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)

Este artículo se centra en describir la problemática acerca de si los humanos deben seguir atrapados en una ciega evolución biológica o bien ellos deben pasar a elegir qué desean asumir. Ante tal disyuntiva se recuerdan la hipótesis optimista y la hipótesis pesimista. Al parecer, la especie humana, como el resto de las especies vivas, ha surgido en un proceso de evolución; es la única con capacidad de ser consciente de ello y, en parte, ha sido capaz, mediante las técnicas, (...) de poder adaptarse y de planificar en parte su futuro. Las biotecnologías están utilizándose cada vez más para el mejoramiento y perfeccionamiento de lo humano, convirtiéndose de ese modo en antropotecnias. Así, al orientarse estas nuevas tecnologías hacia y sobre su autor, el ser humano puede también convertirse en un peligro para él mismo. Los «transhumanistas » estiman, sin embargo, que los humanos deben arrebatar su destino biológico al proceso ciego de la evolución de la variación aleatoria y la adaptación, y pasar a la siguiente etapa como especie: la elección de nuestro ser. En la conclusión se patentizan las implicancias y consecuencias del hecho de ser humano y racional. (shrink)

La Universidad como centro de investigación y conocimiento debe propiciar una cultura para investigar. El artículo tiene como objetivo presentar la construcción y análisis estructural de una escala para evaluar la cultura investigativa en universitarios, constituida en seis dimensiones y treinta ítems calificados en escala Likert con cinco opciones de respuesta. La escala fue aplicada a 438 estudiantes del último año de estudios de dieciséis Escuelas de una Universidad del norte peruano, luego de su validación por cinco expertos. El análisis (...) factorial exploratorio y confirmatorio permitió validar la estructura multidimensional y su fiabilidad se estableció con el coeficiente omega (w=0.96). (shrink)

Tarihte herhalde çok az soru Tanrı’nın varlığı sorusu kadar sık sorulmuş, çok yanıtlanmış ve verilen birbirinden farklı onca yanıta rağmen kesin bir sonuca ulaştırılamayıp tartışılmaya devam etmiştir. Yine de geçmişe dönüp baktığımızda bu soruya verilen farklı yanıtların farklı uygarlıkların inşa edilmesine, bazılarının yıkılmasına, acımasız çatışmalara ve her şeye rağmen kucaklaşmalara da vesile olduğunu görüyoruz. Tanrı var mı? Varsa onu nasıl bilebiliriz? Tanrı yoksa her şey mubah mı? İnsan aklı ilahi olanı kavrayabilir mi? Tanrı’nın varlığı ahlaklı olmanın şartı mı? Evren akıllı (...) bir tasarımcının imzasını taşıyor mu? Bu kitapta felsefeci William David Beck, bu sorulara tarihte verilen yanıtları ve bu konudaki tartışmaları ele alarak meselenin genel ve tarihsel bir tablosunu bize sunuyor. Platon, Aristoteles, Marcus Aurelius gibi Eski Yunan ve Roma düşünürlerinden Anselmus, Thomas Aquinas, Augustinus ve Yahudi-Hıristiyan geleneğine, Doğu’nun bilgelerine, İbni Rüşd, Fârâbî ve Gazzâlî gibi İslam düşünürlerinden Alvin Plantinga, Graham Oppy, Sam Harris, Richard Dawkins, Max Tegmark gibi Batılı modern ilahiyatçılara, bilim insanlarına ve Yeni Ateizm hareketine kadar uzanan bir çizgide “Tanrı var mı?” sorusuna verilen çeşitli yanıtları ve bu yanıtlara sunulan akılcı gerekçeleri ortaya koyarak soruya felsefece bir yanıt vermenin nasıl bir iş olduğunu da gösteriyor. (shrink)

Constitutional Charters or Bill of Rights have been applauded because of the protection they provide to minorities and also in ensuring and protecting fundamental rights, however, Charters have been criticized for being considered morally and politically objectionable. The author responds to Charter critics most serious objections and offers some reasons for adopting an alternative framework.Resumen:Las cartas constitucionales o declaraciones de derechos han sido aplaudidas por la protección que brindan a las minorías y su función de asegurar derechos fundamentales; sin embargo, (...) también han sido criticadas por ser consideradas moral y políticamente refutables. El autor responde a las objeciones más serias de los críticos y ofrece algunas razones para adoptar un marco alternativo, de acuerdo al cual, las cartas no aspiran a establecer puntos de acuerdo y compromisos previos. (shrink)

El autor plantea que la cosmovisión científica moderna tiene el desafío de adaptarse a las nuevas evidencias, lo que reviste una gran dificultad por la densa red de supuestos teóricos en que ella está envuelta. Aclara que no busca atacar el espíritu de la ciencia sino motivar su propia evolución, que debe ir en la dirección de una ciencia más holística o ciencia de la totalidad, de la que describe sus características, para la cual considera que el tiempo está maduro.

Los intentos más recientes de repensar las normas democráticas están ejemplificados por dos pensadores franceses contemporáneos. Pierre Rosavallon critica los movimientos de protesta y trata de institucionalizar sus fuerzas. Jacques Rancière, por otra parte, ha definido notoriamente la política democrática de forma que se da sólo en momentos en los que se re-imagina caóticamente el orden existente. Su enfoque se revela de forma que reclama más atención hacia las normas razonables de ese orden de lo que el propio Rancière admite. (...) Tales normas constituyen un modelo de la democracia disidente, y puede inspirarse en los radicales populares de la era de la fundación americana. (shrink)

El autor nos invita a considerar la paradoja de que siendo una cosmovisión científica tan efectivamente demostrable de tantas maneras, no tenga espacio para concebir la mente y el espíritu; y que, siendo la ciencia una manera de entender que se basa en la creación de modelos o metáforas, se produce un daño cuando restringimos estos modelos y metáforas y los consideramos como la “verdadera” descripción de la realidad. Frente a esto, el artículo explora la posibilidad de incorporar metáforas alternativas, (...) y en particular la metáfora de la conciencia, para aportar con ella una más amplia comprensión del mundo para la ciencia. (shrink)

En las tres últimas décadas del siglo XX, muchos filósofos analíticos han abordado cuestiones de ética práctica, ampliando radicalmente el campo de la filosofía moral más allá de los temas metaéticos que habían sido su foco principal durante la mayor parte del siglo. Sin embargo, abordar este tipo de controversias prácticas rápidamente hizo surgir la cuestión de cómo justificar las afirmaciones morales normativas. Muchos filósofos analíticos se basaron en el intuicionismo, que tiene un linaje muy antiguo dentro de la filosofía (...) moral anglófona. Este artículo evalúa tres formas en las que los filósofos analíticos del siglo XX recurrieron a las intuiciones para apoyar o rebatir las afirmaciones morales. Argumentamos que esos métodos fracasaron en su objetivo de promover un conocimiento moral digno de confianza porque se basaron en supuestos que, cuando se presumen en contextos de injusticia epistémica estructural, son sistemáticamente engañosos. A pesar de que las intuiciones se encuentran entre las fuentes de conocimiento en las que los agentes morales deben confiar, la epistemología moral debe prestar especial atención a los procesos sociales a través de los cuales se recogen, refinan y evalúan las intuiciones y otras formas de evidencia. Producir un conocimiento moral digno de confianza requiere procesos de razonamiento democráticos que sean sensibles a la omnipresencia de la injusticia epistémica y la dominación, así como desarrollar estrategias para contrarrestarlas. (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)

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)

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)

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)

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)

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)

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)

This article considers the Undercover Surrealism exhibition curated at London’s Hayward Gallery and reflects on the practices of documentation, archiving and exhibition when the topic of the exhibition, as in this case, is a journal that in its most radical intention was set up to critique the practices of exhibition and documentation. The short and controversial life of Georges Bataille’s Documents unfolds as an often deliberately confusing juxtaposition of images and articles. The exhibition aims to represent both the sometimes incompatible (...) interests of the journal’s collaborators and the public dispute between Bataille and Breton over the aims of Surrealism. The article explores the intentions, risks, and possible effects of the exhibition in the context of Bataille’s own philosophy and his own peculiar part in the publication of Documents, which in its time was a contemporary review of diverse cultural phenomena interspersed with subversive dictionary entries. The article thus raises the question of what happens to the subversive intentions of a project like Documents in the scholarly historicist environment of public exhibition space. (shrink)