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)

Objectives: To study the attitudes of both medical and non-medical students towards the do-not-resuscitate decision in a university in Hong Kong, and the factors affecting their attitudes.Methods: A questionnaire-based survey conducted in the campus of a university in Hong Kong. Preferences and priorities of participants on cardiopulmonary resuscitation in various situations and case scenarios, experience of death and dying, prior knowledge of DNR and basic demographic data were evaluated.Results: A total of 766 students participated in the study. There were statistically (...) significant differences in their DNR decisions in various situations between medical and non-medical students, clinical and preclinical students, and between students who had previously experienced death and dying and those who had not. A prior knowledge of DNR significantly affected DNR decision, although 66.4% of non-medical students and 18.7% of medical students had never heard of DNR. 74% of participants from both medical and non-medical fields considered the patient’s own wish as the most important factor that the healthcare team should consider when making DNR decisions. Family wishes might not be decisive on the choice of DNR.Conclusions: Students in medical and non-medical fields held different views on DNR. A majority of participants considered the patient’s own wish as most important in DNR decisions. Family wishes were considered less important than the patient’s own wishes. (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)

Amyloid-beta peptide plaque in the brain is the primary diagnostic criterion of Alzheimer's disease . The physiological role of Abeta are poorly understood. We have previously determined an Abeta interacting domain in the promoters of AD-associated genes . This AbetaID interacts in a DNA sequence-specific manner with Abeta. We now demonstrate novel Abeta activity as a possible transcription factor. Herein, we detected Abeta-chromatin interaction in cell culture by ChIP assay. We observed that human neuroblastoma cells treated with FITC conjugated Abeta1-40 (...) localized Abeta to the nucleus in the presence of H2O2-mediated oxidative stress. Furthermore, primary rat fetal cerebrocortical cultures were transfected with APP and BACE1 promoter-luciferase fusions, and rat PC12 cultures were transfected with polymorphic APP promoter-CAT fusion clones. Transfected cells were treated with different Abeta peptides and/or H2O2. Abeta treatment of cell cultures produced a DNA sequence-specific response in cells transfected with polymorphic APP clones. Our results suggest the Abeta peptide may regulate its own production through feedback on its precursor protein and BACE1, leading to amyloidogenesis in AD. (shrink)

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)

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)

ABSTRACTThe rapid expansion of primary education in Ethiopia has enabled most children to attend primary education—or at least to start schooling. This expansion, however, is largely “symbolic” rat...

Mitigating response distortion in answers to sensitive questions is an important issue for business ethics researchers. Sensitive questions may be asked in surveys related to business ethics, and respondents may intend to avoid exposing sensitive aspects of their character by answering such questions dishonestly, resulting in response distortion. Previous studies have provided evidence that a surveying procedure called the randomized response technique is useful for mitigating such distortion. However, previous studies have mainly applied the RRT to individual dichotomous questions in (...) face-to-face survey settings. In this study, we focus on behavioral research examining the relationships between latent variables, which are unobserved variables measured by multiple items on Likert or bipolar scales. To demonstrate how the RRT can be applied to obtain valid answers from respondents answering a self-administered online questionnaire with Likert and bipolar scales, we build a behavioral model to study the effect of punishment severity on employees’ attitudes toward misuse of information systems resources in the workplace, which in turn influence misuse behavior. The survey findings meet our expectations. The respondents are generally more willing to disclose sensitive data about their attitudes and actual behavior related to misuse when the RRT is implemented. The RRT’s implications for causal modeling and the advantages and challenges of its use in online environments are also discussed. (shrink)

Employees perceive illegitimate tasks as inappropriate assignments because such tasks are beyond what they expect to do in any given job position. Extant literature indicates that, in addition to creating psychological strain and reducing well-being, illegitimate task assignments can result in counterproductive work behavior. This study extends the literature by examining whether illegitimate tasks may lead to two specific forms of CWB targeting organizations: destructive voice and time theft. To understand how and when this happens, we investigate the mediating role (...) of moral disengagement and the moderating role of psychological entitlement. Survey results based on 258 supervisor–subordinate dyads in China reveal that illegitimate tasks are positively related to destructive voice and time theft through moral disengagement. Furthermore, psychological entitlement strengthens the positive relationship between illegitimate tasks and moral disengagement and the indirect effect of illegitimate tasks on destructive voice and time theft. Overall, the findings provide insightful theoretical and managerial implications for research related to illegitimate tasks and CWB. (shrink)

Although the same environmental regulations apply to all regions in China, legal enforcement can be different due to local economic development priorities. There is still a lack of knowledge about how regional disparities affect the operating performance results of the implementation of corporate environmental management practices, thus providing little information for foreign companies when they invest and develop their production base in China. To fill this research gap, this paper collects data from the Fortune 500 Chinese firms to investigate the (...) moderating role of regional disparities in affecting the performance results of corporate environmental management efforts based on the institutional theory. The disclosed corporate environmental responsibility practices serve as proxy to represent corporate environmental management practices. Content analysis approach was applied to collect and analyze CER practices published in the corporate reports of Chinese manufacturers. The results show that CER has a positive impact on operating income, while regional disparities influence the relationship between CER and corporate operating income. Specifically, CER and operating income are positively related in Eastern China; on the contrary, they are negatively related in Western China. This paper adds to the body of knowledge about environmental discrepancies in the same emerging economy, and provides insights for systematic consideration in terms of the issues of government environmental regulations and corporate environmental strategies. (shrink)

Medical paternalism has long been a common medical practice. However, patient autonomy in healthcare has been recently adopted by doctors and patients alike. This study explored whether doctors and patients in a tertiary care hospital in Saudi Arabia preferred autonomy or paternalism in shared decision‐making. A total of 118 participants (51 patients requiring total knee replacement, owing to stages 3–4 of osteoarthritis, and 67 doctors) from the Eastern province, Saudi Arabia. responded to a 17‐question category‐based questionnaire involving four scales of (...) autonomy. Descriptive statistics and chi‐square test results revealed that in this hospital, patients preferred a paternalistic approach toward their medical care along with a full disclosure of the risks related to surgical procedures. We recommend health education regarding the specific autonomy subscales (doctor knows best, patient should decide, right to non‐participation, and obligatory risk information), and the implementation of protocols that protect patients' rights and enhance personal autonomy. (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)

This paper explores how consumers perceive retailer ethics. Based on a review of the marketing and consumer research literature, we conceptualize consumer perceptions of the ethics of retailers as a multidimensional construct and propose that its effects on consumer purchase behavior and word-of-mouth communication are more salient when consumers have strong rather than weak ethical beliefs. The model was validated using a random sample of 399 respondents in a collectivist society. The results of structural equation modeling confirmed that CPER is (...) a second-order construct comprising product fairness, price fairness, non-deception, fair trade, and green products. CPER positively predicted consumer purchase behavior and word-of-mouth communication. Moreover, ethical beliefs moderated the positive relationship between CPER and the word-of-mouth communication of consumers with strong ethical beliefs but did not moderate the relationship between CPER and purchase behavior. The implications of the findings are discussed. (shrink)

Background This paper describes the design, implementation, and process outcomes from three public deliberations held in three tribal communities. Although increasingly used around the globe to address collective challenges, our study is among the first to adapt public deliberation for use with exclusively Indigenous populations. In question was how to design deliberations for tribal communities and whether this adapted model would achieve key deliberative goals and be well received.Methods We adapted democratic deliberation, an approach to stakeholder engagement, for use with (...) three tribal communities to respect tribal values and customs. Public deliberation convenes people from diverse backgrounds in reasoned reflection and dialogue in search of collective solutions. The deliberation planning process and design were informed by frameworks of enclave deliberation and community-based participatory research, which share key egalitarian values. The deliberations were collaboratively designed with tribal leadership and extensive partner input and involvement in the deliberations. Each deliberation posed different, locally relevant questions about genomic research, but used the same deliberation structure and measures to gauge the quality and experience of deliberation.Results A total of 52 individuals participated in the deliberations across all three sites. Deliberants were balanced in gender, spanned decades in age, and were diverse in educational attainment and exposure to health research. Overall, the deliberations were positively evaluated. Participant perceptions and external observer datasets depict three deliberations that offered intensive conversation experiences in which participants learned from one another, reported feeling respected and connected to one another, and endorsed this intensive form of engagement.Conclusion The adapted deliberations achieved key deliberative goals and were generally well received. Limitations of the study are described. (shrink)

This research provides an exploratory investigation of whether gift/help-receiving contexts that elicit mixed emotional variants of gratitude can be distinguished from typical gratitude-eliciting situations in their associated appraisals, action tendencies, and psychosocial effects. We examined 473 participants (159 males, 312 females, 2 others; Mage = 31.07) using a one-way four-conditions between-subjects experiment. Participants were randomly assigned to complete recall tasks describing four different gratitude-eliciting situations. Emotions, cognitive appraisals, action tendencies, and general psychosocial outcomes were assessed. Relative to a control condition (...) involving receiving a gift or help (gift/help condition), receiving something at the expense of a benefactor (benefactor-inconvenience condition) elicited gratitude-guilt; receiving something with an expectation of return (return-favour condition) elicited gratitude-disappointment and gratitude-anger; while receiving a disliked gift or receiving assistance that made things worse (backfire condition) primarily elicited gratitude-disappointment while also eliciting gratitude-anger and gratitude-guilt. Each condition was differentiable from control in their appraisals, action tendencies, and psychosocial effects. Notably, contexts which elicited mixed emotional variants of gratitude were characterised by the co-occurrence of conflicting appraisals such as pleasantness and unpleasantness or goal-congruence and goal-incongruence. Additionally, the return-favour and backfire conditions were most dissimilar from control, and were associated with the most negative action tendencies and psychosocial outcomes. (shrink)

Although performance pressure has desirable consequences, there is evidence that it can produce unintended outcomes as employees tend to engage in dysfunctional and unethical behaviors to meet performance goals. Thus, the process through which employees think and behave unethically under performance pressure deserves more research attention. This study goes beyond the stress-appraisal perspective and investigates whether and when performance pressure influences individual work mindsets and behaviors from a moral reasoning perspective. Specifically, we contend that performance pressure is related to employee (...) expediency through moral decoupling. We further hypothesize dialectical thinking and moral identity to be the boundary conditions of the proposed relationships. Analyses of data from a field study in three waves provide support for most of the hypotheses. In particular, we find that moral decoupling accounts for additional variance after we control for the stress-appraisal effect of performance pressure on employee expediency. The study offers several contributions to the literature on performance pressure and unethical behavior. (shrink)

The majority of the extant languages have one of three dominant basic word orders: SVO, SOV or VSO. Various hypotheses have been proposed to explain this word order bias, including the existence of a universal grammar, the learnability imposed by cognitive constraints, the descent of modern languages from an ancestral protolanguage, and the constraints from functional principles. We run simulations using a multi-agent computational model to study this bias. Following a local order approach, the model simulates individual language processing mechanisms (...) in production and comprehension. The simulation results demonstrate that the semantic structures that a language encodes can constrain the global syntax, and that local syntax can help trigger bias towards the global order SOV/SVO. (shrink)

Past research has provided some evidence of positive relationships between leisure and cognitive functioning, but questions remain regarding their mechanisms. We argue that specific negative emotio...

Objectives The objectives of the study are to understand the current practice of informed consent in medical research in public hospitals in Shanghai, and to share our views with other countries, especially developing countries. Methods In the study, 145 consent forms (CFs) of the selected research projects in eight public hospitals with ethics committees in Shanghai were audited, and the principle investigators (PIs) of these research projects and 40 student subjects who had participated in clinical drug tests were surveyed by (...) questionnaires. Results The CFs of medical researches in public hospitals with ethics committees in Shanghai were generally acceptable. However, there were some defects in the CFs. Although most of the surveyed PIs had correct recognition of informed consent, some processes of informed consent were not in accordance with generally accepted requirements. A large number of the PIs considered the greatest difficulty with informal consent was lack of correct recognition of subjects or legally authorised representatives on medical research. Discussion Informed consent in medical research should consider the research ethics, the background of potential subjects, the local resources and culture of medical research. In addition, special protection is needed for student subjects in informed consent as well as efforts for building and restoring the public's trust in biomedical research. Conclusion The informed consent in Shanghai's public hospitals with ethics committees was generally acceptable and the achievement of adequate informed consent is influenced by many factors. (shrink)

A recent series of experiments have demonstrated that a classical fluid mechanical system, constituted by an oil droplet bouncing on a vibrating fluid surface, can be induced to display a number of behaviours previously considered to be distinctly quantum. To explain this correspondence it has been suggested that the fluid mechanical system provides a single-particle classical model of de Broglie’s idiosyncratic ‘double solution’ pilot wave theory of quantum mechanics. In this paper we assess the epistemic function of the bouncing oil (...) droplet experiments in relation to quantum mechanics. We find that the bouncing oil droplets are best conceived as an analogue illustration of quantum phenomena, rather than an analogue simulation, and, furthermore, that their epistemic value should be understood in terms of how-possibly explanation, rather than confirmation. Analogue illustration, unlike analogue simulation, is not a form of ‘material surrogacy’, in which source empirical phenomena in a system of one kind can be understood as ‘standing in for’ target phenomena in a system of another kind. Rather, analogue illustration leverages a correspondence between certain empirical phenomena displayed by a source system and aspects of the ontology of a target system. On the one hand, this limits the potential inferential power of analogue illustrations, but, on the other, it widens their potential inferential scope. In particular, through analogue illustration we can learn, in the sense of gaining how-possibly understanding, about the putative ontology of a target system via an experiment. As such, the potential scientific value of these extraordinary experiments is undoubtedly a significant one. (shrink)