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)

I argue that the three strongest arguments against metaphysical libertarianism—the randomness objection, the constitutive luck objection, and the physicalist objection—are actually unsuccessful and therefore that metaphysical libertarianism is more plausible than the common philosophical wisdom allows. My more positive thesis, what I will refer to as “Agent Exceptionalism,” is that, when making decisions and performing actions, human beings can indeed satisfy the four conditions of metaphysical libertarianism: the control condition, the rationality condition, the ultimacy condition, and the physicalism condition.

I argue for three conclusions. First, responsibility skeptics are committed to the position that the criminal justice system should adopt a universal nonresponsibility excuse. Second, a universal nonresponsibility excuse would diminish some of our most deeply held values, further dehumanize criminals, exacerbate mass incarceration, and cause an even greater number of innocent people (nonwrongdoers) to be punished. Third, while Saul Smilansky's ‘illusionist’ response to responsibility skeptics – that even if responsibility skepticism is correct, society should maintain a responsibility‐realist/retributivist criminal justice (...) system – is generally compelling, it would not work if a majority of society were to convert, theoretically and psychologically, to responsibility skepticism. In this (highly improbable) scenario, and only in this (highly improbable) scenario, the criminal justice system would need to be reformed in such a way that it aligned with the majority's responsibility‐skeptical beliefs and attitudes. (shrink)

This paper analyses the activities of five organizations shaping the debate over the global governance of genome editing in order to assess current approaches to public engagement (PE). We compare the recommendations of each group with its own practices. All recommend broad engagement with the general public, but their practices vary from expert-driven models dominated by scientists, experts, and civil society groups to citizen deliberation-driven models that feature bidirectional consultation with local citizens, as well as hybrid models that combine elements (...) of both approaches. Only one group practices PE that seeks community perspectives to advance equity. In most cases, PE does little more than record already well-known views held by the most vocal groups, and thus is unlikely to produce more just or equitable processes or policy outcomes. Our exploration of the strengths, weaknesses, and possibilities of current forms of PE suggests a need to rethink both “public” and “engagement.”. (shrink)

This invited entry offers a brief overview of criminal responsibility. -/- The first part starts with a question: is Clyde criminally responsible for killing his girlfriend Bonnie? The answer: it depends. Particular circumstances determine whether Clyde is guilty of murder, guilty of manslaughter, not guilty because he has a good excuse, or not guilty because he has a good justification. -/- The second part addresses the complicated relationship between criminal responsibility and moral responsibility. Until recently, both concepts were considered to (...) be more or less interchangeable. But there is a growing movement, which I refer to as "responsibility skepticism," which maintains that moral responsibility is either physically or metaphysically impossible. If the responsibility skeptics are right (that moral responsibility is impossible), then what are the implications for criminal responsibility and just criminal punishment? Should we abandon these as well? Or can they survive without moral responsibility? I try to answer these questions. -/- The third part addresses social causation. The criminal justice system tends to be "dispositionalist"; it tends, that is, to assume that criminal responsibility resides entirely within the defendant. Dispositionalism, however, overlooks the fact that who we are and what we do are significantly determined by environmental influences. I then try to show that this "situationist" alternative to dispositionalism should not radically alter our approach to criminal punishment. -/- The final part briefly discusses the difficulty in evaluating criminal responsibility when the defendant is both an offender and a victim - especially when the defendant is an offender *because* of his victimization. (shrink)

Background: A growing literature has raised—skeptically—the question of whether cutting-edge scientific research can identify and address broader ethical and policy considerations in real time. In genomics, the question is: Can ELSI contribute to genomics in real time, or will it be relegated to its historical role of after-the-fact outsider critique? We address this question against the background of a genomic screening project where we participated as embedded, real-time ELSI researchers and observers, from its initial design through its conclusion.Methods: As part (...) of the ELSI study design, the project included an ongoing reflexive ethnography in which the authors studied the process of its design and implementation. The authors were true participant observers, serving as members of various task-oriented groups while recording meetings and other events for ongoing qualitative analysis. We also conducted and analyzed interviews of multiple participants at the conclusion of the project.Results: Our real-time ELSI initiative had a mixed record of successes and challenges. If we define success as ELSI researchers having had an opportunity to participate fully in the project and to make the ELSI perspective heard, then our assessment is largely positive. If, however, we define successes as instances where real-time ELSI contributions changed the direction of the genomic or public health aspects of the GeneScreen project or, after careful deliberation, confirmed the appropriateness of the status quo, then we can identify only a few examples. While we had a seat at the table, we were, for the most part, tolerated guests.Conclusions: We conclude that there are significant barriers to real-time ELSI influence. The difficulty does not reside in any intended exclusion of an ELSI perspective, but in factors endemic to genomic research, including knowledge disparities, epistemological biases, and the pressures of time and money. (shrink)

At the time of this writing, a widely publicized, waived-consent trial is underway. Sponsored by Northfield Laboratories, Inc. (Evanston, IL) the trial is intended to evaluate the emergency use of PolyHeme®, an oxygen-carrying resuscitative fluid that might prevent deaths from uncontrolled bleeding. The protocol allows patients in hemorrhagic shock to be randomized between PolyHeme® and saline in the field and, still without consent, randomized between PolyHeme® and blood after arrival at an emergency department. The Federal regulations that govern the waiver (...) of consent restrict its applicability to circumstances where proven, satisfactory treatments are unavailable. Blood - the standard treatment for hemorrhagic shock - is not available in ambulances but is available in hospitals. The authors argue that the in-hospital stage of the study fails to meet ethical and regulatory standards. (shrink)

Julie Childers and Bob Arnold’s (2019) article, “The Inner Lives of Doctors: Physician Emotion in the Care of the Seriously Ill,” uses Kübler-Ross’s influential work on death and dying to remind us...

The current ethical norms of genomic biobanking creating and maintaining large repositories of human DNA and/or associated data for biomedical research have generated criticism from every angle, at both the practical and theoretical levels. The traditional research model has involved investigators seeking biospecimens for specific purposes that they can describe and disclose to prospective subjects, from whom they can then seek informed consent. In the case of many biobanks, however, the institution that collects and maintains the biospecimens may not itself (...) be directly involved in research, instead banking the biospecimens and associated data for other researchers. Moreover, the future uses of biospecimens may be unknown, if not unknowable, at the time of collection. Biobanking may thus stretch the meanings of inform and consent to their breaking point: if you cannot inform subjects about what their biospecimens will be used for, what can they consent to? Given that informed consent by individual subjects is the ethical gold standard, the seeming dilution of the concept in the context of biobanking is a profound problem. (shrink)

The structure of people’s conceptual knowledge of concrete nouns has traditionally been viewed as hierarchical (Collins & Quillian, 1969). For example, superordinate concepts (vegetable) are assumed to reside at a higher level than basic‐level concepts (carrot). A feature‐based attractor network with a single layer of semantic features developed representations of both basic‐level and superordinate concepts. No hierarchical structure was built into the network. In Experiment and Simulation 1, the graded structure of categories (typicality ratings) is accounted for by the flat (...) attractor network. Experiment and Simulation 2 show that, as with basic‐level concepts, such a network predicts feature verification latencies for superordinate concepts (vegetable ). In Experiment and Simulation 3, counterintuitive results regarding the temporal dynamics of similarity in semantic priming are explained by the model. By treating both types of concepts the same in terms of representation, learning, and computations, the model provides new insights into semantic memory. (shrink)

Executives of many publicly held firms agree to compensation packages that create immense exposure to their employer’s stock. Corporate boards, aspiring to motivate executives to make value-maximizing decisions, often tie an executive’s earnings to stock price performance through stock or option awards. However, this engenders a significant ethical dilemma for many executives who are uncomfortable with sizable, firm-specific risk and desire to reduce it through hedging activities. Recent research has shown that executive hedging has become more prevalent. In essence, managers (...) are unwinding the acute economic incentive to act in the best interest of the owners. This appears to violate the spirit of the compensation contract and from a normative standpoint, is not how executives should act. In this article, we describe how some executives are acting in regard to this issue (descriptive ethics), how they should act (normative ethics) and how they can be helped to get from what they are doing, to what they should be doing (prescriptive ethics). (shrink)

The lateral mobility of membrane lipids and proteins is presumed to play an important functional role in biomembranes. Photobleaching studies have shown that many proteins in the plasma membrane have diffusion coefficients at least an order of magnitude lower than those obtained when the same proteins are reconstituted in artificial bilayer membranes. Depending on the protein, it has been shown that either the cytoplasmic domain or the ectodomain is the key determinant of its lateral mobility. Single particle tracking microscopy, which (...) allows the motions of single or small groups of membrane molecules to be followed, promises not only to reveal new features of membrane dynamics, but also to help explain longstanding puzzles presented by the photobleaching studies, particularly the so‐called immobile fraction. The combination of the two complementary technologies should measurably enhance our understanding of membrane microstructure. (shrink)

At the time of this writing, a widely publicized, waived-consent trial is underway. Sponsored by Northfield Laboratories, Inc. (Evanston, IL) the trial is intended to evaluate the emergency use of PolyHeme®, an oxygen-carrying resuscitative fluid that might prevent deaths from uncontrolled bleeding. The protocol allows patients in hemorrhagic shock to be randomized between PolyHeme® and saline in the field and, still without consent, randomized between PolyHeme® and blood after arrival at an emergency department. The Federal regulations that govern the waiver (...) of consent restrict its applicability to circumstances where proven, satisfactory treatments are unavailable. Blood—the standard treatment for hemorrhagic shock—is not available in ambulances but is available in hospitals. The authors argue that the in-hospital stage of the study fails to meet ethical and regulatory standards. (shrink)

Securities lending has been a lucrative business for mutual funds and exchange-traded funds over the past decade. Unfortunately for investors, the sponsors of these funds have not been very transparent with the details of their securities lending programs, and consequently most investors in these funds are unaware of their exposure to the risks inherent in securities lending. Interestingly, most funds do not return the full profits from securities lending activities to their investors. In this paper, we examine and discuss the (...) ethical considerations related to the securities lending activities of mutual funds and ETFs and offer a series of best practices that we believe will provide better transparency of these activities to fund investors. (shrink)

RAID-II is a high-bandwidth, network-attached storage server designed and implemented at the University of California at Berkeley. In this paper, we measure the performance of RAID-II and evaluate various architectural decisions made during the design process. We first measure the end-to-end performance of the system to be approximately 20 MB/s for both disk array reads and writes. We then perform a bottleneck analysis by examining the performance of each individual subsystem and conclude that the disk subsystem limits performance. By adding (...) a custom interconnect board with a high-speed memory and bus system and parity engine, we are able to achieve a performance speedup of 8 to 15 over a comparative system using only off-the-shelf hardware. (shrink)

We summarize several experiments indicating that the saccadic system is capable of simultaneously programming two movements toward different goals. This concurrent processing of saccades can lead to the execution of two saccades separated by an extremely short intersaccadic interval. This supports the idea of target competition proposed in Findlay & Walker's article, but suggests a greater degree of parallel processing. We provide evidence that concurrent processing of two saccades is not limited to higher-level planning subsystems; rather, it also involves both (...) regions close enough to the motor output that it can systematically affect saccade trajectory. (shrink)

This is the Second Edition of a well-received book that reflects a fresh, integrated coverage of the concepts and scientific measurement of stress and welfare of animals including humans. This book explains the basic biological principles of coping with many forms of adversity. The major part of this work is devoted to explaining scientifically usable concepts in stress and welfare. A wide range of welfare indicators are highlighted in detail with examples being drawn from man and other species. The necessity (...) for combining information from disciplines is emphasized with a one-health, one-welfare approach. This information forms the basis for a synthesis of new ideas. Among the issues covered are: - How brain and body systems regulate using feelings, physiological responses, behaviour and responses to pathology - Limits to adaptation - Assessing positive and negative welfare during both short-term and long-term situations - Ethical problems and suggested solutions A proper assessment of animal welfare is essential to take informed decisions about what is morally acceptable in terms of practice and in the development of a more effective legislation. This work encapsulates a very wide body of literature on scientific aspects of animal welfare and will thus prove a valuable asset for animal welfare scientists, psychologists, students and teachers of all forms of biology, behaviour, medicine, veterinary medicine and animal usage. (shrink)

The growing practice of returning individual results to research participants has revealed a variety of interpretations of the multiple and sometimes conflicting duties that researchers may owe to participants. One particularly difficult question is the nature and extent of a researcher’s duty to facilitate a participant’s follow-up clinical care by placing research results in the participant’s medical record. The question is especially difficult in the context of genomic research. Some recent genomic research studies — enrolling patients as participants — boldly (...) address the question with protocols dictating that researchers place research results directly into study participants’ existing medical records, without participant consent. Such privileging of researcher judgment over participant choice may be motivated by a desire to discharge a duty that researchers perceive themselves as owing to participants. However, the underlying ethical, professional, legal, and regulatory duties that would compel or justify this action have not been fully explored. (shrink)

The growing practice of returning individual results to research participants has revealed a variety of interpretations of the multiple and sometimes conflicting duties that researchers may owe to participants. One particularly difficult question is the nature and extent of a researcher’s duty to facilitate a participant’s follow-up clinical care by placing research results in the participant’s medical record. The question is especially difficult in the context of genomic research. Some recent genomic research studies — enrolling patients as participants — boldly (...) address the question with protocols dictating that researchers place research results directly into study participants’ existing medical records, without participant consent. Such privileging of researcher judgment over participant choice may be motivated by a desire to discharge a duty that researchers perceive themselves as owing to participants. However, the underlying ethical, professional, legal, and regulatory duties that would compel or justify this action have not been fully explored. (shrink)

Aworkshop was held August 26–28, 2015, by the Earth- Life Science Institute (ELSI) Origins Network (EON, see Appendix I) at the Tokyo Institute of Technology. This meeting gathered a diverse group of around 40 scholars researching the origins of life (OoL) from various perspectives with the intent to find common ground, identify key questions and investigations for progress, and guide EON by suggesting a roadmap of activities. Specific challenges that the attendees were encouraged to address included the following: What key (...) questions, ideas, and investigations should the OoL research community address in the near and long term? How can this community better organize itself and prioritize its efforts? What roles can particular subfields play, and what can ELSI and EON do to facilitate research progress? (See also Appendix II.) The present document is a product of that workshop; a white paper that serves as a record of the discussion that took place and a guide and stimulus to the solution of the most urgent and important issues in the study of the OoL. This paper is not intended to be comprehensive or a balanced representation of the opinions of the entire OoL research community. It is intended to present a number of important position statements that contain many aspirational goals and suggestions as to how progress can be made in understanding the OoL. The key role played in the field by current societies and recurring meetings over the past many decades is fully acknowledged, including the International Society for the Study of the Origin of Life (ISSOL) and its official journal Origins of Life and Evolution of Biospheres, as well as the International Society for Artificial Life (ISAL). (shrink)

Bowman-Smart et al. (2023) argue for a framework to examine the ethical issues associated with genetic screening for non-medical traits in the context of noninvasive prenatal testing (NIPT). Such s...

In this paper, I argue that accounts of the normative basis of morality face the following puzzle, drawing on a case found in Susan Wolf’s influential discussion of conflicts between the moral and personal points of view. On the one hand, morality appears to constitute an independent point of view that can intelligibly conflict with, and can conceivably be overruled by, the verdicts of other points of view. On the other hand, moral demands appear to carry a distinctive sort of (...) authority; moral reasons normally seem to take priority over other kinds of considerations, and the verdicts of morality seem to possess a distinctive place in our deliberations, in that they appear to represent standards that we are open to legitimate complaint for failing to honor. After clarifying the nature of the problem, I argue that a contractualist theory of morality can resolve the puzzle by offering a compelling vindication of the independence of the moral perspective, the normal priority of moral reasons, and the deliberative significance of moral verdicts, within a unified theoretical framework. Furthermore, I claim that this contractualist analysis can help account for the sense of deep conflict that is characteristic of the sort of troubling moral choices that Wolf calls to our attention. (shrink)

There is an epistemological skepticism that I might be dreaming now, or I might be a brain in a vat (BIV). There is also a demonstration that derives the skeptical conclusion about knowledge of the external world from the premise C1, i.e., I do not know “I am not dreaming (not a BIV) now.” Pessimistic critics (e.g., F. Strawson, B. Stroud) consider that the refutation of C1 is impossible, whereas others have attempted the direct refutation of C1 (e.g., G. E. (...) Moore, H. Putnam, C. Wright), and some (e.g., F. Dretske, R. Nozick) have attempted to refute the closure principle of knowledge used in the demonstration while permitting the validity of C1. Another scholar, M. Williams, maintains that the skeptical demonstration is true only if we presuppose the epistemological premise that we choose to accept or reject at will. It seems that most critics tend to adopt a strategy that allows them to effectively avoid the skeptical consequence, thereby conceding the validity of C1. However, it is difficult to say whether their attempts succeeded, and in my opinion, they are indeed unsuccessful. This is because their concession to Descartes’ argument is insufficient. Their lack of success could also stem from the incompletion of Descartes’ own methodological doubt. The somewhat paradoxical‐sounding aim of this thesis is to show that the skeptical paradox about knowledge can be dissolved only if the Cartesian skepticism is extended far beyond the endpoint of his attempt. The argument of this thesis is based on the important arguments of Wittgenstein's On Certainty （OC）. (shrink)

Over fifty years ago, H.M. was treated for chronic epilepsy by a bilateral hippocampectomy. Among the lasting side effects of this treatment was that H.M. could no longer form certain types of long term memories, although he could form others. One of the many morals philosophers and psychologists have sometimes drawn from this sad case (and others) is that information about the brain can be used to guide theorizing about the mind. More specifically, it has been claimed that differences in (...) the way in which psychological properties are realized in the brain can be used in the delimitation of distinct psychological properties. In this paper, we build on the Dimensioned theory of realization and a companion theory of multiple realization to argue that the discovery of differences in neurobiological realization do not by themselves lead to the splitting of psychological properties. Such differences in realizers could constitute unique realizations of distinct psychological types or multiple realizations of one psychological type. Whether one has unique realizations or multiple realizations—whether psychological properties are split or not—is not determined by the neuroscience alone, but by the psychological theory under examination. Thus, one might say that, in the splitting or non-splitting of properties, psychology enjoys a kind of autonomy from neuroscience. (shrink)

Carl Gillett Department of Philosophy Northern Illinois University Suppose that scientists discover a high level property G that is prima facie multiply realized by two sets of lower level properties, F1, F2, …, Fn, and F*1, F*2, …, F*m. One response would be to take this situation at face value and conclude that G is in fact so multiply realized. A second response, however, would be to eliminate the property G and instead hypothesize subtypes of G, G1 and G2, and (...) say that G1 is uniquely realized by F1, F2, …, Fn, and that G2 is uniquely realized by F*1, F*2, …, F*m. This second response would eliminate a multiply realized property in favor of two uniquely realized properties.[1] Clearly these are two logically possible responses to this type of situation, so when faced with it how do scientists respond in real cases? This is a matter of providing a descriptively adequate account of actual scientific practice. In support of the view that scientists opt for the “eliminate-and-split” strategy, one might propose that it is illustrated by the way scientists responded in the case of memory. Once upon a time, it was thought that there existed a single kind of memory. With the advance of science, however, it was discovered that it is possible to perform certain sorts of brain lesions that would lead to the selective loss of certain memory functions, while certain other sorts of brain lesions would lead to selective loss of certain other memory functions. These neurobiological dissociation experiments, one might say, support the view that, instead of a single overarching type of memory, there are distinct subtypes of memory, procedural memory and declarative memory. Thus, generalizing from this example, it might be suggested that the eliminate-and-split strategy is always the approach of scientists in such cases. We believe that this argument is based upon serious oversimplifications. To begin with, note that there is the assumption that scientists treat all discoveries about differences in realizers in the same way.. (shrink)

Wright, Ken Review(s) of: Universe from nothing: Why there is something rather than nothing, by Lawrence M. Krauss, Free Press, New York 2012; xix + 202 pp.; hardback, $29.99.

We explicate and evaluate arguments both for and against the insanity defense itself, different versions of the insanity defense (M'Naghten, Model Penal Code, and Durham (or Product)), the Irresistible Impulse rule, and various reform proposals.