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)

In order to introduce protists to philosophers, we outline the diversity, classification, and evolutionary importance of these eukaryotic microorganisms. We argue that an evolutionary understanding of protists is crucial for understanding eukaryotes in general. More specifically, evolutionary protistology shows how the emphasis on understanding evolutionary phenomena through a phylogeny-based comparative approach constrains and underpins any more abstract account of why certain organismal features evolved in the early history of eukaryotes. We focus on three crucial episodes of this history: the origins (...) of multicellularity, the origin of sex, and the origin of the eukaryote cell. Despite ongoing uncertainty about where the root of the eukaryote tree lies, and residual questions about the precise endosymbioses that have produced a diversity of photosynthesizing eukaryotes, evolutionary protistology has illuminated with considerable clarity many aspects of protist evolution. Our main message in light of evolutionary protistology is that these ‘other eukaryotes’ are in fact the organisms through which the rest of the eukaryotes should be understood. (shrink)

We are pleased that all the commentators seem to agree that a theory-driven integration across disciplines is a worthwhile endeavor to better understand the social constitution of emotion. In our reply, we first take up the idea of relating affect control theory (ACT) to cultural priming and suggest links to an ACT-inspired constraint satisfaction explanation of priming. Second, we address reservations concerning ACT’s capability to account for emotions with nonconceptual content and to explain stability and change in affective meanings. Third, (...) we clarify the relation of affect control theory to psychological constructionism, in particular with regard to conceptualizations of culture and society. Finally, we suggest that computational models are an adequate tool to address multilevel issues in the study of emotion. (shrink)

ROGER E. BISSELL points out scholarly and ahistorical lapses in Kamhi and Torres's Journal of Ayn Rand Studies essay, "Critical Neglect of Ayn Rand's Theory of Art" . He argues that they have misrepresented and neglected the views of others, and have inaccurately depicted the extent to which his own essays liken and contrast music with the other arts. Bissell criticizes their failure to acknowledge Rand's "microcosm" view of art as "re-creation of reality," which is fundamentally at odds with (...) the Kamhi-Torres perspective. (shrink)

Variations in levels of apolipoprotein E have been tied to the risk and progression of Alzheimer's disease . Our group has previously compared and contrasted the promoters of the mouse and human ApoE gene promoter sequences and found notable similarities and significant differences that suggest the importance of the APOE promoter's role in the human disease. We examine here three specific single-nucleotide polymorphisms within the human APOE promoter region, specifically at -491 , -427 , and at -219 upstream from the (...) +1 transcription start site. The -219 and -491 polymorphic variations have significant association with instance of AD, and -491AA has significant risk even when stratified for the APOEepsilon4 allele. We also show significant effects on reporter gene expression in neuronal cell cultures, and, notably, these effects are modified by species origin of the cells. The -491 and -219 polymorphisms may have an interactive effect in addition to any independent activity. DNA-protein interactions differ between each polymorphic state. We propose SP1 and GATA as candidates for regulatory control of the -491 and -219 polymorphic sites. This work's significance lies in drawing connection among APOE promoter polymorphisms' associations with AD to functional promoter activity differences and specific changes in DNA-protein interactions in cell culture-based assays. Taken together, these results suggest that APOE expression levels are a risk factor for AD irrespective of APOEepsilon4 allele status. (shrink)

Empirical advances in biology led to the popularity of a view known as gene selectionism, most recently championed by Richard Dawkins' "The Selfish Gene" . On this view, natural selection "looked through" the organism right to the genome; evolution was a change in the genomes of a species over time and the process of development is rendered epiphenominal to that process. Recently, support for gene selectionism has waned in favor of a pluralistic view. On this view, natural selection operates at (...) many different levels, including: genes, traits of organisms, organisms, groups, species and clades. Because the process of development occurs at many of these levels, a complete understanding of evolution will include an understanding of the developmental process. This dissertation is a contribution to the integration of evolution and development that has become known as the developmental synthesis. ;I argue that the adaptationism debate has raged for so long because it is based on an incoherent picture of the world, according to which, some traits are due to natural selection and others are due to constraints. In fact, all traits are due to both natural selection and constraints. Whether we explain a trait in terms of natural selection or constraints is a matter of pragmatics. Evolutionary explanations are causal explanations and different types of evolutionary explanations appeal to different aspects of the evolutionary process. ;I also offer two general theories on how natural selection can design organisms capable of complex development. The first focuses on the nature of gene control networks. I argue that they are connectionist networks designed by natural selection to overcome the difficulty of development. The second focuses on the evolvability of ontogeny. I argue that ontogeny can be designed by natural selection for increased evolvability, primarily through designed functional modularity. (shrink)

Book reviewed in this article: In That Case: Medical Ethics in Everyday Practice. By Alastair Campbell and Roger Higgs. Medical Genetics Casebook: A Clinical Introduction to Medical Ethics Systems Theory. By Colleen D. Clements. Cases in Bioethics from the Hastings Center Report. Edited by Carol Levine and Robert M. Veatch. Hastings‐on‐Hudson.

One aspect of social constructionist thought, which seldom receives the kind of explicit attention it warrants, has considerable potential: namely, the observation that our limited knowings of the world are achieved in numerous, yet deeply particularized, relational engagements in and with it. Foregrounding and elaborating such relational engagements provides an alternate way of developing a typology of constructionist thought. By emphasizing relationality as inherent in both social constructionism and many environmental and deep ecological positions, a potentially useful and powerful way (...) of bringing the so-called warring factions to the treaty table emerges. A tripartite scheme of “natures,” focusing on relationality with the natural world, can provide a framework for dissolving some of the disputes in the literature, such as deep ecology’s current discomfort with constructionist thought. (shrink)

In recent years, scholars have come to understand emotions as dynamic and socially constructed—the product of interdependent cultural, relational, situational, and biological influences. While researchers have called for a multilevel theory of emotion construction, any progress toward such a theory must overcome the fragmentation of relevant research across various disciplines and theoretical frameworks. We present affect control theory as a launching point for cross-disciplinary collaboration because of its empirically grounded conceptualization of social mechanisms operating at the interaction, relationship, and cultural (...) levels, and its specification of processes linking social and individual aspects of emotion. After introducing the theory, we illustrate its correspondence with major theories of emotion construction framed at each of four analytical levels: cultural, interactional, individual, and neural. (shrink)

The legacy of classical antiquity -- War and peace in the medieval world -- Holy wars, crusades, and religious wars -- Humanism and Neo-Stoicism -- The search for a science of peace.

Molecular genetic data have greatly improved our ability to test hypotheses about human evolution. During the past decade, a large amount of nuclear and mitochondrial data have been collected from diverse human populations. Taken together, these data indicate that modern humans are a relatively young species. African populations show the largest amount of genetic diversity, and they are the most genetically divergent population. Modern human populations expanded in size first on the African continent. These findings support a recent African origin (...) of modern humans, but this conclusion should be tempered by the possible effects of factors such as gene flow, population size differences, and natural selection. BioEssays 20:126–136, 1998. © 1998 John Wiley & Sons, Inc. (shrink)