Wlodek Rabinowicz suggested in an e-mail conversation (2001) to me that one might be able to use a particular Hats Puzzle to make a Dutch Book against a group of individually rational persons. I present a fanciful story here that has the same structure as Rabinowicz’s Dutch Book.

On the face of it both aggregation and deliberation represent alternative ways of producing a consensus. I argue, however, that the adequacy of aggregation mechanisms should be evaluated with an eye to the effects, both possible and actual, of public deliberation. Such an evaluation is undertaken by sketching a Bayesian model of deliberation as learning from others.

AimWhite matter changes in individuals at ultra-high risk for psychosis (UHR) may be involved in the transition to psychosis. Sleep-wake disturbances commonly precede the first psychotic episode and predict development of psychosis. We examined associations between white matter microstructure and sleep-wake disturbances in UHR individuals compared to healthy controls (HC), as well as explored the confounding effect of medication, substance use, and level of psychopathology.MethodsSixty-four UHR individuals and 35 HC underwent clinical interviews and diffusion weighted imaging. Group differences on global (...) and callosal mean fractional anisotropy (FA) was tested using general linear modeling. Sleep-wake disturbances were evaluated using the subjective measures disturbed sleep index (DSI) and disturbed awakening index (AWI) from the Karolinska Sleep Questionnaire, supported by objective sleep measures from one-night actigraphy. The primary analyses comprised partial correlation analyses between global FA/callosal FA and sleep-wake measures. Secondary analyses investigated multivariate patterns of covariance between measures of sleep-wake disturbances and FA in 48 white matter regions of interest using partial least square correlations.ResultsUltra-high risk for psychosis individuals displayed lower global FA (F = 14.56, p < 0.001) and lower callosal FA (F = 11.34, p = 0.001) compared to HC. Subjective sleep-wake disturbances were significantly higher among the UHR individuals (DSI: F = 27.59, p < 0.001, AWI: F = 36.42, p < 0.001). Lower callosal FA was correlated with increased wake after sleep onset (r = −0.34, p = 0.011) and increased sleep fragmentation index (r = −0.31, p = 0.019) in UHR individuals. Multivariate analyses identified a pattern of covariance in regional FA which were associated with DSI and AWI in UHR individuals (p = 0.028), but not in HC. Substance use, sleep medication and antipsychotic medication did not significantly confound these associations. The association with objective sleep-wake measures was sustained when controlling for level of depressive and UHR symptoms, but symptom level confounded the covariation between FA and subjective sleep-wake measures in the multivariate analyses.ConclusionCompromised callosal microstructure in UHR individuals was related to objectively observed disruptions in sleep-wake functioning. Lower FA in ventrally located regions was associated with subjectively measured sleep-wake disturbances and was partly explained by psychopathology. These findings call for further investigation of sleep disturbances as a potential treatment target. (shrink)

Background: More and more quantitative information is becoming available about the risks of complications arising from medical treatment. In everyday practice, this raises the question whether each and every risk, however low, should be disclosed to patients. What could be good reasons for doing or not doing so? This will increasingly become a dilemma for practitioners.Objective: To report doctors’ views on whether to disclose or withhold information on low risks of complications.Methods: In a qualitative study design, 37 respondents were included. (...) Focus group interviews were held with 22 respondents and individual in-depth interviews with 15.Results: Doctors have doubts about disclosing or withholding information on complication risk, especially in a risk range of 1 in 200 to 1 in 10 000. Their considerations on whether to disclose or to withhold information depend on a complicated mix of patient and doctor-associated reasons; on medical and personal considerations; and on the kind and purpose of intervention.Discussion: Even though the degree of a risk is important in a doctor’s considerations, the severity of the possible complications and patients’ wishes and competencies have an important role as well. Respondents said that low risks should always be communicated when there are alternatives for the intervention or when the patient may prevent or mitigate the risk. When the appropriateness of disclosing risks is doubtful, doctors should always tell their patients that no intervention is without risk, give them the opportunity to gather all the information they need or want, and enable them to detect a complication at an early stage. (shrink)

Through discourse with international groups of physicians, we conducted a cross-cultural analysis of the types of ethical dilemmas physicians face. Qualitative analysis was used to categorise the dilemmas into seven themes, which we compared among the physicians by country of practice. These themes were a-theoretically-driven and grounded heavily within the text. We then subjected the dilemmas to an analysis of moral intensity, which represents an important theoretical perspective of ethical decision making. These constructs represent salient determinants of ethical behaviour and (...) our cross-cultural sample afforded us the opportunity to consider both the pragmatic aspects of culture, as they are perceived by physicians, as well as the theory-driven concept of moral intensity. By examining both culture and moral intensity, we hope to better elucidate the complexities of ethical decision-making determinants among physicians in their daily practice. Doing so may potentially have practical implications for ethics training of medical students and foreign physicians. (shrink)

The US neutrino community gathered at the Workshop on the Intermediate Neutrino Program at Brookhaven National Laboratory February 4-6, 2015 to explore opportunities in neutrino physics over the next five to ten years. Scientists from particle, astroparticle and nuclear physics participated in the workshop. The workshop examined promising opportunities for neutrino physics in the intermediate term, including possible new small to mid-scale experiments, US contributions to large experiments, upgrades to existing experiments, R&D plans and theory. The workshop was organized into (...) two sets of parallel working group sessions, divided by physics topics and technology. Physics working groups covered topics on Sterile Neutrinos, Neutrino Mixing, Neutrino Interactions, Neutrino Properties and Astrophysical Neutrinos. Technology sessions were organized into Theory, Short-Baseline Accelerator Neutrinos, Reactor Neutrinos, Detector R&D and Source, Cyclotron and Meson Decay at Rest sessions.This report summarizes discussion and conclusions from the workshop. (shrink)

Understanding terrestrial carbon metabolism is critical because terrestrial ecosystems play a major role in the global carbon cycle. Furthermore, humans have severely disrupted the carbon cycle in ways that will alter the climate system and directly affect terrestrial metabolism. Changes in terrestrial metabolism may well be as important an indicator of global change as the changing temperature signal. Improving our understanding of the carbon cycle at various spatial and temporal scales will require the integration of multiple, complementary and independent methods (...) that are used by different research communities. Tools such as air sampling networks, inverse numerical methods, and satellite data allow us to study the strength and location of the global- and continental-scale carbon sources and sinks. Bottom-up studies provide estimates of carbon fluxes at finer spatial scales and examine the mechanisms that control fluxes at the ecosystem, landscape, and regional scales. Bottom-up approaches include comparative and process studies that provide the necessary mechanistic information to develop and validate terrestrial biospheric models. An iteration and reiteration of top-down and bottom-up approaches will be necessary to help constrain measurements at various scales. We propose a major international effort to coordinate and lead research programs of global scope of the carbon cycle. (shrink)

The focus of this study was to analyze the content, distribution, and comparative genome relationships of 996 chromosome bin-mapped expressed sequence tags accounting for 2266 restriction fragments on the homoeologous group 3 chromosomes of hexaploid wheat. Of these loci, 634, 884, and 748 were mapped on chromosomes 3A, 3B, and 3D, respectively. The individual chromosome bin maps revealed bins with a high density of mapped ESTs in the distal region and bins of low density in the proximal region of the (...) chromosome arms, with the exception of 3DS and 3DL. These distributions were more localized on the higher-resolution group 3 consensus map with intermediate regions of high-mapped-EST density on both chromosome arms. Gene ontology classification of mapped ESTs was not significantly different for homoeologous group 3 chromosomes compared to the other groups. A combined analysis of the individual bin maps using 537 of the mapped ESTs revealed rearrangements between the group 3 chromosomes. Approximately 232 of the consensus mapped ESTs matched sequences on rice chromosome 1 and revealed large- and small-scale differences in gene order. Of the group 3 mapped EST unigenes ∼21 and 32% matched the Arabidopsis coding regions and proteins, respectively, but no chromosome-level gene order conservation was detected. (shrink)

This chapter highlighted some salient trends in pediatric ethicsEthics, pediatric from different parts of the globe. It is interesting to note that although diverse, there are many similarities between ethical challenges in pediatrics in different parts of the world.

Stanovich & West distinguish between evolutionary rationality and normative rationality, and System 1 and System 2 mental processes. They hold that the main function of System 2 has to do with normative and not evolutionary rationality. We ask how System 2 could then be an adaptation, especially given S&W's own work on individual differences.

A total of 944 expressed sequence tags generated 2212 EST loci mapped to homoeologous group 1 chromosomes in hexaploid wheat. EST deletion maps and the consensus map of group 1 chromosomes were constructed to show EST distribution. EST loci were unevenly distributed among chromosomes 1A, 1B, and ID with 660, 826, and 726, respectively. The number of EST loci was greater on the long arms than on the short arms for all three chromosomes. The distribution of ESTs along chromosome arms (...) was nonrandom with EST clusters occurring in the distal regions of short arms and middle regions of long arms. Duplications of group 1 ESTs in other homoeologous groups occurred at a rate of 35.5%. Seventy-five percent of wheat chromosome 1 ESTs had significant matches with rice sequences, where large regions of conservation occurred between wheat consensus chromosome 1 and rice chromosome 5 and between the proximal portion of the long arm of wheat consensus chromosome 1 and rice chromosome 10. Only 9.5% of group 1 ESTs showed significant matches to Arabidopsis genome sequences. The results presented are useful for gene mapping and evolutionary and comparative genomics of grasses. (shrink)

Context. The identification of the sources that reionized the Universe and their specific contribution to this process are key missing pieces of our knowledge of the early Universe. Faint star-forming galaxies may be the main contributors to the ionizing photon budget during the epoch of reionization, but their escaping photons cannot be detected directly due to inter-galactic medium opacity. Hence, it is essential to characterize the properties of faint galaxies with significant Lyman continuum photon leakage up to z 4 to (...) define indirect indicators allowing analogues to be found at the highest redshift. Aims. Long gamma-ray bursts explode typically in star-forming regions of faint, star-forming galaxies. Through LGRB afterglow spectroscopy it is possible to detect directly LyC photons. Our aim is to use LGRBs as tools to study LyC leakage from faint, star-forming galaxies at high redshift. Methods. Here we present the observations of LyC emission in the afterglow spectra of GRB 191004B at z = 3:5055, together with those of the other two previously known LyC-emitting LGRB, to determine their LyC escape fraction and compare their properties. Results. From the afterglow spectrum of GRB 191004B we determine a neutral hydrogen column density at the LGRB redshift of og =17:2 0:15, and negligible extinction. The only metal absorption lines detected are C iv and Si iv. In contrast to GRB 050908 and GRB 060607A, the host galaxy of GRB 191004B displays significant Ly emission. From its Ly emission and the non-detection of Balmer emission lines we constrain its star-formation rate to 1 SFR 4:7 M yr. 1. We fit the Ly emission with a shell model and find parameters values consistent with the observed ones. The absolute LyC escape fractions we find for GRB 191004B, GRB 050908 and GRB 060607A are of 0:35+0:10.0:11, 0:08+0:05.0:04 and :20+0:05.0:05, respectively. We compare the LyC escape fraction of LGRBs to the values of other LyC emitters found from the literature, showing that LGRB afterglows can be powerful tools to study LyC escape for faint high-redshift star-forming galaxies. Indeed we could push LyC leakage studies to much higher absolute magnitudes. The host galaxies of the three LGRB presented here have all M1600 >.19:5 mag, with the GRB 060607A host at M1600 >.16 mag. LGRB hosts may therefore be particularly suitable for exploring the ionizing escape fraction in galaxies that are too faint or distant for conventional techniques. Furthermore the time investment is very small compared to galaxy studies. (shrink)

© 2016 Regents of the University of California.The Review summarizes much of particle physics and cosmology. Using data from previous editions, plus 3,062 new measurements from 721 papers, we list, evaluate, and average measured properties of gauge bosons and the recently discovered Higgs boson, leptons, quarks, mesons, and baryons. We summarize searches for hypothetical particles such as supersymmetric particles, heavy bosons, axions, dark photons, etc. All the particle properties and search limits are listed in Summary Tables. We also give numerous (...) tables, figures, formulae, and reviews of topics such as Higgs Boson Physics, Supersymmetry, Grand Unified Theories, Neutrino Mixing, Dark Energy, Dark Matter, Cosmology, Particle Detectors, Colliders, Probability and Statistics. Among the 117 reviews are many that are new or heavily revised, including those on Pentaquarks and Inflation. The complete Review is published online in a journal and on the website of the Particle Data Group. The printed PDG Book contains the Summary Tables and all review articles but no longer includes the detailed tables from the Particle Listings. A Booklet with the Summary Tables and abbreviated versions of some of the review articles is also available. (shrink)

Recent Work on Intrinsic Value brings together for the first time many of the most important and influential writings on the topic of intrinsic value to have appeared in the last half-century. During this period, inquiry into the nature of intrinsic value has intensified to such an extent that at the moment it is one of the hottest topics in the field of theoretical ethics. The contributions to this volume have been selected in such a way that all of the (...) fundamental questions concerning the nature of intrinsic value are treated in depth and from a variety of viewpoints. These questions include how to understand the concept of intrinsic value, what sorts of things can have intrinsic value, and how to compute intrinsic value. The editors have added an introduction that ties these questions together and places the contributions in context, and they have also provided an extensive bibliography. The result is a comprehensive, balanced, and detailed picture of current thinking about intrinsic value, one that provides an indispensable backdrop against which future writings on the topic may be assessed. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:RECLAIMING LIBERALISM * DOUGLAS B. RASMUSSEN St. John's University Jamaica, New York Through the shift of emphasis from natural duties or obligations to natural rights, the individual, the ego, had become the center and origin of the moral world, since man-as distinguished from man's end-had become that center or origin. -Leo Strauss T:HE CONCEPTION of individuality that lies at the oundation of natural rights classical liberalism has been (...) a arget of criticism for some time. This is not news. What is news and what is becoming more apparent to those who examine the issue is that the alternatives Strauss presents in the above quotation are not mutually exclusive. Indeed, as I and my colleague, Douglas J. Den Uyl, have recently observed: Making the individual the moral center of the universe does not require that one accept nominalism, mechanism, or hedonism, nor does accepting essentialism, teleology, and eudaimonism... require rejecting individualism. It is possible for the fulfillment of the individual to be interpreted in terms of the requirements for human wellbeing. There can be a view of the ego or self that is neither otherwordly nor Hobbesian, but Aristotelian. Further, the achievement of man's natural end need not be interpreted along Platonic lines. There is no such thing as the flourishing of "man." There is only the flourishing of individual men. The human good neither exists apart from the chokes and actions of individual human beings nor independent of the particular " mix " of goods that the individual human being must determine as appropriate for his circumstances. *This essay is based on a paper presented at a meeting of the American Association for the Philosophic Study of Society, American Philosophical Association (Eastern Division) convention, December 29, 1991 in New York City. This meeting was devoted to David L. Norton's book Democracy and Moral Development (Berkeley: University of California Press, 1991). 109 110 DOUGLAS B. RASMUSSEN Strauss's dichotomy betrays a disturbing tendency, often found among proponents of natural right and natural law, to reify the concept " natural end " and make it some good that competes with the good of individual human beings.1 David L. Norton in his recent work, Democracy and Moral Development, has also noted the nonexclusivity of Strauss's alternatives. Conditioned as we are by modernity's conception of the individual, the question of replacing avarice as the thematic motivation in lives of persons is likely to leave us at a loss. What else could possibly serve? The purpose of this book is to propose the eudaimonistic answer, and that answer is love in the meaning of Eros. Thus understood, love is not exclusively or primarily interpersonal; it is first of all the right relationship of each person with himself or herself. The self to which love is in the first instance directed is the ideal self that is aspired to and by which random change is transformed into the directed development we term growth. When the ideal of the individual is rightly chosen, it realizes objective values that subsisted within the individual as innate potentialities, thereby achieving in the individual the self-identity that is termed "integrity" and that constitutes the foundation of other virtues.2 Norton desires to reconceptualize the individualism historically associated with classical liberalism so as both to retain the gains of classical liberalism and to overcome its moral minimalism. According to Norton, the crucial problem with the conception of individuality historically associated with classical liberalism is that it is "non-developmental," or rather, there is only development within a single stage, namely, for self-preservation. There is nothing more. There is no standard of self-perfection by which to distinguish satisfaction of desire from satisfaction of right desire -no way to distinguish Socrates's satisfaction from that of a fool's. Norton thus seeks to replace classical liberalism's non-developmental conception of individuality with a eudaimonistic conception of the individual. 1 Douglas B. Rasmussen and Douglas J. Den Uy!, Liberty and Nature: An Aristotelian Defense of Liberal Order (La Salle, IL: Open Court, 1991), pp. 2 Democracy and Moral Development, p. 40. 92-93. RECLAIMING LIBERALISM 111 By replacing classical liberalism's conception of individuality with a... (shrink)

Major hallmarks of Alzheimer's disease include brain deposition of the amyloid-beta peptide , which is proteolytically cleaved from a large Abeta precursor protein by beta and gamma- secretases. A transmembrane aspartyl protease, beta-APP cleaving enzyme , has been recognized as the beta-secretase. We review the structure and function of the BACE1 protein, and of 4129 bp of the 5'-flanking region sequence of the BACE1 gene and its interaction with various transcription factors involved in cell signaling. The promoter region and 5'-untranslated (...) region contain multiple transcription factor binding sites, such as AP-1, CREB and MEF2. A 91 bp fragment is the shortest region with significant reporter gene activity and constitutes the minimal promoter element for BACE1. The BACE1 promoter contains six unique functional domains and three structural domains of increasing sequence complexity as the "ATG" start codon is approached. Notably, the BACE1 gene promoter contains basal regulatory elements, inducible features and sites for regulation by various important transcription factors. Herein, we also discuss and speculate how the interaction of these transcription factors with the BACE1 promoter can modulate synaptic plasticity, neuronal apoptosis and oxidative stress, which are pertinent to the pathogenesis and progression of AD. (shrink)

Professional identity and competent ethical behaviors of nursing students are commonly developed through curricular inclusion of professional nursing values education. Despite the enactment of this approach, nursing students continue to express difficulty in managing ethical conflicts encountered in their practice. This descriptive correlational study explores the relationships between professional nursing values, self-esteem, and ethical decision making among senior baccalaureate nursing students. A convenience sample of 47 senior nursing students from the United States were surveyed for their level of internalized professional (...) nursing values (Revised Professional Nursing Values Scale), level of self-esteem (Rosenberg’s Self-Esteem Scale), and perceived level of confidence in ethical decision making. A significant positive relationship (p < 0.05) was found between nursing students’ professional nursing values and levels of self-esteem. The results of this study can be useful to nursing educators whose efforts are focused on promoting professional identity development and competent ethical behaviors of future nurses. (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)

The rapid rise of international collaborative science has enabled access to genomic data. In this article, it is argued that to move beyond mapping genomic variation to understanding its role in complex disease aetiology and treatment will require extending data sharing for the purposes of clinical research translation and implementation.

This paper argues that professionals who make boundary-related decisions should be guided by relationship-based practice. In our roles as service users and professionals, drawing from our lived experiences of professional relationships, we argue we need to move away from distance-based practice. This includes understanding the boundary stories and narratives that exist for all of us – including the people we support, other professionals, as well as the organisations and systems within which we work. When we are dealing with professional boundary (...) issues, we should centre relationship-building skills that are central to many other aspects of our work. Skills that foster relationships at all levels – between professionals, service users, and services – need to be revalued. Our final recommendation is to create, develop, and foster safer spaces within and outside of organisations, as well as inter-professionally, for the discussion and exploration of boundary-related issues and practice. We are interested in hearing from those with experiences of being marginalised by boundaries so that they can inform a reshaping of our collective ideas around boundary related practices. To foster relationship-based practices in organisations, we have outlined several recommendations here; however, we recognize that these do not go far enough, and that collective action is needed to inform systemic change. (shrink)

The aim of the present investigation was to describe and to classify significant ethical problems encountered by the members of the staff during the daily clinical work at a hospital medical department. A set of definitions was prepared for the purpose, including the definition of a 'significant ethical problem'. During a three month period 426 inpatients and 173 outpatients were admitted. Significant ethical problems were encountered during the management of 106 in-patients (25 per cent) and 9 out-patients (5 per cent). (...) No significant difference was found between the frequency of ethical problems in female and male patients, but a positive correlation was noted between the number of problems and the patients' age. The problem types were classified according to a problem list. The results of this investigation suggest that greater attention must be paid to discussions about ethical problems among doctors and other categories of health personnel and that, among others, medical students ought to be taught the analysis of ethical problems. (shrink)

Introduction While quizzing during informed consent for research to ensure understanding has become commonplace, it is unclear whether the quizzing itself is problematic for potential participants. In this study, we address this issue in a multinational HIV prevention research trial enrolling injection drug users in China and Thailand. Methods Enrolment procedures included an informed consent comprehension quiz. An informed consent survey followed. Results 525 participants completed the informed consent survey (Heng County, China=255, Xinjiang, China=229, Chiang Mai, Thailand=41). Mean age was (...) 33 and mean educational level was 8 yrs. While quizzing was felt to be a good way to determine if a person understands the nature of clinical trial participation (97%) and participants did not generally find the quiz to be problematic, minorities of respondents felt pressured (6%); anxious (5%); bored (5%); minded (5%); and did not find the questions easy (13%). In multivariate analysis, lower educational level was associated with not minding the quizzing (6–10 yrs vs 0–5 yrs: OR=0.27, p=0.03; more than 11 yrs vs 0–5 yrs: OR=0.18, p=0.03). There were also site differences (Heng County vs Xinjiang) in feeling anxious (OR=0.07; p=<0.01), not minding (OR=0.26; p=0.03), being bored (OR=0.25; p=0.01) and not finding the questions easy (OR=0.10; p=<0.01). Conclusions Quizzing during the informed consent process can be problematic for a minority of participants. These problems may be associated with the setting in which research takes place and educational level. Further research is needed to develop, test and implement alternative methods of ensuring comprehension of informed consent. Trial Registration clinicaltrials.gov number NCT00270257. (shrink)

Purpose – To review and discuss Luciano Floridi’s 2019 book The Logic of Information: A Theory of Philosophy as Conceptual Design, the latest instalment in his philosophy of information (PI) tetralogy, particularly with respect to its implications for library and information studies (LIS). Design/methodology/approach – Nine scholars with research interests in philosophy and LIS read and responded to the book, raising critical and heuristic questions in the spirit of scholarly dialogue. Floridi responded to these questions. Findings – Floridi’s PI, including (...) this latest publication, is of interest to LIS scholars, and much insight can be gained by exploring this connection. It seems also that LIS has the potential to contribute to PI’s further development in some respects. Research implications – Floridi’s PI work is technical philosophy for which many LIS scholars do not have the training or patience to engage with, yet doing so is rewarding. This suggests a role for translational work between philosophy and LIS. Originality/value – The book symposium format, not yet seen in LIS, provides forum for sustained, multifaceted and generative dialogue around ideas. (shrink)

Ethical guidance for genomic research is increasingly sought and perceived to be necessary. Although there are pressing ethical issues in genomic research – concerning for example the recruitment of patients/participants; the process of taking consent; data sharing; and returning results to patients/participants – there is still limited useful guidance available for researchers/clinicians or for the research ethics committees who review such projects. This report outlines the ethical principles and guidance for genomic research co-produced with stakeholders during two workshops which took (...) place in the UK between November 2016 and May 2017. The stakeholders involved in these workshops included: healthcare professionals, genomic research teams, academics, patients, biobank managers, and representatives from the Health Research Authority, NHS Research Ethics Committees, patient support groups, pharmaceutical industry, and health policy think tanks. The co-produced principles and guidance are specifical... (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)