Mammalian AMP‐activated protein kinase is the central component of a protein kinase cascade which inactivates three key enzymes involved in the synthesis or release of free fatty acids and cholesterol inside the cell. The kinase cascade is activated by elevation of AMP, and perhaps also by fatty acid and cholesterol metabolites. The system may fulfil a protective function, preventing damage caused by depletion of ATP or excessive intracellular release of free lipids, a type of stress response. Recent evidence suggests that (...) it may have been in existence for at least a billion years, since a very similar protein kinase cascade is present in higher plants. This system therefore represents an early eukaryotic protein kinase cascade, which is unique in that it is regulated by intracellular metabolites rather than extracellular signals or cell cycle events. (shrink)

Variations in levels of apolipoprotein E have been tied to the risk and progression of Alzheimer's disease . Our group has previously compared and contrasted the promoters of the mouse and human ApoE gene promoter sequences and found notable similarities and significant differences that suggest the importance of the APOE promoter's role in the human disease. We examine here three specific single-nucleotide polymorphisms within the human APOE promoter region, specifically at -491 , -427 , and at -219 upstream from the (...) +1 transcription start site. The -219 and -491 polymorphic variations have significant association with instance of AD, and -491AA has significant risk even when stratified for the APOEepsilon4 allele. We also show significant effects on reporter gene expression in neuronal cell cultures, and, notably, these effects are modified by species origin of the cells. The -491 and -219 polymorphisms may have an interactive effect in addition to any independent activity. DNA-protein interactions differ between each polymorphic state. We propose SP1 and GATA as candidates for regulatory control of the -491 and -219 polymorphic sites. This work's significance lies in drawing connection among APOE promoter polymorphisms' associations with AD to functional promoter activity differences and specific changes in DNA-protein interactions in cell culture-based assays. Taken together, these results suggest that APOE expression levels are a risk factor for AD irrespective of APOEepsilon4 allele status. (shrink)

Progressive supranuclear palsy is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP and 3,247 controls followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the (...) stage 1 SNPs that yielded P ≤ 10-3. We found significant previously unidentified signals associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component. © 2011 Nature America, Inc. All rights reserved. (shrink)

Le culte grandiose de Kali, la Mère, son incomparable symbolisme, ses litanies et ses chants, embrasse l'âme de l'univers qu'il glorifie comme aucune conception religieuse ne le fit jamais. La terrifiante déesse sème la peste et les pires ravages sur ses pas, tout en accordant sa grâce et sa clémence à ses enfants assez hardis pour soulever l'horrible masque derrière lequel elle se cache la figure. Ceux-là retrouveront les traits radieux qui ont enchanté leur enfance. La sublime conception de Kali, (...) la Mère, découle d'une philosophie moniste qui s'écarte pourtant sensiblement de la philosophie Védanta de Shankara. Tous deux partent, il est vrai, de la même idée. Ils admettent l'un et l'autre une substance une, indivisible et éternelle, que les Védantins appellent Brahma et les adorateurs de Kali, la Mère, Siva. Mais il y a divergence quant aux manifestations. Pour Shankara il n'y a qu'illusion. Il tranche le lien qui rattache le phénomène à l'absolu. Il se demande qui a pu susciter l'apparence. Mais, l'absolu étant la vérité même, il n'a pu engendrer l'apparence pas plus que la lumière n'aurait pu engendrer l'obscurité. Qu'y avait-il donc de commun entre les Brahmas et Maya? A première vue il semble qu'il n'y a aucun rapport. Pour Shankara il n'était besoin d'aucune relation, puisque Maya n'existe pas en réalité et que le monde n'est que mirage. Le monde n'existe que pour l'esprit qui est lui-même sujet aux hallucinations. Adorer la Mère, c'est accepter l'univers dans ses aspects les plus terrifiants. Cette philosophie est diamétralement opposée au christianisme dans son culte du Dieu d'amour, du Père plein de miséricorde. Le christianisme enseigne que tout se fait pour notre bien, tandis que pour les adorateurs de Kali, l'univers est féroce et hostile à l'homme, qui avant tout doit se montrer supérieur aux événements. Mais Kali n'est pas seulement la destructrice. Si elle démolit inexorablement toutes les formes vitales qui ont fait leur temps et qui se détériorent, elle en crée au fur et à mesure des nouvelles. C'est dans cette conception de la Mère qu'il faut chercher tout d'abord le mystère de l'esprit indien. Dans son essence la plus intime la mère du monde est l'absolu, est Siva même. Comme telle elle représente la connaissance, l'entité et la joie absolues. Pour les adorateurs de Kali les mots Mantram Saham (je suis elle) renferment la clef de la vie et dissipent crainte et tristesse. (shrink)

In a recent article [Mertz 2001] in this journal I argued for the virtues of a realist ontology of relation instances (unit attributes). A major strength of this ontology is an assay of ontic ('material') predication that yields an account of individuation without the necessity of positing and defending 'bare particulars'. The crucial insight is that it is the unifying agency or combinatorial aspect of a relation instance as predicable that is for ontology the principium individuationis [Mertz 2002; 1996]. Or (...) in short, what is ontically predicable, precisely as such, is the cause of individuation. As a preface to this positive doctrine I offered arguments against the coherence of bare particulars as defended in an article by J. P. Moreland [1998]. In a reply contained in this issue Moreland and Timothy Pickavance (hereafter M/P) propose to answer my objections [2002]. The response that follows provides reasons why, I contend, M/P have not succeeded in parrying my objections to bare particulars. (shrink)

López-Escobar, E. G. K. Introduction.--Kueker, D. W. Back-and-forth arguments and infinitary logics.--Green, J. Consistency properties for finite quantifier languages.--Cunningham, E. Chain models.--Gregory, J. On a finiteness condition for infinitary languages.

This book is available either individually, or as part of the specially-priced Arguments of the Philosphers Collection.

It is through our actions that we affect the way the world goes. Whenever we face a choice of what to do, we also face a choice of which of various possible worlds to actualize. Moreover, whenever we act intentionally, we act with the aim of making the world go a certain way. It is only natural, then, to suppose that an agent's reasons for action are a function of her reasons for preferring some of these possible worlds to others, (...) such that what she has most reason to do is to bring about the possible world which, of all those available to her, is the one that she has most reason to want to obtain. This is what is known as the `teleological conception of practical reasons'. Whether this is the correct conception of practical reasons is important not only in its own right, but also in virtue of its potential implications for what sort of moral theory we should accept. Below, I argue that the teleological conception is indeed the correct conception of practical reasons. (shrink)

OBJECTIVES: To study empirically whether ethical theory (from the mainstream principles-based, virtue-based, and feminist schools) usefully describes the approaches doctors and nurses take in everyday patient care. DESIGN: Ethnographic methods: participant observation and interviews, the transcripts of which were analysed to identify themes in ethical approaches. SETTING: A British old-age psychiatry ward. PARTICIPANTS: The more than 20 doctors and nurses on the ward. RESULTS: Doctors and nurses on the ward differed in their conceptions of the principles of beneficence and respect (...) for patient autonomy. Nurses shared with doctors a commitment to liberal and utilitarian conceptions of these principles, but also placed much greater weight on relationships and character virtues when expressing the same principles. Nurses also emphasised patient autonomy, while doctors were more likely to advocate beneficence, when the two principles conflicted. CONCLUSION: The study indicates that ethical theory can, contrary to the charges of certain critics, be relevant to everyday health care-if it (a) attends to social context and (b) is flexible enough to draw on various schools of theory. (shrink)

In the earlier sections of part one of the "critique of judgment," discussing natural beauty, Kant describes the aesthetical or beautiful in strongly formalistic terms. In the closing sections of this part, Discussing fine art, He characterizes the aesthetical or beautiful in predominantly expressionistic terms. The puzzle is not that these views are different but that our philosopher seems to think they are identical. Various hypotheses that claim to explain this puzzle are examined. The key suggested is kant's background or (...) approach. In analysing the aesthetical, Kant is looking for evidence of a harmony between natural fact and moral aspiration, Nature and freedom. For this purpose the aesthetical as form seems best in the field of natural beauty, And the aesthetical as expression in the field of fine art. (shrink)

Central to Elements is an assay of the attributional union properties and relations have with their subjects, a topic historically left metaphorical. The work critiques eight Aristotelian assumptions concerning attribute dependence and ‘inherence’, per se subjects, attributes as agent-organizers, and unity-by-a-shared-one. Groups of these assumptions are seen to yield contradiction, vicious regress, or other problems. This analysis, joined with insights from an assay of ubiquitous structure, motivate ten theses explicating attribution and its primary ontic status. The theses detail: attributes proper (...) as individuated instances, structure as instance-generated facts and their two forms of composition, the conditioning role and universal nature of instances’ component intensions, the primacy of attribute instances for generating all forms of composition and complex entities, and identity and indiscernibility criteria for the latter. Principal is the insight that attribution is intension-determined combinatorial agency. It is its systematizing implications that provide solutions to classic problems, e.g., Composition, Individuation, and Universals, and in net generate a comprehensive one-category structuralist ontology. (shrink)

There has been a good deal of interest in recent years in what Franz Brentano had to say about the notion of ‘intentional objects’ and about intentionality as a criterion of the mental. There has been less interest in his classification of mental phenomena. In his Psychology from an Empirical Standpoint Brentano asserts and argues for the thesis that mental phenomena can be classified in terms of three kinds of mental act or activity, all of which are directed towards an (...) immanent object. These are, respectively, presentation, judgment and what he calls the phenomena of love and hate. Once again, less interest has been shown in what he has to say about the last of these three than in what he says about the others. I wish to take Brentano's views as the point of departure for a discussion of love and hate, since these notions seem to me to have a good deal of philosophical interest, for at least two main reasons. First, I have recently had some concern with the part that personal relations play in our understanding of others and of ourselves, and love and hate seem to be very important elements in such relations. Second, love and hate have long seemed to me to provide important counter-examples to some prevalent philosophical theories about the emotions. I shall take this issue first. (shrink)

D W Hamlyn; The Concept of Development, Journal of Philosophy of Education, Volume 9, Issue 1, 30 May 2006, Pages 26–39, https://doi.org/10.1111/j.1467-9752.197.

A model of spontaneous collapse of fermionic degrees of freedom in a quantum field is presented which has the advantages that it explicitly maintains energy conservation and gives results in agreement with an existing numerical method for calculating quantum state evolution, namely the quantum trajectories model.