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)

lecting statistics about missing bindings and macros, and other errors. This guides debugging and development efforts, leading to iterative improvements in both the tools and the quality of the converted corpus. The build system thus serves as both a production conversion engine and software test harness. We have now processed the complete arχiv collection through 2006 consisting of more than 400,000 documents (a complete run is a processor-yearsize undertaking), continuously improving our success rate. We are now able to convert more (...) than 90% of these documents to XHTML+MathML. We consider over 60% to be successes, converted with no or minor warnings. While the remaining 30% can also be converted, their quality is doubtful, due to unsupported macros or conversion errors. (shrink)

'Why did the window break when it was hit by the stone? Because the window is brittle and the stone is hard; hardness and brittleness are powers, dispositional properties or dispositions.' Dispositions are essential to our understanding of the world. This book is a record of the debate on the nature of dispositions between three distinguished philosophers - D. M. Armstrong, C. B. Martin and U. T. Place - who have been thinking about dispositions all their working lives. Their distinctive (...) accounts cover many of the issues surrounding dispositions such as the nature of mind, matter, universals, existence, laws of nature and causation. Dispositions illuminates this central topic in analytic philosophy and at the same time highlights deeper concerns of metaphysics. (shrink)

Bizarre delusions are not specific to schizophrenia and can be found in other psychotic disorders. However, to date, there are no studies investigating socio-demographic and clinical characteristics associated with BizD across the psychosis spectrum. In this study 819 subjects with a diagnosis of SZ, schizoaffective disorder and bipolar I disorder were included. Patients with history of BizD and with no BizD were compared with respect to socidemographic and clinical variables, and predictors of BizD were explored. Patients with BizD were less (...) educated, less likely to be married, had higher Positive and Negative Syndrome Scale negative scores and lower Young Mania Rating Scale scores. Younger age, SZ and SZA diagnoses, higher PANSS positive scores, presence of reference delusions, tactile and olfactory hallucinations were predictors. Our results indicate that BizD are associated with higher illness severity, lower functionality and specific set of symptoms. (shrink)

Psychopaths routinely disregard social norms by engaging in selfish, antisocial, often violent behavior. Commonly characterized as mentally disordered, recent evidence suggests that psychopaths are executing a well-functioning, if unscrupulous strategy that historically increased reproductive success at the expense of others. Natural selection ought to have favored strategies that spared close kin from harm, however, because actions affecting the fitness of genetic relatives contribute to an individual’s inclusive fitness. Conversely, there is evidence that mental disorders can disrupt psychological mechanisms designed to (...) protect relatives. Thus, mental disorder and adaptation accounts of psychopathy generate opposing hypotheses: psychopathy should be associated with an increase in the victimization of kin in the former account but not in the latter. Contrary to the mental disorder hypothesis, we show here in a sample of 289 violent offenders that variation in psychopathy predicts a decrease in the genetic relatedness of victims to offenders; that is, psychopathy predicts an increased likelihood of harming non-relatives. Because nepotistic inhibition in violence may be caused by dispersal or kin discrimination, we examined the effects of psychopathy on (1) the dispersal of offenders and their kin and (2) sexual assault frequency (as a window on kin discrimination). Although psychopathy was negatively associated with coresidence with kin and positively associated with the commission of sexual assault, it remained negatively associated with the genetic relatedness of victims to offenders after removing cases of offenders who had coresided with kin and cases of sexual assault from the analyses. These results stand in contrast to models positing psychopathy as a pathology, and provide support for the hypothesis that psychopathy reflects an evolutionary strategy largely favoring the exploitation of non-relatives. (shrink)

Hull et al.'s analysis of operant behavior in terms of interaction and replication does not seem consistent with a genuine selection model. The putative replicators do not replicate, and the overall process is more reminiscent of directed mutation than of natural selection. General analogies between natural selection and operant reinforcement are too superficial to be of much scientific use.

In this paper we describe the objectives of teaching medical ethics to undergraduates and the teaching methods used. We describe a workshop used in the University of Liverpool Department of Psychiatry, designed to enhance ethical sensitivity in psychiatry. The workshop reviews significant historical and current errors in the ethical practice of psychiatry and doctors' defence mechanisms against accepting responsibility for deficiencies in ethical practice. The workshop explores the student doctors' own group ethos in response to ethical dilemmas, and demonstrates how (...) the individual contributes to and is responsible for the group ethos through participation and also through nonparticipation. The student feedback about the workshop is reviewed. The Toronto Ethical Sensitivity Instrument was used to assess whether or not the workshop altered sensitivity. Compared to a control group the attenders' sensitivity was significantly increased (on Student's t-test p equals or is less than 0.002). (shrink)

Shortages of new therapeutics to treat coronavirus disease (COVID-19) have forced clinicians, public health officials, and health systems to grapple with difficult questions about how to fairly allocate potentially life-saving treatments when there are not enough for all patients in need (1). Shortages have occurred with remdesivir, tocilizumab, monoclonal antibodies, and the oral antiviral Paxlovid (2) -/- Ensuring equitable allocation is especially important in light of the disproportionate burden experienced during the COVID-19 pandemic by disadvantaged groups, including Black, Hispanic/Latino and (...) Indigenous communities, individuals with certain disabilities, and low-income persons. However, many health systems have resorted to first-come, first-served approaches to allocation, which tend to disadvantage individuals with barriers in access to care (3). There is mounting evidence of racial, ethnic, and socioeconomic disparities in access to medications for COVID-19 (4, 5). -/- One potential method to promote equitable allocation is to use a weighted lottery, which is an allocation strategy that gives all eligible patients a chance to receive the scarce treatment while also allowing the assignment of higher or lower chances according to other ethical considerations (6). We sought to assess the feasibility of implementing a weighted lottery to allocate scarce COVID-19 medications in a large U.S. health system and to determine whether the weighted lottery promotes equitable allocation. (shrink)

Smart grids are rolling out internationally, with the United States nearing completion of a significant USD4-plus-billion federal program funded under the American Recovery and Reinvestment Act. The emergence of smart grids is widespread across developed countries. Multiple approaches to analyzing the benefits of smart grids have emerged. The goals of this white paper are to review these approaches and analyze examples of each to highlight their differences, advantages, and disadvantages. This work was conducted under the auspices of a joint U.S.-China (...) research effort, the Climate Change Working Group Implementation Plan, Smart Grid. We present comparative benefits assessments of smart grid demonstrations in the U.S. and China along with a BA of a pilot project in Europe. In the U.S., we assess projects at two sites: the University of California, Irvine campus, which consists of two distinct demonstrations: Southern California Edison’s Irvine Smart Grid Demonstration Project and the UCI campus itself; and the Navy Yard area in Philadelphia, which has been repurposed as a mixed commercial-industrial, and possibly residential, development. In China, we cover several smart-grid aspects of the Sino-Singapore Tianjin Eco-city and the Shenzhen Bay Technology and Ecology City. In Europe, we look at a BA of a pilot smart grid project in the Malagrotta area west of Rome, Italy, contributed by the Joint Research Centre of the European Commission. The Irvine sub-project BAs use the U.S. Department of Energy Smart Grid Computational Tool, which is built on methods developed by the Electric Power Research Institute. The TEC sub-project BAs apply Smart Grid Multi-Criteria Analysis developed by the State Grid Corporation of China based on the analytic hierarchy process with fuzzy logic. The B-TEC and TNY sub-project BAs are evaluated using new approaches developed by those project teams. JRC has adopted an approach similar to EPRI’s but tailored to the Malagrotta distribution grid. (shrink)