual embryos. Such intra- and intergenomic conflicts result in perpetual antagonistic coevolution, thereby accelerating interpopulation postzygotic isolation. In addition, by generating intrapopulation genetic incompatibility, viviparity-driven conflict favors polyandry and limits the potential for precopulatory divergence. Mammalian diversification is characterized by rapid evolution of incompatible feto-maternal interactions, asymmetrical postzygotic isolation, disproportionate effects of genomically-imprinted genes, and “F2 hybrid enhancement.” The viviparity-driven conflict hypothesis provides a parsimonious explanation for these patterns in mammalian evolution. BioEssays 22:938–946, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

Systemic autoimmune diseases are characterized by the production of antibodies against a broad range of self-antigens. Recent evidence indicates that the majority of these autoantigens are modified in various ways during cell death. This has led to the hypothesis that the primary immune response in the development of autoimmunity is directed to components of the dying cell. In this article, we summarize data on the modification of autoantigens during cell death and the possible consequences of this for autoimmunity. BioEssays 22:627–636, (...) 2000. © 2000 John Wiley & Sons, 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)

Among all organisms, the size of each body part or organ scales with overall body size, a phenomenon called allometry. The study of shape and form has attracted enormous interest from biologists, but the genetic, developmental and physiological mechanisms that control allometry and the proportional growth of parts have remained elusive. Recent progress in our understanding of body‐size regulation provides a new synthetic framework for thinking about the mechanisms and the evolution of allometric scaling. In particular, insulin/IGF signaling, which plays (...) major roles in longevity, diabetes and the regulation of cell, organ and body size, might also be centrally involved in regulating organismal shape. Here we review recent advances in the fields of growth regulation and endocrinology and use them to construct a developmental model of static allometry expression in insects. This model serves as the foundation for a research program that will result in a deeper understanding of the relationship between growth and form, a question that has fascinated biologists for centuries. BioEssays 29:536–548, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Type II DNA topoisomerase activity is required to change DNA topology. It is important in the relaxation of DNA supercoils generated by cellular processes, such as transcription and replication, and it is essential for the condensation of chromosomes and their segregation during mitosis. In mammals this activity is derived from at least two isoforms, termed DNA topoisomerase IIα and β. The α isoform is involved in chromosome condensation and segregation, whereas the role of the β isoform is not yet clear. (...) DNA topoisomerase IIβ was first reported in 1987. Here we review the research on DNA topoisomerase IIβ over the last 10 years. BioEssays 20:215–226, 1998.© 1998 John Wiley & Sons, Inc. (shrink)

The genetic stability of living cells is continuously threatened by the presence of endogenous reactive oxygen species and other genotoxic molecules. Of particular threat are the thousands of DNA single-strand breaks that arise in each cell, each day, both directly from disintegration of damaged sugars and indirectly from the excision repair of damaged bases. If un-repaired, single-strand breaks can be converted into double-strand breaks during DNA replication, potentially resulting in chromosomal rearrangement and genetic deletion. Consequently, cells have adopted multiple pathways (...) to ensure the rapid and efficient removal of single-strand breaks. A general feature of these pathways appears to be the extensive employment of protein–protein interactions to stimulate both the individual component steps and the overall repair reaction. Our current understanding of DNA single-strand break repair is discussed, and testable models for the architectural coordination of this important process are presented. BioEssays 23:447–455, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Both genetic and environmental factors have key roles in determining aggressive tendencies. In particular, reaction to stress appears to be an important factor in precipitating aggressive episodes and individuals may vary in their ability to cope with stressful environments depending on their genetic make up. Evidence from humans and primates indicates that adverse rearing conditions may interact with variants in stress and neurotransmitter pathway genes leading to antisocial and/or violent behaviour. Common alleles of some serotonin pathway genes, including those involved (...) in its degradation (monoamine oxidase A, MAOA), or its re‐uptake into pre‐synaptic neurones (serotonin transporter, SERT) have been shown to confer functional variation. Examination of the interaction between the alleles of such polymorphisms (in particular those affecting MAOA) and environmental stressors suggest that they may provide protection against, or increase sensitivity to, abusive upbringing; an observation that may explain part of the variability in developmental outcomes associated with maltreatment. BioEssays 29: 227–236, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

In spite of advances in medicine and public health, malaria and other mosquito‐borne diseases are on the rise worldwide. Although vaccines, genetically modified mosquitoes and safer insecticides are under development, herein we examine a promising new approach to malaria control through better repellents. Current repellents, usually based on DEET, inhibit host finding by impeding insect olfaction, but have significant drawbacks. We discuss how comparative genomics, using data from the Anopheles genome project, allows the rapid identification of members of three protein (...) classes critical to insect olfaction: odorant‐binding proteins, G‐protein‐coupled receptors, and odorant‐degrading enzymes. A rational design approach similar to that used by the pharmaceutical industry for drug development can then be applied to the development of products that interfere with mosquito olfaction. Such products have the potential to provide more complete, safer and longer lasting protection than conventional repellents, preventing disease transmission by interrupting the parasite life cycle. BioEssays 25:1011–1020, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

The final assembly of the protein synthesis machinery occurs during translation initiation. This delicate process involves both ends of eukaryotic messenger RNAs as well as multiple sequential protein–RNA and protein–protein interactions. As is expected from its critical position in the gene expression pathway between the transcriptome and the proteome, translation initiation is a selective and highly regulated process. This synopsis summarises the current status of the field and identifies intriguing open questions. BioEssays 25:1201–1211, 2003 © 2003 Wiley Periodicals, Inc.

The virulence of a virus is determined by its ability to adversely affect the host cell, host organism or population of host organisms. Influenza A viruses have been responsible for four pandemics of severe human respiratory disease this century. Avian species harbour a large reservoir of influenza virus strains, which can contribute genes to potential new pandemic human strains. The fundamental importance of understanding the role of each of these genes in determining virulence in birds and humans was dramatically emphasised (...) by the recent direct transmission of avian influenza A viruses to humans, causing fatal infection but not community spread. An understanding of the factors involved in transmission between avian and mammalian species should assist in the development of better surveillance strategies for early recognition of influenza A virus strains having human pandemic potential, and possibly in the design of anti‐viral strategies. BioEssays 25:657–671, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

A notion of resource‐bounded Baire category is developed for the classPC[0,1]of all polynomial‐time computable real‐valued functions on the unit interval. The meager subsets ofPC[0,1]are characterized in terms of resource‐bounded Banach‐Mazur games. This characterization is used to prove that, in the sense of Baire category, almost every function inPC[0,1]is nowhere differentiable. This is a complexity‐theoretic extension of the analogous classical result that Banach proved for the classC[0, 1] in 1931. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim).

Neural crest cells are multipotent progenitors, capable of producing diverse cell types upon differentiation. Recent studies have identified significant heterogeneity in both the fates produced and genes expressed by different premigratory crest cells. While these cells may be specified toward particular fates prior to migration, transplant studies show that some may still be capable of respecification at this time. Here we summarize evidence that extracellular signals in the local environment may act to specify premigratory crest and thus generate diversity in (...) the population. Three main classes of signals–Wnts, BMP2/BMP4 and TGFβ1,2,3–have been shown to directly influence the production of particular neural crest cell fates, and all are expressed near the premigratory crest. This system may therefore provide a good model for integration of multiple signaling pathways during embryonic cell fate specification. BioEssays 22:708–716, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

Brain function depends on the cooperation between highly specialized cells. Neurons generate electrical signals and glial cells provide structural and metabolic support. Here, I propose a new kind of job‐sharing between neurons and astrocytes. Recent studies on primary cultures of highly purified neurons from the rodent central nervous system (CNS) suggest that, during development, neurons reduce or even abandon cholesterol synthesis to save energy and import cholesterol from astrocytes via lipoproteins. The cholesterol shuttle may be restricted to compartments distant from (...) the soma including synapses and may be regulated by electrical activity. Testing these hypotheses will help to improve our still insufficient understanding of brain cholesterol metabolism and its role in neurodegeneration. BioEssays 25:72–78, 2003. © 2002 Wiley Periodicals, Inc. (shrink)

The human blood coagulation system comprises a series of linked glycoproteins that upon activation induce the generation of downstream enzymes ultimately forming fibrin. This process is primarily important to arrest bleeding (hemostasis). Hemostasis is a typical example of a molecular machine, where the assembly of substrates, enzymes, protein cofactors and calcium ions on a phospholipid surface markedly accelerates the rate of coagulation. Excess, pathological, coagulation activity occurs in “thrombosis”, the formation of an intravascular clot, which in the most dramatic form (...) precipitates in the microvasculature as disseminated intravascular coagulation. Thrombosis occurs according to a biochemical machine model in the case of atherothrombosis on a ruptured atherosclerotic plaque, but may develop at a slower rate in venous thrombosis, illustrating that the coagulation machinery can act at different velocities. The separate coagulation enzymes are also important in other biological processes, including inflammation for which the rapid conversion of one coagulation factor by the other is not a prerequisite. The latter role of coagulation enzymes may be related to the old and probably maintained function of the coagulation machine in innate immunity. BioEssays 25:1220–1228, 2003. © 2003 Wiley Perioicals, Inc. (shrink)

Different patterns of mitochondrial and Y-chromosome diversity have been cited as evidence of long-term patrilocality in human populations. However, what patterns are expected depends on the nature of the sampling scheme. Samples from a local region reveal only the recent demographic history of that region, whereas sampling over larger geographic scales accesses older demographic processes. A historical change in migration becomes evident first at local geographic scales, and alters global patterns of genetic diversity only after sufficient time has passed. Analysis (...) of forager populations in the ethnographic record suggests that patrilocality may not have predominated among pre-agricultural humans. The higher female migration rate inferred by some genetic studies may reflect a shift to patrilocality in association with the emergence of agriculture. A recent global survey does not show the expected effects of higher female migration, possibly because the sampling scheme used for this study is accessing pre-agricultural human migration patterns. In this paper, we show how the demographic shift associated with agriculture might affect genetic diversity over different spatial scales. We also consider the prospects for studying sex-biased migration using the X-linked and autosomal markers. These multi-locus comparisons have the potential of providing more robust estimates of sex differences than Y-linked and mitochondrial data, but only if a very large number of loci are included in the analysis. BioEssays 28: 290–300, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Included in the acute response of lowlanders exposed to reduced oxygen availability is an elevated red blood cell count due to increased erythropoietin (Epo) synthesis. According to current thinking, hypoxia is “sensed” by hydroxylases that permit Hypoxia Inducible Factor 1α (HIF‐1α) to complex with HIF‐1β to form a transcriptional activator (HIF‐1) that drives expression of hypoxia‐sensitive genes (such as EPO) under hypoxic conditions. In altitude‐adapted Andean natives, the Epo hypoxic response may be blunted; however, our data indicate that the DNA (...) sequences of the genes encoding Epo (including the 3′ regulatory region) and HIF‐1α appear to be conserved. Hence, adaptive changes in the Andean hypoxic response are not a consequence of changes in the primary sequence of these proteins or of known transcriptional regulatory domains of EPO. These results suggest that the altered erthropoietic response in Andean natives reflects adaptations in hypoxia sensing, rather than hypoxia response, mechanisms. BioEssays 25:515–519, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

The Krüppel‐like factors (KLFs) comprise a family of evolutionarily conserved zinc finger transcription factors that regulate numerous biological processes including proliferation, differentiation, development and apoptosis. KLF4 and KLF5 are two closely related members of this family and are both highly expressed in epithelial tissues. In the intestinal epithelium, KLF4 is expressed in terminally differentiated epithelial cells at the villus borders of the mucosa and inhibits cell growth, while KLF5 is expressed in proliferating epithelial cells at the base of the intestinal (...) crypts and promotes cell growth. KLF4 and KLF5 respond to a myriad of external stress stimuli and are likely involved in restoring cellular homeostasis following exposure to stressors. Confirming their importance in maintaining tissue integrity, KLF4 and KLF5 are both dysregulated in various types of cancer. Here we review the recent advances in defining the physiological and pathobiological roles of KLF4 and KLF5, focusing on their functions in the intestinal epithelium. BioEssays 29:549–557, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Cell size is an important determinant of body size. While the genetic mechanisms of cell size regulation have been well studied in yeast, this process has only recently been addressed in multicellular organisms. One recent report by Wang et al. (2002) shows that in the nematode C. elegans, the TGFβ‐like pathway acts in the hypodermis to regulate cell size and consequently body size.1 This finding is an exciting step in discovering the molecular mechanisms that control cell and body size. BioEssays (...) 25:305–308, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

The occurrence of hiccoughs (hiccups) is very widespread and yet their neuronal origin and physiological significance are still unresolved. Several hypotheses have been proposed. Here we consider a phylogenetic perspective, starting from the concept that the ventilatory central pattern generator of lower vertebrates provides the base upon which central pattern generators of higher vertebrates develop. Hiccoughs are characterized by glottal closure during inspiration and by early development in relation to lung ventilation. They are inhibited when the concentration of inhaled CO2 (...) is increased and they can be abolished by the drug baclofen (an agonist of the GABAB receptor). These properties are shared by ventilatory motor patterns of lower vertebrates, leading to the hypothesis that hiccough is the expression of archaic motor patterns and particularly the motor pattern of gill ventilation in bimodal breathers such as most frogs. A circuit that can generate hiccoughs may persist in mammals because it has permitted the development of pattern generators for other useful functions of the pharynx and chest wall muscles, such as suckling or eupneic breathing. BioEssays 25:182–188, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

The feasibility of reversing human aging within a matter of decades has traditionally been dismissed by all professional biogerontologists, on the grounds that not only is aging still poorly understood, but also many of those aspects that we do understand are not reversible by any current or foreseeable therapeutic regimen. This broad consensus has recently been challenged by the publication, by five respected experimentalists in diverse subfields of biogerontology together with three of the present authors, of an article (Ann NY (...) Acad Sci 959, 452–462) whose conclusion was that all the key components of mammalian aging are indeed amenable to substantial reversal (not merely retardation) in mice, with technology that has a reasonable prospect of being developed within about a decade. Translation of that panel of interventions to humans who are already alive, within a few decades thereafter, was deemed potentially feasible (though it was not claimed to be likely). If the prospect of controlling human aging within the foreseeable future cannot be categorically rejected, then it becomes a matter of personal significance to most people presently alive. Consequently, we suggest that serious public debate on this subject is now warranted, and we survey here several of the biological, social and political issues relating to it. BioEssays 24:667–676, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Somatic or inherited mutations in the adenomatous polyposis coli (APC) gene are a frequent cause of colorectal cancer in humans. APC protein has an important tumor suppression function to reduce cellular levels of the signaling protein β‐catenin and, thereby, inhibit β‐catenin and T‐cell‐factor‐mediated gene expression. In addition, APC protein binds to microtubules in vertebrate cells and localizes to actin‐rich adherens junctions in epithelial cells of the fruit fly Drosophila (Fig. 1). Very little is known, however, about the function of these (...) cytoskeletal associations. Recently, Hamada and Bienz have described a potential role for Drosophila E‐APC in cellular adhesion,1 which offers new clues to APC function in embryonic development, and potentially colorectal adenoma formation and tumor progression in humans. BioEssays 24:771–774, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Meiosis is the process by which diploid germ cells divide to produce haploid gametes for sexual reproduction. The process is highly conserved in eukaryotes, however the recent availability of mouse models for meiotic recombination has revealed surprising regulatory differences between simple unicellular organisms and those with increasingly complex genomes. Moreover, in these higher eukaryotes, the intervention of physiological and sex-specific factors may also influence how meiotic recombination and progression are monitored and regulated. This review will focus on the recent studies (...) involving mouse mutants for meiosis, and will highlight important differences between traditional model systems for meiosis (such as yeast) and those involving more complex cellular, physiological and genetic criteria. BioEssays 23:996–1009, 2001. © 2001 John Wiley & Sons, Inc. (shrink)