The problem of the human individual and the multiple manifestations of the essence of that individual made its appearance along with that of human beings themselves. Having arisen at the dawn of history, as a product of the as-yet-primitive consciousness of the primeval human, this problem, constantly developing and changing in form in accordance with the socio-economic conditions of the life of society, is assuming increasingly pervasive significance. The mandate of the ancients to "Know thyself" today has the ring not (...) only of a troubling need for individual self-awareness, and therefore of a heuristic problem in natural science and philosophy, but also of a categorical social imperative. (shrink)

The present review highlights an association between autism, Alzheimer disease , and fragile X syndrome . We propose a conceptual framework involving the amyloid-beta peptide , Abeta precursor protein , and fragile X mental retardation protein based on experimental evidence. The anabolic effect of the secreted alpha form of the amyloid-beta precursor protein may contribute to the state of brain overgrowth implicated in autism and FXS. Our previous report demonstrated that higher plasma sAPPalpha levels associate with more severe symptoms of (...) autism, including aggression. This molecular effect could contribute to intellectual disability due to repression of cell-cell adhesion, promotion of dense, long, thin dendritic spines, and the potential for disorganized brain structure as a result of disrupted neurogenesis and migration. At the molecular level, APP and FMRP are linked via the metabotropic glutamate receptor 5 . Specifically, mGluR5 activation releases FMRP repression of APP mRNA translation and stimulates sAPP secretion. The relatively lower sAPPalpha level in AD may contribute to AD symptoms that significantly contrast with those of FXS and autism. Low sAPPalpha and production of insoluble Abeta would favor a degenerative process, with the brain atrophy seen in AD. Treatment with mGluR antagonists may help repress APP mRNA translation and reduce secretion of sAPP in FXS and perhaps autism. (shrink)

Sextus Empiricus does not reveal anything of himself as distinct from ‘the Sceptic’ except in a passing and incidental way. He does not refer to his contemporaries, nor to his country, nor to any personal experiences, in such a way as to provide a definite picture of his life and times. The few references he makes to his involvement in the medical profession are as perplexing as they are enlightening. The only attachments which Sextus strongly identifies with in his extant (...) writings are the demands of the Pyrrhonean philosophy. (shrink)

I question whether the flourishing that McMullin presents as negotiating the demands of three distinct normative domains is itself normative. If it is, I argue it must be incremental in some way to...

Weil’s essay on Homer’s Iliad contains a philosophical analysis of la force that divides it into two phenomena with one metaphysical ground. Her analysis is a corrective to misunderstandings of force as something that can be possessed. The first half of my elaboration of Weil’s analysis is devoted to the phenomena she identifies in relation to la force, which I call might. In the second half, I elaborate the varieties of misunderstanding of la force. First, might is an illusion sustained (...) by the shared belief of those in submission to might. Second, forces, i.e. the material forces on which weaponry depends, cannot be possessed. Third, what lies behind material forces is necessity, a third meaning of la force, which functions as a superordinate or ultimate force to which everyone and everything is subject. Understanding the last of these is the corrective that Weil means to present. (shrink)

Provision of additional food supplements for the purpose of biological conservation has been widely researched both theoretically and experimentally. The study of these biosystems is usually done using predator–prey models. In this paper, we consider an additional food provided predator–prey system in the presence of the inhibitory effect of the prey. This model is analyzed in the control parameter space using the control parameters, quality and quantity of additional food. The findings suggest that with appropriate choice of additional food to (...) predators, the biosystem can be controlled and steered to a desirable state. It is also possible to eliminate either of the interacting species. The vital role of the quality and quantity of the additional food in the system dynamics cautions the eco manager on the choice of the additional food for realizing the goal in the biological conservation programme. (shrink)

The public revelation in 2003 that medical students perform intimate examinations without patient consent has engendered much debate in the press and scientific journals. Using this case as a springboard for discussion, I will argue that medical schools should encourage students to raise their ethical concerns and call for a change of policy making it easier for students to do so. I will also address the question of medical students’ moral obligations towards their patients, and conclude that medical students ought (...) to express their discontent when faced with unethical practices or attitudes.In early January 2003, a study appeared in the British Medical Journal revealing that nearly a quarter of rectal and vaginal examinations on anaesthetised patients were performed by medical students without patient consent.1 Although the study did not generate the firestorm of controversy many expected, it engendered much discussion on ethical issues surrounding informed consent and patient autonomy, as well as stressing the need for greater ethics training for medical students. As an ethical problem, however, the case of intimate examinations is, to my mind, relatively uninteresting. If we agree that it is wrong for doctors to perform a vaginal examination on a conscious person without their consent, then it follows that it will still be …. (shrink)

This study examined the relationship between unethical employee behavior and the dimensions of the Ethical Climate Questionnaire (ECQ). In order to explore the relationship between the dimensions of the ECQ and unethical behavior, the factor structure of five previously identified empirical models and the hypothesized nine-dimension model for the ECQ was tested with a confirmatory factor analysis. The analysis revealed that the hypothesized nine-dimension model provided as good or even better fit to the data than the five empirically derived models. (...) Therefore, the nine-dimensional model was used to examine the criterion-related validity of the ECQ. The results demonstrated that the nine ethical climate dimensions were correlated with some of the unethical behaviors examined in this study, but not others. However, the results clearly demonstrated that most of the ethical climate dimensions were significantly related to an aggregate measure of unethical behavior. It was suggested that these results might account for the differences in previous studies on the criterion-related validity of the ECQ. The results also replicated a previous report that the association between unethical behavior and ethical climate is stronger in organizations that do not have a code of ethics. Finally, a difference was observed in the ethical climates for organizations with a code of ethics and organizations without a code of ethics. (shrink)

It is conventional to try to arrive at the Boltzmann principle and the Second Law starting with the laws of dynamics at the microscopic level. In this article the opposite view is presented: Starting with the Second Law, microscopic properties are derived. A classical result of Wien is developed into a general theorem, and the possibility of deriving the Boltzmann principle as a consequence of Carnot's theorem is discussed.

Scientific developments of the last 20 years have made the transplantation of cadaveric solid organs a viable and expected treatment alternative for patients suffering from various forms of End Stage Organ Disease. Of the number of organs that could be utilized for this, only a small percentage of them are actually made available. North American legislation explicitly categorizes the transfer of cadaveric organs as an anatomical or tissue “gift”. The concept of the gift is mediated by transculturally consistent unwritten, but (...) powerfully felt, rules of conduct. Among the most profound elements of the concept is the obligatory gift-exchange which is central to the gift-relationship. Obviously, neither of these are permitted by the organ transplant scenario. As a result, dissonance is created within the thought process of the individual which cannot be easily resolved, paralyzing many into inaction. We maintain that the present legal framework, designed to facilitate the transfer of organs, clashes with the human phenomenon of giving, and may actually prevent organs from being made available. In a search for a solution to this gift-relationship dilemma, giving organs is contrasted with taking organs as a basis upon which to ground ethically sound public policy. Liberty-limiting principles and the concept of harm are considered within this context. (shrink)

Context: Few professional philosophers have addressed in any detail radical constructivism, but have focused instead on the related assumptions and limitations of postmodern epistemology, various anti-realisms, and subjective relativism. Problem: In an attempt to supply a philosophical answer to the guest editors’ question, “Why isn’t everyone a radical constructivist?” I address the realist (hence non-radical) implications of the theory’s invocation of “others” as an invariable, observer-independent, “external” constraint. Results: I argue that constructivists cannot consistently defend a radically subjectivist theory of (...) knowing while remaining entirely agnostic about the nature and existence of the larger world (including independent others). That is, any non-solipsistic account of human experience must explicitly acknowledge its extra-subjective, ontological dimension. Implications: It follows that no pedagogical, social, philosophical, or commonsensical insight associated with so-called “trivial” or “social” constructivism survives or receives any support from the move to radical constructivism. (shrink)

Theoretical and experimental studies on prey–predator systems where predator is supplied with alternate sources of food have received significant attention over the years due to their relevance in achieving biological conservation and biological control. Some of the outcomes of these studies suggest that with appropriate quality and quantity of additional food, the system can be steered towards any desired state eventually with time. One of the limitations of previous studies is that the desired state is reached asymptotically, which makes the (...) outcomes not easily applicable in practical scenarios. To overcome this limitation, in this work, we formulate and study optimal control problems to achieve the desired outcomes in minimum (finite) time. We consider two different models of additional food provided prey–predator systems involving Holling type IV functional response (with inhibitory effect of prey). In the first scenario, additional food is incorporated implicitly into the predator’s functional response with a possibility of achieving biological conservation through co-existence of species and biological control by maintaining prey at a level that is least harmful to the system. In the second, the effect of additional food is incorporated explicitly into the predator’s compartment with the goal of pest management by maintaining prey density at a very minimal damaging level. For both cases, appropriate optimal control strategies are derived and the theoretical findings are illustrated by numerical simulations. We also discuss the ecological significance of the theoretical findings for both models. (shrink)

The interest in supererogation and supererogatory actions derives from the perception that there is something problematic about them. I shall argue that there is nothing problematic about them. The perception to the contrary arises from preconceptions common in ethical theory. When these are relaxed or dismissed, supererogatory actions are easily assimilated as well-motivated, responses to moral situations. Assimilating, rather than denying, them is important for a sound moral philosophy.

In the work of Nietzsche, sacrifice can only sacrifice itself over and over (in an eternal return of the same) because what it seeks to overcome (the nihilistic revelation of truth that sublates sacrifice's negation) makes this sacrifice of itself both necessary and useless. The truth is eternally postponed in a necessary sacrificial gesture that can only sacrifice itself, thereby rendering itself useless. In the attempt to step beyond nihilism, that is, in the attempt to negate (or sacrifice) nihilism, one (...) repeats the negation characteristic of nihilism. One becomes inextricably implicated in the move of nihilistic sacrifice. The sacrifice of the sacrifice characteristic of nihilism, that is, the sacrifice of sacrifice, can only take place as (perform itself as) the impossibility (or eternally postponed possibility) of its realization. One, therefore, produces or performs an interminable step/not beyond, an incessant step beyond that eternally returns. (shrink)

Alzheimer's disease is characterized by formation of neuritic plaque primarily composed of a small filamentous protein called amyloid-beta peptide . The rate-limiting step in the production of Abeta is the processing of Abeta precursor protein by beta-site APP-cleaving enzyme . Hence, BACE1 activity plausibly plays a rate-limiting role in the generation of potentially toxic Abeta within brain and the development of AD, thereby making it an interesting drug target. A phase II trial of the promising LY2886721 inhibitor of BACE1 was (...) suspended in June 2013 by Eli Lilly and Co., due to possible liver toxicity. This outcome was apparently a surprise to the study's team, particularly since BACE1 knockout mice and mice treated with the drug did not show such liver toxicity. Lilly proposed that the problem was not due to LY2886721 anti-BACE1 activity. We offer an alternative hypothesis, whereby anti-BACE1 activity may induce apparent hepatotoxicity through inhibiting BACE1's processing of beta-galactoside alpha-2,6-sialyltransferase I . In knockout mice, paralogues, such as BACE2 or cathepsin D, could partially compensate. Furthermore, the short duration of animal studies and short lifespan of study animals could mask effects that would require several decades to accumulate in humans. Inhibition of hepatic BACE1 activity in middle-aged humans would produce effects not detectable in mice. We present a testable model to explain the off-target effects of LY2886721 and highlight more broadly that so-called off-target drug effects might actually represent off-site effects that are not necessarily off-target. Consideration of this concept in forthcoming drug design, screening, and testing programs may prevent such failures in the future. (shrink)

BACKGROUND: Alzheimer's disease is intimately tied to amyloid-beta peptide. Extraneuronal brain plaques consisting primarily of Abeta aggregates are a hallmark of AD. Intraneuronal Abeta subunits are strongly implicated in disease progression. Protein sequence mutations of the Abeta precursor protein account for a small proportion of AD cases, suggesting that regulation of the associated gene may play a more important role in AD etiology. The APP promoter possesses a novel 30 nucleotide sequence, or "proximal regulatory element" , at -76/-47, from the (...) +1 transcription start site that confers cell type specificity. This PRE contains sequences that make it vulnerable to epigenetic modification and may present a viable target for drug studies. We examined PRE-nuclear protein interaction by gel electrophoretic mobility shift assay and PRE mutant EMSA. This was followed by functional studies of PRE mutant/reporter gene fusion clones. RESULTS: EMSA probed with the PRE showed DNA-protein interaction in multiple nuclear extracts and in human brain tissue nuclear extract in a tissue-type specific manner. We identified transcription factors that are likely to bind the PRE, using competition gel shift and gel supershift: Activator protein 2 , nm23 nucleoside diphosphate kinase/metastatic inhibitory protein , and specificity protein 1 . These sites crossed a known single nucleotide polymorphism . EMSA with PRE mutants and promoter/reporter clone transfection analysis further implicated PuF in cells and extracts. Functional assays of mutant/reporter clone transfections were evaluated by ELISA of reporter protein levels. EMSA and ELISA results correlated by meta-analysis. CONCLUSIONS: We propose that PuF may regulate the APP gene promoter and that AD risk may be increased by interference with PuF regulation at the PRE. PuF is targeted by calcium/calmodulin-dependent protein kinase II inhibitor 1, which also interacts with the integrins. These proteins are connected to vital cellular and neurological functions. In addition, the transcription factor PuF is a known inhibitor of metastasis and regulates cell growth during development. Given that APP is a known cell adhesion protein and ferroxidase, this suggests biochemical links among cell signaling, the cell cycle, iron metabolism in cancer, and AD in the context of overall aging. (shrink)