Integrating concepts of maintenance and of origins is essential to explaining biological diversity. The unified theory of evolution attempts to find a common theme linking production rules inherent in biological systems, explaining the origin of biological order as a manifestation of the flow of energy and the flow of information on various spatial and temporal scales, with the recognition that natural selection is an evolutionarily relevant process. Biological systems persist in space and time by transfor ming energy from one state (...) to another in a manner that generates structures which allows the system to continue to persist. Two classes of energetic transformations allow this; heat-generating transformations, resulting in a net loss of energy from the system, and conservative transformations, changing unusable energy into states that can be stored and used subsequently. All conservative transformations in biological systems are coupled with heat-generating transformations; hence, inherent biological production, or genealogical proesses, is positively entropic. There is a self-organizing phenomenology common to genealogical phenomena, which imparts an arrow of time to biological systems. Natural selection, which by itself is time-reversible, contributes to the organization of the self-organized genealogical trajectories. The interplay of genealogical (diversity-promoting) and selective (diversity-limiting) processes produces biological order to which the primary contribution is genealogical history. Dynamic changes occuring on times scales shorter than speciation rates are microevolutionary; those occuring on time scales longer than speciation rates are macroevolutionary. Macroevolutionary processes are neither redicible to, nor autonomous from, microevolutionary processes. (shrink)

Design patterns are generalized solutions to frequently recurring problems. They were initially developed by architects and computer scientists to create a higher level of abstraction for their designs. Here, we extend these concepts to cell biology to lend a new perspective on the evolved designs of cells' underlying reaction networks. We present a catalog of 21 design patterns divided into three categories: creational patterns describe processes that build the cell, structural patterns describe the layouts of reaction networks, and behavioral patterns (...) describe reaction network function. Applying this pattern language to the E. coli central metabolic reaction network, the yeast pheromone response signaling network, and other examples lends new insights into these systems. (shrink)

The current informal practice of pharmacometrics as a combination art and science makes it hard to appreciate the role that informatics can and should play in the future of the discipline and to comprehend the gaps that exist because of its absence. The development of pharmacometric informatics has important implications for expediting decision making and for improving the reliability of decisions made in model-based development. We argue that well-defined informatics for pharmacometrics can lead to much needed improvements in the efficiency, (...) effectiveness, and reliability of the pharmacometrics process. The purpose of this paper is to provide a description of the pervasive yet often poorly appreciated role of informatics in improving the process of data assembly, a critical task in the delivery of pharmacometric analysis results. First, we provide a brief description of the pharmacometric analysis process. Second, we describe the business processes required to create analysis-ready data sets for the pharmacometrician. Third, we describe selected informatic elements required to support the pharmacometrics and data assembly processes. Finally, we offer specific suggestions for performing a systematic analysis of existing challenges as an approach to defi ning the next generation of pharmacometric informatics. (shrink)

This book proposes guidelines for constructing and evaluating definitions of terms, i.e. words or phrases of general application. The guidelines extend to adoption of nomenclature. The book is meant to be a practical guide for people who find themselves in their daily lives or their employment producing or evaluating definitions of terms. It can be consulted rather than being read through. The book’s theoretical framework is a distinction, due to Robert H. Ennis, of three dimensions of definitions: the act of (...) the definer, the content of the definition, and its form. The act of a definer is what the definer does in defining a term; the book distinguishes, following Ennis, three basic acts of defining: reporting, stipulating, and advocating. The content of a definition is in one sense the information that the definition conveys and in another sense the words in its defining part. The form of a definition is the way it is expressed, for example as a definition by genus and differentia. (shrink)

This chapter describes the potential far‐reaching consequences of contemplative higher education for the fields of science and medicine.

The auteur theory of film-making (usually attributed in film to the French director Francais Truffaut) is explored with specific reference to the films of Alfred Hitchcock. It is argued that Hitchcocks’s films, in particular his later films, present a common theme which is in fact quite consistent with the outlook of Phenomenological Existentialism, especially as it was espoused by the philosophers Jean-Paul Sartre and Martin Heidegger.To support this position, textual analyses of various films directed and produced by Hitchcock (...) are presented, including Rear Window, The Trouble with Harry, The Wrong Man, and Vertigo. The effects of this approach and its philosophical implications far the film-going audience are also examined. (shrink)

The auteur theory of film-making (usually attributed in film to the French director Francais Truffaut) is explored with specific reference to the films of Alfred Hitchcock. It is argued that Hitchcocks’s films, in particular his later films, present a common theme which is in fact quite consistent with the outlook of Phenomenological Existentialism, especially as it was espoused by the philosophers Jean-Paul Sartre and Martin Heidegger.To support this position, textual analyses of various films directed and produced by Hitchcock (...) are presented, including Rear Window, The Trouble with Harry, The Wrong Man, and Vertigo. The effects of this approach and its philosophical implications far the film-going audience are also examined. (shrink)

A trait is robust to a genetic or environmental variable if its variation is weakly correlated with variation in that variable. The source of robustness lies in the fact that the developmental processes that give rise to complex traits are nonlinear. A consequence of this nonlinearity is that not all genes are equally correlated with the trait whose ontogeny they control. Here we explore how developmental mechanisms determine and alter the correlation structure between genes and the traits that they control. (...) A formula is developed by which the correlation of a gene or environmental variable with a trait can be calculated if the mechanism that gives rise to the trait is known. The nature of robustness and the ways in which robustness can evolve are discussed in the context of the problems that arise in the analysis of inherently nonlinear systems. BioEssays 24:553–563, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Two recent hypotheses have proposed that non‐green plant colouration evolved as a defence against herbivores, either as protective colouration promoting handicap signals indicating plant fitness or by undermining their crypsis. The handicap hypothesis posits a co‐evolutionary process between plants and herbivores, whereas the anti‐crypsis hypothesis suggests that an arms race between insects and plants is the evolutionary mechanism. Both explanations assume that insects are the evolutionary origin causing plants' colouration. Here, we propose a different hypothesis, termed the “Defence Indication hypothesis”. (...) This idea focuses on the multiple protective functions of anthocyanins and carotenoids as pigments, and suggests that plant colouration evolved primarily in response to various stressors. Because pigments and defensive compounds share a common biosynthesis, the production of pigments also provides elevated defensive strengths against herbivores, a process termed priming. In effect, the Defence Indication hypothesis predicts that pleiotropic effects of the pigments and, more generally, plants' shared defence responses, explain why insects might react to plant colouration. BioEssays 28:65–71, 2006. © 2005 Wiley Periodicals, Inc. (shrink)

Heterotrimeric G proteins, consisting of α, β, and γ subunits, couple ligand-bound seven transmembrane domain receptors to the regulation of effector proteins and production of intracellular second messengers. G protein signaling mediates the perception of environmental cues in all higher eukaryotic organisms, including yeast, Dictyostelium, plants, and animals. The nematode Caenorhabditis elegans is the first animal to have complete descriptions of its cellular anatomy, cell lineage, neuronal wiring diagram, and genomic sequence. In a recent paper, Jansen et al.(1) used sequence (...) searches of the C. elegans genome database to identify all heterotrimeric G protein genes (20 Gα, 2 Gβ, 2 Gγ). C. elegans encodes one ortholog of each of the four Gα classes found in metazoans and 16 new Gα genes. The orthologous genes are widely expressed, whereas 14 of the divergent Gα genes are almost exclusively expressed in sensory neurons where they may regulate perception and chemotaxis.BioEssays 21:713–717, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

Epistasis plays an important role in the genetic architecture of common human diseases and can be viewed from two perspectives, biological and statistical, each derived from and leading to different assumptions and research strategies. Biological epistasis is the result of physical interactions among biomolecules within gene regulatory networks and biochemical pathways in an individual such that the effect of a gene on a phenotype is dependent on one or more other genes. In contrast, statistical epistasis is defined as deviation from (...) additivity in a mathematical model summarizing the relationship between multilocus genotypes and phenotypic variation in a population. The goal of this essay is to review definitions and examples of biological and statistical epistasis and to explore the relationship between the two. Specifically, we present and discuss the following two questions in the context of human health and disease. First, when does statistical evidence of epistasis in human populations imply underlying biomolecular interactions in the etiology of disease? Second, when do biomolecular interactions produce patterns of statistical epistasis in human populations?Answers to these two reciprocal questions will provide an important framework for using genetic information to improve our ability to diagnose, prevent and treat common human diseases. We propose that systems biology will provide the necessary information for addressing these questions and that model systems such as bacteria, yeast and digital organisms will be a useful place to start. BioEssays 27:637–646, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Lysophosphatidic acid (LPA) is a lipid mediator with a wide variety of biological actions, particularly as an inducer of cell proliferation, migration and survival. LPA binds to specific G‐protein‐coupled receptors and thereby activates multiple signal transduction pathways, including those initiated by the small GTPases Ras, Rho, and Rac. LPA signaling has been implicated in such diverse processes as wound healing, brain development, vascular remodeling and tumor progression. Knowledge of precisely how and where LPA is produced has long proved elusive. Excitingly, (...) it has recently been discovered that LPA is generated from precursors by ‘autotaxin’, a once enigmatic exo‐phosphodiesterase implicated in tumor cell motility. Exogenous phospholipases D can also produce LPA, which may contribute to their toxicity. Here we review recent progress in our understanding of LPA bioactivity, signaling and synthesis. BioEssays 26:870–881, 2004. © 2004 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)

Gerbera hybrida is a member of the large sunflower family (Asteraceae). Typical of Asteraceae, Gerbera bears different types of flowers in its inflorescence. The showy marginal flowers comprise elongate, ligulate corollas that are female, whereas the central and inconspicuous disc flowers are complete, with both male and female organs. As such, Gerbera offers great potential for comparative developmental research within a single genotype. Moreover, different Gerbera varieties show an impressive spectrum of color patterns, directly displaying responses to developmental cues at (...) all important morphological levels (flower type, flower organ and within organs). Further, Gerbera harbors an arsenal of Asteraceae‐type secondary metabolites, not present in other model plants. With powerful reverse genetics methods, a large collection of EST sequences and a new cDNA microarray, Gerbera has become a model plant of the sunflower family. BioEssays 28: 756–767, 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)

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 DAP (Death Associated Protein) kinase family is a novel subfamily of pro-apoptotic serine/threonine kinases. All five DAP kinase family members identified to date are ubiquitously expressed in various tissues and are capable of inducing apoptosis. The sequence homology of the five kinases is largely restricted to the N-terminal kinase domain. In contrast, the adjacent C-terminal regions are very diverse and link individual family members to specific signal transduction pathways. There is increasing evidence that DAP kinase family members are involved (...) in both extrinsic and intrinsic pathways of apoptosis and may play a role in tumor progression. This review will focus on structural composition and subcellular localization of DAP kinase family members and on signal transduction pathways leading to their activation. Potential mechanisms of DAP kinase family-mediated apoptosis will be discussed. BioEssays 23:352–358, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Asymmetric RNA localization is required for many developmental processes in a wide range of organisms. For example, wingless and pair‐rule transcripts are localized to the apical membrane of polarized cells. It has been unclear, however, if this localization is important for biological activity and, in addition, how the transcripts are transported. Two recent studies(1,2) have identified cis‐elements and trans‐acting factors that are required for the asymmetric localization of mRNAs. Correct localization is shown to be required for biological activity, and a (...) mechanism of RNA transport involving the microtubule motor dynein has been revealed. BioEssays 23:869–872, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

A major challenge for The Cancer Genome Atlas (TCGA) Project is solving the high level of genetic and epigenetic heterogeneity of cancer. For the majority of solid tumors, evolution patterns are stochastic and the end products are unpredictable, in contrast to the relatively predictable stepwise patterns classically described in many hematological cancers. Further, it is genome aberrations, rather than gene mutations, that are the dominant factor in generating abnormal levels of system heterogeneity in cancers. These features of cancer could significantly (...) reduce the impact of the sequencing approach, as it is only when mutated genes are the main cause of cancer that directly sequencing them is justified. Many biological factors (genetic and epigenetic variations, metabolic processes) and environmental influences can increase the probability of cancer formation, depending on the given circumstances. The common link between these factors is the stochastic genome variations that provide the driving force behind the cancer evolutionary process within multiple levels of a biological system. This analysis suggests that cancer is a disease of probability and the most‐challenging issue to the TCGA project, as well as the development of general strategies for fighting cancer, lie at the conceptual level. BioEssays 29:783–794, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Developmental processes in complex animals are directed by a hardwired genomic regulatory code, the ultimate function of which is to set up a progression of transcriptional regulatory states in space and time. The code specifies the gene regulatory networks (GRNs) that underlie all major developmental events. Models of GRNs are required for analysis, for experimental manipulation and, most fundamentally, for comprehension of how GRNs work. To model GRNs requires knowledge of both their overall structure, which depends upon linkage amongst regulatory (...) genes, and the modular building blocks of which GRNs are heirarchically constructed. The building blocks consist of basic transcriptional control processes executed by one or a few functionally linked genes. We show how the functions of several such building blocks can be considered in mathematical terms, and discuss resolution of GRNs by both “top down” and “bottom up” approaches. BioEssays 24:1118–1129, 2002. © 2002 Wiley‐Periodicals, Inc. (shrink)

Two reports have shown that mammalian artificial chromosomes (MAC) can be constructed from cloned human centromere DNA and telomere repeats, proving the principle that chromosomes can form from naked DNA molecules transfected into human cells. The MACs were mitotically stable, low copy number and bound antibodies associated with active centromeres. As a step toward second-generation MACs, yeast and bacterial cloning systems will have to be adapted to achieve large MAC constructs having a centromere, two telomeres, and genomic copies of mammalian (...) genes. Available construction techniques are discussed along with a new P1 artificial chromosome (PAC)-derived telomere vector (pTAT) that can be joined to other PACs in vitro, avoiding a cloning step during which large repetitive arrays often rearrange. The PAC system can be used as a route to further define the optimal DNA elements required for efficient MAC formation, to investigate the expression of genes on MACs, and possibly to develop efficient MAC-delivery protocols. BioEssays 1999;21:76–83. © 1999 John Wiley & Sons, Inc. (shrink)

Amyloid beta precursor protein (APP) and prion protein (PrP) are cell membrane elements implicated in neurodegenerative diseases. Both proteins undergo endoproteolysis. Evidence is adduced from the literature hinting that the process in the two proteins could be related, their functions may overlap and their distributions coincide. It is proposed that PrP catalyses its own cleavage, the C-terminal fragment functions as an α secretase and the N-terminal segment chaperones the active site; the α secretase releases anticoagulant and neurotrophic ectodomains from APP. (...) The proposals explain some features of spongiform encephalopathies. BioEssays 23:456–462, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Mutations in the daf-2 and age-1 genes cause constitutive dauer larva formation and double adult life span in C. elegans. Their effect on life span has excited considerable interest and their effect on dauer formation has facilitated rapid progress in their genetic and molecular analysis. Two recent papers12,13 report that daf-2 encodes a member of the insulin-receptor family and that age-1 encodes a PI3 kinase subunit, a second-messenger producing enzyme known to act downstream of the mammalian insulin receptor. These findings (...) provide the first mechanistic insight into the well-established link between metabolism and aging. BioEssays 20:113–115, 1998. © 1998 John Wiley & Sons, Inc. (shrink)

General knowledge of the role of vitamin D3 in human physiology has been shaped by its discovery as a preventive agent of nutritional rickets, a defect in bone development due to inadequate uptake of dietary calcium. Studies on the function of the hormonal form of vitamin D3, 1α,25‐dihydroxyvitamin D3, have been greatly accelerated by the molecular cloning and structural analysis of the vitamin D3 receptor, which is a ligand‐activated regulator of gene transcription. Molecular genetic techniques including genomics have helped reveal (...) that 1α,25‐dihydroxyvitamin D3 can control more than calcium homeostasis. It has widespread effects on cellular differentiation and proliferation, and can modulate immune responsiveness, and central nervous system function. Moreover, accumulating epidemiological and molecular evidence suggests that 1α,25‐dihydroxyvitamin D3 acts as a chemopreventive agent against several malignancies including cancers of the prostate and colon. Here, we survey the most‐recent findings and discuss their implications for the potential therapeutic uses of vitamin D analogues. BioEssays 26:21–28, 2004. © 2003 Wiley Periodicals, Inc. (shrink)

By using instrumentation initially designed for counting white blood cells, sperm counts have been utilized by clinicians since 1929, particularly to evaluate cases of suspected infertility. Although this basic biological parameter might be assumed to be stable over time, several studies over the past 20 years have suggested a decline in sperm count or density. The most controversial of these analyses was published in 1992. A flood of criticism followed this analysis of 61 studies that found a 50% decline in (...) sperm density between 1938 and 1990. Critics suggested that historical methods (of counting sperm or conducting studies) were variable and unreliable, differing from modern methods both qualitatively and quantitatively. To address this issue we analyzed these studies for trends in counting methods or their variability. We found neither. Alternative analyses produced some differences in trend estimates, but statistical factors alone could not account for the total decline in sperm density. We reviewed study populations to identify trends in population characteristics, such as abstinence time, that might explain the decline. However, controlling analytically for such factors only increased the rate of decline. We conclude that historical data on sperm density, despite large random error, are surprisingly reliable. Nonetheless, understanding causes of temporal and geographic differences in sperm density must await contemporary data. BioEssays 21:614–621, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

The ectoplasmic specialization (ES) is a testis‐specific, actin‐based hybrid anchoring and tight junction. It is confined to the interface between Sertoli cells at the blood–testis barrier, known as the basal ES, as well as between Sertoli cells and developing spermatids designated the apical ES. The ES shares features of adherens junctions, tight junctions and focal contacts. By adopting the best features of each junction type, this hybrid nature of ES facilitates the extensive junction‐restructuring events in the seminiferous epithelium during spermatogenesis. (...) For instance, the α6β1‐integrin–laminin 333 complex, which is usually limited to the cell–matrix interface in other epithelia to facilitate cell movement, is a putative apical ES constituent. Furthermore, JAM‐C and CAR, two tight junction integral membrane proteins, are also components of apical ES involving in spermatid orientation. We discuss herein the mechanisms that maintain the cross‐talk between ES and blood–testis barrier to facilitate cell movement and orientation in the seminiferous epithelium. BioEssays 29: 36–48, 2007. © 2006 Wiley Periodicals, Inc. (shrink)

Chromosomes that harbor dominant sex determination loci are predicted to erode over time—losing genes, accumulating transposable elements, degenerating into a functional wasteland and ultimately becoming extinct. The Drosophila melanogaster Y chromosome is fairly far along this path to oblivion. The few genes on largely heterochromatic Y chromosome are required for spermatocyte‐specific functions, but have no role in other tissues. Surprisingly, a recent paper shows that divergent Y chromosomes can substantially influence gene expression throughout the D. melanogaster genome.1 These results show (...) that variation on Y has an important influence on the deployment of the genome. BioEssays 30:409–411, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Together, DNA repair and checkpoint responses ensure the integrity of the genome. Coordination of cell cycle checkpoints and DNA repair are especially important following genotoxic radiation or chemotherapy, during which unusually high loads of DNA damage are sustained. In mammalian cells, the checkpoint kinase, Cds1 (also known as Chk2) is activated by ATM in response to DNA damage. The role of Cds1 as a checkpoint kinase depends on its ability to phosphorylate cell cycle regulators such p53, Cdc25 and Brca1. A (...) role for Cds1 in repair is suggested by the finding that it interacts with the Holliday junction resolving activity Mus81. This review focuses on the many questions generated by recent progress in understanding the function and regulation of human Cds1. BioEssays 24:502–511, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

The RNAi machinery is not only involved with post‐transcriptional degradation of messenger RNAs, but also used for targeting of chromatin changes associated with transcriptional silencing. Two recent papers determine the global patterns of gene expression and chromatin modifications produced by the RNAi machinery in fission yeast.(9, 10) The major sites include the outer centromere repeats, the mating‐type locus and subtelomeric regions. By comparison, studies of Arabidopsis heterochromatin also implicate transposons as a major target for silencing. Analyses of siRNA libraries from (...) Drosophila, nematodes and Arabidopsis indicate that major repeats at centromeres, telomeres and transposable elements are likely targets of RNAi. Also, intergenic regions are implicated as targets in Arabidopsis. BioEssays 27:1209–1212, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Several ant species are known with genetic effects on caste determination but, for termites, the role of environment has been assumed to be omnipotent. Now Hayashi et al. report that commitment to the nymph and worker pathways in Reticulitermes speratus follows a simple model involving two alleles at a sex‐linked locus.1 The spread of this system of genetic caste determination seems best explained by selection at the colony level. This remarkable system may be widely applicable throughout termites, although it cannot (...) be universal, and may provide a window into causal aspects of the molecular biology of caste determination. BioEssays 30:299–302, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Angiogenesis is central to both the growth and metastasis of solid tumours. Anti‐angiogenic strategies result in blood vessel regression accompanied by tumour cell apoptosis. Radiotherapy and many chemotherapeutic agents kill tumours by inducing apoptotic cell death. We propose that, in addition to its role as an angiogenic factor, vascular endothelial growth factor (VEGF) can act as a survival factor for tumour cells protecting them from apoptosis. Thus anti‐angiogenics, in particular those directed against VEGF, have multiple anti‐tumour effects. We suggest that (...) anti‐VEGF strategies prevent vessel growth and block a tumour cell survival factor, VEGF, rendering tumour cells more sensitive to chemotherapy and radiotherapy. In addition, as chemotherapy and radiotherapy have been shown to increase VEGF expression, anti‐VEGF strategies may overcome therapy‐ induced tumour cell resistance. BioEssays 24:280–283, 2002. © 2002 Wiley Periodicals, Inc.; DOI 10.1002/bies.10043. (shrink)

Eukaryotic chromosomes undergo dramatic changes and movements during mitosis. These include the individualization and compaction of the two copies of replicated chromosomes (the sister chromatids) and their subsequent segregation to the daughter cells. Two multisubunit protein complexes termed ‘cohesin’ and ‘condensin’, both composed of SMC (Structural Maintenance of Chromosomes) and kleisin subunits, have emerged as crucial players in these processes. Cohesin is required for holding sister chromatids together whereas condensin, together with topoisomerase II, has an important role in organizing individual (...) axes of sister chromatids prior to their segregation during anaphase. SMC and kleisin complexes also regulate the compaction and segregation of bacterial nucleoids. New research suggests that these ancient regulators of chromosome structure might function as topological devices that trap chromosomal DNA between 50 nm long coiled coils. BioEssays 25:1178–1191, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

In this essay, we consider helicases, defined as enzymes that use the free energies of binding and hydrolysis of ATP to drive the unwinding of double‐stranded nucleic acids, and ask how they function within, and are “coupled” to, the macromolecular machines of gene expression. To illustrate the principles of the integration of helicases into such machines, we consider the macromolecular complexes that direct and control DNA replication and DNA‐dependent RNA transcription, and use these systems to illustrate how machines centered around (...) coupled polymerase–helicase systems can be regulated by small changes in the interactions of their functional components. BioEssays 25:1168–1177, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

In this paper, I respond to papers on my Manifest Rationality (2000) by Leo Groarke, Hans Hansen, David Hitchcock, and Christopher Tindale presented at the meetings of the Ontario Philosophical Society, October 2000. From the many useful challenges they have directed at my position, I have chosen to focus on two. The dominant issue raised by their papers concerns my definition of argument, and particularly problems with the idea of a dialectical tier. I have selected that as the first (...) strand. Second, several have raised questions that deal with the relationship between logic, rhetoric and dialectic. That is the second strand. (shrink)

The "tree of life" iconography, representing the history of life, dates from at least the latter half of the 18th century, but evolution as the mechanism providing this bifurcating history of life did not appear until the early 19th century. There was also a shift from the straight line, scala naturae view of change in nature to a more bifurcating or tree-like view. Throughout the 19th century authors presented tree-like diagrams, some regarding the Deity as the mechanism of change while (...) others argued for evolution. Straight-line or anagenetic evolution and bifurcating or cladogenetic evolution are known in biology today, but are often misrepresented in popular culture, especially with anagenesis being confounded with scala naturae. Although well known in the mid 19th century, the geologist Edward Hitchcock has been forgotten as an early, if not the first author to publish a paleontologically based "tree of life" beginning in 1840 in the first edition of his popular general geology text Elementary Geology. At least 31 editions were published and those between 1840 and 1859 had this "paleontological chart" showing two trees, one for fossil and living plants and another for animals set within a context of geological time. Although the chart did not vary in later editions, the text explaining the chart did change to reflect newer ideas in paleontology and geology. Whereas Lamarck, Chambers, Bronn, Darwin, and Haeckel saw some form of transmutation as the mechanism that created their "trees of life," Hitchcock, like his contemporaries Agassiz and Miller, who also produced "trees of life," saw a deity as the agent of change. Through each edition of his book Hitchcock denounced the newer transmutationist hypotheses of Lamarck, then Chambers, and finally Darwin in an 1860 edition that no longer presented his tree-like "paleontological chart.". (shrink)

The sex chromosomes of many species differ in dosage but the total gene expression output is similar, a phenomenon referred to as dosage compensation. Previously, diverse mechanisms were postulated to account for compensation in distantly related taxa. However, two recent papers present evidence that dosage compensation in Drosophila, mammals and nematodes share the property that there is an approximately two‐fold upregulation of the single active X chromosome in each case.1,2 The results suggest that a common mechanism might operate in these (...) different cases. BioEssays 28: 565–568, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

In the recent past, several papers have pointed to the possibility that tumour removal generates a permissive environment in which tumour growth is potentiated. This phenomenon has been coined “perioperative tumour growth” and whilst it represents a departure in terms of our attitude to the surgical process, this concept was first hinted at by Paget1Sir James Paget (1814–1899) was a surgeon and physiologist who is widely held (along with Rudolph Virchow) to be the father of the science of pathology. Paget (...) described Paget's disease of the nipple as well as Paget's disease of bone. himself. Despite this, the time interval immediately before and after cancer surgery (i.e. the perioperative period) remains an underutilised interval during which chemotherapeutic regimens are rarely implemented. Herein, we present a summarised review of the literature that supports the concept that tumour removal may potentiate the growth of residual neoplastic disease. We also outline current knowledge regarding underlying mechanisms and in this manner highlight potential therapeutic entry points. Finally, we emphasise the urgent need for trials of agents that could protect patients against the harmful host–tumour interactions that may occur during the perioperative period. BioEssays 28: 433–437, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

The discussion over the roles of genes and environment on the phenotypical specification of organisms has held a central role in science philosophy since the late 19th century and has re‐emerged in today's debate over genetic determinism and developmental plasticity. In fin‐de‐siecle Vienna, this debate coincided with a philosophical debate over empiricism/materialism versus idealism/vitalism. Turn‐of‐the‐century Vienna's highly interdisciplinary environment was also the birthplace for the model system of the un‐opposed molar. The un‐opposed molar system features new tissue formation at the (...) roots of teeth and tooth drift once opposing teeth are lost. The un‐opposed molar model system was revived by a group of Viennese scientists who left Vienna during the Nazi period to address Vienna's questions about evolution and heredity and about genes and environment in Chicago's post‐WWII scientific exile community. Here we are using the colorful history of the un‐opposed molar to investigate the role of culture and method in the scientific evolution of a model system. BioEssays 29:819–830, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

The evolutionarily conserved Notch signaling pathway regulates a broad spectrum of cell fate decisions and differentiation processes during fetal and postnatal life. It is involved in embryonic organogenesis as well as in the maintenance of homeostasis of self‐renewing systems. In this article, we review the role of Notch signaling in the hematopoietic system with particular emphasis on lymphocyte development and highlight the similarities in Notch function between Drosophila and mammalian differentiation processes. Recent studies indicating that aberrant NOTCH signaling is frequently (...) linked to the induction of T leukemia in humans will also be discussed. BioEssays 27:1117–1128, 2005. © 2005 Wiley Periodicals, Inc. (shrink)