The transition of gene switch induced by external noises and external signals is investigated in the genetic regulatory system. Results show that the state-to-state transition of gene switch as well as resonant behaviors, such as the explicit coherence resonance, implicit coherence resonance and control parameter coherence biresonance, can appear when noises are injected into the genetic regulatory system. The ECR is increased with the increase of the control parameter value when starting from the supercritical Hopf bifurcation parameter point, (...) and there exists a critical control parameter value for the occurrence of ECR. However, the ICR is decreased as the control parameter value is increased when starting from the subcritical Hopf bifurcation point. In particular, the coherence of ECR is higher and more sensitive to noise than that of ICR. When an external signal is introduced into the system, the enhancement or suppression of the CPCBR and the number of peaks strongly depend on the frequency and amplitude of the external signal. Furthermore, the gene regulation system can selectively enhance or decrease the noise-induced oscillation signals at preferred frequency and amplitude of an external signal. (shrink)

A major problem in developing an effective gene therapy for the nervous system lies in understanding the principles that maintain or turn off the expression of genes following their transfer into the CNS.

Nonsense‐mediated RNA decay (NMD) represents an established quality control checkpoint for gene expression that protects cells from consequences of gene mutations and errors during RNA biogenesis that lead to premature termination during translation. Characterization of NMD‐sensitive transcriptomes has revealed, however, that NMD targets not only aberrant transcripts but also a broad array of mRNA isoforms expressed from many endogenous genes. NMD is thus emerging as a master regulator that drives both fine and coarse adjustments in steady‐state RNA levels (...) in the cell. Importantly, while NMD activity is subject to autoregulation as a means to maintain homeostasis, modulation of the pathway by external cues provides a means to reprogram gene expression and drive important biological processes. Finally, the unanticipated observation that transcripts predicted to lack protein‐coding capacity are also sensitive to this translation‐dependent surveillance mechanism implicates NMD in regulating RNA function in new and diverse ways. (shrink)

Genomic imprinting is an epigenetic mechanism resulting in the preferential expression of the maternal or paternal alleles of a specific subset of genes in the mammalian genome. A key but relatively unexplored question is how imprints are established in the germline. New observations(1) on two classical imprinting disorders, the Prader‐Willi (PWS) and Angleman (AS) syndromes, offer the first genetic insight into this process. Molecular analysis of imprinting mutations that interfere with the appropriate establishment of the maternal and paternal epigenotypes has (...) led to the identification of imprinted transcripts that could be involved in switching imprints in the germlines. (shrink)

Many targets of the Wnt/β-catenin signaling pathway are regulated by TCF transcription factors, which play important roles in animal development, stem cell biology, and oncogenesis. TCFs can regulate Wnt targets through a “transcriptional switch,” repressing gene expression in unstimulated cells and promoting transcription upon Wnt signaling. However, it is not clear whether this switch mechanism is a general feature of Wnt gene regulation or limited to a subset of Wnt targets. Co-repressors of the TLE family are known to (...) contribute to the repression of Wnt targets in the absence of signaling, but how they are inactivated or displaced by Wnt signaling is poorly understood. In this mini-review, we discuss several recent reports that address the prevalence and molecular mechanisms of the Wnt transcription switch, including the finding of Wnt-dependent ubiquitination/inactivation of TLEs. Together, these findings highlight the growing complexity of the regulation of gene expression by the Wnt pathway. Wnt targets are regulated by a “switch” where TLE co-repressors are displaced from TCFs by β-catenin, leading to activation of transcription. Recent reports challenge this view and suggest that additional processes, including exchange of specific TCF proteins and Wnt-dependent ubiquitination of TLEs, play important roles in the Wnt transcriptional switch. (shrink)

Network motifs are small patterns of connections, found over‐represented in gene regulatory networks. An example is the negative feedback loop (e.g. factor A represses itself). This opposes its own state so that when ‘on’ it tends towards ‘off’ – and vice versa. Here, we argue that such self‐opposition, if considered dimensionlessly, is analogous to the liar paradox: ‘This statement is false’. When ‘true’ it implies ‘false’ – and vice versa. Such logical constructs have provided philosophical consternation for over 2000 (...) years. Extending the analogy, other network topologies give strikingly varying outputs over different dimensions. For example, the motif ‘A activates B and A. B inhibits A’ can give switches or oscillators with time only, or can lead to Turing‐type patterns with both space and time (spots, stripes or waves). It is argued here that the dimensionless form reduces to a variant of ‘The following statement is true. The preceding statement is false’. Thus, merely having a static topological description of a gene network can lead to a liar paradox. Network diagrams are only snapshots of dynamic biological processes and apparent paradoxes can reveal important biological mechanisms that are far from paradoxical when considered explicitly in time and space. (shrink)

Poly(ADP‐ribosyl)ation is a post‐translational modification occurring in the nucleus. The most abundant and best‐characterized enzyme catalyzing this reaction, poly(ADP‐ribose) polymerase 1 (PARP1), participates in fundamental nuclear events. The enzyme functions as molecular “nick sensor”. It binds with high affinity to DNA single‐strand breaks resulting in the initiation of its catalytic activity. Activated PARP1 promotes base excision repair. In addition, PARP1 modifies several transcription factors and thereby precludes their binding to DNA. We propose that a major function of PARP1 includes the (...) silencing of transcription preventing expression of damaged genes. Concomitant stimulation of DNA repair suggests that PARP1 acts as a switch between transcription and DNA repair. Another PARP‐type enzyme, tankyrase, is involved in the regulation of telomere elongation. Tankyrase modifies a telomere‐associated protein and thereby prevents it masking telomeric repeats providing access of telomerase for telomere elongation. Therefore, poly(ADP‐ribosyl)ation reactions may act as molecular switches in DNA metabolism. BioEssays 23:543–548, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Alternative splicing (AS) greatly expands the coding capacities of genomes by allowing the generation of multiple mature mRNAs from a limited number of genes. Although the massive switch in AS profiles that often accompanies variations in gene expression patterns occurring during cell differentiation has been characterized for a variety of models, their causes and mechanisms remain largely unknown. Here, we integrate foundational and recent studies indicating the AS switches that govern the processes of cell fate determination. We include some (...) distinct AS events in pluripotent cells and somatic reprogramming and discuss new progresses on alternative isoform expression in adipogenesis, myogenic differentiation and stimulation of immune cells. Finally, we cover novel insights on AS mechanisms during neuronal differentiation, paying special attention to the role of chromatin structure. (shrink)

Construction of the trunk/caudal region of the vertebrate embryo involves a set of distinct molecules and processes whose relationships are just coming into focus. In addition to the subdivision of the embryo into head and trunk domains, this “caudalisation” process requires the establishment and maintenance of a stem zone. This sequentially generates caudal tissues over a long period which then undergo differentiation and patterning in the extending body axis. Here we review recent studies that show that changes in the signalling (...) properties of the paraxial mesoderm act as a switch that controls onset of differentiation and pattern in the spinal cord. These findings identify distinct roles for different caudalising factors; in particular, Fibroblast Growth Factor (FGF) inhibits differentiation in the caudal stem zone, while Retinoic acid (RA) provided rostrally by somitic mesoderm is required for neuronal differentiation and establishment of ventral neural pattern. Furthermore, the mutual opposition of FGF and RA pathways controls not only neural differentiation but also mesoderm segmentation and might also underlie the progressive assignment of rostrocaudal identity by regulating Hox gene availability and activation. BioEssays 26:857–869, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

A small proportion of clinical strains of Candida albicans undergo white–opaque switching. Until recently it was not clear why, since most strains carry the genes differentially expressed in the unique opaque phase. The answer to this enigma lies in the mating process. The majority of C. albicans strains are heterozygous for the mating type locus MTL (a/α) and cannot undergo white–opaque switching. However, when these cells undergo homozygosis at the mating type locus (i.e., become a/a or α/α), they (...) can switch, and they must switch in order to mate. Even though the newly identified stages of mating mimic those of Saccharomyces cerevisiae, the process differs in its dependency on switching, and the effects switching has on gene regulation. This unique feature of C. albicans mating appears to be intimately intertwined with its pathogenesis. The unique, newly discovered dependencies of switching on homozygosis at the MTL locus and of mating on switching are, therefore, reviewed within the context of pathogenesis. BioEssays 26:10–20, 2004. © 2003 Wiley Periodicals, Inc. (shrink)

Conserved upstream open reading frames (uORFs) are found within many eukaryotic transcripts and are known to regulate protein translation. Evidence from genetic and bioinformatic studies implicates disturbed uORF‐mediated translational control in the etiology of human diseases. A genetic mouse model has recently provided proof‐of‐principle support for the physiological relevance of uORF‐mediated translational control in mammals. The targeted disruption of the uORF initiation codon within the transcription factor CCAAT/enhancer binding protein β (C/EBPβ) gene resulted in deregulated C/EBPβ protein isoform expression, (...) associated with defective liver regeneration and impaired osteoclast differentiation. The high prevalence of uORFs in the human transcriptome suggests that intensified search for mutations within 5′ RNA leader regions may reveal a multitude of alterations affecting uORFs, causing pathogenic deregulation of protein expression. (shrink)

In BioEssays, vol. I. no. 5, p. 227, P. A. Lawrence discussed the selector gene hypothesis and its implications for development. In the following article, D. Gubb presents an alternative view of the genetic control of development.

Day length provides an important environmental cue by signalling conditions favourable for flowering. While Arabidopsis promotes flowering in response to long days, rice promotes flowering in response to short days. Despite this difference, a recent paper reveals that the network controlling this response is highly conserved in these distantly related plants, only the activity of one component is reversed.1 This reveals how an important developmental process can be diversified for adaptation by using the same set of genes, but regulating them (...) differently. BioEssays 25:829–832, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

This study is the most comprehensive account to date of modern treatments of the love commandment. Gene Outka examines the literature on agape from Nygren's Agape and Eros in 1930. Both Roman Catholic and Protestant writings are considered, including those of D'Arcy, Niebuhr, Ramsey, Tillich, and above all, Karl Barth. The first seven chapters focus on the principal treatments in the theological literature as they relate to major topics in ethical theory. The last chapter explores further the basic normative (...) content of agape and discusses some of the most characteristic problems. "The book is in my judgment the best recent work in religious ethics. Outka brings together analytic moral philosophy and theological ethics, providing a masterly survey of views and issues arising in the past forty years.... I can think of few books of interest to scholars in both philosophy and theology, but Outka's is one. Unlike some scholars who are at home in continental theology, Outka is also at home in secular analytic philosophy; he brings them together in a mutually illuminating way."--Donald Evans "Outka has mastered this vast literature on love, and has brought a critical and clarifying analysis to bear upon it. This is a most important book on a most important subject, and brings the whole discussion into a new phase."--John Macquarrie "The first thing to be said about Outka's book quite simply is that it is excellent; in fact, it is probably the very best available book about contemporary Christian ethical theory."--The Humanities Association Review. (shrink)

This experimental study evaluated the influence of stated organizational concern for ethical conduct upon managerial behavior. Using an in-basket to house the manipulation, a sample of 113 MBA students with some managerial experience reacted to scenarios suggesting illegal conduct and others suggesting only unethical behavior. Stated organizational concern for ethical conduct was varied from none (control group) to several other situations which included a high treatment consisting of a Code of Ethics, an endorsement letter by the CEO and specific sanctions (...) for managerial misconduct. Only in the case of suggested illegal behavior tempered by high organizational concern were managers influenced by organizational policy to modify the morality of their actions. However, the responses to the illegal scenarios were significantly more ethical than the reactions given to the unethical (but not illegal) situations. The implications of these findings are then discussed. (shrink)

Abstract:This study examined the relationship between the individual difference variables of personal moral philosophy, locus of control, Machiavellianism, and just world beliefs and ethical judgments and behavioral intentions. A sample of 602 marketing practitioners participated in the study. Structural equation modeling was used to test hypothesized relationships. The results either fully or partially supported hypothesized direct effects for idealism, relativism, and Machiavellianism. Findings also suggested that Machiavellianism mediated the relationship between individual difference variables and ethical judgments/behavioral intentions.

The Ethical Journalist gives aspiring journalists the tools they need to make responsible professional decisions. Provides a foundation in applied ethics in journalism Examines the subject areas where ethical questions most frequently arise in modern practice Incorporates the views of distinguished print, broadcast and online journalists, exploring such critical issues as race, sex, and the digitalization of news sources Illustrated with 24 real-life case studies that demonstrate how to think in 'shades of gray' rather than 'black and white' Includes questions (...) for class discussion and guides for putting important ethical concepts to use in the real world Accompanying website includes model course schedules, discussion guides, PowerPoint slides, sample quiz and exam questions and links to additional readings online: www.wiley.com/go/foreman. (shrink)

ONE OF THE MOST prominent theorists of anarcho-capitalism is Hans- Hermann Hoppe. In what is perhaps his most famous result, the argumentation ethic for libertarianism, he purports to establish an a priori defense of the justice of a social order based exclusively on pri- vate property. Hoppe claims that all participants in a debate must presuppose the libertarian principle that every person owns himself, since the principle underlies the very concept of argumentation. Some libertarians (e.g., Rothbard 1988) have celebrated Hoppe’s (...) argument as the final nail in the coffin for collectivism of any type; following Hoppe, they believe that to deny the libertarian ethic is not only wrong, but also internally contradictory. On the other hand, a number of other prominent libertarians characterized Hoppe’s initial statement of his case as “one muddle after another” (Steele 1988, p. 47) or “a tissue of bald assertions” (Yeager 1988, p. 45). (shrink)

This paper begins by examining several potentially unethical recent marketing practices. Since most marketing managers face ethical dilemmas during their careers, it is essential to study the moral consequences of these decisions. A typology of ways that managers might confront ethical issues is proposed. The significant organizational, personal and societal costs emanting from unethical behavior are also discussed. Both relatively simple frameworks and more comprehensive models for evaluating ethical decisions in marketing are summarized. Finally, the fact that organizational commitment to (...) fostering ethical marketing decisions can be accomplished by top management leadership, codes of ethics, ethics seminars/programs and ethical audits is examined. (shrink)

Peter Winch famously critiqued Michael Oakeshott's view of human conduct. He argued that Oakeshott had missed the fact that truly human conduct is conduct that 'follows a rule.' This paper argues that, as is sometimes the case with Oakeshott, what seems, on the surface, to be a disagreement with another, somewhat compatible thinker about a matter of detail in some social theory in fact turns out to point to a deeper philosophical divide. In particular, I contend, Winch, as typical of (...) those who only picked up on Oakeshott's work in the 1940s and 1950s, when Oakeshott became known for his critique of rationalism, failed to understand the idealist metaphysics underlying that critique. (shrink)

The political systems of the Roman Republic were based almost entirely on tradition, “the way of the ancestors”, rather than on a written constitution. While the founders of the American Republic looked to ancient Rome as a primary model for their enterprise, nevertheless, in line with the rationalist spirit of their age, the American founders attempted to create a rational set of rules that would guide the conduct of American politics, namely, the US Constitution.These two examples offer a striking case (...) of the ideal types, famously delineated by Michael Oakeshott in “Rationalism in Politics” and elsewhere, between politics as a practice grounded in tradition and politics as a system based on principles flowing from abstract reasoning.This book explores how the histories of the two republics can help us to understand Oakeshott’s claims about rational versus traditional politics. Through examining such issues we may come to understand better not only Oakeshott’s critique of rationalism, but also modern constitutional theory, issues in the design of the European Union, and aspects of the revival of republicanism. (shrink)

This volume centers on debates about how far moral judgments bind across traditions and epochs. Nowadays such debates appear especially volatile, both in popular culture and intellectual discourse: although there is increasing agreement that the moral and political criteria invoked in human rights documents possess cross-cultural force, many modern and postmodern developments erode confidence in moral appeals that go beyond a local consensus or apply outside a particular community. Often the point of departure for discussion is the Enlightenment paradigm of (...) a common morality, in which it is assumed that certain unchanging beliefs inhere in the structure of human reason. Whereas some thinkers continue to defend this paradigm, others modify it in diverse ways without abandoning entirely the attempt to address a universal audience, and still others jettison virtually all of its distinguishing features. Exhibiting a range of positions Western participants take in these debates, this volume seeks to advance the substance of the debates themselves without prejudging the outcome. Rival assessments of the Enlightenment paradigm are offered from various philosophical and theological points of view. In addition to the editors, the contributors include Robert Merrihew Adams, Annette C. Baier, Alan Donagan, Margaret A. Farley, Alan Gewirth, David Little, Richard Rorty, Jeffrey Stout, and Lee H. Yearley. (shrink)

The role of imagery in encoding event-based prospective memories has yet to be fully clarified. Herein, it is argued that imagery augments a cue-to-context association that supports event-based prospective memory performance. By this account, imagery encoding not only improves prospective memory performance but also reduces interference to intention-related information that occurs outside of context. In the current study, when lure words occurred outside of the appropriate responding context, the use of imagery encoding strategies resulted in less interference when compared with (...) a standard event-based intention condition. This difference was eliminated when participants were not given a specific context to associate their intention . These results support a cue-to-context association account of how imagery operates in certain event-based prospective memory tasks. (shrink)

While self-report data is a staple of modern psychological studies, they rely on participants accurately self-reporting. Two constructs that impede accurate results are insufficient effort responding and response styles. These constructs share conceptual underpinnings and both utilized to reduce cognitive effort when responding to self-report scales. Little research has extensively explored the relationship of the two constructs. The current study explored the relationship of the two constructs across even-point and odd-point scales, as well as before and after data cleaning procedures. (...) We utilized IRTrees, a statistical method for modeling response styles, to examine the relationship between IER and response styles. To capture the wide range of IER metrics available, we employed several forms of IER assessment in our analyses and generated IER factors based on the type of IER being detected. Our results indicated an overall modest relationship between IER and response styles, which varied depending on the type of IER metric being considered or type of scale being evaluated. As expected, data cleaning also changed the relationships of some of the variables. We posit the difference between the constructs may be the degree of cognitive effort participants are willing to expend. Future research and applications are discussed. (shrink)

A number of social theorists have contended that the essence of historical analysis is the employment of ideal types to comprehend past goings-on. But, while acknowledging that the study of history through ideal types can yield genuine insight, we may still ask if it represents the full emancipation of historical understanding from other modes of conceiving the past. This paper follows Michael Oakeshott's work on the philosophy of history in arguing that explaining the historical past by means of ideal types, (...) even though offering a coherent and fruitful enterprise, nevertheless falls short of fully embodying the characteristics that differentiate historical understanding. -/- This dispute involves fundamental issues regarding the nature of the social sciences. Furthermore, I suggest that it is of more than purely theoretical interest, in that social theorists who have accepted the Weberian view of historical inquiry will tend to be unaware of the defects inherent in all attempts to capture the nature of past events in a net of generalizations, and thus may be lead to ignore the inherent partiality of the understanding of historical happenings provided by ideal typification. (shrink)

The paper aims to explore what it means for something to be a social cycle, for a theory to be a social cycle theory, and to offer a suggestion for a simple, yet, we believe, fundamentally grounded schema for categorizing them. We show that a broad range of cycle theories can be described within the concept of disruption and adjustments. Further, many important cycle theories are true endogenous social cycle theories in which the theory provides a reason why the cycle (...) should recur. We find that many social cycle theories fit with a two-population disruption and adjustment model similar to the well-known predator-prey model. This implies that a general modeling framework could be established for creating agent-based models of many social cycle theories. (shrink)

: The medical and clinical promise of stem cell research is widely heralded, but moral judgments about it collide. This article takes general stock of such judgments and offers one specific resolution. It canvasses a spectrum of value judgments on sources, complicity, adult stem cells, and public and private contexts. It then examines how debates about abortion and stem cell research converge and diverge. Finally, it proposes to extend the principle of "nothing is lost" to current debates. This extension links (...) historic discussions of the ethics of direct killing with unprecedented possibilities that in vitro fertilization procedures yield. A definite normative region to inhabit is located, within a larger range of rival value judgments. The creation of embryos for research purposes only should be resisted, yet research on "excess" embryos is permissible by virtue of an appeal to the "nothing is lost" principle. (shrink)

This volume centers on debates about how far moral judgments bind across traditions and epochs. Nowadays such debates appear especially volatile, both in popular culture and intellectual discourse: although there is increasing agreement that the moral and political criteria invoked in human rights documents possess cross-cultural force, many modern and postmodern developments erode confidence in moral appeals that go beyond a local consensus or apply outside a particular community. Often the point of departure for discussion is the Enlightenment paradigm of (...) a common morality, in which it is assumed that certain unchanging beliefs inhere in the structure of human reason. Whereas some thinkers continue to defend this paradigm, others modify it in diverse ways without abandoning entirely the attempt to address a universal audience, and still others jettison virtually all of its distinguishing features. Exhibiting a range of positions Western participants take in these debates, this volume seeks to advance the substance of the debates themselves without prejudging the outcome. Rival assessments of the Enlightenment paradigm are offered from various philosophical and theological points of view. In addition to the editors, the contributors include Robert Merrihew Adams, Annette C. Baier, Alan Donagan, Margaret A. Farley, Alan Gewirth, David Little, Richard Rorty, Jeffrey Stout, and Lee H. Yearley. (shrink)

Often different schools or styles of doing economics are seen as inevitably at odds with each other, so that one must be crowned 'correct' and the others vanquished as defective. However, if they actually represent alternative but potentially enlightening views of economic phenomena, then it will be foolish exclusively to pursue one approach at the expense of all others. This paper argues that the latter is a more accurate view of economics than is the former.

A themed issue on the work of Michael Oakeshott.

Recent work by Jaegwon Kim and others suggest that functionalism leaves mental properties causally inefficacious in some sense. I examine three lines of argument for this conclusion. The first appeals to Occam's Razor; the second appeals to a ban on overdetermination; and the third charges that the kind of response I favor to these arguments forces me to give up "the homogeneity of mental and physical causation". I show how each argument fails. While I concede that a positive theory of (...) mental causation is desirable, there is no reason to think that functionalism renders such a theory unattainable. (shrink)