© Copyright 2015, Mary Ann Liebert, Inc..Signal transducer and activator of transcription factor 3 is hyperactivated in head and neck squamous cell carcinomas. Cumulative evidence indicates that IL-6 production by HNSCC cells and/or stromal cells in the tumor microenvironment activates STAT3 and contributes to tumor progression and drug resistance. A library of 94,491 compounds from the Molecular Library Screening Center Network was screened for the ability to inhibit interleukin-6 -induced pSTAT3 activation. For contractual reasons, the primary high-content screening campaign was (...) conducted over several months in 3 distinct phases; 1,068 primary HCS actives remained after cytotoxic or fluorescent outliers were eliminated. One thousand one hundred eighty-seven compounds were cherry-picked for confirmation; actives identified in the primary HCS and compounds selected by a structural similarity search of the remaining MLSCN library using hits identified in phases I and II of the screen. Actives were confirmed in pSTAT3 IC50 assays, and an IFNγ-induced pSTAT1 activation assay was used to prioritize selective inhibitors of STAT3 activation that would not inhibit STAT1 tumor suppressor functions. Two hundred three concentration-dependent inhibitors of IL-6-induced pSTAT3 activation were identified and 89 of these also produced IC50s against IFN-γ-induced pSTAT1 activation. Forty-nine compounds met our hit criteria: they reproducibly inhibited IL-6-induced pSTAT3 activation by ≥70% at 20 μM; their pSTAT3 activation IC50s were ≤25 μM; they were ≥2-fold selective for pSTAT3 inhibition over pSTAT1 inhibition; a cross target query of PubChem indicated that they were not biologically promiscuous; and they were ≥90% pure. Twenty-six chemically tractable hits that passed filters for nuisance compounds and had acceptable drug-like and ADME-Tox properties by computational evaluation were purchased for characterization. The hit structures were distributed among 5 clusters and 8 singletons. Twenty-four compounds inhibited IL-6-induced pSTAT3 activation with IC50s ≤20 μM and 13 were ≥3-fold selective versus inhibition of pSTAT1 activation. Eighteen hits inhibited the growth of HNSCC cell lines with average IC50s ≤ 20 μM. Four chemical series were progressed into lead optimization: the guanidinoquinazolines, the triazolothiadiazines, the amino alcohols, and an oxazole-piperazine singleton. (shrink)

The analysis of a previous paper, in which it was shown that the energy for the Aharonov-Bohm effect could be traced to the interaction energy between the magnetic field of the electron and the background magnetic field, is extended to cover the case in which the magnetic field of the electron is shielded from the background magnetic field by a superconducting material. The paradox that arises from the fact that such a shielding would apparently preclude the possibility of an interaction (...) energy is resolved and, within the limits of the ideal situation considered, the observed experimental result is derived. (shrink)

It is shown that the time-dependent WKB expansion highlights some of the hidden properties of the Schrödinger equation and forms a natural bridge between that equation and the functional integral formulation of quantum mechanics. In particular it is shown that the leading (zero- and first-order in ħ) terms in the WKB expansion are essentially classical, and the relationship of this result to the classical nature of the WKB partition function, and of the anomalies in quantum field theory, is discussed.

Bathos - remarque -- Pt. 1. Le champ de bataille -- Pt. 2. Kant et ses juges -- Pt. 3. Traité de bathologie.

One of Hume's most well-known works and a masterpiece of philosophy, A Treatise of Human Nature is indubitably worth taking the time to read.

While there are numerous doubts, controversies and lack of consensus on alternative definitions of human death, it is argued that it is more ethical to allow people to choose either cessation of cardio-respiratory function or loss of entire brain function as the definition of death based on their own views. This paper presents the law of organ transplantation in Japan, which allows people to decide whether brain death can be used to determine their death in agreement with their family. Arguably, (...) Japan could become a unique example of individual choice in the definition of death if the law is revised to allow individuals choose definition of death independently of their family. It suggests that such an approach is one of the reasonable policy options a country can adopt for legislation on issues related to the definition of death. (shrink)

Ludwig Wittgenstein (1889-1951) was an extraordinarily original thinker, whose influence on twentieth-century thinking far outside the bounds of philosophy alone. In this engaging Introduction, A.C. Grayling makes Wittgenstein's thought accessible to the general reader by explaining the nature and impact of Wittgenstein's views. He describes both his early and later philosophy, the differences and connections between them, and gives a fresh assessment of Wittgenstein's continuing influence on contemporary thought.

Background: The magnitude of bullying and harassment among psychiatrists is reportedly high, yet no peer-review published studies addressing this issue could be found. Therefore, it was decided to conduct a pilot study to assess the degree of the problem, the types of bullying/harassment and to provide some insights into the situation.Methods and Principal Findings: Following multiple focus group meetings, a yes/no response type questionnaire was developed to assess the degree and type of bullying and harassment experienced by psychiatrists. Over a (...) 3-month period the questionnaire was administered to a random sample of 60 psychiatrists. 57 out of the 60 psychiatrists reported harassment and bullying. Frequencies of the following response variables are presented in descending order: rumours 40% ; defamation 20% ; passing remarks 20% ; false accusations 15% ; threats 13.3% ; verbal abuse 13.3% ; unjustified complaints 13.3% ; promotion blocked 13.3% ; humiliation 13% ; bad reference given 10% ; credentials questioned 8.3% ; physical attacks 5% ; termination 5% ; derogatory remarks 1.7% and 1.7% were subjected to personal work. As a result of being subjected to harassment, 66.7% of the psychiatrists did not take any action, whereas 33.3% confronted the person they believed responsible. Asked whether the bullying and harassment caused distress, 18.3% of the psychiatrists did not report any effect, 30% reported mild distress, 40% moderate distress and severe distress was reported by 11.7%.Conclusions: It was concluded that the magnitude of bullying and harassment among psychiatrists may be quite high, as evidenced by this pilot study. There is a need for extensive systematic studies on this subject and to establish strategies to prevent and address this issue at a national and regulatory level. (shrink)

Is unethical conduct necessarily irrational? Answering this question requires giving an account of practical reason, of practical good, and of the source or point of wrongdoing. By the time most contemporary philosophers have done the first two, they have lost sight of the third, chalking up bad action to rashness, weakness of will, or ignorance. In this book, Candace Vogler does all three, taking as her guides scholars who contemplated why some people perform evil deeds. In doing so, she sets (...) out to at once engage and redirect contemporary debates about ethics, practical reason, and normativity. -/- Staged as a limited defense of a standard view of practical reason (an ancestor of contemporary instrumentalist views), Vogler's essay develops Aquinas's remark about three ways an action might be desirable into an exhaustive system for categorizing reasons for acting. Drawing on Elizabeth Anscombe's pioneering work on intention, Vogler argues that one sort (means/end or calculative reasons for acting) sets the terms for all sound work on practical rationality. -/- She takes up Aquinas's work on evil throughout, arguing that he provides us with a systematic theory of immorality that takes seriously the goods at issue in wrongdoing and the reasons for unethical conduct. Vogler argues that, shorn of its theological context, this theory leaves us with no systematic, uncontroversial way of arguing that wrongdoing is necessarily contrary to reason. (shrink)

The urgency of the research topic is that the theoretical and methodological principles of psychology of managerial activity of the head in the conditions of the information society help to increase the levers of management and guidance. The purpose of management - the receipt of the desired result, which must be obtained after the actions of the management of the head as the main operating force, which is heading for transformations, tries to increase the self-governing principle in the organization. The (...) problem of research is that for effective management it is necessary to develop reliable mechanisms for the identification and development of manager's abilities, to increase the level of professionalism and competence of the head to the highest level, so that the management organism does not disorient. A person who works as a specialist, a professional, a competent person can be qualified to carry out the work of a manager. The hypothesis is put forward that the manager of a high level of professionalism and competence is able to form the psychological foundations of the organization, so that it worked as a single social organism. The task of the research is to analyze the psychological foundations of management activity in the conditions of the information society, which would allow the most optimal management of a particular organization. The methodological foundations of the psychology of management as the basis of effective leadership include methods of cultural development, which are used to solve the problems of organization, the formation of psychological culture, devoid of conflicts, contradictions, disasters. Methodological basis of scientific research of psychological principles of administrative activity as the basis of effective management are methods, such as system, structural, structural-functional, historical, comparative, which allow to achieve a higher level of organization and self-organization at the expense of skilful leadership. Therefore, the manager must use the whole set of methods, techniques, algorithms of actions, techniques, methods of achieving certain results that will lead to the management of a high level. It is concluded that the determinants of the optimization of the managerial psychology of the head is a model aimed at regulating relationships, which would use the resources of the information society, which is based on high information provision for improving the efficiency of management work. (shrink)

This introduction to the basic ideas of structural proof theory contains a thorough discussion and comparison of various types of formalization of first-order logic. Examples are given of several areas of application, namely: the metamathematics of pure first-order logic (intuitionistic as well as classical); the theory of logic programming; category theory; modal logic; linear logic; first-order arithmetic and second-order logic. In each case the aim is to illustrate the methods in relatively simple situations and then apply them elsewhere in much (...) more complex settings. There are numerous exercises throughout the text. In general, the only prerequisite is a standard course in first-order logic, making the book ideal for graduate students and beginning researchers in mathematical logic, theoretical computer science and artificial intelligence. For the new edition, many sections have been rewritten to improve clarity, new sections have been added on cut elimination, and solutions to selected exercises have been included. (shrink)

This exciting new Handbook offers a comprehensive overview of the contemporary state of the field. The editors' introduction and forty-five essays cover feminist critical engagements with philosophy and adjacent scholarly fields, as well as feminist approaches to current debates and crises across the world. Authors cover topics ranging from the ways in which feminist philosophy attends to other systems of oppression, and the gendered, racialized, and classed assumptions embedded in philosophical concepts, to feminist perspectives on prominent subfields of philosophy. The (...) first section contains chapters that explore feminist philosophical engagement with mainstream and marginalized histories and traditions, while the second section parses feminist philosophy's contributions to with numerous philosophical subfields, for example metaphysics and bioethics. A third section explores what feminist philosophy can illuminate about crucial moral and political issues of identity, gender, the body, autonomy, prisons, among numerous others. The Handbook concludes with the field's engagement with other theories and movements, including trans studies, queer theory, critical race, theory, postcolonial theory, and decolonial theory. The volume provides a rigorous but accessible resource for students and scholars who are interested in feminist philosophy, and how feminist philosophers situate their work in relation to the philosophical mainstream and other disciplines. Above all it aims to showcase the rich diversity of subject matter, approach, and method among feminist philosophers. (shrink)

The Problem of Perception offers two arguments against direct realism--one concerning illusion, and one concerning hallucination--that no current theory of ...

Extraterrestrial Altruism examines a basic assumption of the Search for Extraterrestrial Intelligence (SETI): that extraterrestrials will be transmitting messages to us for our benefit. This question of whether extraterrestrials will be altruistic has become increasingly important in recent years as SETI scientists have begun contemplating transmissions from Earth to make contact. Technological civilizations that transmit signals for the benefit of others, but with no immediate gain for themselves, certainly seem to be altruistic. But does this make biological sense? Should we (...) expect altruism to evolve throughout the cosmos, or is this only wishful thinking? Is it dangerous to send messages to other worlds, as Stephen Hawking has suggested, or might humankind benefit from an exchange with intelligence elsewhere in the galaxy? Would extraterrestrial societies be based on different ethical principles, or would we see commonalities with Earthly notions of morality? Extraterrestrial Altruism explores these and related questions about the motivations of civilizations beyond Earth, providing new insights that are critical for SETI. Chapters are authored by leading scholars from diverse disciplines—anthropology, astronomy, biology, chemistry, computer science, cosmology, engineering, history of science, law, philosophy, psychology, public policy, and sociology. The book is carefully edited by Douglas Vakoch, Director of Interstellar Message Composition at the SETI Institute and professor of clinical psychology at the California Institute of Integral Studies. The Foreword is by Frank Drake. This interdisciplinary book will benefit everybody trying to understand whether evolution and ethics are unique to Earth, or whether they are built into the fabric of the universe. (shrink)

Comment devient-on philosophe? Par quel sursaut un Aristoclès se fait-il Platon, jusqu'à s'imposer dans la liste des " auteurs philo " Il faut enquêter, non pas sur la vie privée, mais sur la vie intime : rumination intellectuelle, ton sur lequel on parle, motivations amoureuses... Ce qui fait un philosophe, c'est un immense travail sur soi, et la rencontre d'autres philosophes, vivants, de leurs problématiques. Mémoire sémantique + obsession métaphysique, voilà le code génétique du philosophe. Il débute par un attentat (...) religieux, puisqu'il commence sa carrière en niant tel ou tel sacré. Bien sûr, il vaut mieux être mâle, communiquer par les livres adopter la langue dominante, écrire quand on est célibataire. Comment gagner sa vie? Pas forcément en étant enseignant, comme c'est le cas aujourd'hui. Le profil du philosophe nous le révèle orphelin, vivant à l'étranger, souvent laid, jamais fou, et serial thinker, prêt à changer de philosophie pourvu qu'il reste, lui, à menacer le monde donnera ou donnera pas du sens à notre vie? Le philosophe est l'être inquiet qui pense inquiéter l'Être par deux trois mots bien aiguisés. (shrink)

How (Not) to Be Secular is what Jamie Smith calls "your hitchhiker's guide to the present" -- it is both a reading guide to Charles Taylor's monumental work A Secular Age and philosophical guidance on how we might learn to live in our times. Taylor's landmark book A Secular Age (2007) provides a monumental, incisive analysis of what it means to live in the post-Christian present -- a pluralist world of competing beliefs and growing unbelief. Jamie Smith's book is a (...) compact field guide to Taylor's insightful study of the secular, making that very significant but daunting work accessible to a wide array of readers. Even more, though, Smith's How (Not) to Be Secular is a practical philosophical guidebook, a kind of how-to manual on how to live in our secular age. It ultimately offers us an adventure in self-understanding and maps out a way to get our bearings in today's secular culture, no matter who "we" are -- whether believers or skeptics, devout or doubting, self-assured or puzzled and confused. This is a book for any thinking person to chew on. (shrink)

The philosophy of Epictetus, a freed slave in the Roman Empire, has been profoundly influential on Western thought: it offers not only stimulating ideas but practical guidance in living one's life. A. A. Long, a leading scholar of later ancient philosophy, gives the definitive presentation of the thought of Epictetus for a broad readership. Long's fresh and vivid translations of a selection of the best of Epictetus' discourses show that his ideas are as valuable and striking today as they were (...) amost two thousand years ago. This is a book for anyone interested in what we can learn from ancient philosophy about how to live our lives. (shrink)

Introduction: Conversion and the practice of transformation -- The philosophical structure of Jonathan Edwards's religious affections -- Habit, habit change, and conversion in C.S. Peirce -- Reconstructing faith : religious overcoming in Dewey's pragmatism -- Transforming obligation in William James -- Dwelling in absence: the reflective origin of conversion -- Creative transformation : the work of conversion -- The evasion of conversion in recent American philosophy.

Provability, Computability and Reflection.

In this article, we present results from a literature review of intrinsic, instrumental, and relational values of nature conducted for the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services, as part of the Methodological Assessment of the Diverse Values and Valuations of Nature. We identify the most frequently recurring meanings in the heterogeneous use of different value types and their association with worldviews and other key concepts. From frequent uses, we determine a core meaning for each value type, which is (...) sufficiently inclusive to serve as an umbrella over different understandings in the literature and specific enough to help highlight its difference from the other types of values. Finally, we discuss convergences, overlapping areas, and fuzzy boundaries between different value types to facilitate dialogue, reduce misunderstandings, and improve the methods for valuation of nature's contributions to people, including ecosystem services, to inform policy and direct future research. © 2023 The Author(s). Published by Oxford University Press on behalf of the American Institute of Biological Sciences. (shrink)

To Serve With Honor should be required reading for all members of the officer corps of the United States military. Beyond that, it should be made required reading for all United States military academies, ROTC and officer candidate programs. This treatise on military ethics goes a long way in bridging the gap between the military and society's understanding of the military's ethical dilemma. It is a must for the student of military affairs. International Social Science Review To Serve With Honor (...) is the first book by an American to focus on the validity of current standards of military ethics in more than a century. This thoughtful study begins with the premise that the military profession is qualitatively different from any other profession. Author Richard Gabriel uses this assumption to address such vital questions as What are the limits of military obedience? and When does a soldier have an obligation to resist the orders of his superiors? (shrink)

We apply Hrushovski-Fraïssé's amalgamation procedure to obtain a theory of fields of prime characteristic of Morley rank 2 equipped with a definable additive subgroup of rank 1.