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)

An edition of the letters of Erasmus, regarded as one of the greatest humanist writers. All 12 volumes of this work have been reissued, complete with their scholarly apparatus of commentary and notes, as well as plates.

An edition of the letters of Erasmus, regarded as one of the greatest humanist writers. All 12 volumes of this work have been reissued, complete with their scholarly apparatus of commentary and notes, as well as plates.

This volume collects P. M. S. Hacker's papers on Wittgenstein and related themes written over the last decade. Hacker provides comparative studies of a range of topics--including Wittgenstein's philosophy of psychology, conception of grammar, and treatment of intentionality--and defends his own Wittgensteinian conception of philosophy.

The purpose of this essay is to investigate and critically analyse some of the formative factors which led to the spiritual maturation of a leading Vīraśaiva saint, Basava. This inquiry focuses on a single event in the life of this great reformer of medieval times, i.e. his spiritual conflict leading to his rejection of the upanayana ceremony. The study will proceed through an investigation of the earliest and subsequent sources which veil the personality of Basava. The traditional view will be (...) challenged as one-sided. By critically comparing the sources, a more comprehensive and plausible account will be suggested. (shrink)

Bhattacharyya, K. The Advaita concept of subjectivity.--Deutsch, E. Reflections on some aspects of the theory of rasa.--Nakamura, H. The dawn of modern thought in the East.--Organ, T. Causality, Indian and Greek.--Chatterjee, M. On types of classification.--Lacombe, O. Transcendental imagination.--Bahm, A. J. Standards for comparative philosophy.--Herring, H. Appearance, its significance and meaning in the history of philosophy.--Chang Chung-yuan. Pre-rational harmony in Heidegger's essential thinking and Chʼan thought.--Staal, J. F. Making sense of the Buddhist tetralemma.--Enomiya-Lassalle, H. M. The mysticism of Carl Albrecht (...) and Zen.--Parrinder, G. The nature of mysticism.--Cairns, G. E. Axiological contributions of East and West to the spiritual development of mankind.--Mayeda, S. Śaṇkara's view of ethics.--Mercier, A. On peace.--Barlingay, S. S. A discussion of some aspects of Gaudapāda's philosophy. (shrink)

James Conant, a proponent of the ‘New American Wittgenstein’, has argued that the standard inter- pretation of Wittgenstein is wholly mistaken in respect of Wittgenstein’s critique of metaphysics and the attendant conception of nonsense. The standard interpretation, Conant holds, misascribes to Wittgenstein Carnapian views on the illegitimacy of metaphysical utterances, on logical syntax and grammar, and on the nature of nonsense. Against this account, I argue that (i) Carnap is misrepresented; (ii) the so-called standard interpretation (in so far as I (...) have contributed to it) is misrepresented; (iii) Wittgenstein’s views, early and late, are misrepresented. I clarify Wittgen- stein’s conception of logical syntax and of the nonsense that results from transgressing it. (shrink)

Research on whistle-blowing has been hampered by a lack of a sound theoretical base. In this paper, we draw upon existing theories of motivation and power relationships to propose a model of the whistle-blowing process. This model focuses on decisions made by organization members who believe they have evidence of organizational wrongdoing, and the reactions of organization authorities. Based on a review of the sparse empirical literature, we suggest variables that may affect both the members' decisions and the organization's responses.

In recent years philosophers have given much attention to the ‘ontological problem’ of events. Donald Davidson puts the matter thus: ‘the assumption, ontological and metaphysical, that there are events is one without which we cannot make sense of much of our common talk; or so, at any rate, I have been arguing. I do not know of any better, or further, way of showing what there is’. It might be thought bizarre to assign to philosophers the task of ‘showing what (...) there is’. They have not distinguished themselves by the discovery of new elements, new species or new continents, nor even of new categories, although there has often been more dreamt of in their philosophies than can be found in heaven or earth. It might appear even stranger to think that one can show what there actually is by arguing that the existence of something needs to be assumed in order for certain sentences to make sense. More than anything, the sober reader will doubtlessly be amazed that we need to assume, after lengthy argument, ‘that there are events’. (shrink)

The purpose of this note is to examine the notion of obligations to future generations, a notion that finds increasing use in discussions of social policies and programs, particularly as concerns population distribution and control and environment control. Thus, it may be claimed, the solution of problems in these areas is not merely a matter of enhancing our own good, improving our own conditions of life, but is also a matter of discharging an obligation to future generations.

Background: Hospital nurses are frequently the first care givers to receive a patient’s request for euthanasia or physician-assisted suicide (PAS). In France, there is no consensus over which medical practices should be considered euthanasia, and this lack of consensus blurred the debate about euthanasia and PAS legalisation. This study aimed to investigate French hospital nurses’ opinions towards both legalisations, including personal conceptions of euthanasia and working conditions and organisation. Methods: A phone survey conducted among a random national sample of 1502 (...) French hospital nurses. We studied factors associated with opinions towards euthanasia and PAS, including contextual factors related to hospital units with random-effects logistic models. Results: Overall, 48% of nurses supported legalisation of euthanasia and 29%, of PAS. Religiosity, training in pallative care/pain management and feeling competent in end-of-life care were negatively correlated with support for legalisation of both euthanasia and PAS, while nurses working at night were more prone to support legalisation of both. The support for legalisation of euthanasia and PAS was also weaker in pain treatment/palliative care and intensive care units, and it was stronger in units not benefiting from interventions of charity/religious workers and in units with more nurses. Conclusions: Many French hospital nurses uphold the legalisation of euthanasia and PAS, but these nurses may be the least likely to perform what proponents of legalisation call “good” euthanasia. Improving professional knowledge of palliative care could improve the management of end-of-life situations and help to clarify the debate over euthanasia. (shrink)

Background In 2002, Belgium set a legal framework for euthanasia, whereby granting and performing euthanasia is entrusted entirely to physicians, and—as advised by Belgian Medical Deontology—in the context of a trusted patient–physician relationship. Euthanasia is, however, rarely practiced, so the average physician will not attain routine in this matter. Aim To explore how general practitioners in Flanders (Belgium) deal with euthanasia. This was performed via qualitative analysis of semistructured interviews with 52 general practitioners (GPs). Results Although GPs can understand a (...) patient's request for euthanasia, their own willingness to perform it is limited, based on their assumption that legal euthanasia equates to an injection that ends life abruptly. Their willingness to perform euthanasia is affected by the demanding nature of a patient's request, by their views on what circumstances render euthanasia legitimate and by their own ability to inject a lethal dose. Several GPs prefer increasing opioid dosages and palliative sedation to a lethal injection, which they consider to fall outside the scope of euthanasia legislation. Conclusions Four attitudes can be identified: (1) willing to perform euthanasia; (2) only willing to perform as a last resort; (3) feeling incapable of performing; (4) refusing on principle. The situation where GPs have to consider the request and—if they grant it—to perform the act may result in arbitrary access to euthanasia for the patient. The possibility of installing transparent referral and support strategies for the GPs should be further examined. Further discussion is needed in the medical profession about the exact content of the euthanasia law. (shrink)

P.M.S. Hacker 1. _The problems of Intentionality_ The problems of intentionality have exercised philosophers since the dawn of their subject. In the last century they were brought afresh into the limelight by Brentano. Famously he remarked that.

This white paper aims to identify an open problem in 'Quantum Physics and the Nature of Reality' -namely whether quantum theory and special relativity are formally compatible-, to indicate what the underlying issues are, and put forward ideas about how the problem might be addressed.

Objectives To investigate empirically the motivations for not consenting to DNA biobanking in a Swedish population-based study and to discuss the implications. Design Structured questionnaires and semistructured interviews. Setting A longitudinal epidemiological project (PART) ongoing since 1998 in Stockholm, Sweden. The DNA-collection wave took place during 2006–7. Participants 903 individuals completed the questionnaire (participation rate 36%) and 23 were interviewed. All individuals had participated in both non-genetic waves of the project, but refused to contribute saliva samples during the DNA-collection wave. (...) Main outcome measures Motivations behind refusing to consent to DNA biobanking, with subsequent focus on participants' explanations regarding this unwillingness. Results Public refusal to consent to DNA biobanking, as revealed by the questionnaire, was mainly explained by a lack of personal relevance of DNA contribution and feelings of discomfort related to the DNA being used for purposes other than the respective study. Interviews of individuals representing the second motivation, revealed a significant mistrust of DNA biobank studies. The underlying beliefs and attitudes were associated with concerns about integrity, privacy, suspiciousness and insecurity. However, most interviewees were supportive of genetic research per se and interpreted their mistrust in the light of distressing environmental influences. Conclusion The results suggest a need for guidelines on benefit sharing, as well as trustworthy and stable measures to maintain privacy, as a means for increasing personal relevance and trust among potential participants in genetic research. Measures taken from biobanks seem insufficient in maintaining and increasing trust, suggesting that broader societal measures should be taken. (shrink)

Bioethics needs an expanded moral vision. It is now time for bioethics to take full account of the problems of health disparities and structural injustice that are made newly urgent by the COVID-19 pandemic and the effects of climate change. Nancy M. P. King, Gail E. Henderson, and Larry R. Churchill make the case for a more social understanding and application of justice, a deeper humility in assessing expertise in bioethics consulting, a broader and more relevant research agenda, and greater (...) appreciation of the profound health implications of global warming. (shrink)

The logical positivists’ critical attitude towards metaphysics is sketched. Strawson’s conception of descriptive and revisionary metaphysics is described. Revisionary metaphysics is argued to be chimerical, and descriptive metaphysics is argued not to be a form of metaphysics at all. Strawson’s failure to account for the status of propositions of descriptive metaphysics is held to be remediable by reference to Wittgenstein’s conception of grammatical propositions that express norms of representation.

Bronze Age Bureaucracy: Writing and the Practice of Government in Assyria. By Nicholas Postgate. Cambridge: Cambridge University Press, 2013. Pp. xi + 484, illus. $99.

The relativistic three-particle systems are studied within the framework of Relativistic Schrödinger Theory, with emphasis on the determination of the energy functional for the stationary bound states. The phenomenon of entanglement shows up here in form of the exchange energy which is a significant part of the relativistic field energy. The electromagnetic interactions become unified with the exchange interactions into a relativistic U gauge theory, which has the Hartree–Fock equations as its non-relativistic limit. This yields a general framework for treating (...) entangled states of relativistic many-particle systems, e.g., the N-electron atoms. (shrink)

When people engage in conversation, they tailor their utterances to their conversational partners, whether these partners are other humans or computational systems. This tailoring, or adaptation to the partner takes place in all facets of human language use, and is based on a mental model or a user model of the conversational partner. Such adaptation has been shown to improve listeners' comprehension, their satisfaction with an interactive system, the efficiency with which they execute conversational tasks, and the likelihood of achieving (...) higher level goals such as changing the listener's beliefs and attitudes. We focus on one aspect of adaptation, namely the tailoring of the content of dialogue system utterances for the higher level processes of persuasion, argumentation and advice-giving. Our hypothesis is that algorithms that adapt content for these processes, according to a user model, will improve the usability, efficiency, and effectiveness of dialogue systems. We describe a multimodal dialogue system and algorithms for adaptive content selection based on multi-attribute decision theory. We demonstrate experimentally the improved efficacy of system responses through the use of user models to both tailor the content of system utterances and to manipulate their conciseness. (shrink)