Research findings on addiction are contradictory. According to biographical records and widely used diagnostic manuals, addicts use drugs compulsively, meaning that drug use is out of control and independent of its aversive consequences. This account is supported by studies that show significant heritabilities for alcoholism and other addictions and by laboratory experiments in which repeated administration of addictive drugs caused changes in neural substrates associated with reward. Epidemiological and experimental data, however, show that the consequences of drug consumption can significantly (...) modify drug intake in addicts. The disease model can account for the compulsive features of addiction, but not occasions in which price and punishment reduced drug consumption in addicts. Conversely, learning models of addiction can account for the influence of price and punishment, but not compulsive drug taking. The occasion for this target article is that recent developments in behavioral choice theory resolve the apparent contradictions in the addiction literature. The basic argument includes the following four statements: First, repeated consumption of an addictive drug decreases its future value and the future value of competing activities. Second, the frequency of an activity is a function of its relative (not absolute) value. This implies that an activity that reduces the values of competing behaviors can increase in frequency even if its own value also declines. Third, a recent experiment (Heyman & Tanz 1995) shows that the effective reinforcement contingencies are relative to a frame of reference, and this frame of reference can change so as to favor optimal or suboptimal choice. Fourth, if the frame of reference is local, reinforcement contingencies will favor excessive drug use, but if the frame of reference is global, the reinforcement contingencies will favor controlled drug use. The transition from a global to a local frame of reference explains relapse and other compulsive features of addiction. (shrink)

The purpose of this paper is to show the agreement of Camus and Aristotle on the cultural function of the art community, in particular their criticism of what should be called barbarian or nihilistic practices of art. Camus' art and criticism have been frequent targets of modern critics, but his point is and would be that such critics have the wrong idea of the purpose of art. His answer to such critics and the parallelism of his ideas with Aristotle's (...) criticism of barbarian culture, show that the real issue between Camus and his critics is cultural. (shrink)

This reading of Plato's Ion shows that the philosophic action mimed and engendered by the dialogue thoroughly reverses its (and Plato's) often supposed philosophical point, revealing that poetry is just as defensible as philosophy, and only in the same way. It is by Plato's indirections we find true directions out: the war between philosophy and poetry is a hoax on Plato's part, and a mistake on the part of his literalist readers. The dilemma around which the dialogue moves is false, (...) and would have been recognized as such by Plato's contemporaries. Further, it is intrinsically related to a false, but popular, view of language. So the way out of the false dilemma of the dialogue is the way out of the war between philosophy and poetry, and also makes one see what is false about the view of language which makes such war plausible. (shrink)

The article presents three models of radical cultural practice: Adorno’s dissonant modernism, Brecht’s “functional transformation” or “re-functioning” of institutions through estrangement and dialectical realism, and Debord’s Situationist détournement of art, aiming to rupture and decolonize naturalized everyday life. The three models all begin with a critical appropriation of the traditions of art and aims at resisting the social power that passes through art, as an institutionalized field of production and activity. Each of the three modes establishes a set of productive (...) strategies. (shrink)

The question of whether (and, within the believing communities, the agreement that) scripture is a source and canon for moral discernment and judgment must be distinguished from the question of what this source provides or how this canon functions as a norm.1.

ABSTRACT Clinicians, researchers and the informed public have come to view addiction as a brain disease. However, in nature even extreme events often reflect normal processes, for instance the principles of plate tectonics explain earthquakes as well as the gradual changes in the face of the earth. In the same way, excessive drug use is predicted by general principles of choice. One of the implications of this result is that drugs do not turn addicts into compulsive drug users; they retain (...) the capacity to say ?no?. In support of the logical implications of the choice theory approach to addiction, research reveals that most addicts quit using drugs by about age 30, that most quit without professional help, that the correlates of quitting are the correlates of decision making, and, according to the most recent epidemiological evidence, the probability of quitting remains constant over time and independent of the onset of dependence. This last result implies that, after an initial period of heavy drug use, remission is independent of any further exposure to drugs. In short, there is much empirical support for the claim that addiction emerges as a function of the rules of everyday choice. (shrink)

The purpose of this paper is to show the agreement of Camus and Aristotle on the cultural function of the art community, in particular their criticism of what should be called barbarian or nihilistic practices of art. Camus' art and criticism have been frequent targets of modern critics, but his point is and would be that such critics have the wrong idea of the purpose of art. His answer to such critics and the parallelism of his ideas with Aristotle's (...) criticism of barbarian culture, show that the real issue between Camus and his critics is cultural. (shrink)

Based on brain imaging findings, we present a model according to which addiction emerges as an imbalance in the information processing and integration among various brain circuits and functions. The dysfunctions reflect (a) decreased sensitivity of reward circuits, (b) enhanced sensitivity of memory circuits to conditioned expectations to drugs and drug cues, stress reactivity, and (c) negative mood, and a weakened control circuit. Although initial experimentation with a drug of abuse is largely a voluntary behavior, continued drug use can eventually (...) impair neuronal circuits in the brain that are involved in free will, turning drug use into an automatic compulsive behavior. The ability of addictive drugs to co‐opt neurotransmitter signals between neurons (including dopamine, glutamate, and GABA) modifies the function of different neuronal circuits, which begin to falter at different stages of an addiction trajectory. Upon exposure to the drug, drug cues or stress this results in unrestrained hyperactivation of the motivation/drive circuit that results in the compulsive drug intake that characterizes addiction. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Reviewed by:Mimesis: Culture, Art, SocietyGene FendtMimesis: Culture, Art, Society, by Gunter Gebauer and Christoph Wulf; translated by Don Reneau; 400 pp. Berkeley: University of California Press, 1995, $45.00 cloth, $18.00 paper.The purpose of this book is to develop “a historical reconstruction of important phases in the development of mimesis” (p. 1) from a brief discussion of its pre-Platonic Greek significance through contemporary thinkers. It is, then, not strictly a (...) philosophical text, as are most of the texts and authors the book takes up. It is, however, a significant effort in the history of ideas, and as such it is shot through with traces of the traditional tropes, shaping power, ideology, and even social relations of that discipline, particularly as it is practiced in the venerable school of German scholarship. That is, the structure, tone, and argument of the book are shaped mimetically. This book’s problematic is, then, not simply historical, as Republic’s problem with the poets is not simply philosophical. Rather, both books partake of mimesis, even while each one aims to criticize or set forth the concept’s historical development.Let this stand as notice of a deep philosophical problem with the method of historical criticism. In fairness we should note that the authors are not unconscious of their difficulty here: “The fact that mimesis cannot be represented without the use of mimetic processes poses the fundamental problem of theory formation in reference to our object. What is the relation between the representational and the represented world? Is the representation of representation structurally equivalent to simple representation?” (p. 21). The authors hope to moot the power of those questions, if not the questions themselves, by attending “first of all to representations of mimesis found in texts best selected for that purpose and only afterward begin to offer considerations of a more generalizing nature” (p. 21). Their reasoning and choice of texts here is the traditional trope of the discipline: a mimema. Among other things, this methodos requires that the authors treat Girard as developing a “literary critical examination of [mimesis in] nineteenth and twentieth century novels” (p. 359n1) and a “new ordering of nineteenth century social relations” (p. 235), rather than, as he claims, a comprehensive anthropological thesis. At least, this method requires treating the former as essential, and the latter as less justifiable, for if Girard’s anthropological thesis about mimesis were justifiable a history of the idea of mimesis would be merely a heresiology. This problem can be restated mutatis mutandis for such thinkers as Plato and Augustine, whose theses—if they have theses—about mimesis are deeply anthropological.Two further questions arise early on and remain at the end. If, as the authors hold (and show), “the concept of mimesis necessarily loses its intellectual centrality with the rise of rational thought,” so much so that “the field of art, which comes to be regarded in the process as autonomous, undergoes a complete and fundamental restructuring” (p. 3), must we not begin to [End Page 199] suspect—as recent philosophers like Derrida attempt to show—that there is a dialectical relationship between the intentional, truth-functional relations of modern rational thought and the mimetic, unformalizable and “ambivalent” (pp. 2–3) processes of mimesis? Rather than conclude that “the question what is mimesis? is one which demonstratively leads to error” (p. 309), does it not begin to seem that intentional representation, as most visible in science, and mimetic assimilations, as most obviously effective in art, are together the necessary dialectical elements of culture, art and science? While it seems that the rise of rational scientific thought pushes mimesis to the social fringes of the arts, isn’t scientific activity and writing still just as much subject, and just as much a product, of the power of mimesis as art? Similarly art is just as bound as science to “probability” or “the convincing impossibility,” to recall Aristotle. This idea is not entirely foreign to the book; it appears subliminally as a plausible explication of the work of theorists like Benjamin and Adorno (pp. 267–93).The third difficulty is a question about selection. As in Auerbach’s renowned precursor, Wulf... (shrink)

After gene duplication, mutations cause the gene copies to diverge. The classical model predicts that these mutations will generally lead to the loss of function of one gene copy; rarely, new functions will be created and both duplicate genes are conserved. In contrast, under the subfunctionalization model both duplicates are preserved due to the partition of different functions between the duplicates. A recent study(1) provides support for the subfunctionalization model, identifying several expressed gene duplicates common (...) to humans and mice that contain regions conserved in one duplicate but variable in the other (and vice versa). We discuss both the methodology used in this study and also how gene phylogeny may lead to additional evidence for the importance of subfunctionalization in the evolution of new genes. BioEssays 23:873–876, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

It is tempting to invoke organismal selection as perpetually optimizing the function of any given gene. However, natural selection can drive genic functional change without improvement of biochemical activity, even to the extinction of gene activity. Detrimental mutations can creep in owing to linkage with other selectively favored loci. Selection can promote functional degradation, irrespective of genetic drift, when adaptation occurs by loss of gene function. Even stabilizing selection on a trait can lead to divergence (...) of the underlying molecular constituents. Selfish genetic elements can also proliferate independent of any functional benefits to the host genome. Here we review the logic and evidence for these diverse processes acting in genome evolution. This collection of distinct evolutionary phenomena – while operating through easily understandable mechanisms – all contribute to the seemingly counterintuitive notion that maintenance or improvement of a gene's biochemical function sometimes do not determine its evolutionary fate. (shrink)

Despite decades of research, morphogenesis along the various body axes remains one of the major mysteries in developmental biology. A milestone in the field was the realisation that a set of closely related regulators, called Hox genes, specifies the identity of body segments along the anterior–posterior (AP) axis in most animals. Hox genes have been highly conserved throughout metazoan evolution and code for homeodomain‐containing transcription factors. Thus, they exert their function mainly through activation or repression of downstream genes. However, (...) while much is known about Hox gene structure and molecular function, only a few target genes have been identified and studied in detail. Our knowledge of Hox downstream genes is therefore far from complete and consequently Hox‐controlled morphogenesis is still poorly understood. Genome‐wide approaches have facilitated the identification of large numbers of Hox downstream genes both in Drosophila and vertebrates, and represent a crucial step towards a comprehensive understanding of how Hox proteins drive morphological diversification. In this review, we focus on the role of Hox genes in shaping segmental morphologies along the AP axis in Drosophila, discuss some of the conclusions drawn from analyses of large target gene sets and highlight methods that could be used to gain a more thorough understanding of Hox molecular function. In addition, the mechanisms of Hox target gene regulation are considered with special emphasis on recent findings and their implications for Hox protein specificity in the context of the whole organism. BioEssays 30:965–979, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

How transcription factors achieve their in vivo specificities is a fundamental question in biology. For the Homeotic Complex (HOM/Hox) family of homeoproteins, specificity in vivo is likely to be in part determined by subtle differences in the DNA binding properties inherent in these proteins. Some of these differences in DNA binding are due to sequence differences in the N‐terminal arms of HOM/Hox homeodomains. Evidence also exists to suggest that cofactors can modify HOM/Hox function by cooperative DNA binding interactions. The (...) Drosophila homeoprotein extradenticle (exd) is likely to be one such cofactor. In HOM/Hox proteins, both the conserved ‘YPWM’ peptide motif and the homeodomain are important for interacting with exd. Although exd provides part of the answer as to how specificity is achieved, there may be additional cofactors and mechanisms that have yet to be identified. (shrink)

Graphical AbstractMuller found halving gene dosage, as in males with one X chromosome, did not affect specific gene function. Why then was dosage “compensated?” This paradox was solved by invoking collective gene functions such as self/not self discrimination afforded by protein aggregation pressure. This predicts female susceptibility to autoimmune disease.

We have achieved a residue‐level resolution of genetic interaction mapping – a technique that measures how the function of one gene is affected by the alteration of a second gene – by analyzing point mutations. Here, we describe how to interpret point mutant genetic interactions, and outline key applications for the approach, including interrogation of protein interaction interfaces and active sites, and examination of post‐translational modifications. Genetic interaction analysis has proven effective for characterizing cellular processes; however, to (...) date, systematic high‐throughput genetic interaction screens have relied on gene deletions or knockdowns, which limits the resolution of gene function analysis and poses problems for multifunctional genes. Our point mutant approach addresses these issues, and further provides a tool for in vivo structure‐function analysis that complements traditional biophysical methods. We also discuss the potential for genetic interaction mapping of point mutations in human cells and its application to personalized medicine. (shrink)

Plant MADS‐box genes encode transcriptional regulators that are critical for a number of developmental processes. In the angiosperms (the flowering plants), these include the specification of floral organ identities, flowering time and fruit development. It appears that the MADS box gene family has undergone considerable gene duplication and sequence divergence within the angiosperms. Here I discuss the possibility that these events have allowed the recruitment of these genes to new developmental pathways in particular angiosperm lineages. Recent analyses of (...) sequence changes, expression patterns and, in a few cases, gene function are beginning to provide tantalizing evidence for deciphering when and how such genetic diversification has led to particular morphological innovations. In the future, comparative studies of large numbers of species will be required to assess the extent of such variation as well as to fully understand the mechanisms by which evolution of these developmental regulators has played a role in shaping new morphologies. BioEssays 25:637–646, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

The history of research on pseudoalleles, closely linked genes that have similar functions, is rich and complex. Because pseudoalleles’ proximity on the chromosome makes their distinction by the complementation tests traditionally used by geneticists difficult, and because they have similar functions, they were initially often considered as allelic forms of the same gene, hence their name. The Hox cluster is an emblematic example of a pseudoallelic gene complex. The first observations of pseudoalleles were made very early but remained (...) puzzling until a simple model explaining their formation and characteristics emerged in the middle of the 1930s. This model suggested that pseudoalleles originated by gene.. (shrink)

At the beginning of the 21st century, biology will try to address the function of a large number of new genes. From the perspective of technologies applied today to functional genomics, this task appears to be more complex than the effort invested in the sequencing of the human genome. Conceptually, a high-throughput approach permitting correlation between newly discovered genes and functional properties of their protein products has yet to be developed. To address relationships between tens of thousands of genes (...) and their cognate proteins, novel interdisciplinary technologies need to emerge. In this paper, a new idea of immunomics is presented and an experimental strategy is outlined to circumvent some of the restrictions associated with methodologies currently in use. It is proposed that cloned segments of genomic DNA are used for genetic immunization to obtain a large collection of antibodies, and to generate microarrays of these antibodies for tracing differentially expressed cellular proteins. (shrink)

It is widely accepted that the way information transfers across networks depends importantly on the structure of the network. Here, we show that the mechanism of information transfer is crucial: in many respects the effect of the specific transfer mechanism swamps network effects. Results are demonstrated in terms of three different types of transfer mechanism: germs, genes, and memes. With an emphasis on the specific case of transfer between sub-networks, we explore both the dynamics of each of these across networks (...) and a measure of their comparative fitness. Germ and meme transfer exhibit very different dynamics across linked networks. For germs, measured in terms of time to total infection, network type rather than degree of linkage between sub-networks is the primary factor. For memes or belief transfer, measured in terms of time to consensus, it is the opposite: degree of linkage trumps network type in importance. The dynamics of genetic information transfer is unlike either germs or memes. Transfer of genetic information is robust across network differences to which both germs and memes prove sensitive. We also consider function: how well germ, gene, and meme transfer mechanisms can meet their respective objectives of infecting the population, mixing and transferring genetic information, and spreading a message. A shared formal measure of fitness is introduced for purposes of comparison, again with an emphasis on linked sub-networks. Meme transfer proves superior to transfer by genetic reproduction on that measure, with both memes and genes superior to infection dynamics across all networks types. What kinds of network structure optimize fitness also differ among the three. Both germs and genes show fairly stable fitness with added links between sub-networks, but genes show greater sensitivity to the structure of sub-networks at issue. Belief transfer, in contrast to the other two, shows a clear decline in fitness with increasingly connected networks. When it comes to understanding how information moves on networks, our results indicate that questions of information dynamics on networks cannot be answered in terms of networks alone. A primary role is played by the specific mechanism of information transfer at issue. We must first ask about how a particular type of information moves. (shrink)

The explosion in sequencing technologies has provided us with an instrument to describe mammalian transcriptomes at unprecedented depths. This has revealed that alternative splicing is used extensively not only to generate protein diversity, but also as a means to regulate gene expression post‐transcriptionally. Intron retention (IR) is overwhelmingly perceived as an aberrant splicing event with little or no functional consequence. However, recent work has now shown that IR is used to regulate a specific differentiation event within the haematopoietic system (...) by coupling it to nonsense‐mediated mRNA decay (NMD). Here, we highlight how IR and, more broadly, alternative splicing coupled to NMD (AS‐NMD) can be used to regulate gene expression and how this is deregulated in disease. We suggest that the importance of AS‐NMD is not restricted to the haematopoietic system but that it plays a prominent role in other normal and aberrant biological settings. (shrink)

Nicotinic acetylcholine receptors (nAChRs) are ligand‐gated ion channels that bring about a diversity of fast synaptic actions. Analysis of the Caenorhabditis elegans genome has revealed one of the most‐extensive and diverse nAChR gene families known, consisting of at least 27 subunits. Striking variation with possible functional implications has been observed in normally conserved motifs at the acetylcholine‐binding site and in the channel‐lining region. Some nAChR subunits are particular to neurons whilst others are present in both neurons and muscles. The (...) localization of subunits in non‐synaptic regions suggests novel roles for nAChRs. Genetic and heterologous expression studies have identified a subset of nAChR subunits that are important drug targets while the study of mutants has identified genes functionally‐linked to nAChRs. Future studies using C. elegans offer the prospect of increasing our understanding of the functional diversity of a complex nAChR gene family as well as addressing the role of nAChRs and associated proteins in human disorders. BioEssays 26:39–49, 2004.© 2003 Wiley Periodicals, Inc. (shrink)

Hereditary retinal degeneration due to mutations in visual genes may be amenable to therapeutic interventions that modulate, either positively or negatively, the amount of protein product. Some of the proteins involved in phototransduction are rapidly moved by a lightdependent mechanism between the inner segment and the outer segment in rod photoreceptor cells, and this phenomenon is important in phototransduction.

Understanding the dynamics of information is crucial to many areas of research, both inside and outside of philosophy. Using computer simulations of three kinds of information, germs, genes, and memes, we show that the mechanism of information transfer often swamps network structure in terms of its effects on both the dynamics and the fitness of the information. This insight has both obvious and subtle implications for a number of questions in philosophy, including questions about the nature of information, whether there (...) is genetic information, and how to arrange scientific communities. (shrink)

The term functional domain is often used to describe the region containing the cis acting sequences that regulate a gene locus. “Strong” domain models propose that the domain is a spatially isolated entity consisting of a region of extended accessible chromatin bordered by insulators that have evolved to act as functional boundaries. However, the observation that independently regulated loci can overlap partially or completely raises questions about functional requirements for physically isolated domain structures. An alternative model, the “weak” domain (...) model, proposes that domain structure is determined by the distribution of binding sites for positively acting factors, without a requirement for functional boundaries. The domain would effectively be the region that contains these factor-binding sites. Specificity of promoter-enhancer interactions would play a major role in maintaining the functional autonomy of adjacent genes. Sequences that interfere with these interactions (frequently characterised as insulators) would be selected against if they occurred within the domain but not at the edges, or in the interdomain regions. As a result, insulators would often be found near the borders of domains without necessarily being selected to act as boundaries. BioEssays 22:657–665, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

Genes are gained and lost over the course of evolution. A recent study found that over 1,800 new genes have appeared during primate evolution and that an unexpectedly high proportion of these genes are expressed in the human brain. But what are the molecular functions of newly evolved genes and what is their impact on an organism's fitness? The acquisition of new genes may provide a rich source of genetic diversity that fuels evolutionary innovation. Although gene manipulation experiments are (...) not feasible in humans, studies in model organisms, such as Drosophila melanogaster, have shown that new genes can quickly become integrated into genetic networks and become essential for survival or fertility. Future studies of new genes, especially chimeric genes, and their functions will help determine the role of genetic novelty in the adaptation and diversification of species. (shrink)

Background: We define compassion as an enduring disposition that centers upon empathetic concern for another person's suffering and the motivation to act to alleviate it. The contribution of specific candidate genes to the development of dispositional compassion for others is currently unknown. We examine candidate genes in the oxytocin and dopamine signaling pathways.Methods: In a 32-year follow-up of the Young Finns Study, we examined with multiple indicators latent growth curve modeling the molecular genetic underpinnings of dispositional compassion for others across (...) the life span. We selected five single nucleotide polymorphisms whose functions are known in humans: rs2268498, rs3796863, rs1800497, rs4680, and rs1611115. Compassion was measured with Cloninger's Temperament and Character Inventory on three repeated observations spanning 15 years. Differences between gender were tested.Results: We did not find an effect of the five SNPs in oxytocin and dopamine pathway genes on the initial levels of dispositional compassion for others. Individuals who carry one or two copies of the T-allele of DBH rs1611115, however, tend to increase faster in compassion over time than those homozygotes for the C-allele, b = 0.063. This effect was largely driven by male participants, 0.206, and was not significant in female participants when analyzed separately.Conclusions: Men who are known to have, on average, lower compassion than women seem to reduce this difference over time if they carry the T-allele of DBH rs1611115. The direction of the association indicates that dopamine signaling activity rather than overall dopamine levels might drive the development of compassion. (shrink)

The α‐actinins are an ancient family of actin‐binding proteins that play structural and regulatory roles in cytoskeletal organisation and muscle contraction. α‐actinin‐3 is the most‐highly specialised of the four mammalian α‐actinins, with its expression restricted largely to fast glycolytic fibres in skeletal muscle. Intriguingly, a significant proportion (∼18%) of the human population is totally deficient in α‐actinin‐3 due to homozygosity for a premature stop codon polymorphism (R577X) in the ACTN3 gene. Recent work in our laboratory has revealed a strong (...) association between R577X genotype and performance in a variety of athletic endeavours. We are currently exploring the function and evolutionary history of the ACTN3 gene and other α‐actinin family members. The α‐actinin family provides a fascinating case study in molecular evolution, illustrating phenomena such as functional redundancy in duplicate genes, the evolution of protein function, and the action of natural selection during recent human evolution. BioEssays 26:786–795, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Somatic complementation by fusion of two mutant cells and mixing of their cytoplasms occurs when the genetic defect of one fusion partner is cured by the functional gene product provided by the other. We have found that complementation of mutational defects in the network mediating stimulus‐induced commitment and sporulation of Physarum polycephalum may reflect time‐dependent changes in the signaling state of its molecular building blocks. Network perturbation by fusion of mutant plasmodial cells in different states of activation, and the (...) time‐resolved analysis of somatic complementation effects can be used to systematically probe network structure and dynamics. Time‐resolved somatic complementation quantitatively detects regulatory interactions between the functional modules of a network, independent of their biochemical composition or subcellular localization, and without being limited to direct physical interactions. BioEssays 25:950–960, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

In this paper I begin by examining a particularly disturbing eliminativist argument from Evelyn Fox Keller against the continued use of the very concept of the gene. If Fox Keller’s argument were to work, then any attempt to continue with or attempt to revise behavioral genetics would be doomed. In the course of replying to Fox Keller’s argument a revised, functional concept of the gene is presented and defending. Using this revised conception of the gene I then (...) consider how appeal to a functional approach to the gene can itself lead to a more general functionalist revision of the basic behavioral genetics project. In the third part of the paper I then turn to examining the advantages with respect to scientific explanation that such a functionalist account can provide. And, I end by considering how such an account might provide some help in dealing with additional ethical worries, including additional ethical arguments from Fox Keller against the continued use of the concept of the gene as well as ethical concerns that have been raised regarding behaviorally designed babies. (shrink)

Amyloid-beta peptide plaque in the brain is the primary diagnostic criterion of Alzheimer's disease . The physiological role of Abeta are poorly understood. We have previously determined an Abeta interacting domain in the promoters of AD-associated genes . This AbetaID interacts in a DNA sequence-specific manner with Abeta. We now demonstrate novel Abeta activity as a possible transcription factor. Herein, we detected Abeta-chromatin interaction in cell culture by ChIP assay. We observed that human neuroblastoma cells treated with FITC conjugated Abeta1-40 (...) localized Abeta to the nucleus in the presence of H2O2-mediated oxidative stress. Furthermore, primary rat fetal cerebrocortical cultures were transfected with APP and BACE1 promoter-luciferase fusions, and rat PC12 cultures were transfected with polymorphic APP promoter-CAT fusion clones. Transfected cells were treated with different Abeta peptides and/or H2O2. Abeta treatment of cell cultures produced a DNA sequence-specific response in cells transfected with polymorphic APP clones. Our results suggest the Abeta peptide may regulate its own production through feedback on its precursor protein and BACE1, leading to amyloidogenesis in AD. (shrink)

Contrary to Müller's claims, and in support of modular theories, genetic factors play a substantial and significant role in language. The finding that some children with specific language impairment (SLI) have nonlinguistic impairments may reflect improper diagnosis of SLI or impairments that are secondary to linguistic impairments. Thus, such findings do not argue against the modularity thesis. The lexical/functional distinction appears to be innate and specifically linguistic and could be instantiated in either symbolic or connectionist systems.

In the last few years, the molecular and genetic nature of the granulocyte colonystimulating factor, which controls proliferation and differentiation of neutrophils, has been characterized. Recent clinical application of G‐CSF proves that this hormone is effective in the treatment of patients suffering from neutropenia.

Mammals have an XX:XY system of chromosomal sex determination in which a small heterochromatic Y controls male development. The Y contains the testis determining factor SRY, as well as several genes important in spermatogenesis. Comparative studies show that the Y was once homologous with the X, but has been progressively degraded, and now consists largely of repeated sequences as well as degraded copies of X linked genes. The small original X and Y have been enlarged by cycles of autosomal addition (...) to one partner, recombination onto the other and continuing attrition of the compound Y. This addition–attrition hypothesis predicts that the pseudoautosomal region of the human X is merely the last relic of the latest addition. Genes (including SRY) on the conserved or added region of the Y evolved functions in male sex determination and differentiation distinct from the general functions of their X‐linked partners. Although the gonadogenesis pathway is highly conserved in vertebrates, its control has probably changed radically and rapidly in vertebrate – even mammalian – evolution. (shrink)

Large protein assemblies are usually the effectors of major cellular processes. The intricate cell homeostasis network is divided into numerous interconnected pathways, each controlled by a set of protein machines. One of these master regulators is the CCR4‐NOT complex, which ultimately controls protein expression levels. This multisubunit complex assembles around a scaffold platform, which enables a wide variety of well‐studied functions from mRNA synthesis to transcript decay, as well as other tasks still being identified. Solving the structure of the entire (...) CCR4‐NOT complex will help to define the distribution of its functions. The recently published three‐dimensional reconstruction of the complex, in combination with the known crystal structures of some of the components, has begun to address this. Methodological improvements in structural biology, especially in cryoelectron microscopy, encourage further structural and protein‐protein interaction studies, which will advance our comprehension of the gene expression machinery. (shrink)

It is often overlooked that, in addition to the integrity of protein‐coding sequences (PCSs), human health is crucially linked to the normal expression of genes by cis‐regulatory sequences (CRSs). These CRSs often lie at some considerable distance from the PCSs whose expression they control and often within other genes. The resulting gene interdigitation can make long‐range CRS identification and characterisation difficult. We propose that the need to conserve long‐range CRSs in cis with their target PCSs through evolution, in combination (...) with gene interdigitation and co‐regulation of many genes by individual CRSs, has contributed to the persistence of conserved synteny blocks between diverse species. We further hypothesise that examination of the varying extents of synteny blocks between multiple species in combination with phylogenetic footprinting to find CRSs might provide important clues to the existence of crucial functional CRS–PCS linkages. Identifying CRS–PCS linkages crucial to human health will lead to a better understanding of how their disruption by CRS mutation or chromosome translocation might contribute to many distressing human diseases. BioEssays 26:1217–1224, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

The powerful combination of genetic, developmental and molecular approaches possible with the fruit fly, Drosophila melanogaster, has led to a profound understanding of the genetic control of early developmental events. However, Drosophila is a highly specialized long germ insect, and the mechanisms controlling its early development may not be typical of insects or Arthropods in general. The beetle, Tribolium castaneum, offers a similar opportunity to integrate high resolution genetic analysis with the developmental/molecular approaches currently used in other organisms. Early results (...) document significant differences between insect orders in the functions of genes responsible for establishing developmental commitments. (shrink)

The c‐Jun N‐terminal kinases (JNKs) are members of the mitogen‐activated protein kinase (MAPK) family. In mammalian genomes, three genes encode the JNK family. To evaluate JNK function, mice have been created with deletions in one or more of three Jnk genes. Initial studies on jnk1−/− or jnk2−/− mice have shown roles for these JNKs in the immune system whereas studies on jnk3−/− mice have highlighted roles for JNK3 in the nervous system. Further studies have highlighted the contributions of JNK1 (...) and/or JNK2 to a range of biological and pathological processes. These include bone remodelling and joint disease, inflammatory and autoimmune diseases, obesity, diabetes, cardiovascular disease, liver disease and tumorigenesis in addition to effects in neurons. These results emphasise the differences in the roles played by JNK isoforms in vivo and suggest that the design of JNK inhibitors for subsequent therapeutic uses may benefit from selective inhibition of individual JNK isoforms. BioEssays 28: 923–934, 2006. © 2006 Wiley periodicals, Inc. (shrink)