Signaling through the Wnt/β‐catenin pathway is relayed through three multiprotein complexes: (1) the membrane‐associated signalosome, which includes the activated Wnt receptors, (2) the cytoplasmic destruction complex that regulates turnover of the transcriptional coactivator β‐catenin, and (3) the nuclear enhanceosome that mediates pathway‐specific transcription. Recent discoveries have revealed that Wnt receptor activities are tightly regulated to maintain proper tissue homeostasis and that aberrant receptor upregulation enhances Wnt signaling to drive tumorigenesis, highlighting the importance of signalosome control. These studies have focused on (...) the detailed process by which Wnt ligands engage their coreceptors, LRP5/6 and Frizzled. However, the components that constitute the signalosome and the regulation of their assembly remain undefined. In this review, we discuss Wnt/β‐catenin signalosome composition and the mechanisms that regulate signalosome assembly, including the role of biomolecular condensates and ubiquitylation. We also summarize the evidence for the presence of Wnt ligand‐independent signalosome formation. (shrink)

Indirect speech acts—responding “I forgot to wear my watch today” to someone who asked for the time—are ubiquitous in daily conversation, but are understudied in current neurobiological models of language. To comprehend an indirect speech act like this one, listeners must not only decode the lexical-semantic content of the utterance, but also make a pragmatic, bridging inference. This inference allows listeners to derive the speaker’s true, intended meaning—in the above dialog, for example, that the speaker cannot provide the time. In (...) the present work, we address this major gap by asking non-aphasic patients with behavioral variant frontotemporal dementia and brain-damaged controls with amnestic mild cognitive impairment to judge simple question-answer dialogs of the form: “Do you want some cake for dessert?” “I’m on a very strict diet right now,” and relate the results to structural and diffusion MRI. Accuracy and reaction time results demonstrate that subjects with bvFTD, but not MCI, are selectively impaired in indirect relative to direct speech act comprehension, due in part to their social and executive limitations, and performance is related to caregivers’ judgment of communication efficacy. MRI imaging associates the observed impairment in bvFTD to cortical thinning not only in traditional language-associated regions, but also in fronto-parietal regions implicated in social and executive cerebral networks. Finally, diffusion tensor imaging analyses implicate white matter tracts in both dorsal and ventral projection streams, including superior longitudinal fasciculus, frontal aslant, and uncinate fasciculus. These results have strong implications for updated neurobiological models of language, and emphasize a core, language-mediated social disorder in patients with bvFTD. (shrink)

In this Open Peer Commentary, we draw on our clinical experience to argue that instrumental paternalism carves a pathway to competent refusal of medical intervention. Whether C successfully navigat...

Proof-theoretic semantics (P-tS) is an innovative approach to grounding logical meaning in terms of proofs rather than traditional truth-conditional semantics. The point is not that one provides a proof system, but rather that one articulates meaning in terms of proofs and provability. To elucidate this paradigm shift, we commence with an introduction that contrasts the fundamental tenets of P-tS with the more prevalent model-theoretic approach to semantics. The contribution of this paper is a P-tS for a substructural logic, intuitionistic multiplicative (...) linear logic (IMLL). Specifically, we meticulously examine and refine the established P-tS for intuitionistic propositional logic. Subsequently, we present two novel and comprehensive forms of P-tS for IMLL. Notably, the semantics for IMLL in this paper embodies its resource interpretation through its number-of-uses reading (restricted to atoms). This stands in contrast to the conventional model-theoretic semantics of the logic, underscoring the value that P-tS brings to substructural logics. (shrink)

This translation of Carlo Michelstaedter’s _Persuasion and Rhetoric_ brings the powerful and original work of a seminal cultural figure to English-language readers for the first time. Ostensibly a commentary on Plato’s and Aristotle’s relation to the pre-Socratic philosophers, Michelstaedter’s deeply personal book is an extraordinary rhetorical feat that reflects the author’s struggle to make sense of modern life. This edition includes an introduction discussing his life and work, an extensive bibliography, notes to introduce each chapter, and critical notes illuminating the (...) text. Within hours of completing _Persuasion and Rhetoric, _his doctoral thesis, 23-year-old Michelstaedter shot himself to death. The text he left behind has proved to be one of the most trenchant and influential studies in modern rhetoric, a work that develops Nietzschean themes and anticipates the conclusions of, among others, Martin Heidegger. Publication of the book in English is an event of great magnitude for students of Italian philosophy, rhetoric, and literature as well as the culture of Mitteleuropa. (shrink)

This brief overview argues that the evidence of the images themselves, as well as their contexts, suggests that some Franco‐Cantabrian Upper Paleolithic cave art was, at least in part, intimately associated with various shamanic practices. Universal features of altered states of consciousness and the deep caves combined to create notions of a subterranean spirit‐world that became, amongst other ritual areas, the location of vision quests.

We consider a situation in which individuals search for accurate decisions without direct feedback on their accuracy, but with information about the decisions made by peers in their group. The “wisdom of crowds” hypothesis states that the average judgment of many individuals can give a good estimate of, for example, the outcomes of sporting events and the answers to trivia questions. Two conditions for the application of wisdom of crowds are that estimates should be independent and unbiased. Here, we study (...) how individuals integrate social information when answering trivia questions with answers that range between 0% and 100%. We find that, consistent with the wisdom of crowds hypothesis, average performance improves with group size. However, individuals show a consistent bias to produce estimates that are insufficiently extreme. We find that social information provides significant, albeit small, improvement to group performance. Outliers with answers far from the correct answer move toward the position of the group mean. Given that these outliers also tend to be nearer to 50% than do the answers of other group members, this move creates group polarization away from 50%. By looking at individual performance over different questions we find that some people are more likely to be affected by social influence than others. There is also evidence that people differ in their competence in answering questions, but lack of competence is not significantly correlated with willingness to change guesses. We develop a mathematical model based on these results that postulates a cognitive process in which people first decide whether to take into account peer guesses, and if so, to move in the direction of these guesses. The size of the move is proportional to the distance between their own guess and the average guess of the group. This model closely approximates the distribution of guess movements and shows how outlying incorrect opinions can be systematically removed from a group resulting, in some situations, in improved group performance. However, improvement is only predicted for cases in which the initial guesses of individuals in the group are biased. (shrink)

Background and purpose Changes to deceased organ donation policy in the USA, including opt-out and priority systems, have been proposed to increase registration and donation rates. To study attitudes towards such policies, we surveyed healthcare students to assess support for opt-out and priority systems and reasons for support or opposition. Methods We investigated associations with supporting opt-out, including organ donation knowledge, altruism, trust in the healthcare system, prioritising autonomy and participants’ evaluation of the moral severity of incorrectly assuming consent in (...) opt-in systems or opt-out systems, by conducting an online survey among healthcare students at a large academic institution. Results Of 523 respondents, 86% supported opt-out, including 53% who strongly supported the policy. The most popular reason for supporting opt-out was the potential for increased donation rates, followed by convenience for those not registered but willing to donate. The most popular reason for opposing opt-out was the belief that presuming consent is morally wrong. Those strongly supporting opt-out viewed the opt-in error as more morally unacceptable, and had higher knowledge and altruism scores. Those opposing opt-out viewed the opt-out error as more unacceptable, and had higher autonomy scores. 48% of respondents supported priority within opt-in systems; 31% supported priority in opt-out. Conclusions There is strong support for opt-out organ donation among healthcare students, influenced by both practical and moral considerations. (shrink)

People who score high in the jumping to conclusions bias (JTC) require relatively little evidence to reach highly confident conclusions. However, they often feel as though they have done ample research in informing their decisions. What factors could account for this discrepancy? The current research examines one potential factor: how individuals (with varying degrees of the JTC bias) generate hypotheses to explain uncertain events prior to searching for evidence. Study 1 demonstrated that high JTC participants generated fewer hypotheses but were (...) more confident that one was right (compared to low JTC participants). Study 2 showed that, when given the choice between generating alternative hypotheses and supporting initial hypotheses, individuals high in JTC chose to support their initial hypotheses more often. Thus, while the JTC bias is associated with limited hypothesising for unexplained events, it also corresponds with “doubling down” and investing research efforts in confirming initial hunches. (shrink)

Death in the Clinic fills a gap in contemporary medical education by explicitly addressing the concrete clinical realities about death with which practitioners, patients, and their families continue to wrestle. Visit our website for sample chapters!

This book argues against the common view that there are no essential differences between Plato and the Neoplatonist philosopher, Plotinus, on the issues of mysticism, epistemology, and ethics. Beginning by examining the ways in which Plato and Plotinus claim that it is possible to have an ultimate experience that answers the most significant philosophical questions, David J. Yount provides an extended analysis of why we should interpret both philosophers as mystics. The book then moves on to demonstrate that both (...) philosophers share a belief in non-discursive knowledge and the methods to attain it, including dialectic and recollection, and shows that they do not essentially differ on any significant views on ethics. Making extensive use of primary and secondary sources, Plato and Plotinus on Mysticism, Epistemology and Ethics shows the similarities between the thought of these two philosophers on a variety of philosophical questions, such as meditation, divination, wisdom, knowledge, truth, happiness and love. (shrink)

Diderot is widely praised as a master of lively, dramatic and original dialogue. This book studies the developing role of dialogue in his early writings (1745 to 1754). Diderot's earlier experiments with the dialogue form, meticulously charted and analysed by D. J. Adams, opened the way to the exploration of human communication and cooperation which lies at the heart of the Encyclopédie. At first for Diderot dialogue ended in the triumph of monologue, with one speaker reducing another to silence. But (...) one of his central problems was precisely that of solipsism. Is it possible for people to communicate effectively with each other? By engaging with this problem in his early writings Diderot gradually came to realise the epistemological importance of true dialogue as an escape from the solipsistic trap; and, slowly and hesitantly, he developed the form of communicative dialogue which was to flourish in the masterpieces of his later years. (shrink)

[This is an edited version of a keynote talk at the conference on Neural Information Processing Systems (NeurIPS) on November 28, 2022, with some minor additions and subtractions.] -/- There has recently been widespread discussion of whether large language models might be sentient or conscious. Should we take this idea seriously? I will break down the strongest reasons for and against. Given mainstream assumptions in the science of consciousness, there are significant obstacles to consciousness in current models: for example, their (...) lack of recurrent processing, a global workspace, and unified agency. At the same time, it is quite possible that these obstacles will be overcome in the next decade or so. I conclude that while it is somewhat unlikely that current large language models are conscious, we should take seriously the possibility that successors to large language models may be conscious in the not-too-distant future. (shrink)

Does consciousness collapse the quantum wave function? This idea was taken seriously by John von Neumann and Eugene Wigner but is now widely dismissed. We develop the idea by combining a mathematical theory of consciousness (integrated information theory) with an account of quantum collapse dynamics (continuous spontaneous localization). Simple versions of the theory are falsified by the quantum Zeno effect, but more complex versions remain compatible with empirical evidence. In principle, versions of the theory can be tested by experiments with (...) quantum computers. The upshot is not that consciousness-collapse interpretations are clearly correct, but that there is a research program here worth exploring. (shrink)

There is a long tradition in philosophy of using a priori methods to draw conclusions about what is possible and what is necessary, and often in turn to draw conclusions about matters of substantive metaphysics. Arguments like this typically have three steps: first an epistemic claim , from there to a modal claim , and from there to a metaphysical claim.

This essay re-examines and challenges the conventional wisdom regarding American laissez-faire capitalism, illuminates the extent of government activism and the currents of social democracy, and underscores the significance of the federal structure of the United States political system. We propose Critical Institutionalism to facilitate understanding of the complex, dynamic and contested nature of our political economy.

This article discusses the ethical responsibilities that psychology faculty have when psychological information is seriously misrepresented or psychological techniques are misued by nonpsychology faculty. General values derived from the American Psychological Association's (APA) ethical principles are identified and reviewed. The APA ethical code recommends that psychologists limit the misrepresentation of psychological information and protect students from the misuse of psychological techniques. Examples from my experience are presented to illustrate these ethical principles and responsibilities.

I argue that virtual reality is a sort of genuine reality. In particular, I argue for virtual digitalism, on which virtual objects are real digital objects, and against virtual fictionalism, on which virtual objects are fictional objects. I also argue that perception in virtual reality need not be illusory, and that life in virtual worlds can have roughly the same sort of value as life in non-virtual worlds.

Is there progress in philosophy? A glass-half-full view is that there is some progress in philosophy. A glass-half-empty view is that there is not as much as we would like. I articulate a version of the glass-half-empty view, argue for it, and then address the crucial question of what explains it.

Is conceptual analysis required for reductive explanation? If there is no a priori entailment from microphysical truths to phenomenal truths, does reductive explanation of the phenomenal fail? We say yes . Ned Block and Robert Stalnaker say no.

The philosophical interest of verbal disputes is twofold. First, they play a key role in philosophical method. Many philosophical disagreements are at least partly verbal, and almost every philosophical dispute has been diagnosed as verbal at some point. Here we can see the diagnosis of verbal disputes as a tool for philosophical progress. Second, they are interesting as a subject matter for first-order philosophy. Reflection on the existence and nature of verbal disputes can reveal something about the nature of concepts, (...) language, and meaning. In this article I first characterize verbal disputes, spell out a method for isolating and resolving them, and draw out conclusions for philosophical methodology. I then use the framework to draw out consequences in first-order philosophy. In particular, I argue that the analysis of verbal disputes can be used to support the existence of a distinctive sort of primitive concept and that it can be used to reconstruct a version of an analytic/synthetic distinction, where both are characterized in dialectical terms alone. (shrink)

This offering in Routledge's acclaimed History of Philosophy series completes the acclaimed 10-volume collection. This work explores the schools of thought that developed in the wake of Platonism through the time of Augustine. The 11 separately authored in-depth articles include: Aristotle the scientist-- David Furley, Princeton University; Aristotle: logic and metaphysics-- Alan Code, Ohio State University; Aristotle: aesthetics and philosophy of mind -- David Gallop, Trent University, Ontario; Aristotle: ethics and politics-- Stephen White, University of Texas at Austin; (...) The peripatetic school-- Robert Sharples, University College, London; Hellenistic science and mathematics-- Alan C. Bowen, Institute for Research in Classical Philosophy and Science, New Jersey; Epicureanism-- Philip Mitsis, Cornell University; Stoicism-- Brad Inwood, University of Toronto; Ancient skepticism-- Michael Frede, Keble College, Oxford; Neo-Platonism-- Eyjdfur Kjalar Emilsson, University of Iceland; Augustine-- G.J.P. O'Daly, University College London. Order the entire Routledge History of Philosophy series and save 10% off each volume! (shrink)

What happens when machines become more intelligent than humans? One view is that this event will be followed by an explosion to ever-greater levels of intelligence, as each generation of machines creates more intelligent machines in turn. This intelligence explosion is now often known as the “singularity”. The basic argument here was set out by the statistician I.J. Good in his 1965 article “Speculations Concerning the First Ultraintelligent Machine”: Let an ultraintelligent machine be defined as a machine that can far (...) surpass all the intellectual activities of any man however clever. Since the design of machines is one of these intellectual activities, an ultraintelligent machine could design even better machines; there would then unquestionably be an “intelligence explosion”, and the intelligence of man would be left far behind. Thus the first ultraintelligent machine is the last invention that man need ever make. The key idea is that a machine that is more intelligent than humans will be better than humans at designing machines. So it will be capable of designing a machine more intelligent than the most intelligent machine that humans can design. So if it is itself designed by humans, it will be capable of designing a machine more intelligent than itself. By similar reasoning, this next machine will also be capable of designing a machine more intelligent than itself. If every machine in turn does what it is capable of, we should expect a sequence of ever more intelligent machines. This intelligence explosion is sometimes combined with another idea, which we might call the “speed explosion”. The argument for a speed explosion starts from the familiar observation that computer processing speed doubles at regular intervals. Suppose that speed doubles every two years and will do so indefinitely. Now suppose that we have human-level artificial intelligence 1 designing new processors. Then faster processing will lead to faster designers and an ever-faster design cycle, leading to a limit point soon afterwards. The argument for a speed explosion was set out by the artificial intelligence researcher Ray Solomonoff in his 1985 article “The Time Scale of Artificial Intelligence”.1 Eliezer Yudkowsky gives a succinct version of the argument in his 1996 article “Staring at the Singularity”: “Computing speed doubles every two subjective years of work.. (shrink)