The Wnt family of developmental regulators were named after the Drosophila segmentation gene wingless and the murine proto‐oncogene int‐1. Homology between these two genes connected oncogenesis to cell‐cell signals in development. I review how wingless was initially characterized, and cloned, as part of the quest to identify developmental cell‐to‐cell signals, based on predictions of the Positional Information Model, and on the properties of homeotic and segmentation gene mutants. The requirements and cell‐nonautonomy of wingless in patterning multiple embryonic and (...) adult structures solidified its status as a candidate signaling molecule. The physical location of wingless mutations and transcription unit defined the gene and its developmental transcription pattern. When the Drosophila homolog of int‐1 was then isolated, and predicted to encode a secreted proto‐oncogene homolog, it's identity to the wingless gene confirmed that a developmental cell‐cell signal had been identified and connected cancer to development. (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)

The Wnt signalling cascade is a highly conserved signalling pathway throughout the animal kingdom. In Xenopus, Wnt signalling functions in mesodermal dorsoventral patterning. Earlier work on deciphering the components of the wnt signalling cascade left a gap between cytosolic β‐catenin, the final member of the cascade, and the nuclear target genes. Several recent papers now reveal how the Wnt signal is transmitted into the nucleus. Surprisingly, β‐catenin directly interacts with the transcription factor LEF‐1/XTCF‐3, and thereby is not only translocated into (...) the nucleus but also modulates the properties of LEF‐1/XTCF‐3 as a transcription factor(1–5). (shrink)

Recent studies indicate that plakoglobin may have a similar function to that of β-catenin within the Wnt signaling pathway. β-catenin is known to be an oncogene in many forms of human cancer, following acquisition of stabilizing mutations in amino terminal sequences. Kolligs1 and coworkers show, however, that unlike β-catenin, plakoglobin induces neoplastic transformation of rat epithelial cells in the absence of such stabilizing mutations. Cellular transformation by plakoglobin also appears to be distinct from that of β-catenin in that it requires (...) activation of the proto-oncogene c-myc. Surprisingly, c-myc is activated more efficiently by plakoglobin than β-catenin, despite its previous identification as a target of Tcf/β-catenin.2 In contrast, a synthetic Tcf reporter gene is activated to a much greater extent by β-catenin than plakoglobin. Plakoglobin and β-catenin may therefore have different roles in Wnt signaling and cancer, which reflect their differential effects on target gene activity. BioEssays 22:961–965, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

Wnt signaling plays pivotal roles during our entire lives, from conception to death, through the regulation of morphogenesis in developing embryos and the maintenance of tissue homeostasis in adults. The regulation of Wnt signaling occurs on several levels: at the receptor level on the plasma membrane, at the β‐catenin protein level in the cytoplasm, and through transcriptional regulation in the nucleus. Several recent studies have focused on the mechanisms of Wnt receptor regulation, following the discovery that the Wnt receptor frizzled (...) (Fzd) is a target of the ubiquitin ligases, RNF43 and ZNRF3. RNF43 and ZNRF3 are homologous genes that are mutated in several cancers. The details underlying their mechanism of action continue to unfold, while at the same time raising many new questions. In this review, we discuss advances and controversies in our understanding of Wnt receptor regulation. (shrink)

Wnt glycoproteins are signaling molecules that control a wide range of developmental processes in organisms ranging from the simple metazoan Hydra to vertebrates. Wnt signaling also plays a key role in the development of the nematode C. elegans, and is involved in cell fate specification and determination of cell polarity and cell migration. Surprisingly, the first genetic studies of Wnt signaling in C. elegans revealed major differences with the established (canonical) Wnt signaling pathways of Drosophila and vertebrates. Thus, the Wnt-dependent (...) induction of endoderm in the early embryo and the specification of several asymmetric cell divisions during larval development are mediated by as yet novel Wnt signaling pathways that repress, rather than activate the TCF/LEF-1 transcription factor POP-1. Recently, however, it has been shown that, in addition to these divergent Wnt pathways, C. elegans also has a canonical Wnt pathway that converts POP-1 into an activator and controls the expression of several homeobox genes. Interestingly, these different Wnt pathways use distinct beta-catenins to control POP-1 function: the endoderm induction pathway requires the beta-catenin WRM-1 and parallel input from a mitogen-activated kinase (MAPK) pathway to downregulate POP-1, whereas the canonical Wnt pathway employs the beta-catenin BAR-1 to activate Wnt target gene expression. (shrink)

The link between oncogenesis and normal development is well illustrated by the study of the Wnt family of proteins. The first Wnt gene (int‐1) was identified over a decade ago as a proto‐oncogene, activated in response to proviral insertion of a mouse mammary tumor virus. Subsequently, the discovery that Drosophila wingless, a developmentally important gene, is homologous to int‐1 supported the notion that int‐1 may have a role in normal development. In the last few years it has been (...) recognized that int‐1 and Wingless belong to a large family of related glyco‐proteins found in vertebrates and invertebrates. In recognition of this, members of this family have been renamed Wnts, an amalgam of int and Wingless. Investigation of Wnt genes in Xenopus and mouse indicates that Wnts have a role in cell proliferation, differentiation and body axis formation. Further analysis in Drosophila has revealed that Wingless function is required in several developmental processes in the embryo and imaginal discs. In addition, a genetic approach has identified some of the molecules required for the transmission and reception of the Wingless signal. We will review recent data which have contributed to our growing understanding of the function and mechanism of Drosophila Wingless signaling in cell fate determination, growth and specification of pattern. (shrink)

Wnts are a recently described family of secreted glycoproteins related to the Drosophila segment polarity gene, wingless, and to the proto‐oncogene, int‐1. Wnts are thought to function as developmental modulators, with signalling distances of only a few cell diameters. In Xenopus, at least six Wnts, including Xwnts‐1, ‐3A, and ‐4, are expressed initially in the developing central nervous system, with some regions expressing multiple Xwnts. Xwnt‐8 is expressed by mid‐blastula stage, in ventral and lateral mesoderm. Xwnt‐5A mRNAs are stored (...) in the egg, and later are expressed throughout the embryo in both ectoderm and mesoderm, but with a pronounced enrichment in the head and tail. Recent studies in Xenopus have pursued the diverse roles of Xwnts in early development, the mechanisms by which Xwnts signal information between cells, and the cell physiological responses to Xwnt signals. (shrink)

The social structures and thought patterns of the modern world are the fruits of the Enlightenment, which begins by eliminating final causal explanations in favour of purely material and efficient causes. The development and great technical success of Enlightenment procedures has, however, produced a cultural blindness about the good. Camus's novel shows us this cultural blindness through characters who themselves suffer from it; for modern man, it is almost a natural evil—we are born into it. Camus' hope must have been (...) that the vision of the characters' incapacity might help break us from the same incapacity. What the cured life looks like Camus does not say; in the world of our plague, it appears as either odd or mystery. (shrink)

Until recently, sex determination in mammals has often been described as a male determination process, with male differentiation being the active and dominant pathway, and only in its absence is the passive female pathway followed. This picture has been challenged recently with the discovery that the gene encoding R-spondin1 is mutated in human patients with female-to-male sex reversal.((1)) These findings might place R-spondin1 in the exceptional position of being the female-determining gene in mammals. In this review, possible roles (...) of R-spondin1 during sex determination as well as questions arising from this study will be discussed. (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)

A substantial guide providing an overview of both physicalism and metaphysical naturalism, reviewing both questions of formulation and justification for both doctrines. Includes a diagnostic strategy for understanding talk of naturalism as a metaphysical thesis.

The advance of technology has influenced marketing in a number of ways that have ethical implications. Growth in use of the Internetand e-commerce has placed electronic “cookies,” spyware, spam, RFIDs, and data mining at the forefront of the ethical debate. Some marketers have minimized the significance of these trends. This overview paper examines these issues and introduces the two articles that follow. It is hoped that these entries will further the important “marketing and technology” ethical debate.

The advance of technology has influenced marketing in a number of ways that have ethical implications. Growth in use of the Internetand e-commerce has placed electronic “cookies,” spyware, spam, RFIDs, and data mining at the forefront of the ethical debate. Some marketers have minimized the significance of these trends. This overview paper examines these issues and introduces the two articles that follow. It is hoped that these entries will further the important “marketing and technology” ethical debate.

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)

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)

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)

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)

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)

We all live our daily lives surrounded by the products of technology that make what we do simpler, faster, and more efficient. These are benefits we often just take for granted. But at the same time, as these products disburden us of unwanted tasks that consumed much time and effort in earlier eras, many of them also leave us more disengaged from our natural and even human surroundings. It is the task of what Gene Moriarty calls focal engineering to (...) create products that will achieve a balance between disburdenment and engagement: “How much disburdenment will be appropriate while still permitting an engagement that enriches one’s life, elevates the spirit, and calls forth a good life in a convivial society?” One of his examples of a focally engineered structure is the Golden Gate Bridge, which “draws people to it, enlivens and elevates the human spirit, and resonates with the world of its congenial setting. Humans, bridge, and world are in tune.” These values of engagement, enlivenment, and resonance are key to the normative approach Moriarty brings to the profession of engineering, which traditionally has focused mainly on technical measures of evaluation such as efficiency, productivity, objectivity, and precision. These measures, while important, look at the engineered product in a local and limited sense. But “from a broader perspective, what is locally benign may present serious moral problems,” undermining “social justice, environmental sustainability, and health and safety of affected parties.” It is this broader perspective that is championed by focal engineering, the subject of Part III of the book, which Moriarty contrasts with “modern” engineering in Part I and “pre-modern” engineering in Part II. (shrink)

Poetic and dramatic readings of selected Platonic dialogues show the fallacy of the philosophical and political positions usually attributed to Plato. Dialogues dealt with include Apology, Meno, Ion, Republic, Theaetetus, Euthyphro, Laws.

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)

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)

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 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)

Although the concept of ‘true infinity’ is undoubtedly central to Hegel's philosophy, the Anglophone rehabilitation of Hegel as a post-Kantian critical philosopher has avoided any sustained interpretive confrontation with the concept. In this paper, I provide a revisionary reconstruction of Hegelian true infinity by engaging with Martin Hägglund's argument in This Life (2019) for the centrality of finitude to Hegel's philosophy. For Hägglund, Hegel's philosophy effects a ‘secular reconciliation’ with finitude by demonstrating that our mortality is not a negative condition (...) to be overcome; rather, mortality is constitutive of rational social agency or ‘spiritual life’. While Hägglund's interpretive emphasis on finitude prima facie occludes a consideration of the concept of true infinity, I show that Hägglund's understanding of spiritual life in terms of the dynamic of self-maintenance implicitly articulates a revisionary understanding of true infinity as instantiated in and through the activity of finite living rational beings. More specifically, I show that Hägglund's understanding of finitude as constitutive of spiritual life is grounded in three closely interrelated Hegelian meta-concepts, all of which Hegel derives in the second chapter of the Logic (‘Existence’): (a) the distinction between abstract and determinate negation; (b) the form of individuality as constituted through determinate negation; and (c) true infinity as the form of individuality understood in explicitly processual terms. I thus ground a deflationary interpretation of true infinity in Hegel's logical account of determinate individuality, and at the same time, contribute to This Life's ongoing critical reception by articulating its Hegelian logical infrastructure. (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 first half of Plato’s Hippias Major exhibits the interfacing of the first teacher (Socrates) with the first version of a post-colonial, multi-cultural information technology system (Hippias). In this interface the purposes, results, and values of two contradictory types of operating system for educational servicing units are exhibited to, and can be discovered by, anyone who is not an information technologist.

The first half of Plato’s Hippias Major exhibits the interfacing of the first teacher (Socrates) with the first version of a post-colonial, multi-cultural information technology system (Hippias). In this interface the purposes, results, and values of two contradictory types of operating system for educational servicing units are exhibited to, and can be discovered by, anyone who is not an information technologist.

Responsibility as a dual to human rights is presented as a moral alternative to extended, complex systems of animal and ecological rights. This simple idea of responsibility is then applied to four levels of agricultural technology: animal (nature) rights, conservation, organization of agriculture, and people versus planet relationships. The stewardship argument is freed from at least some of the complications of animal rights and ecology, but leaves responsibility with humans to do the right thing.

Time was when you could bite a tomato and not ingest fish genes. Time was when you could eat french fries and just worry about the fat and salt, not the bacterial genes that produce insecticides in the potato. Those times are over, thanks to corporate control over both genetic engineering and the lack of food-labeling. Unless you are a “hard core” consumer of organic foods, you eat genetically engineered foods everyday. While 80-90% of US consumers believe genetically engineered foods (...) should be labeled, only 3% know they already on the market.[1] Today 60-70% of the food in a grocery store contains components from genetically modified crops. Moreover, this technology was unleashed on over 45 million acres of US farmland last year alone, after having been commercially introduced only four years ago.[2] Here we will provide a brief background on the types of genetically engineered crops that are being surreptitiously forced upon consumers, then argue against their current widespread use. (shrink)

The advance of technology has influenced marketing in a number of ways that have ethical implications. Growth in use of the Internetand e-commerce has placed electronic “cookies,” spyware, spam, RFIDs, and data mining at the forefront of the ethical debate. Some marketers have minimized the significance of these trends. This overview paper examines these issues and introduces the two articles that follow. It is hoped that these entries will further the important “marketing and technology” ethical debate.

As Shakespeare is closer in time and spirit to medieval psychology than to popular modern explanations of psyche, this article presents a fourfold analysis of ecstasy from Aquinas' Summa Theologiae to examine the characters of the play. I also suggest performance choices which make a variety of these ecstasies of soul more visible.