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.

The physician-patient relationship has changed over the last several decades, requiring a systematic reevaluation of the competing demands of patients, physicians, and families. In the era of genetic testing, using a model of patient care known as the family covenant may prove effective in accounting for these demands. The family covenant articulates the roles of the physician, patient, and the family prior to genetic testing, as the participants consensually define them. The initial agreement defines the boundaries of autonomy and benefit (...) for all participating family members. The physician may then serve as a facilitator in the relationship, working with all parties in resolving potential conflicts regarding genetic information. The family covenant promotes a fuller discussion of the competing ethical claims that may come to bear after genetic test results are received. (shrink)

In this paper we compare the propositional logic of Frege’s Grundgesetze der Arithmetik to modern propositional systems, and show that Frege does not have a separable propositional logic, definable in terms of primitives of Grundgesetze, that corresponds to modern formulations of the logic of “not”, “and”, “or”, and “if…then…”. Along the way we prove a number of novel results about the system of propositional logic found in Grundgesetze, and the broader system obtained by including identity. In particular, we show that (...) the propositional connectives that are definable in terms of Frege’s horizontal, negation, and conditional are exactly the connectives that fuse with the horizontal, and we show that the logical operators that are definable in terms of the horizontal, negation, the conditional, and identity are exactly the operators that are invariant with respect to permutations on the domain that leave the truth-values fixed. We conclude with some general observations regarding how Frege understood his logic, and how this understanding differs from modern views. (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)

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)

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)

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)

untangled and ordered in a theoretical framework focusing on evaluations doing no harm, tackling bad and doing good. Divided into four parts a diverse group of subject experts present a practical look at ethics, utilizing practical experience to analyze how ethics have been applied in evaluations, and how new approaches can shape the future of ethics. The chapters collectively create a common understanding of the potential role of ethics to infuse policy decisions and stakeholder initiatives with evaluations that provide better (...) insight and potential solutions for problems, going beyond "what works" to what needs to be done and what would help. The methodological scope ranges from working in contexts of fragility, conflict and violence, to participatory and decolonised approaches, including the ethical imperatives posed by global crises such as climate change, inequity and exploitative international relations. Ethics for Evaluation presents evaluators, commissioners of evaluation, policy makers and practitioners with inspiration for an ethical perspective on how evaluation can contribute towards solving problems. It presents a solid foundation for inclusive terminology and ethics guidance that would be the heart of a global exercise in professionalization of ethical evaluation practice. (shrink)

Live donor kidney transplantation is the best treatment option for most patients with late-stage chronic kidney disease; however, the rate of living kidney donation has declined in the United States. A consensus conference was held June 5-6, 2014 to identify best practices and knowledge gaps pertaining to live donor kidney transplantation and living kidney donation. Transplant professionals, patients, and other key stakeholders discussed processes for educating transplant candidates and potential living donors about living kidney donation; efficiencies in the living donor (...) evaluation process; disparities in living donation; and financial and systemic barriers to living donation. We summarize the consensus recommendations for best practices in these educational and clinical domains, future research priorities, and possible public policy initiatives to remove barriers to living kidney donation. (shrink)

An increasing amount of data is now available from public and private sources. Furthermore, the types, formats, and number of sources of data are also increasing. Techniques for extracting, storing, processing, and analyzing such data have been developed in the last few years for managing this bewildering variety based on a structure called a knowledge graph. Industry has devoted a great deal of effort to the development of knowledge graphs, and knowledge graphs are now critical to the functions of intelligent (...) virtual assistants such as Siri, Alexa, and Google Assistant. The goal of the Ontology Summit 2020 was to understand not only what knowledge graphs are but also where they originated, why they are so popular, the current issues, and their future prospects. The summit sessions examined many examples of knowledge graphs and surveyed the relevant standards that exist and are in development for knowledge graphs. The purpose of this Communiqué is to summarize our understanding from the Summit in order to foster research and development of knowledge graphs. (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)

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)