Alzheimer's disease is characterized by plaques of amyloid-beta peptide, cleaved from amyloid-beta protein precursor . Our hypothesis is that lifespan profiles of AD-associated mRNA and protein levels in monkeys would differ from mice and that differential lifespan expression profiles would be useful to understand human AD pathogenesis. We compared profiles of AbetaPP mRNA, AbetaPP protein, and Abeta levels in rodents and primates. We also tracked a transcriptional regulator of the AbetaPP gene, specificity protein 1 , and the beta amyloid precursor (...) cleaving enzyme . In mice, AbetaPP and SP1 mRNA and their protein products were elevated late in life; Abeta levels declined in old age. In monkeys, SP1, AbetaPP, and BACE1 mRNA declined in old age, while protein products and Abeta levels rose. Proteolytic processing in both species did not match production of Abeta. In primates, AbetaPP and SP1 mRNA levels coordinate, but an inverse relationship exists with corresponding protein products as well as Abeta levels. Comparison of human DNA and mRNA sequences to monkey and mouse counterparts revealed structural features that may explain differences in transcriptional and translational processing. These findings are important for selecting appropriate models for AD and other age-related diseases. (shrink)

The sporadic nature of Alzheimer's disease argues for an environmental link that may drive AD pathogenesis; however, the triggering factors and the period of their action are unknown. Recent studies in rodents have shown that exposure to lead during brain development predetermined the expression and regulation of the amyloid precursor protein and its amyloidogenic beta-amyloid product in old age. Here, we report that the expression of AD-related genes [APP, BACE1 ] as well as their transcriptional regulator were elevated in aged (...) monkeys exposed to Pb as infants. Furthermore, developmental exposure to Pb altered the levels, characteristics, and intracellular distribution of Abeta staining and amyloid plaques in the frontal association cortex. These latent effects were accompanied by a decrease in DNA methyltransferase activity and higher levels of oxidative damage to DNA, indicating that epigenetic imprinting in early life influenced the expression of AD-related genes and promoted DNA damage and pathogenesis. These data suggest that AD pathogenesis is influenced by early life exposures and argue for both an environmental trigger and a developmental origin of AD. (shrink)

Alzheimer's disease is characterized by amyloid-beta peptide -loaded plaques in the brain. Abeta is a cleavage fragment of amyloid-beta protein precursor and over production of APP may lead to amyloidogenesis. The regulatory region of the APP gene contains consensus sites recognized by the transcription factor, specificity protein 1 , which has been shown to be required for the regulation of APP and Abeta. To understand the role of SP1 in APP biogenesis, herein we have characterized the relative distribution and localization (...) of SP1, APP, and Abeta in various brain regions of rodent and primate models using immunohistochemistry. We observed that overall distribution and cellular localization of SP1, APP, and Abeta are similar and neuronal in origin. Their distribution is abundant in various layers of neocortex, but restricted to the Purkinje cell layer of the cerebellum, and the pyramidal cell layer of hippocampus. These findings suggest that overproduction of Abeta in vivo may be associated with transcriptional pathways involving SP1 and the APP gene. (shrink)

A critical evaluation of Deane-Peter Baker’s use of Charles Taylor to overcome perceived inadequacies in Reformed epistemology. Baker claims that a successful response to the de jure objection must provide motivation for the unbeliever to seriously consider the truth of Christianity, but this very test is undone by Taylor’s A Secular Age.

In this chapter I consider the place of the topic of racial and ethnic urban residential segregation factors into political philosophy. I begin with a short history of residential segregation and the ghetto, and their role in systems of racial domination and oppression, and remarks on the general neglect of this topic in contemporary political philosophy, including in nonideal political philosophy, which proports to take on examples of real-world injustices and inequalities. I then examine, from the standpoint of liberal-egalitarian political (...) theory, what segregation, as a concept, entails, and its harms to individuals, communities, and societies. Segregation in all its forms (residential, educational, and employment, as well as in political and legal systems) is an instance of injustice and inequality and a major component of processes that maintain injustice and inequality, so it requires correction and rectification of some sort. Desegregation and integration are typically forwarded as solutions to the ills and injustices of segregation. They seem synonymous, but are they? To answer this question, I survey the prominent conceptualizations of both during the civil rights movement and the contemporary debate over those terms and political theoretical positions. In the conclusion I outline my partial defense of the idea of integration. (shrink)

This article presents a new criticisms of reductive approaches to knowledge-‘wh’ (i.e., those approaches on which whether one stands in the knowledge-‘wh’ relation to a question is determined by whether one stands in the knowledge-‘that’ relation to some answer(s) to the question). It argues in particular that the truth of a knowledge-‘wh’ attribution like ‘Janna knows where she can buy an Italian newspaper’ depends not only on what Janna knows about the availability of Italian newspapers, but on what she believes (...) about the matter. This dependence of Janna's knowledge-‘wh’ on her (possibly false) beliefs is incompatible with the reductive approach. (shrink)

Humans are predisposed to form in-groups and out-groups that are remarkably flexible in their definition due largely to the complex language that has evolved in them. Language has allowed for the creation of shared “background stories” that can unite people who do not know each other. Second, the discovery of agriculture has resulted in the critical need to negotiate boundaries, a process that can lead to peace (but also war).

Heyes discounts findings of imitation and self recognition in nonhuman primates based on flimsy speculation and then indicates that even positive findings would not provide evidence of theory of mind. Her proposed experiment is unlikely to work, however, because, even if the animals have a theory of mind, a number of assumptions, not directly related to theory of mind, must be made about their reasoning ability.

Biopolitical analyses of census -taking usually focus on human censuses and consider how human experience is shaped by the practice. Instead, this article looks at the proposed global biodiversity census, which aims to take inventory of every species on earth as a response to anthropogenic species extinction. I suggest that it is possible to extend and modify Foucault's concept of biopower to consider contemporary human-nonhuman interactions. Specifically, I argue that an ecologically-extended version of biopower offers a useful way to conceptualise (...) how power circulates in the practices that surround the biodiversity census, and that it points us towards thinking about how analyses of power, authority, and community can consider ecological, rather than purely human, locations and networks. (shrink)

Moral problems such as climate change and global poverty result from widespread human action, and hence, are unaffected by changes in any individual's behavior—for instance, the harms of climate change will obtain whether I drive my car or not. This problem of causal impotence seems potentially devastating for consequentialists, but more easily addressed by deontologists. The deontologist can argue that (e.g.) even if our acts will have no effect on climate change, our using fossil fuels makes us complicit in, and (...) hence, blameworthy for, these wrongs. We argue that, despite initial appearances, appeals to complicity do not extricate deontologists from this problem. When our actions do not make a difference, we cannot be held responsible for being complicit in wrongs such as climate change and global poverty. As a result, we conclude that the problem of causal impotence is as vexing for deontologists as it is for consequentialists. (shrink)

Honesty and integrity are key attributes of an ethically competent physician. However, academic misconduct, which includes but is not limited to plagiarism, cheating, and falsifying documentation, is common in medical colleges across the world. The purpose of this study is to describe differences in the self-reported attitudes and behaviours of medical students regarding academic misconduct depending on gender, year of study and type of medical institution in Pakistan.

The paper focuses on a recent challenge brought forward against the interventionist approach to the meaning of counterfactual conditionals. According to this objection, interventionism cannot account for the interpretation of right-nested counterfactuals, the problem being its strict interventionism. We will report on the results of an empirical study supporting the objection. Furthermore, we will extend the well-known logic of intervention with a new operator expressing an alternative notion of intervention that does away with strict interventionism. This new notion of intervention (...) operates on the valuation of the variables in a causal model, and not on their functional dependencies. (shrink)

It is argued that the Tractatus Project of Logical Atomism, in which the world is conceived of as the totality of independent atomic facts, can usefully be understood by conceiving of each fact as a bit in logical space. Wittgenstein himself thinks in terms of logical space. His elementary propositions, which express atomic facts, are interpreted as tuples of co-ordinates which specify the location of a bit in logical space. He says that signs for elementary propositions are arrangements of names. (...) Here, the names are understood as numerical symbols specifying coordinates. It is argued that, using this approach, the so-called colour-exclusion problem, which was Wittgensteins reason for abandoning the Tractatus, is in fact soluble. However, if logical space is a continuum then some coordinates will need to be expressed by numerical symbols that are infinite in size. How is this to be understood in Tractatus terms? It is shown that, in the Tractatus, Wittgenstein did recognise the possibility of infinite propositions and sentences expressing them. At first sight his approach to infinite sentences, and the approach of the present paper, seem to differ, but it is argued that the difference is superficial. Finally, we address the question of whether Logical Atomism is viable and this raises issues concerning its relationship to natural science. (shrink)

In concluding section 2, chapter VI of part II of [6], Duhem claimed:... the physicist can never subject an isolated hypothesis to experimental test, but only a whole group of hypotheses...... when the experiment is in disagreement with his predictions, what he learns is that at least one of the hypotheses constituting this group is unacceptable and ought to be modified; but the experiment does not designate which one should be changed'.

This paper considers two of the most prominent kinds of evidence that have been used to argue that certain embedded questions receive weakly exhaustive interpretations. The first kind is exemplified by judgments of consistency for declarative sentences that attribute knowledge of a wh-question and ignorance of the negation of that question to the same person, and the second concerns asymmetries between the role of positive and negative information in validating question-embedding surprise ascriptions, and similar judgments for other attitudes. I argue (...) that neither type suffices to show weak exhaustivity. The first can be analyzed in terms of strong exhaustivity in combination with domain restriction effects, while the second can be analyzed in terms of a mention-some interpretation. These kinds of evidence have served as the empirical basis for many claims about weakly exhaustive readings, so the observation that they are unreliable calls into questions a large body of established work on the semantics of question embedding. (shrink)

It is clear that corruption as the abuse of power is an enormous bioethical issue in the public health sector in SA, but as a challenge, it has not elicited much discussion from a global bioethical perspective. The Universal Declaration of Bioethics and Human Rights on corruption considers three matters. First, the existence of corruption as a problem of power is recognised in the health environment and condemned. Second, corruption is indicated as an immoral phenomenon that harms the interests of (...) the patient, ignores vulnerable people and neglects social responsibility. Third, it can be concluded that the UDBHR expresses the opinion that corruption has to be combated by a process of ethical decision-making, the use of ethics committees and ethics education. (shrink)

Resumen: El presente estudio tiene como finalidad el análisis e interpretación del componente erótico en la novela Daimón. Bajo este presupuesto teórico, se promueve un enfoque contradiscursivo en el que América es transfigurada en espacio erótico, donde el tiempo pagano se superpone a la temporalidad oficial, desatando una crítica continua que desafía lo que se considera como la verdad oficial de los hechos.: The article is an analysis and interpretation of the erotic element in the novel Daimón. Based on this (...) theoretical premise, it proposes a counter-discursive approach in which America is transfigured in an erotic space in which pagan time overlaps accepted temporality, unleashing a continuous critique that challenges the official truth of historical events. (shrink)