The apolipoprotein E gene plays an important role in the pathogenesis of Alzheimer's disease , and amyloid plaque comprised mostly of the amyloid-beta peptide ) is one of the major hallmarks of AD. However, the relationship between these two important molecules is poorly understood. We examined how A treatment affects APOE expression in cultured cells and tested the role of the transcription factor NF-B in APOE gene regulation. To delineate NF-B's role, we have characterized a 1098 nucleotide segment containing the (...) 5'-flanking region of the human APOE gene . Sequence analysis of this region suggests the presence of two potential NF-B elements. To demonstrate promoter activity, the region was cloned upstream of a promoterless luciferase gene. This segment was able to drive expression of luciferase in transient transfections of human fetal glial cells. Promoter activity was stimulated twofold by A treatment. Pretreatment with double-stranded DNA decoy oligonucleotides against NF-B reduced A stimulation. Deletion and mutagenetic analyses demonstrated that the distal NF-B element was functional and showed a strong DNA-protein complex band in gel shift analysis, similar to that from control NF-B consensus element. An anti-inflammatory and anti-NF-B drug, sodium salicylate, significantly blocked A-induced APOE promoter function. Our data provide evidence that upregulation of APOE by A in astroglial cells is mediated by an NF-B-element present in the 5'-flanking region of the APOE gene. (shrink)

We hypothesize that heritable epigenetic changes can affect rates of fitness increase as well as patterns of genotypic and phenotypic change during adaptation. In particular, we suggest that when natural selection acts on pure epigenetic variation in addition to genetic variation, populations adapt faster, and adaptive phenotypes can arise before any genetic changes. This may make it difficult to reconcile the timing of adaptive events detected using conventional population genetics tools based on DNA sequence data with environmental drivers of adaptation, (...) such as changes in climate. Epigenetic modifications are frequently associated with somatic cell differentiation, but recently epigenetic changes have been found that can be transmitted over many generations. Here, we show how the interplay of these heritable epigenetic changes with genetic changes can affect adaptive evolution, and how epigenetic changes affect the signature of selection in the genetic record. (shrink)

Let n ≥ 3 be an integer. We show that it is consistent that every σ1n-set of reals is universally Baire yet there is a projective well-ordering of the reals. The proof uses “David’s trick” in the presence of inner models with strong cardinals.

Using the corpus of JSTOR articles, we investigate the role of gender in collaboration patterns across the scholarly landscape by analyzing gender-based homophily--the tendency for researchers to co-author with individuals of the same gender. For a nuanced analysis of gender homophily, we develop methodology necessitated by the fact that the data comprises heterogeneous sub-disciplines and that not all authorships are exchangeable. In particular, we distinguish three components of gender homophily in collaborations: a structural component that is due to demographics and (...) non-gendered authorship norms of a scholarly community, a compositional component which is driven by varying gender representation across sub-disciplines, and a behavioral component which we define as the remainder of observed homophily after its structural and compositional components have been taken into account. Using minimal modeling assumptions, we measure and test for behavioral homophily. We find that significant behavioral homophily can be detected across the JSTOR corpus and show that this finding is robust to missing gender indicators in our data. In a secondary analysis, we show that the proportion of female representation in a field is positively associated with significant behavioral homophily. (shrink)

In this interview with Jan Hendrik van den Berg, the Dutch phenomenologist and psychiatrist addresses the origins of his work, his most significant influences, and the purpose of metabletic phenomenology in the modern age. In the course of the interview. Dr. Van den Berg provides a basic overview of his work, and highlights the central finding of his metabletic analyses: a loss of wonder before nature, which results from the more fundamental loss of genuine spirituality in the modern (...) world. (shrink)

The focus on animal welfare in society has increased during the last 50 years. Animal welfare legislation and private standards have developed, and today many farmers within animal production have both governmental legislation and private standards to comply with. In this paper intentions and values are described that were expressed in 14 animal welfare legislation and standards in four European countries; Sweden, United Kingdom, Germany and Spain. It is also discussed if the legislation and standards actually accomplish what they, in (...) their overall description and ethics, claimed to do, i.e. if this is followed up by relevant paragraphs in the actual body of the text in the legislation and standards respectively. The method used was an on-line questionnaire from the EconWelfare research project and text analyses. This study shows that the ethical values within a set of legislation or private standards are not always consistently implemented, and it is not always possible to follow a thread between the intentions mentioned initially and the actual details of the legislation or standard. Since values will differ so will also the animal welfare levels and the implications of similar concepts in the regulations. In general, the regulations described were not based on animal welfare considerations only, but also other aspects, such as food safety, meat quality, environmental aspects and socio-economic aspects were taken into account. This is understandable, but creates a gap between explicit and implicit values, which we argue, can be overcome if such considerations are made more transparent to the citizens/consumers. (shrink)

This dissertation presents a theory of online propaganda and radicalization which highlights the interaction between communication, epistemology, and technology. The central focus is providing an analysis of online media communications, content posted on social media platforms and transmitted by automated recommendation systems, which better explains how propaganda and radicalization have adapted so well to this technological environment. First, propaganda is interpreted as a unique approach to communication which manipulates the expectations an audience has of successful communications, and not simply as (...) a collection of individual acts with characteristic properties. A major aspect to this interpretation of propaganda is an emphasis on those environmental factors and sociological conditions involved in communication, which can have a direct impact on our experience and interpretation of reality. Second, considering these aspects a detailed account of how users experience the technical machinery facilitating social media platforms is presented, highlighting the problematic epistemic states users are forced to inhabit. Finally, online radicalization is explained through this new propaganda interpretation, the user experience of the technology underpinning social media platforms, and the epistemic states forced by online automation. (shrink)

Prior studies provide consistent evidence of deficits for psychopaths in processing verbal emotional material but are inconsistent regarding nonverbal emotional material. To examine whether psychopaths exhibit general versus specific deficits in nonverbal emotional processing, 34 psychopaths and 33 nonpsychopaths identified with Hare's (R. D. Hare, 1991) Psychopathy Checklist-Revised were asked to complete a facial affect recognition test. Slides of prototypic facial expressions were presented. Three hypotheses regarding hemispheric lateralization anomalies in psychopaths were also tested (right-hemisphere dysfunction, reduced lateralization, and reversed (...) lateralization). Psychopaths were less accurate than nonpsychopaths at classifying facial affect under conditions promoting reliance on right-hemisphere resources and displayed a specific deficit in classifying disgust. These findings demonstrate that psychopaths exhibit specific deficits in nonverbal emotional processing. (shrink)

This research investigates 3- and 5-year-olds' relative fairness in distributing small collections of even or odd numbers of more or less desirable candies, either with an adult experimenter or between two dolls. The authors compare more than 200 children from around the world, growing up in seven highly contrasted cultural and economic contexts, from rich and poor urban areas, to small-scale traditional and rural communities. Across cultures, young children tend to optimize their own gain, not showing many signs of self-sacrifice (...) or generosity. Already by 3 years of age, self-optimizing in distributive justice is based on perspective taking and rudiments of mind reading. By 5 years, overall, children tend to show more fairness in sharing. What varies across cultures is the magnitude of young children's self-interest. More fairness (less self-interest) in distributive justice is evident by children growing up in small-scale urban and traditional societies thought to promote more collective values. (shrink)

Humans can learn complex functional relationships between variables from small amounts of data. In doing so, they draw on prior expectations about the form of these relationships. In three experiments, we show that people learn to adjust these expectations through experience, learning about the likely forms of the functions they will encounter. Previous work has used Gaussian processes—a statistical framework that extends Bayesian nonparametric approaches to regression—to model human function learning. We build on this work, modeling the process of learning (...) to learn functions as a form of hierarchical Bayesian inference about the Gaussian process hyperparameters. (shrink)

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)

Here we suggest a formal using of N.A. Vasil’ev’s logical ideas in categorical logic: the idea of “accidental” assertion is formalized with topoi and the idea of the notion of nonclassical negation, that is not based on incompatibility, is formalized in special cases of monoidal categories. For these cases, the variant of the law of “excluded n-th” suggested by Vasil’ev instead of the tertium non datur is obtained in some special cases of these categories. The paraconsistent law suggested by Vasil’ev (...) is also demonstrated with linear and tensor logics but in a form weaker than he supposed. As we have, in fact, many truth-values in linear logic and topos logic, the admissibility of the traditional notion of inference in the categorical interpretation of linear and intuitionistic proof theory is discussed. (shrink)

Purpose of the paper is to establish the emergence and evolution of a gender problematics from the foundations of classical philosophy, namely, from the phenomenon of will-to-truth as the spontaneous desire of man to understand the life. To achieve this purpose, the following tasks are solved: 1) to investigate the way in which philosophy constitutes itself; 2) to establish how the category of "sex" manifests, both in the natural and in the social contexts; 3) to determine the correlation of gender (...) studies and philosophy. Theoretical basis. If for the methodology of gender studies it is inherent to proceed from the contextuality and value foundations of knowledge, then in this paper gender is considered directly from the being-in-world, human presence. Originality. The distinction between will-to-truth and will-to-knowledge, conducted for the first time by Michel Foucault, is used as a method by which the ontological demand of sex is revealed. Conclusions. As a result of the study, it was found that scientific developments in the field of gender issues in their subject matter are not mainly descended from subject sphere of classical philosophy. Sex is not substantiated metaphysically, and it is ontical, not ontological attribute of the human kind; its presentation as the determining factor of the cultural history in context of femininity/masculinity dichotomy is biased. This quality is similar to Nietzsche’s will to power, i.e., determination of definite knowledge that is later used in legal, socio-political discourse, corrects language practice, determines scientific researches making them dependant on axiological component of culture. As the social justice problem is solved, gender as the subject of social study loses its actuality. (shrink)

Libraries provide access to large amounts of library metadata. Unfortunately, many libraries only offer textual interfaces for searching and browsing their holdings. Visualizations provide simpler, faster, and more efficient ways to navigate, search and study large quantities of metadata. This paper presents GlamMap, a visualization tool that displays library metadata on an interactive, computer-generated geographic map. We provide detailed discussion of how GlamMap benefits the work of librarians and researchers. We show how geographic representations help librarians to perform tasks such (...) as collection assessment and how geographic information helps researchers to identify important scientific resources. (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)