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)

© 2017. The American Astronomical Society. All rights reserved.We present new observations of the low-mass companion to HD 984 taken with the Gemini Planet Imager as a part of the GPI Exoplanet Survey campaign. Images of HD 984 B were obtained in the J and H bands. Combined with archival epochs from 2012 and 2014, we fit the first orbit to the companion to find an 18 au orbit with a 68% confidence interval between 14 and 28 au, an eccentricity (...) of 0.18 with a 68% confidence interval between 0.05 and 0.47, and an inclination of 119°with a 68% confidence interval between 114°and 125°. To address the considerable spectral covariance in both spectra, we present a method of splitting the spectra into low and high frequencies to analyze the spectral structure at different spatial frequencies with the proper spectral noise correlation. Using the split spectra, we compare them to known spectral types using field brown dwarf and low-mass star spectra and find a best-fit match of a field gravity M6.5 ±1.5 spectral type with a corresponding temperature of K. Photometry of the companion yields a luminosity of log=2.88 ± 0.07 dex with DUSTY models. Mass estimates, again from DUSTY models, find an age-dependent mass of 34 ±1 to 95 ±4 M Jup. These results are consistent with previous measurements of the object. (shrink)

"First published by Oxford University Press, 1916."--Title page verso.

Seneca ‘Rhetor’ was last critically edited by H. J. Müller in 1887; the editions of H. Bornecque and W. A. Edward lack an apparatus criticus, though the latter's notes give some attention to textual points. Whoever next addresses himself to the task can take heart from Eduard Norden : ‘der Text ist schwer korrupt, für Konjekturalkritik noch viel zu tun.’ It may be added that he will do a service by jettisoning a large proportion of what Konjekturalkritik has already produced-too (...) much of this nature in Müller's text and apparatus, to say nothing of later contributions, is merely depressing. (shrink)

Seneca ‘Rhetor’ was last critically edited by H. J. Müller in 1887; the editions of H. Bornecque and W. A. Edward lack an apparatus criticus, though the latter's notes give some attention to textual points. Whoever next addresses himself to the task can take heart from Eduard Norden : ‘der Text ist schwer korrupt, für Konjekturalkritik noch viel zu tun.’ It may be added that he will do a service by jettisoning a large proportion of what Konjekturalkritik has already produced-too (...) much of this nature in Müller's text and apparatus, to say nothing of later contributions, is merely depressing. (shrink)

An English language translation accompanies the original Greek text of Aristotle's book about the nature of the state, constitutions, revolutions, democracy, and oligarchy.

A relaxed and short road to peace of mind uncomplicated by the intellect and personal history. This renowned German teacher advocates deconstructing the tyrants called "feelings" and the egocentered programming of many lifetimes.

First published in 1938. The aim of this book is to expound Kant’s _Critique of Judgement _by interpreting all the details in the light of what Kant himself declares to be his fundamental problem. _A Commentary on Kant’s Critique of Judgement _provides an excellent introduction to Kant’s third critique, and will be of interest to students of philosophy.

This paper defends the view of continuants as 'four-dimensional worms' against an argument of Geach's. This is to the effect that if continuants are four-dimensional worms then their stages either do, or do not, fall under the very general terms satisfied by the continuants themselves (a stage of a man either is, or is not, a man); but that either alternative is untenable. I try to show how the former alternative may be defended by appealing to some of Geach's own (...) ideas about identity; then go on to defend the four-dimensionalist view from a criticism of it by Mellor, and finish with an account of the intuitive distinction between process and continuant terms. (shrink)

First published in 2002. Routledge is an imprint of Taylor & Francis, an informa company.

The recent discussions about alternative sources of human embryonic stem cells , while stirring new interest in the developmental potential of the various abnormal embryos or constructs proposed as such sources, also raise questions about the potential of the derived embryonic stem cells. The data on the developmental potential of embryonic stem cells that seem relevant for ethical considerations and aspects of patentability are discussed. Particular attention is paid to the meaning of “totipotency, omnipotency and pluripotency” as illustrated by a (...) comparison of the developmental potential of three-dimensional clusters of blastomeres , embryonic stem cells, somatic or stem cells or other somatic cells. This paper focuses on embryoid bodies and on direct cloning by tetraploid complementation. Usage and patenting of these cells cannot be considered to be ethically sound as long as totipotency and tetraploid complementability of embryonic stem cells are not excluded for the specific cell line in question. Testing this poses an ethical problem in itself and needs to be discussed in the future. (shrink)

This article reconstructs Nietzsche's shifting views on democracy in the period 1870–86 with reference to his enduring preoccupation with tyrannical concentrations of power and the conviction that radical pluralism offers the only effective form of resistance. As long as he identifies democracy with pluralism , he sympathizes with it as a site of resistance and emancipation. From around 1880 on, however, Nietzsche increasingly links it with tyranny, in the form of popular sovereignty, and with the promotion of uniformity, to the (...) exclusion of genuine pluralism. Democracy's emancipatory claims are reinterpreted as "misarchism," or hatred of authority, and Nietzsche looks to the "exceptional beings" excluded by democracy for sources of resistance to the "autonomous herd" and "mob rule." Against elitist readings of this move, it is argued that Nietzsche opposes the domination of the herd type under democracy from a standpoint in human diversity and a generic concern with the future of humankind. Exceptional individuals are conceived in pluralistic, agonal terms, as a community of legislators engaged in a process of transvaluation that serves the interests not of one or a few but of all of us: "the self-overcoming of the human.". (shrink)

There is preserved in Suidas' Lexicon a story about Polycrates of Samos and the island of Delos. It is offered by the lexicographer as an explanation of the phrase τατ σοι κα πύθια κα δλια , when used in a colloquial sense to mean ‘it's all the same to you’. Polycrates had instituted a festival on Delos and asked the Pythia whether to call it by the one name or the other. The phrase, which was supposed to have been the (...) Pythia's reply, was taken to mean that it was all the same to Polycrates whatever he called it, and the death of Polycrates, coming soon after, was interpreted as the fulfilment of the prophecy. Suidas cites Epicurus and Menander for the phrase itself, which was therefore in familiar use by the end of the fourth century B.C. As for the story about Polycrates, it is quite likely that Suidas' ultimate source was some writer of about that period, such as Demon, περ παροιμιν. It is very much in the manner of his fragments. (shrink)

British accounts of medical ethics concentrate on confidentiality to the exclusion of wider questions of privacy. This paper argues for consideration of privacy within medical ethics, and illustrates through the television series `Hospital', what may go awry when this wider concept is forgotten.

This article presents an analysis of "spirituality." Ryle said that a belief is not known to be truly held unless one bases crucial action on it; but the qualifications "truly" and "crucial" can be stripped away. Spirituality then becomes consistency of actual action with a belief; or in behavior analytic terms, spirituality is "rule-governed" behavior. Beliefs can function not only as "discriminative stimuli" but also as "reinforcing stimuli." A belief need not correspond to the world as experienced in order to (...) have these functions. Spirituality, thus far in the analysis, is only rule-governed behavior, regardless of the source of the rule and regardless of the content of the rule except that the rule must specify actually performable behavior so that consistency of the action with the belief can be assessed. The separation of action from belief is a form of alienation in a Marxian sense ; to paraphrase Kant, beliefs without actions are empty and actions without beliefs are blind. That is, a belief that is not acted upon is literally useless, and action that is not based on a belief is literally irrational. Alienation is resolved when action is based on "right" motives, which are motives based on a set of principles. Analogously, spirituality is a special kind of rule-governed behavior because the rules that govern this behavior are part of a coherent system that defines "rightness.". (shrink)

Philosophical analyses can aid scientists in several ways. For example, they can help resolve disagreements among scientists about issues such as the relative value of facts versus theories and observations versus inferences; they provide historical descriptions of how science went when it went well or badly and scientists can imitate these descriptions as though they were prescriptive rules; they identify "families" of theories and methodologies on the basis of common uses of key words, which can help scientists understand theories and (...) methodologies other than their own; and they can provide essential backgrounds for scientistsí debates about issues such as final causality, chance causality, and context effects. However, philosophical analyses cannot provide support for empirical findings or theoretical concepts. (shrink)