Cyclin-dependent kinase 5 has been implicated in Alzheimer's disease pathogenesis. Here, we demonstrate that overexpression of p25, an activator of cdk5, led to increased levels of BACE1 mRNA and protein in vitro and in vivo. A p25/cdk5 responsive region containing multiple sites for signal transducer and activator of transcription was identified in the BACE1 promoter. STAT3 interacts with the BACE1 promoter, and p25-overexpressing mice had elevated levels of pSTAT3 and BACE1, whereas cdk5-deficient mice had reduced levels. Furthermore, mice with a (...) targeted mutation in the STAT3 cdk5 responsive site had lower levels of BACE1. Increased BACE levels in p25 overexpressing mice correlated with enhanced amyloidogenic processing that could be reversed by a cdk5 inhibitor. These data demonstrate a pathway by which p25/cdk5 increases the amyloidogenic processing of APP through STAT3-mediated transcriptional control of BACE1 that could have implications for AD pathogenesis. (shrink)

How and why did comparative political economy lose sight of the sources of growing macroeconomic and political instability, a problem that encompassed a growing financial bubble and then a crash in the housing market, a period of sluggish growth that plausibly constitutes secular stagnation, and a crisis of political legitimacy manifesting itself in the rise of antisystem “populist” parties? A gradual shift in CPE’s research agenda from macroeconomic to microeconomic concerns, and from demand-side to supply-side explanations, diminished its ability to (...) analyze adequately the central economic and political problems of the past twenty years. This article traces CPE’s evolution through successive “supermodels” that constituted its core research foci. To understand the current crisis, CPE needs to revisit and update its original roots in Keynes, macroeconomics, and the demand side. This shift is already happening at the margins, as CPE scholars struggle to understand the current crisis. (shrink)

The US neutrino community gathered at the Workshop on the Intermediate Neutrino Program at Brookhaven National Laboratory February 4-6, 2015 to explore opportunities in neutrino physics over the next five to ten years. Scientists from particle, astroparticle and nuclear physics participated in the workshop. The workshop examined promising opportunities for neutrino physics in the intermediate term, including possible new small to mid-scale experiments, US contributions to large experiments, upgrades to existing experiments, R&D plans and theory. The workshop was organized into (...) two sets of parallel working group sessions, divided by physics topics and technology. Physics working groups covered topics on Sterile Neutrinos, Neutrino Mixing, Neutrino Interactions, Neutrino Properties and Astrophysical Neutrinos. Technology sessions were organized into Theory, Short-Baseline Accelerator Neutrinos, Reactor Neutrinos, Detector R&D and Source, Cyclotron and Meson Decay at Rest sessions.This report summarizes discussion and conclusions from the workshop. (shrink)

In this article, we present three basic elements of a neoDavidsonian semantics. The first element is the denial that semantic content is identical to the content conveyed by an utterance; second, the adoption of a minimal semantics as the most natural way to develop a semantic theory for natural language, and third, speech act pluralism, understood as the best way to account for when two utterances say the same thing. These elements taken together give an account of one of the (...) central concerns of 20th century philosophy of language, namely how content can be shared across contexts. (shrink)

Life as a complicated process is composed of causal phenomena. But even if we know the reasons of all that happens in a living organism, we do not know what life really is. The problem of intercausal relation, of “causal structure” remains. The reason why a process takes place, must be found by analysis, causal structures are found by synthesis of the results of this analysis. Causal structures are characterized by two kinds of equilibrium: energetic and specific equilibrium. A state (...) of physical equilibrium is characterized by a minimum of free energy; a biological energetic equilibrium is an organized one, where the vital factors activate the production of energy by each other and force each other to limit that production to the necessary measure. A specific equilibrium is characterized by the properties of its factors, properties by which those factors act as a cause after having received a specific stimulation. Every factor possesses two specific properties, in accordance with the properties of two neighbouring factors, as a link between two other links in a chain . Both forms of equilibrium authorise us to speak of living systems as a “whole”. In the second part of this paper we treat the dynamic aspect of the functions of living systems as a “whole”. This dynamic aspect manifests itself in growth and probably in cortical functions. Blastomeres represent, when isolated, the “whole” of growing potentialities of a germe. In normal contact with each other they restrict themselves to produce a part of that “whole”, in harmony with that which other blastomeres produce. This harmonious restriction can be explained by interaction between all the blastomeres by which every blastomere suppresses in other blastomeres all that it will produce itself. Blastomeres must therefore act on other blastomees not according to their isolate “being”, but according to the influences which they undergo by all other blastomeres, that means according to their “rôle”. There must be a causal net of interaction between all the blastomeres and that net “as a whole” determines every step of growth. Such a net of relation determines also human history and sociology. Materialism only took account of isolated causes, vitalism only of the effect of the net of causal relations without understanding that such a net might be analysed. In reality there is neither materialism nor vitalism.La vie est un phénomène complexe, se composant de différents phénomènes causals, qui un jour peut-être seront réduits à la causalité physique et chimique. Cependant connaitre toutes les causes des phénomènes vitaux ne signifie pas connaître la vie. Le problème de la vie ne se borne pas aux rapports causals, mais implique surtout les rapports intercausals, c'est à dire l'harmonie ou l'équilibre de ses parties constituantes. La vie comme phénomène est provoquée par une „structure causale”. Tandis que les causes sont trouvées par l'analyse, les rapports intercausals doivent être recherchés par la synthèse, c'est-à-dire par la réconstruction de la réalité de l'organisme vivant en se servant des données analytiques. Le système vivant est en équilibre énergétique et spécifique. Les facteurs énergétiques sont interlacés de telle façon, qu'ils s'activent entre eux et qu'ils se forcent entre eux à se resteindre au développement de l'énergie nécessaire. Un équilibre physique c'est l'état d'énergie libre minimum, tandis que l'équilibre biologique c'est un état d'énergie organisée. Dans un équilibre spécifique on ne peut se borner aux effects causals se manifestant par un phénomène. Il faut décrire les rapports des propriétés spécifiques de tous les facteurs; ce sont ces propriétés qui leur permettent d'agir comme cause, lorsqu'-ils sont atteint d'une excitation spécifique. Les facteurs possèdent au moins deux propriétés spécifiques, adaptées à deux facteurs voisins, comme chaque anneau d'une chaine s'adaptant à deux anneaux voisins . Le fait que l'on trouve dans chaque individu ces deux formes d'équilibre nous donne le droit de créer le concept du „tout” par rapport auquel on peut constater l'harmonie de tous les tacteurs.C'est là le „tout statique”, reste encore le „tout dynamique” qui se manifeste par la croissance et probablement par les phénomènes se produisant dans l'écorce cérébrale, base des actes psychiques. Les parties représentent beaucoup de possibilités qui ne se réalisent pas; p.e. les blastomères peuvent représenter le „tout” de l'organisme, tandis qu'ils se borneront dans la croissance normale à la production d'une part de l'individu. Il y a une interaction entre tous les blastomères, de façon que, par la suppression ou par l'activation mutuelle, chaque partie réalise ce que lui laissent les autres et ce qui est en harmonie avec ce que produiront les autres. De cette façon il y aura de l'harmonie dans tout ce qui sera produit. Les parties agissent par cette interaction, non selon leur „être”, en tant que cellule isolée, mais selon leur „rôle” dans le „tout” du germe, rôle qui est déterminé par cette interaction mutuelle universelle. C'est cette interaction qui détermine le „patron causal”, responsable de chaque étappe de la coissance. Ainsi ce ne sont pas les facteus isolés, mais le réseau des rapports établis entre tous les facteurs, qui gouvernent les phénomènes de la croissance. Ce réseau, par activation ou par suppression, détermine à chaque instant les propriétés causales des parties, d'entre toutes les multiples possibilités. Les possibilités étant données dans les cellules, c'est le „tout” du réseau des rapports qui détermine la croissance. Le matérialisme n'a vu que les causes isolées, telles qu'ellés se manifestent dans les expériences des physiciens, grâce à la technique; le vitalisme n'a vu que le „tout”, sans tâcher de l'analyser afin de trouver à sa base le système causal compliqué, que nous avons tâché de décrire. Dans la réalité la théorie du causalisme ni celle du vitalisme le tiennent plus de bout. (shrink)

Three basic elements for a neodavidsonian semantics are presented in thisarticle. Firstly, a rejection of the thesis according to which the semanticcontent is identical with the speech act content. Secondly, the adoption ofsemantic minimalism as the proper domain where a truth-conditionalsemantics ..

Edward Conze once observed of the thirty-eight books constituting the Praj p ramit S tras that their central message could be summed up in two sentences: (1) One should become a Bodhisattva (or Buddha-to-be), i.e. one who is content with nothing less than all-knowledge attained through the perfection of wisdom for the sake of all beings. (2) There is no such thing as a Bodhisattva or as all-knowledge or as a being or as the perfection of wisdom or as an (...) attainment. [1] It seems to me that Conze was profoundly correct, as far as he went, and that what he said of the Praj p ramit literary corpus might apply to other Mah y na S tras , as well. One test of this broad application of Conze's observation to the whole of the Mah y na scriptural tradition lies in a close reading of one of the Mah y na S tras from that tradition, the Saddharmapundarika S tra, “the scripture of the lotus blossom of the wonderful law”, or the Lotus S utra . The Lotus S tra not only makes Conze's point, as I shall try to show, but it goes further in offering a new middle path between the two summary sentences above. In doing this it brings forth a practical ethical-religious way for Buddhists and others to follow who will be caught in the sufferings and terrors of the 21st century. We shall refer to this way as “the way of the Lotus” or “the Lotus way”. In what follows I want to attempt three things. First, using Edward Conze's summary sentences above, I identify and explicate three ways to liberation in the Lotus Sutra , viz. the way of ethics and attachment, i.e. “the Bodhisattva way” ("One should become a Bodhisattva...”); next, the way of emptiness and unattachment, i.e. “the Buddha way” ("There is no such thing as a Bodhisattva...”); and, finally, the Lotus way wherein the Bodhisattva way and the Buddha way combine to form a single and powerful new way of liberation. This third way is indirectly referred to in the remark which Edward Conze makes in his summary of the Praj p ramit immediately following his previous two sentences: “To accept both of these contradictory facts is to be perfect”. [2] To accept the Bodhisattva way together with the Buddha way yields the Lotus way. Second, I demonstrate the significance of the Lotus way as a practical way of solving moral problems for Buddhists and others in the 21st century. Third, and finally, I raise and attempt to answer and solve several questions and puzzles about the Lotus way as a way to peace and liberation for Buddhists and others in the 21st century. (shrink)

Le libéralisme et la liberté des médias sont-ils intrinsèquement liés, comme les deux faces d’une même pièce ? À première vue, ils semblent des corollaires puisqu’ils dérivent tous les deux du principe de liberté. Les mé­dias auraient donc d’autant plus d’espace que le libéralisme serait soli­de­ment implanté politiquement et économiquement. Inversement, un rejet du libéralisme politique irait de pair avec un rejet de la liberté des médias. Cette simplicité est cependant trompeuse. Les médias ne forment pas un ensemble homogène ; (...) il y a médias et médias. Il en va de même pour l’autre terme de l’équation : le libéralisme, même dans ses formes les plus classiques, fonde d’une manière plus éclectique qu’on le croit les libertés. (shrink)

Planear una "estética plural de la naturaleza" es darle a la obviedad del enunciado que se trata de explorar algo parecido a un impulso haciéndolo avanzar por el camino de la complejidad. Esto en primer lugar. Después, hay que pararse a pensar que la articulación de estos términos, arte y naturaleza, no sólo implica enlazar la actividad relativa al primero con una imagen o arsenal de imágenes en las que esta segunda se representaría; también es vincularla a un concepto que (...) la significa. ¿Cuál? Lógicamente, la imitación, la mímesis. Aunque dadas las variaciones que ha sufrido dicho concepto a lo largo de la historia, parece necesario valorar la necesidad de comprender su objeto, la naturaleza, en lo que llamaría su dinamismo temporal. En otras palabras, habría que intentar una "historia de la naturaleza", cuya oportunidad aconsejaría mantenerla en paralelo con la "historia del arte". Y si este paralelismo -desde luego estético- del arte y la naturaleza implica en sus respectivas trayectorias temporales aquella parte de la reflexión estética que explora cada momento histórico con una atención especial en el "arte como mímesis", entonces el objetivo de dicha reflexión será también la naturaleza, que toca ir a buscar allí donde se encuentra efectivamente: en el pensamiento de la época. Tendríamos así los términos Arte, Naturaleza, Mímesis. Y de este último, la Mímesis, ya sabemos que no es la representación fiel de entidades o configuraciones naturales. ¿Qué es entonces? La proyección en una obra de Arte de unos contenidos mentales que tienen por objeto la Naturaleza. Quedan vinculados así los tres términos barajados en este libro. (shrink)

Modernite et tradition? Modernite ou tradition? Que faire de cette question, elle-meme eminemment moderne? Dans le present recueil, l'auteur tente d'avancer une reponse nuancee. Il refuse de muer les termes-cle de la question initiale - modernite et tradition - en un couple antithetique. Il se situe plutot et deliberement dans un fragile entre-deux culturel et conceptuel permettant de decouvrir, d'explorer et d'accepter aussi la mince frontiere a la fois intellectuelle, morale et quotidiennement vecue ou se rencontrent sans cesse modernite et (...) tradition. Une rencontre - les essais reunis dans ce volume le montrent a suffisance - inevitable mais pas forcement dramatique comme d'aucuns le voudraient. La conclusion? Suivant l'auteur, la modernite est condamnee, simplement, a rester jusqu'a un certain degre traditionnelle, a tout jamais, et elle a a thematiser cette appartenance culturelle, religieuse et sociopolitique. Sinon, il sera impossible de sortir de cette impasse qu'est le 'malaise de la modernite'. Apres une reflexion preliminaire poussee sur la problematique centrale du livre - modernite et desenchantement -, l'auteur s'arrete longuement a deux penseurs qui, grace a leur maniere de penser resolument moderne et surprenante, ont conserve cette etrange et envoutante capacite d'emerveiller le lecteur contemporain: Spinoza et Hume. Dans ces oeuvres d'une profondeur et d'une perspicacite admirables se voient thematises certains aspects fondamentaux de la culture tant traditionnelle que moderne comme la religion, la science, l'ethique et le sens commun. La partie subsequente a alors pour but de mieux cerner les multiples rapports entre modernite et tradition. La derniere partie du recueil traite de deux questions actuelles, celles notamment de la soi-disant "fin de l'histoire" (Fukuyama) et de la "crise de la societe occidentale". L'enjeu de cette reflexion plutot ethico-politique reste le meme qu'ailleurs: y-a-t-il moyen de jeter un pont entre modernite et tradition, d'aboutir a une synthese nuancee et viable? Ce que ce livre ambitionne en fin de compte? L'auteur se propose de fournir aux lecteurs les ebauches d'une philosophie moderne et pourtant aussi fort sensible a tout ce que la tradition nous a legue, comme un don presque. Pour y arriver, il essaie de penser et d'ecrire depuis un entre-deux ou s'entrecroisent le premoderne et le moderne ainsi que deux styles philosophiques juges souvent et a tort antinomiques, les philosophies analytique et continentale. (shrink)

El hombre crea su moral tomando en cuenta las aportaciones más íntimas de su espíritu. Así como la historia de la humanidad presenta una serie gradual y emocional de conquistas espirituales, así también la moral se ha logrado a través de la historia, pero siempre sobre el fundamento de la esencia humana, pues no cabe duda de que la jerarquía de los valores depende de cada ser humano. Ella orienta toda su conducta y señala sus grandes metas. El espíritu religioso (...) coloca, en primer término, a los valores de la religión, el moralista a los éticos, el pragmático a los útiles; el estético a las bellas artes, dando preferencia cada una a su valor favorito. (shrink)

Herman Cappelen investigates how language and other representational devices can go wrong, and how to fix them. We use language to understand and talk about the world, but what if our language has deficiencies that prevent it from playing that role? How can we revise our concepts, and what are the limits on revision?

The standard view of philosophical methodology is that philosophers rely on intuitions as evidence. Herman Cappelen argues that this claim is false: it is not true that philosophers rely extensively on intuitions as evidence. At worst, analytic philosophers are guilty of engaging in somewhat irresponsible use of 'intuition'-vocabulary. While this irresponsibility has had little effect on first order philosophy, it has fundamentally misled meta-philosophers: it has encouraged meta-philosophical pseudo-problems and misleading pictures of what philosophy is.

Cappelen and Dever present a forceful challenge to the standard view that perspective, and in particular the perspective of the first person, is a philosophically deep aspect of the world. Their goal is not to show that we need to explain indexical and other perspectival phenomena in different ways, but to show that the entire topic is an illusion.

We give a precis of our book Insensitive Semantics.

_Insensitive Semantics_ is an overview of and contribution to the debates about how to accommodate context sensitivity within a theory of human communication, investigating the effects of context on communicative interaction and, as a corollary, what a context of utterance is and what it is to be in one. Provides detailed and wide-ranging overviews of the central positions and arguments surrounding contextualism Addresses broad and varied aspects of the distinction between the semantic and non-semantic content of language Defends a distinctive (...) and explanatorily powerful combination of semantic minimalism and speech act pluralism Confronts core problems which not only run to the heart of philosophy of language and linguistics, but which arise in epistemology, metaphysics, and moral philosophy as well. (shrink)

Cappelen and Hawthorne present a powerful critique of fashionable relativist accounts of truth, and the foundational ideas in semantics on which the new relativism draws. They argue compellingly that the contents of thought and talk are propositions that instantiate the fundamental monadic properties of truth and falsity.

Cappelen and Hawthorne present a powerful critique of fashionable relativist accounts of truth, and the foundational ideas in semantics on which the new relativism draws. They argue compellingly that the contents of thought and talk are propositions that instantiate the fundamental monadic properties of truth and falsity.

I call the activity of assessing and developing improvements of our representational devices ‘conceptual engineering’.¹ The aim of this chapter is to present an argument for why conceptual engineering is important for all parts of philosophy (and, more generally, all inquiry). Section I of the chapter provides some background and defines key terms. Section II presents the argument. Section III responds to seven objections. The replies also serve to develop the argument and clarify what conceptual engineering is.

The beginning of the twenty-first century saw something of a comeback for relativism within analytical philosophy. Relativism and Monadic Truth has three main goals. First, we wished to clarify what we take to be the key moving parts in the intellectual machinations of self-described relativists. Secondly, we aimed to expose fundamental flaws in those argumentative strategies that drive the pro-relativist movement and precursors from which they draw inspiration. Thirdly, we hoped that our polemic would serve as an indirect defence of (...) a traditional and natural picture concerning truth. According to this picture, what we call ‘Simplicity’, the fundamental structure of semantic reality is best revealed by construing truth as a simple monadic property of propositions that serve as the objects of belief, assertion, meaning and agreement. Our project was not a straightforward one. So-called relativists are not uniform in their key ideology, are often sloppy, casual, obscure or confused in their self-characterization, and differ in their argumentative emphasis among themselves and over time, thereby presenting a target that is both amorphous and shifty. This is an area where parties will frequently claim not to understand each other and where certain parties will sometimes accuse others of failing to make any sense at all. In such a situation, any effort to impose order will inevitably strike some parties as tendentious and unfair. That said, we felt that we had enough of …. (shrink)

This paper evaluates arguments presented by John Perry (and Ken Taylor) in favor of the presence of an unarticulated constituent in the proposition expressed by utterance of, for example, (1):1 1. It's raining (at t). We contend that these arguments are, at best, inconclusive. That's the critical part of our paper. On the positive side, we argue that (1) has as its semantic content the proposition that it is raining (at t) and that this is a location-neutral proposition. According to (...) the view we propose, an audience typically looks for a location when they hear utterances of (1) because their interests in rain are location- focused: it is the location of rain that determines whether we get wet, carrots grow, and roads become slippery. These are, however, contingent facts about rain, wetness, people, carrots, and roads – they are not built into the semantics for the verb 'rain'. (shrink)

Bundel met aanvullingen op colleges, gegeven aan de landbouwhogeschool te Wageningen, waarin de opvattingen worden besproken van ondermeer de Wiener Kreis (Carnap), Popper, Kuhn, Lakatos en Habermas.

Overzicht van de discussies in Nederland in de twintigste eeuw over historisch besef, gevoerd vanuit verschillende wetenschappelijke disciplines en invalshoeken.

Bad Language is the first textbook on an emerging area in the study of language: non-idealized language use, the linguistic behaviour of people who exploit language for malign purposes. This lively, accessible introduction offers theoretical frameworks for thinking about such topics as lies and bullshit, slurs and insults, coercion and silencing.

In this Introduction, we aim to introduce the reader to the basic topic of this book. As part of this, we explain why we are using two different expressions (‘conceptual engineering’ and ‘conceptual ethics’) to describe the topics in the book. We then turn to some of the central foundational issues that arise for conceptual engineering and conceptual ethics, and finally we outline various views one might have about their role in philosophy and inquiry more generally.

This book explores how physicists, astronomers, chemists, and historians in the late nineteenth and early twentieth centuries employed ‘epistemic virtues’ such as accuracy, objectivity, and intellectual courage. In doing so, it takes the first step in providing an integrated history of the sciences and humanities. It assists in addressing such questions as: What kind of perspective would enable us to compare organic chemists in their labs with paleographers in the Vatican Archives, or anthropologists on a field trip with mathematicians poring (...) over their formulas? While the concept of epistemic virtues has previously been discussed, primarily in the contexts of the history and philosophy of science, this volume is the first to enlist the concept in bridging the gap between the histories of the sciences and the humanities. Chapters research whether epistemic virtues can serve as a tool to transcend the institutional disciplinary boundaries and thus help to attain a ‘post-disciplinary’ historiography of modern knowledge. Readers will gain a contextualization of epistemic virtues in time and space as the book shows that scholars themselves often spoke in terms of virtue and vice about their tasks and accomplishments. This collection of essays opens up new perspectives on questions, discourses, and practices shared across the disciplines, even at a time when the neo-Kantian distinction between sciences and humanities enjoyed its greatest authority. Scholars including historians of science and of the humanities, intellectual historians, virtue epistemologists, and philosophers of science will all find this book of particular interest and value. (shrink)

An introduction to relativism about truth.