Protein Folding Activity of the Ribosome is involved in Yeast Prion Propagation.

6AP and GA are potent inhibitors of yeast and mammalian prions and also specific inhibitors of PFAR, the protein-folding activity borne by domain V of the large rRNA of the large subunit of the ribosome. We therefore explored the link between PFAR and yeast prion [PSI(+)] using both PFAR-enriched mutants and site-directed methylation. We demonstrate that PFAR is involved in propagation and de novo formation of [PSI(+)]. PFAR and the yeast heat-shock protein Hsp104 partially compensate each other for [PSI(+)] propagation. Our data also provide insight into new functions for the ribosome in basal thermotolerance and heat-shocked protein refolding. PFAR is thus an evolutionarily conserved cell component implicated in the prion life cycle, and we propose that it could be a potential therapeutic target for human protein misfolding diseases

Tagging the world : descrying consciousness in cognitive processes

Although having conscious experiences is a fundamental feature of our everyday life, our understanding of what consciousness is is very limited. According to one of the main conclusions of contemporary philosophy of mind, the qualitative aspect of consciousness seems to resist functionalisation, i.e. it cannot be adequately defined solely in terms of functional or causal roles, which leads to an epistemic gap between phenomenal and scientific knowledge. Phenomenal qualities, then, seem to be, in principle, unexplainable in scientific terms. As a reaction to this pessimistic conclusion it is a major trend in contemporary science of consciousness to turn away from subjective experiences and re-define the subject of investigations in neurological and behavioural terms. This move, however, creates a gap between scientific theories of consciousness, and the original phenomenon, which we are so intimately connected with. The thesis focuses on this gap. It is argued that it is possible to explain features of consciousness in scientific terms. The thesis argues for this claim from two directions. On the one hand, a specific identity theory is formulated connecting phenomenal qualities to certain intermediate level perceptual representations which are unstructured for central processes of the embedding cognitive system. This identity theory is hypothesised on the basis of certain similarities recognised between the phenomenal and the cognitive-representational domains, and then utilised in order to uncover further similarities between these two domains. The identity theory and the further similarities uncovered are then deployed in formulating explanations of the philosophically most important characteristics of the phenomenal domain—i.e. why phenomenal qualities resist functionalisation, and why the epistemic gap occurs. On the other hand, the thesis investigates and criticises existing models of reductive explanation. On the basis of a detailed analysis of how successful scientific explanations proceed a novel account of reductive explanation is proposed, which utilises so-called prior identities. Prior identities are prerequisites rather than outcomes of reductive explanations. They themselves are unexplained but are nevertheless necessary for mapping the features to be explained onto the features the explanation relies on. Prior identities are hypothesised in order to foster the formulation of explanatory claims accounting for target level phenomena in terms of base level processes—and they are justified if they help projecting base level explanations to new territories of the target level. The thesis concludes that the identity theory proposed is a prior identity, and the explanations of features of the phenomenal domain formulated with the aid of this identity are reductive explanations proper. In this sense, the thesis introduces the problem of phenomenal consciousness into scientific discourse, and therefore offers a bridge between the philosophy and the science of consciousness: it offers an approach to conscious experience which, on the one hand, tries to account for the philosophically most important features of consciousness, whereas, on the other hand, does it in a way which smoothly fits into the everyday practice of scientific research

Why the Question of Animal Consciousness Might Not Matter Very Much

According to higher-order thought accounts of phenomenal consciousness (e.g. Carruthers, 2000) it is unlikely that many non-human animals undergo phenomenally conscious experiences. Many people believe that this result would have deep and far-reaching consequences. More specifically, they believe that the absence of phenomenal consciousness from the rest of the animal kingdom must mark a radical and theoretically significant divide between ourselves and other animals, with important implications for comparative psychology. I shall argue that this belief is mistaken. Since phenomenal consciousness might be almost epiphenomenal in its functioning within human cognition, its absence in animals may signify only relatively trivial differences in cognitive architecture. Our temptation to think otherwise arises partly as a side-effect of imaginative identification with animal experiences, and partly from mistaken beliefs concerning the aspects of common-sense psychology that carry the main explanatory burden, whether applied to humans or to non-human animals

Lymphatic mapping and sentinel node biopsy in gynecological cancers: a critical review of the literature

Although it does not have a long history of sentinel node evaluation (SLN) in female genital system cancers, there is a growing number of promising study results, despite the presence of some aspects that need to be considered and developed. It has been most commonly used in vulvar and uterine cervivcal cancer in gynecological oncology. According to these studies, almost all of which are prospective, particularly in cases where Technetium-labeled nanocolloid is used, sentinel node detection rate sensitivity and specificity has been reported to be 100%, except for a few cases. In the studies on cervical cancer, sentinel node detection rates have been reported around 80–86%, a little lower than those in vulva cancer, and negative predictive value has been reported about 99%. It is relatively new in endometrial cancer, where its detection rate varies between 50 and 80%. Studies about vulvar melanoma and vaginal cancers are generally case reports. Although it has not been supported with multicenter randomized and controlled studies including larger case series, study results reported by various centers around the world are harmonious and mutually supportive particularly in vulva cancer, and cervix cancer. Even though it does not seem possible to replace the traditional approaches in these two cancers, it is still a serious alternative for the future. We believe that it is important to increase and support the studies that will strengthen the weaknesses of the method, among which there are detection of micrometastases and increasing detection rates, and render it usable in routine clinical practice

Defining the Molecular Basis of Tumor Metabolism: a Continuing Challenge Since Warburg's Discovery

Cancer cells are the product of genetic disorders that alter crucial intracellular signaling pathways associated with the regulation of cell survival, proliferation, differentiation and death mechanisms. the role of oncogene activation and tumor suppressor inhibition in the onset of cancer is well established. Traditional antitumor therapies target specific molecules, the action/expression of which is altered in cancer cells. However, since the physiology of normal cells involves the same signaling pathways that are disturbed in cancer cells, targeted therapies have to deal with side effects and multidrug resistance, the main causes of therapy failure. Since the pioneering work of Otto Warburg, over 80 years ago, the subversion of normal metabolism displayed by cancer cells has been highlighted by many studies. Recently, the study of tumor metabolism has received much attention because metabolic transformation is a crucial cancer hallmark and a direct consequence of disturbances in the activities of oncogenes and tumor suppressors. in this review we discuss tumor metabolism from the molecular perspective of oncogenes, tumor suppressors and protein signaling pathways relevant to metabolic transformation and tumorigenesis. We also identify the principal unanswered questions surrounding this issue and the attempts to relate these to their potential for future cancer treatment. As will be made clear, tumor metabolism is still only partly understood and the metabolic aspects of transformation constitute a major challenge for science. Nevertheless, cancer metabolism can be exploited to devise novel avenues for the rational treatment of this disease. Copyright (C) 2011 S. Karger AG, BaselFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Univ Fed ABC UFABC, CCNH, Santo Andre, BrazilUniversidade Federal de São Paulo UNIFESP, Dept Ciencias Biol, São Paulo, BrazilUniversidade Federal de São Paulo UNIFESP, Dept Bioquim, São Paulo, BrazilUniv Fed Sao Carlos UFSCar, DFQM, Sorocaba, BrazilUniversidade Federal de São Paulo UNIFESP, Dept Ciencias Biol, São Paulo, BrazilUniversidade Federal de São Paulo UNIFESP, Dept Bioquim, São Paulo, BrazilFAPESP: 10/16050-9FAPESP: 10/11475-1FAPESP: 08/51116-0Web of Scienc

The limits of selflessness: semantic relativism and the epistemology of de se thoughts

The final publication is available at link.springer.com. URL: http://link.springer.com/article/10.1007/s11229-013-0262-8It has recently been proposed that the framework of semantic relativism be put to use to describe mental content, as deployed in some of the fundamental operations of the mind. This programme has inspired in particular a novel strategy of accounting for the essential egocentricity of first-personal or de se thoughts in relativist terms, with the advantage of dispensing with a notion of self-representation. This paper is a critical discussion of this strategy. While it is based on a plausible appeal to cognitive economy, the relativist theory does not fully account for the epistemic profile that distinguishes de se thinking, as some of its proponents hope to do. A deeper worry concerns the reliance of the theory on a primitive notion of "centre" that hasn't yet received enough critical attention, and is ambiguous between a thin and a rich reading. I argue that while the rich reading is required if the relativist analysis of the de se is to achieve its most ambitious aims, it also deprives the theory of much of its explanatory power