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)

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)

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)

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)

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 ..

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)

Russell Herman Conwell was an American Baptist minister, orator, philanthropist, lawyer, and writer. He is best remembered as the founder and first president of Temple University in Philadelphia, Pennsylvania, as the Pastor of The Baptist Temple, and for his inspirational lecture Acres of Diamonds. "Acres of Diamonds" originated as a speech which Conwell delivered over 6,000 times around the world. It was first published in 1890 by the John Y. Huber Company of Philadelphia. The central idea of the work (...) is that one need not look elsewhere for opportunity, achievement, or fortune--the resources to achieve all good things are present in one's own community. This theme is developed by an introductory anecdote, told to Conwell by an Arab guide, about a man who wanted to find diamonds so badly that he sold his property and went off in futile search for them; the new owner of his home discovered that a rich diamond mine was located right there on the property. Conwell elaborates on the theme through examples of success, genius, service, or other virtues involving ordinary Americans contemporary to his audience: "dig in your own back-yard!". (shrink)

Martial Gueroult donna un cours au Collège de France sur la Critique de la raison pure de Kant lors de l’année 1957-1958, qui est à ce jour inédit. Le texte qui est présenté ici est l’édition d’une des leçons portant sur la différence entre les deux versions de la déduction transcendantale des catégories. Gueroult y aborde une question classique du commentaire, celle de savoir si la deuxième édition de la Critique a renié la doctrine de la première version. Contre l’interprétation (...) de Herman Jan de Vleeschauwer, Gueroult défend que l’effort de clarification de la déduction, non moins que le souci d’écarter une lecture psychologisante des facultés, ont conduit Kant à emprunter un unique chemin de la déduction des catégories : de haut en bas. (shrink)

Most of us have been brought up on the idea that moral theories divide as they are, at the root, either deontological or consequentialist. A new point of division has been emerging that places deontological and consequentialist theories together against theories of virtue, or a conception of morality constrained at the outset by the requirements of the “personal.” In a series of important essays Bernard Williams has offered striking arguments for the significance of the personal in moral thought based on (...) the role of integrity in human activity and character. His criticisms of both Kantian and utilitarian theories for their deep-seated tendencies to undermine the integrity of persons brings to a new level of seriousness and subtlety long-standing complaints against these theories—the invasive do-gooding of utilitarianism, the coldness and severity toward normal human concerns of Kantian theory. Although Williams is inclined to find the sources of the attack on integrity in these different features of the two traditional theories, in the end his complaint against both of them turns on their demand that the moral agent submit himself to the authority of impartial value. (shrink)

In this text presented here, it has been tried to Show the difference between Heidegger’s first and second era understanding of language. In his first era, to manifest Heidegger’s understanding of language, outlines of Being and Time has been discussed and concerned chapter is read carefully. To manifest his understanding of language in second era, the work of On the Way to the Language has been taken as a base. With this comparative study, it has been tried to shown the (...) change that “language” has undergone in Heidegger philosophy. (shrink)

The present paper studies the general implications of theprinciple of compositionality for the organization of grammar.It will be argued that Janssen''s (1986) requirement that syntax andsemantics be similar algebras is too strong, and that the moreliberal requirement that syntax be interpretable into semanticsleads to a formalization that can be motivated and applied more easily,while it avoids the complications that encumber Janssen''s formalization.Moreover, it will be shown that this alternative formalization evenallows one to further complete the formal theory of compositionality, inthat (...) it is capable of clarifying the role played by translation,model-theoretic interpretation and meaning postulates,of which the latter two aspects received little or no attention inMontague (1970) and Janssen (1986). (shrink)

The uniform halting problem (UH) can be stated as follows.Give a decision procedure which for any given Turing machine (TM) will decide whether or not it has an immortal instantaneous description (ID).An ID is called immortal if it has no terminal successor. As it is generally the case in the literature (see e.g. Minsky [3, p. 118]) we assume that in an ID the tape must be blank except for some finite numbers of squares. If we remove this restriction the (...) UH becomes the immortality problem (IP). The UH should not be confused with the initialised uniform halting problem (whether or not a TM has an immortal ID when started in a specified state) which can easily be shown to be undecidable (see e.g. Minsky [3, p. 151]). (shrink)

We dispute Penn et al.'s claim of the sharp functional discontinuity between humans and nonhumans with evidence in bottlenose dolphins (Tursiops truncatus) of higher-order generalizations: spontaneous integration of previously learned rules and concepts in response to novel stimuli. We propose that species-general explanations that are in approach are more plausible than Penn et al.'s innatist approach of a genetically prespecified supermodule.

This essay concerns the multiple faces of science in ethical environmental decision-making. Environmental crises pose existential threats to human and non-human life. Science is essential to any meaningful response to these crises, but science as it is conventionally understood and practiced is not adequate to the task. Drawing on the work of Bruno Latour in his 2013 Gifford Lectures on ―Facing Gaia: Six Lectures on the Political Theology of Nature,‖1 I will critique this understanding and practice in relation to four (...) faces of science - capacity builder, informer and guide, philosophy, and institution—and propose reforms. (shrink)