Alzheimer's disease is characterized by formation of neuritic plaque primarily composed of a small filamentous protein called amyloid-beta peptide . The rate-limiting step in the production of Abeta is the processing of Abeta precursor protein by beta-site APP-cleaving enzyme . Hence, BACE1 activity plausibly plays a rate-limiting role in the generation of potentially toxic Abeta within brain and the development of AD, thereby making it an interesting drug target. A phase II trial of the promising LY2886721 inhibitor of BACE1 was (...) suspended in June 2013 by Eli Lilly and Co., due to possible liver toxicity. This outcome was apparently a surprise to the study's team, particularly since BACE1 knockout mice and mice treated with the drug did not show such liver toxicity. Lilly proposed that the problem was not due to LY2886721 anti-BACE1 activity. We offer an alternative hypothesis, whereby anti-BACE1 activity may induce apparent hepatotoxicity through inhibiting BACE1's processing of beta-galactoside alpha-2,6-sialyltransferase I . In knockout mice, paralogues, such as BACE2 or cathepsin D, could partially compensate. Furthermore, the short duration of animal studies and short lifespan of study animals could mask effects that would require several decades to accumulate in humans. Inhibition of hepatic BACE1 activity in middle-aged humans would produce effects not detectable in mice. We present a testable model to explain the off-target effects of LY2886721 and highlight more broadly that so-called off-target drug effects might actually represent off-site effects that are not necessarily off-target. Consideration of this concept in forthcoming drug design, screening, and testing programs may prevent such failures in the future. (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 present review highlights an association between autism, Alzheimer disease , and fragile X syndrome . We propose a conceptual framework involving the amyloid-beta peptide , Abeta precursor protein , and fragile X mental retardation protein based on experimental evidence. The anabolic effect of the secreted alpha form of the amyloid-beta precursor protein may contribute to the state of brain overgrowth implicated in autism and FXS. Our previous report demonstrated that higher plasma sAPPalpha levels associate with more severe symptoms of (...) autism, including aggression. This molecular effect could contribute to intellectual disability due to repression of cell-cell adhesion, promotion of dense, long, thin dendritic spines, and the potential for disorganized brain structure as a result of disrupted neurogenesis and migration. At the molecular level, APP and FMRP are linked via the metabotropic glutamate receptor 5 . Specifically, mGluR5 activation releases FMRP repression of APP mRNA translation and stimulates sAPP secretion. The relatively lower sAPPalpha level in AD may contribute to AD symptoms that significantly contrast with those of FXS and autism. Low sAPPalpha and production of insoluble Abeta would favor a degenerative process, with the brain atrophy seen in AD. Treatment with mGluR antagonists may help repress APP mRNA translation and reduce secretion of sAPP in FXS and perhaps autism. (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)

Alzheimer's disease is characterized by plaques of amyloid-beta peptide, cleaved from amyloid-beta protein precursor . Our hypothesis is that lifespan profiles of AD-associated mRNA and protein levels in monkeys would differ from mice and that differential lifespan expression profiles would be useful to understand human AD pathogenesis. We compared profiles of AbetaPP mRNA, AbetaPP protein, and Abeta levels in rodents and primates. We also tracked a transcriptional regulator of the AbetaPP gene, specificity protein 1 , and the beta amyloid precursor (...) cleaving enzyme . In mice, AbetaPP and SP1 mRNA and their protein products were elevated late in life; Abeta levels declined in old age. In monkeys, SP1, AbetaPP, and BACE1 mRNA declined in old age, while protein products and Abeta levels rose. Proteolytic processing in both species did not match production of Abeta. In primates, AbetaPP and SP1 mRNA levels coordinate, but an inverse relationship exists with corresponding protein products as well as Abeta levels. Comparison of human DNA and mRNA sequences to monkey and mouse counterparts revealed structural features that may explain differences in transcriptional and translational processing. These findings are important for selecting appropriate models for AD and other age-related diseases. (shrink)

The sporadic nature of Alzheimer's disease argues for an environmental link that may drive AD pathogenesis; however, the triggering factors and the period of their action are unknown. Recent studies in rodents have shown that exposure to lead during brain development predetermined the expression and regulation of the amyloid precursor protein and its amyloidogenic beta-amyloid product in old age. Here, we report that the expression of AD-related genes [APP, BACE1 ] as well as their transcriptional regulator were elevated in aged (...) monkeys exposed to Pb as infants. Furthermore, developmental exposure to Pb altered the levels, characteristics, and intracellular distribution of Abeta staining and amyloid plaques in the frontal association cortex. These latent effects were accompanied by a decrease in DNA methyltransferase activity and higher levels of oxidative damage to DNA, indicating that epigenetic imprinting in early life influenced the expression of AD-related genes and promoted DNA damage and pathogenesis. These data suggest that AD pathogenesis is influenced by early life exposures and argue for both an environmental trigger and a developmental origin of AD. (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)

BACKGROUND: Serotonin transporter promoter genotype appears to increase risk for depression in the context of stressful life events. However, the effects of this genotype on measures of stress sensitivity are poorly understood. Therefore, this study examined whether 5-HTTLPR genotype was associated with negative information processing biases in early childhood. METHOD: Thirty-nine unselected seven-year-old children completed a negative mood induction procedure and a Self-Referent Encoding Task designed to measure positive and negative schematic processing. Children were also genotyped for the 5-HTTLPR gene. (...) RESULTS: Children who were homozygous for the short allele of the 5-HTTLPR gene showed greater negative schematic processing following a negative mood prime than those with other genotypes. 5-HTTLPR genotype was not significantly associated with positive schematic processing. LIMITATIONS: The sample size for this study was small. We did not analyze more recently reported variants of the 5-HTTLPR long alleles. CONCLUSIONS: 5-HTTLPR genotype is associated with negative information processing styles following a negative mood prime in a non-clinical sample of young children. Such cognitive styles are thought to be activated in response to stressful life events, leading to depressive symptoms; thus, cognitive styles may index the "stress-sensitivity" conferred by this genotype. (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)

OBJECTIVES: Early-emerging, temperamental differences in fear-related traits may be a heritable vulnerability factor for anxiety disorders. Previous research indicates that the serotonin transporter promoter region polymorphism is a candidate gene for such traits. METHODS: Associations between 5-HTTLPR genotype and indices of fearful child temperament, derived from maternal report and standardized laboratory observations, were examined in a community sample of 95 preschool-aged children. RESULTS: Children with one or more long alleles of the 5-HTTLPR gene were rated as significantly more nervous during (...) standardized laboratory tasks than children who were homozygous for the short alleles. Children homozygous for the short alleles were also rated as significantly shyer, by maternal report, than those with at least one copy of the long allele of the 5-HTTLPR gene. CONCLUSIONS: This study extends the literature linking the short alleles of the serotonin transporter promoter region polymorphism to fear and anxiety-related traits in early childhood and adulthood, and is one of very few studies to examine the molecular genetics of preschoolers' temperament using multiple measures of traits in a normative sample. (shrink)

Oxidative damage to DNA has been associated with neurodegenerative diseases. Developmental exposure to lead has been shown to elevate the Alzheimer's disease related beta-amyloid peptide , which is known to generate reactive oxygen species in the aging brain. This study measures the lifetime cerebral 8-hydroxy-2'-deoxyguanosine levels and the activity of the DNA repair enzyme 8-oxoguanine DNA glycosylase in rats developmentally exposed to Pb. Oxo8dG was transiently modulated early in life , but was later elevated 20 months after exposure to Pb (...) had ceased, while Ogg1 activity was not altered. Furthermore, an age-dependent loss in the inverse correlation between Ogg1 activity and oxo8dG accumulation was observed. The effect of Pb on oxo8dG levels did not occur if animals were exposed to Pb in old age. These increases in DNA damage occurred in the absence of any Pb-induced changes in copper/zinc-superoxide dismutase , manganese-SOD , and reduced-form glutathion . These data suggest that oxidative damage and neurodegeneration in the aging brain could be impacted by the developmental disturbances. (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)

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)

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)

“Doğal din” terimi, bazen doğanın kendisinin ilahi olduğu bir panteistik doktrine atıfta bulunur. “Doğal teoloji” terimi ise aksine, başlangıçta gözlemlenen doğal gerçekler temelinde (ve bazen) Tanrı’nın varlığını savunmaya yönelik projeye atıfta bulunur. Bununla birlikte çağdaş felsefede, hem “doğal din” hem de “doğal teoloji” genel olarak, dinî veya teolojik konuları araştırmak için insana, “doğal” olan bilişsel yetilerini – akıl, algı, içgözlem- kullanma projesini ifade eder. Doğal din veya teoloji, mevcut anlayış üzerine, doğayla ilgili ampirik araştırmalarla sınırlı olmamakla birlikte ayrıca panteistik bir (...) sonuçla da bağlantılı değildir. Bununla birlikte o, özel doğal olmayan yetilere (ESP, telepati, mistik deneyim) veya doğaüstü bilgi kaynaklarına (kutsal metinler, vahiy teolojisi, inanç otoriteleri, doğrudan doğaüstü iletişim) hitap etmekten kaçınır. Genel olarak, doğal din veya teoloji (bundan böyle “doğal teoloji” olarak anılacaktır), diğer felsefi ve bilimsel girişimlerle aynı rasyonel inceleme standartlarına uymayı amaçlamaktadır ve aynı değerlendirme ve eleştiri yöntemlerine tabidir. (shrink)

Modal ontolojik argüman, Tanrı’nın varlığını sadece bilfiil gerçek olan bu dünyada değil, bütün mümkün dünyalarda göstermeye yönelik bir argümandır. Anselm’in (1033-1109) Proslogion adlı eserinin 3. bölümünde “kendisinden daha büyüğü düşünülemeyen” şeklinde tanımlanan; Tanrı’nın var olmamasının da düşünülemeyeceğini, bu yüzden de varolmamasının imkansızlığı üzerinde kurulu yeni bir argüman bulunduğunu öne süren bazı araştırmacılar, bu argümanı mümkün dünyalar semantiği yardımıyla formüle edip, “modal ontolojik argüman” şeklinde adlandırmışlardır. Çok farklı şekillerde formüle edilmiş bu argüman kabaca Tanrı’nın mümkünse zorunlu olması, dolayısıyla bilfiil gerçek olan (...) bu dünyada da var olması gerektiğini savunur. (shrink)

Çağdaş epistemoloji içerisinde, dışsalcı, güvenilirci ve erdeme dayalı epistemolojik tartışmaların bir benzerini, dini epistemoloji içerisinde etkili bir şekilde yer edinen ve reformcu epistemoloji olarak bilinen yaklaşım üzerinden görebilmek mümkündür. Alvin Plantinga, Nicholas Wolterstorff ve William Alston gibi filozofların öne çıktığı bu yaklaşımın ana iddiası, kanıta ya da argümana dayanmaksızın, Tanrı’nın varlığına inanmanın bütünüyle doğru, rasyonel, makul ve güvenilir olacağı şeklindeki bir tezdir. Kanıtın, gerekçelendirme için zorunlu bir koşul olmadığı fikri, algısal deneyimlerin gerekçelendirilmesine benzer şekilde, dini deneyimlerin de öyle olduğu ve (...) dolayısıyla, aynı epistemik statüye sahip olması gerektiğini öne süren, eşitlik tezine dayanır. İlk ortaya çıktığı günden bugüne, üzerinde çokça konuşulan ve tartışılan bir yaklaşım olan reformcu epistemoloji, özellikle son beş yıl içerisinde, oldukça farklı bir hale gelmiştir. Zira bu yaklaşımı, kanıtsalcılıkla uyumlu, erdem epistemolojisiyle bağlantılı ve diğer teistik dinler üzerinden değerlendiren yeni çalışmalar ortaya çıkmıştır. Bu nedenle, bu makalede, reformcu epistemoloji ana hatlarıyla ele alınmıştır. Beraberinde, ona yöneltilen itirazlara değinilmiş ve sonrasında, bahsi geçen yenilik iddiaları soruşturulmaya çalışılmıştır. Son olarak, teistik inancın rasyonalitesiyle ilgili, farklı bir bakış açısı sunulmuştur. (shrink)

It is widely recognized that conceptual and theoretical innovations and the employment of new instruments and experimental techniques are important factors in explaining the growth of scientific knowledge in chemistry. This study examines another dimension of research in chemistry, collaboration and co-authorship. I focus specifically on Theodore Richards’ career and publications. During the period in which Richards worked, co-authorship was beginning to become more common than it had been previously. Richards was the first American chemist to be awarded a Nobel (...) Prize and he was at the forefront in this new trend in chemistry. He collaborated more than was typical for his time, with many scientists, in different sized groups, and he often had persistent collaborative relationships, extending over a number of years. Further, it appears that these collaborations benefited Richards, his collaborators, and the field of chemistry as a whole. (shrink)

Studies of epistemic communities and collaborative research in the social sciences have deepened the understanding of how science works, and more specifically how the social dimensions of scientific practice both enable and impede social scientists in realizing their epistemic goals. Two types of studies of epistemic communities are distinguished: general theories of epistemic communities aim to construct accounts of theoretical change applicable to all social scientific specialties, whereas historical studies emphasize the contingencies that affect specific social scientific disciplines, subfields, or (...) institutions. Although collaborative research plays a less pronounced role in the social sciences than in the natural sciences, collaboration has enabled social scientists to investigate topics that would otherwise be difficult to investigate. (shrink)

The article examines Thomas Kuhn's work in the history of science with special attention to its relevance to subsequent developments in social epistemology. The article begins with a discussion of Kuhn's historical work, and the so-called historical turn in philosophy of science. It then examines Kuhn's views on textbook science, followed by an analysis of Kuhn's views on the relationship between the history of science and the philosophy of science. Then it discusses Kuhn's contributions to our understanding of the social (...) dimensions of scientific inquiry. Finally, it discusses his influence on the social epistemology of science and the sociology of science. (shrink)

Alvin Plantinga, analitik felsefe düşüncesi içerisinde yetişmiş ve bu gelenek içinde teistik din felsefesinin oluşumuna katkıda bulunmuş bir filozoftur. Ayrıca teizmin savunusu için yaptığı çalışmalarla, çeşitli üniversitelerden aldığı onur ödülleri ve 2017 yılında kazandığı Templeton Prize ödülüyle, haklı bir üne kavuşmuş bir şahsiyettir. Bu çalışmayı yapmamızdaki en önemli amaç, Plantinga’nın dini epistemoloji üzerine yaptığı çalışmaları analiz edip bu düşüncelerinin ardalanına dair bir tespitte bulunmaktır. Bu çalışmada yararlandığımız öncelikli kaynaklar, Plantinga’nın Nicholas Wolterstorff ile birlikte kaleme aldığı “Faith and Rationality” adlı eser (...) ile birlikte son dönem epistemik fikirlerinin çerçevesini belirleyen üç ciltlik “Warrant and Proper Function”, “Warrant: The Current Debate”, “Warranted: Christian Belief” isimli eserler olmuştur. Plantinga’nın ilk dönem epistemoloji çalışmalarının gayesini bir tür olumsuzlama diyebileceğimiz klasik temelciliğin ve evidentializmin eleştirisi oluştururken, ikinci döneminde bu eleştirilerden yola çıkarak Tanrı inancının haklı bir temelde ve güvenceye sahip olduğunu gösterme amacına yönelmiştir. Plantinga’nın teolojik fikirlerini oluşturan Kalvinci ekol, onun dini epistemolojisinin de özünü oluşturmaktadır. Plantinga’nın dini epistemolojisini iki boyutlu olarak değerlendirdiğimizde, içe dönük olarak Hristiyan inancıyla ilgilense de çalışmalarının dışsal yönünü daha genel olarak teizmin Tanrı’sı ve onun rasyonelliği oluşturmaktadır. Açıkçası Plantinga’nın epistemolojik külliyatı bir tür kavram zenginliğini de beraberinde getirmektedir. Çalışmamız içerisinde ele aldığımız kadarıyla uygun işlevsellik, tasarım planı, güvence (warrant) gibi kavramlar onun Tanrı inancının epistemik mahiyetini ortaya koymak için ne derece kararlı olduğunu göstermektedir. Netice itibariyle Tanrı inancının ve onun bilgisinin rasyonel olabileceğini ifade eden Plantinga, her ne kadar Hristiyan inancının belli bir koluna mensup olsa da diğer mezhepleri dışlamaz. Ayrıca Plantinga, birçok çalışmasında belirttiği üzere projesinin Yahudilik, İslam gibi diğer teistik dinlere yönelik olduğunu da belirtmektedir. (shrink)

The general concept of a trope – that of a non-shareable character-grounder – admits of a distinction between modifier tropes and module tropes. Roughly, a module trope is self-exemplifying whereas a modifier trope is not. This distinction has wide-ranging implications. Modifier tropes are uniquely eligible to be powers and fundamental determinables, whereas module tropes are uniquely eligible to play a direct role in perception and causation. Moreover, each type of trope theory faces unique challenges concerning character- grounding. Modifier trope theory (...) faces challenges concerning the inscrutability of predication and the incompatibility with bundle theory, whereas module trope theory faces challenges concerning character overdetermination and a collapse into austere nominalism. These differences indicate that the modifier/module distinction divides the advantages of general trope theory and thus presents the trope theorist with a pivotal choice. (shrink)

In this paper I explore Michael Loux’s important distinction between “tropes” and “tropers”. First, I argue that the distinction throws into relief an ambiguity and discrepancy in the literature, revealing two fundamentally different versions of trope theory. Second, I argue that the distinction brings into focus unique challenges facing each of the resulting trope theories, thus calling into question an alleged advantage of trope theory—that by uniquely occupying the middle ground between its rivals, trope theory is able to recover and (...) preserve the insights of these views. Ultimately, the distinction suggests that trope theory is a divided house. (shrink)

This paper investigates the emotional import of literary devices deployed in fiction. Reflecting on the often-favored approach in the analytic tradition that locates fictional characters, events, and narratives as sources of readers’ emotions, I attempt to broaden the scope of analysis by accounting for how literary devices trigger non-cognitive emotions. I argue that giving more expansive consideration to literary devices by which authors present content facilitates a better understanding of how fiction engages emotion. In doing so, I also explore the (...) somatic dimension of reading fiction. (shrink)

_Making Sense of Tantric Buddhism_ fundamentally rethinks the nature of the transgressive theories and practices of the Buddhist Tantric traditions, challenging the notion that the Tantras were "marginal" or primitive and situating them instead -- both ideologically and institutionally -- within larger trends in mainstream Buddhist and Indian culture. Critically surveying prior scholarship, Wedemeyer exposes the fallacies of attributing Tantric transgression to either the passions of lusty monks, primitive tribal rites, or slavish imitation of Saiva traditions. Through comparative analysis of (...) modern historical narratives -- that depict Tantrism as a degenerate form of Buddhism, a primal religious undercurrent, or medieval ritualism -- he likewise demonstrates these to be stock patterns in the European historical imagination. Through close analysis of primary sources, Wedemeyer reveals the lived world of Tantric Buddhism as largely continuous with the Indian religious mainstream and deploys contemporary methods of semiotic and structural analysis to make sense of its seemingly repellent and immoral injunctions. Innovative, semiological readings of the influential _Guhyasamaja Tantra_ underscore the text's overriding concern with purity, pollution, and transcendent insight -- issues shared by all Indic religions -- and a large-scale, quantitative study of Tantric literature shows its radical antinomianism to be a highly managed ritual observance restricted to a sacerdotal elite. These insights into Tantric scripture and ritual clarify the continuities between South Asian Tantrism and broader currents in Indian religion, illustrating how thoroughly these "radical" communities were integrated into the intellectual, institutional, and social structures of South Asian Buddhism. (shrink)

Mehdiyev’in Bir Bilme Teorisi adını verdiği eser, içerisinde birçok kavram ve problemi barındırması açısından oldukça zengin ve ufuk açıcı bir teoridir. Onun, bilgi söz konusu olduğunda medeniyet, bilim, teoloji ve sanat gibi sosyal epistemoloji içerisindeki kavramlara atıfla karşılaştırmalar yapması ve inanç, kanı gibi kavramlar üzerinden değerlendirmelerde bulunması; mevcut literatür içindeki kavramlara dair gerek olumlu gerekse olumsuz yeni bakış açılarını bize sağlarken, ayrıca mevcut problemleri, hem çağdaş hem de klasik teoriler içinde ele alması, bize ufuk açıcı yorumlar da kazandırmaktadır.

In this article we show that bi-intuitionistic predicate logic lacks the Craig Interpolation Property. We proceed by adapting the counterexample given by Mints, Olkhovikov and Urquhart for intuitionistic predicate logic with constant domains [13]. More precisely, we show that there is a valid implication $\phi \rightarrow \psi $ with no interpolant. Importantly, this result does not contradict the unfortunately named ‘Craig interpolation’ theorem established by Rauszer in [24] since that article is about the property more correctly named ‘deductive interpolation’ (see (...) Galatos, Jipsen, Kowalski and Ono’s use of this term in [5]) for global consequence. Given that the deduction theorem fails for bi-intuitionistic logic with global consequence, the two formulations of the property are not equivalent. (shrink)

Gökhan Murteza, “Ahlak, İktisat ve Bilim: Adam Smith Felsefesine Giriş” isimli eserinde genellikle İktisat disiplininin birçok farklı konusunu felsefi açıdan tartışmaya açmıştır. Murteza’nın bu eseri, devleti ve toplumu ilgilendiren bu araştırma alanının, A. Smith ile birlikte bir bilim dalı olarak görülmeye başlanmasının sonucunda, gerçekten ahlaki olanı içerip içermediği problemi üzerinde durmaktadır.

In deciding whether to forgive, we often focus on the wrongdoer, looking for an apology or a change of ways. However, to fully consider whether to forgive, we need to expand our focus from the wrongdoer and their wrongdoing, and we need to consider who we are, what we care about, and what we want to care about. The difference between blame and forgiveness is, at bottom, a difference in priorities. When we blame, we prioritize the wrong, and when we (...) forgive, we shift our priorities away from the wrong. Recognizing this essential role for priorities in forgiveness allows us to address a thorny puzzle in thinking about forgiveness: how is it that forgiveness can be both principled and elective? If there is sufficient reason to forgive, as will sometimes be the case because forgiveness is principled, how can it be reasonable to withhold forgiveness? Recognizing that forgiveness is a shift in our priorities dissolves this apparent tension between forgiveness being principled and forgiveness being elective. (shrink)

ÖZ “Tanzanya’da Leibzig Misyoner Cemiyeti Misyonerliği, Karşılaşılan Zorluklar ve Kullanılan Yöntemler” isimli makale “Tanzanya’da Misyonerlik Faaliyetler Lutheran Kilise Örneği” isimli yüksek lisans tezine dayanmaktadır. Makale, Lutheran misyonerliğinin Tanzanya’da faaliyetlerine nasıl başladıkları, ilerleme yöntemleri ve karşılaşılan güçlükleri anlama noktasında önem arz etmektedir. Makalede ana konuya odaklanmadan önce, Tanzanya hakkında genel bir bilgilendirme yapılmış, ardından Leibzig Misyon Cemiyeti’nin (LMS) faaliyetlerine nasıl başladığı, kronolojik bir şekilde açmış olduğu istasyonlar, bu istasyonlarda karşılaşmış olduğu zorluklar ve kullanılan yöntemler hakkında bilgi verilmiştir. Ayrıca, Tanzanya’da Lutheran misyoner (...) cemiyetlerinin, Tanzanya Evanjelik Lutheran Kilisesi (Tanzania Evangelical Lutheran Church in Tanzania) ELCT ile tek bir kilise çatı altında toplanması ele alınmıştır. Son olarak, ELCT’nin kabul etmiş olduğu ilkeler ve Martin Luther’in öğretilerinin Afrika’daki yansımaları üzerinde durulmuştur. Makale, sadece misyonerleri ve misyonerlik faaliyetlerini değil, ayrıca muhatap olunan ve yüzyıllardır sömürgeleştirilen Afrika halkını anlamamıza da yardımcı olmaktadır. Araştırma, Lutheran misyonerliğinin Tanzanya’da başlamış olduğu 19. yüzyıl sonu ve yoğunlaştığı 20. yüzyıl ile sınırlandırılmıştır. Otto von Bismarck’ın (1815-1898) katkılarıyla gerçekleşen Berlin Konferansı sayesinde, batılı ülkelerin bayrakları ile haçları da sömürge topraklarına girmiştir. Tanzanya'da Lutheran Misyon, Johann Ludwig Krapf (1810-1881) ve Johannes Rebmann'ın (1820-1876) CMS tarafından görevlendirilmeleri sonucu başlamıştır. LMS, CMS'den 1892 tarihinde görevi devralmıştır ve Machame, Mamba, Old Moshi, Pare, Meru'da faaliyet göstermiştir. Misyon faaliyetleri süresince, savaşlar, kıtlık ve salgın, çok eşlilik, sünnet uygulaması, tanrı anlayışı gibi birçok zorlukla karşılaşılmıştır. Zorluklar, onları ortadan kaldırmaya yardımcı olacak; eğitim, sağlık, bütüncül hizmet, ortak dil (lingua franca), Kutsal Kitap çevirileri, ev ziyaretleri, yerli yardımcılar ve yerlileştirme gibi yöntemleri de beraberinde getirmiştir. Tanzanya’da LMS dışında; Katolik Kutsal Ruh Babaları (Holy Ghost Father/ Spiritanlar), Katolik Beyaz Babalar (Peres Blancs), Katolik Benediktinler, Anglikan Kilise Misyon Topluluğu (Chuch Missionary Society) CMS, Anglikan Üniversitelerin Orta Afrika Misyonu (The Universities’ Mission to Central Africa) UMCA gibi misyon grupları mevcuttur. Tanzanya'da bulunan Lutheran Misyon toplulukları, Evanjelik Lüteriyen Kilisesi (ELCT) adı altında 1963 yılında tek bir çatı altında toplanmıştır. ELCT bugün 5,2 milyon üyesi ile Tanzanya nüfusu içinde hatırı sayılır bir yere sahiptir. Bu çalışmada, deskriptif yöntem kullanılmıştır. Ulaşılabilen tüm ilk kaynaklara inilerek Lutheran misyonerler ve Tanzanya hakkında bilgi verilmiştir. Çalışmada Türkçe kaynaklara yer verilmekle birlikte yabancı kaynak kullanımına ve misyon topluluklarının bilinen kısaltmalarının kullanılmasına önem gösterilmiştir. Anahtar Kelimeler; Tanzanya, Hıristiyanlık, Misyonerlik, Lutheranizm, Leipzig Misyon Cemiyeti. (shrink)

Kniha až na dva eseje zahrnuje diskusní příspěvky a referáty. Pojednávají o budoucnosti filosofie, malých divadelních formách, antropologických předpokladech moderní kultury, posuzování modelu člověka v dramatickém díle.

Ateistler, kötülük probleminin Tanrı’nın varlığı aleyhine en güçlü argüman olduğu konusunda hâlâ ısrarcılar. Felsefe tarihine baktığımızda da Epikuros’tan Hume’a ve yakın dönemde Mackie’ye kadar uzanan bir yelpazede çeşitli düşünürler tarafından bu konuda birçok eleştirinin dile getirildiğini görmek mümkün. Plantinga bu çalışmasında felsefe tarihinin en köklü sorunlarından biri olan ‘Tanrı’nın varlığı sorusu’nu cevaplamaya çalışmakla kalmayıp felsefi bir yöntem ve soruşturmanın nasıl olması gerektiği konusunda muhteşem bir örnek de sunmaktadır. Plantinga, bu kitabıyla bizi, felsefe tarihinin en temel ilkelerinden birini hatırlamaya çağırıyor: var (...) olanın ardındakini anlamaya çalışmak. (shrink)

Ethical thought experiments such as the trolley dilemma have been investigated extensively in the past, showing that humans act in utilitarian ways, trying to cause as little overall damage as possible. These trolley dilemmas have gained renewed attention over the past few years, especially due to the necessity of implementing moral decisions in autonomous driving vehicles. We conducted a set of experiments in which participants experienced modified trolley dilemmas as drivers in virtual reality environments. Participants had to make decisions between (...) driving in one of two lanes where different obstacles came into view. Eventually, the participants had to decide which of the objects they would crash into. Obstacles included a variety of human-like avatars of different ages and group sizes. Furthermore, the influence of sidewalks as potential safe harbors and a condition implicating self-sacrifice were tested. Results showed that participants, in general, decided in a utilitarian manner, sparing the highest number of avatars possible with a limited influence by the other variables. Derived from these findings, which are in line with the utilitarian approach in moral decision making, it will be argued for an obligatory ethics setting implemented in ADVs. (shrink)

For many philosophers, bad-history wrongdoers are primarily interesting because of what their cases might tell us about the interaction of moral responsibility and history. However, philosophers focusing on blameworthiness have overlooked important questions about blame itself. These bad-history cases are complicated because blame and sympathy are both fitting. When we are careful to consider the rich natures of those two reactions, we see that they conflict in several important ways. We should see bad-history cases as cases about whether and how (...) we should blame, rather than as cases giving us ready insight into the nature of moral responsibility. (shrink)

Human immunodeficiency viruses (HIV) and acquired immunodeficiency syndrome (AIDS), COVID-19 and Ebola have exposed the magnitude of care-related tasks on women. Most often, because of the gendered nature of domestic and reproductive roles, women are expected to assume unpaid care-related, nurturing and domestic work. Despite the valuable duties, women are economically poor and othered. These unpaid care duties are exacerbated by pandemics and ratified even further by religion. For instance, in Nomiya Church (NC), the first African independent church in Kenya, (...) women’s experience narratives and biblical texts such as the story of the Proverbs 31 virtuous woman are used to glorify unpaid charitable work for women. Women’s virtuous personality, hard work and character are upheld in Christian spaces, thus obstructing sound work theologies. This article employed African Women’s theological lens in view of pointing out repressing and transformative tenets in charitable theologies of work for social and gender justice. While applying womanhood hermeneutics in the passage, the article points to valued behavioural postures of hard work in responding to God’s stewardship mandate. An affirmation of fair reward and accumulation of property is embraced as a familial complementary role, especially in pandemic contexts. The article amplifies the accumulation of property as a human right and the mandate of stewardship for all earth communities. Hence, charity work is a stewardship framework that all earth communities must engage in for replenishment and sustenance for all.Contribution: The article challenges literal biblical interpretations that glorify charity work. It advances a stewardship framework in understanding unpaid and charity work that all earth communities must engage in to replenish and sustain all creation. The framework affirms the dignity of all human persons through a transformational understanding of the theology of work as enabled by the African theological hermeneutics. (shrink)

In our article (Zawadzki and Adamczyk 2021), we analyzed threats that novel memory modifying interventions may pose in the future. More specifically, we discussed how optogenetics’ potential for reversible erasure/deactivation of memory “may impact authenticity by producing changes at different levels of personality.” Our article has received many thoughtful open peer commentaries for which we would like to express our great appreciation. We have identified two main threads of objections. They are related to the potential applicability of optogenetics as a (...) therapeutic memory modification technology (MMT) in humans—applicability thread, and the normative value of authenticity, that is, the assumption that preserving authenticity is valuable (either in general or in the particular approach we adopted)—normative thread. Both of these threads concern fundamental issues: The former deals with the scientific credibility of the case vignette on which our discussion is based, and the latter deals with the normative weight of our considerations. We think that addressing both of them can be instructive in a broader context as they reflect a more general disagreement among neuroethicists about the very purpose and method of our discipline. (shrink)

The discourse on the integration of science and Islam is being realised through the establishment of various Islamic religious universities in Indonesia. One of the Islamic universities that accommodates this discourse is the Al-Qur’an Science University, Central Java, Indonesia (UNSIQ). This study aims to examine the basic concept of scientific integration at the UNSIQ and critically analyses the academic tradition and research development patterns based on the Lakatos research development pattern, both of which are hard-core and auxiliary hypotheses. This research (...) shows that the scientific base at the UNSIQ has been structured in an awareness that supports the establishment of a distinctive academic tradition and scientific culture in the framework of al-Qur’an-based academic knowledge. However, research as auxiliary hypotheses in building scientific paradigm is still limited in certain disciplines and needs to be improved. This needs to be a common concern in order to increase the scientific base of the Syajarah al-Qur’an into a solid scientific paradigm.Contribution: This research figured out that the scientific base at the UNSIQ has been structured in an awareness that supports the establishment of a distinctive academic tradition and scientific culture, but this scientific base needs to be supported by research plan and researches in various disciplines. Thus, those researches become the auxiliary hypotheses to build a particular scientific paradigm of this university. (shrink)