© Copyright 2015, Mary Ann Liebert, Inc..Signal transducer and activator of transcription factor 3 is hyperactivated in head and neck squamous cell carcinomas. Cumulative evidence indicates that IL-6 production by HNSCC cells and/or stromal cells in the tumor microenvironment activates STAT3 and contributes to tumor progression and drug resistance. A library of 94,491 compounds from the Molecular Library Screening Center Network was screened for the ability to inhibit interleukin-6 -induced pSTAT3 activation. For contractual reasons, the primary high-content screening campaign was (...) conducted over several months in 3 distinct phases; 1,068 primary HCS actives remained after cytotoxic or fluorescent outliers were eliminated. One thousand one hundred eighty-seven compounds were cherry-picked for confirmation; actives identified in the primary HCS and compounds selected by a structural similarity search of the remaining MLSCN library using hits identified in phases I and II of the screen. Actives were confirmed in pSTAT3 IC50 assays, and an IFNγ-induced pSTAT1 activation assay was used to prioritize selective inhibitors of STAT3 activation that would not inhibit STAT1 tumor suppressor functions. Two hundred three concentration-dependent inhibitors of IL-6-induced pSTAT3 activation were identified and 89 of these also produced IC50s against IFN-γ-induced pSTAT1 activation. Forty-nine compounds met our hit criteria: they reproducibly inhibited IL-6-induced pSTAT3 activation by ≥70% at 20 μM; their pSTAT3 activation IC50s were ≤25 μM; they were ≥2-fold selective for pSTAT3 inhibition over pSTAT1 inhibition; a cross target query of PubChem indicated that they were not biologically promiscuous; and they were ≥90% pure. Twenty-six chemically tractable hits that passed filters for nuisance compounds and had acceptable drug-like and ADME-Tox properties by computational evaluation were purchased for characterization. The hit structures were distributed among 5 clusters and 8 singletons. Twenty-four compounds inhibited IL-6-induced pSTAT3 activation with IC50s ≤20 μM and 13 were ≥3-fold selective versus inhibition of pSTAT1 activation. Eighteen hits inhibited the growth of HNSCC cell lines with average IC50s ≤ 20 μM. Four chemical series were progressed into lead optimization: the guanidinoquinazolines, the triazolothiadiazines, the amino alcohols, and an oxazole-piperazine singleton. (shrink)

世代・分野を超えた論客が集い、「公正な法」とは何かの問題に取り組み、そこで思考した成果を寄稿することで編まれた論文集。.

Judicial Deliberations compares how and why the European Court of Justice, the French Cour de cassation and the US Supreme Court offer different approaches for generating judicial accountability and control, judicial debate and deliberation, and ultimately judicial legitimacy. Examining the judicial argumentation of the United States Supreme Court and of the French Cour de cassation, the book first reorders the traditional comparative understanding of the difference between French civil law and American common law judicial decision-making. It then uses this analysis (...) to offer the first detailed comparative examination of the interpretive practice of the European Court of Justice. Lasser demonstrates that the French judicial system rests on a particularly unified institutional and ideological framework founded on explicitly republican notions of meritocracy and managerial expertise. Law-making per se may be limited to the legislature; but significant judicial normative administration is entrusted to State selected, trained, and sanctioned elites who are policed internally through hierarchical institutional structures. The American judicial system, by contrast, deploys a more participatory and democratic approach that reflects a more populist vision. Shunning the unifying, controlling, and hierarchical French structures, the American judicial system instead generates its legitimacy primarily by argumentative means. American judges engage in extensive debates that subject them to public scrutiny and control. The ECJ hovers delicately between the institutional/argumentative and republican/democratic extremes. On the one hand, the ECJ reproduces the hierarchical French discursive structure on which it was originally patterned. On the other, it transposes this structure into a transnational context of fractured political and legal assumptions. This drives the ECJ towards generating legitimacy by adopting a somewhat more transparent argumentative approach. (shrink)

There has been increasing research into the COVID-19 pandemic and the theological responses to it. However, not much research has been done on the COVID-19 and how women, particularly in Africa, utilised spiritual resources to respond to the pandemic. This article sought to bridge this gap. The article utilised both descriptive and analytical methods, and argued that many African women were more concerned about the health of the community than their male counterparts who concentrated more on arguments about the pandemic. (...) Gleaning from our ethnographic data carried out from the Christ Apostolic Church and the Spirit and Life Family Bible Church in Nigeria, the article used Galen Watts’ theory of ‘spirituality of and for’ to analyse how African Christian women deployed their spirituality and resources to address the existential challenges the pandemic posed. It argued that the African Christian women shunned the ‘spirituality of’ argument that relates with discursive functions of being spiritual, which does not correspond to its practical application, and adopted ‘spirituality for’ which resonates with how spiritual resources are deployed to (re)solve existential challenges towards human flourishing. This, it argued, aligns much with the theology of The Circle of Concerned African Women Theologians.Contribution: The article concluded that most women were accentuated towards ‘spirituality for’ because it is compassion-driven and responds to the existential quest for the health of the community. (shrink)

Editors Wanda Teays, John-Stewart Gordon, and Alison Dundes Renteln have assembled the works of an interdisciplinary, international team of experts in bioethics into a comprehensive, innovative and accessible book. Topics covered range from torture and lethal injection to euthanasia, sex selection, vulnerable human subjects, to health equity, safety and public health, and environmental disasters like Bhopal, Fukushima, and more.

From Chernobyl to Fukushima, it became clear that the technology is a system evolutionary factor, and the consequences of man-made disasters, as the actualization of risk related to changes in the social heredity (cultural transmission) elements. The uniqueness of the human phenomenon is a characteristic of the system arising out of the nonlinear interaction of biological, cultural and techno-rationalistic adaptive modules. Distribution emerging adaptive innovation within each module is in accordance with the two algorithms that are characterized by the (...) dominance of vertical (transgenerational) and horizontal (infection, contagion) adaptive streams of information, respectively. Evolutionary risk is the result of an imbalance of autonomous adaptive systems have an essential attribute of adaptibe strategy of Homo. Technological civilization inherent predisposition to overcome their dependence on biological and physical components. This feature serves as an enhancer of the evolutionary generating conjugate with the scientific and technological development risk We can assume the existence of an intention of Western mentality to a high priority (positive or negative) of technological modifications micro-social environment and post- Soviet (East Slavic) mentality to modification of macro-social system. (shrink)

This paper analyses the concept of the Imagination of Henry Corbin (1903–1978) in relation to Daisetsu T. Suzuki (1870–1966). Besides being a renowned orientalist and scholar of Islamic thought, Corbin was a philosopher par excellence whose original thought deserves to be studied. So, I present this paper as a contribution to the evaluation of Corbin as a philosopher. In doing so, I shall shed light upon the philosophical affinity between Corbin and Suzuki, which has thus far rarely been discussed in (...) depth. Their ideas, in fact, resonate with each other—or Corbin is sympathetic to Suzuki—at a deep level, especially on the argument of Imagination, through Suwedenborgian thought, into whom both channel their interests. An exploration of this relationship of influence with Suzuki shall make a great contribution to a better understanding of Corbin’s own concept of Imagination, which could shake up our taken-for-granted idea of “imagination.”. (shrink)

Throughout much of Chinese history, Mencius (372-289 BC) was considered the greatest Confucian thinker after Confucius himself. Following the enshrinement of the Mencius (an edited compilation of his thought by disciples) as one of the Four Books by Sung neo-Confucianists, he was studied by all educated Chinese. This book begins a reassessment of Mencius by studying his ethical thinking in relation to that of other early Chinese thinkers, including Confucius, Mo Tzu, the Yangists, and Hsün Tzu. The author closely examines (...) his ethical concepts and terms, showing how they were used in the Mencius and other texts. (shrink)

With the emergence of environmental sustainability and green business management, increasing demands have been made on businesses in the areas of environmental corporate social responsibility. Furthermore, the influence of ECSR on green capital investment, environmental performance, and business competitiveness has also been the subject of attention from enterprises. However, in previous studies, the mediating role of green information technology capital in the relationship between ECSR, environmental performance, and business competitiveness, has not been investigated by researchers. In order to bridge this (...) gap in the ECSR literature, this study aims to examine the influence of ECSR on green IT capital, and the consequent effect of green IT capital on environmental performance and business competitiveness. Data were collected from 358 companies from the top 1000 manufacturers in Taiwan. The results confirmed that ECSR has significant positive effects on green IT human capital, green IT structural capital, and green IT relational capital. Green IT structural capital and green IT relational capital have positive effects on environmental performance and business competitiveness, and environmental performance has a positive effect on business competitiveness. In addition, green IT structural capital and green IT relational capital have partial mediating effects on ECSR, environmental performance, and business competitiveness. The implications and suggestions for future research are discussed. (shrink)

The paper presents a perspective on our relation to our environment that is inspired by Confucian thought and that stands in contrast to certain common strands in contemporary philosophical discussions. It conceptualizes our relation to what we encounter on a day-to-day basis primarily in terms of the way we experience and respond to situations, rather than to the objects affected in the situations. From this perspective, the contemporary philosophical distinction between a first- and a third-person point of view is often (...) not suited for describing our responses to situations. Instead, our responses to situations can vary along different dimensions, including the way we direct our attention, our thoughts and sentiments, our motivations, etc., and these variations admit of degrees. Such variations depend on various factors, such as the different ways in which one relates to the object affected in a situation and the kind of person one is. and cannot be adequately described in terms of a shift from one point of view to another. The paper discusses two examples, anger and compassion, to illustrate this alternative perspective, but the discussion can be extended to other areas such as gratitude. (shrink)

In this article, incoherent results of the associations between subjective well-being and economic status at multiple social levels are shown. Although individual-level positive associations are shown within developed countries, national-level associations disappear among developed countries. Group/area-level associations, meanwhile, do exist within Japanese societies. From these inconsistent phenomena, a sociocultural unit is proposed, within which well-being of people is collectively shared based on mutual reciprocity. The simple addition of social scientific results themselves cannot reconstruct the whole range of phenomena. Humanities could (...) be considered as the glue, which adds sociocultural meanings to the generalized scientific results. (shrink)

This chapter presents two cross-linguistic studies of knowledge-how attributions that compare English and Japanese speakers. The first study investigates the felicity judgements of ordinary people about knowledge-how sentences, where we find a large difference in judgements about the sentences in which a person lacks an ability to perform a certain action but is nevertheless attributed the relevant knowledge of how to perform that action. The second study investigates the frequency of the natural occurrences of knowing-how constructions in English and Japanese (...) through Google search and corpora, where we find virtually no natural occurrence of Japanese knowing-how constructions. These results suggest that the attribution of knowledge-how in Japanese is radically different from the English counterpart in that it neither requires nor is required by the relevant physical ability. We then explore the philosophical implications of these radical differences in the use of knowing-how constructions between English and Japanese speakers for the debate between intellectualism and anti-intellectualism. One such implication is that English “know how” sentences themselves may not delineate a philosophically significant category of knowledge. (shrink)

The Chinese ethical tradition has often been thought to oppose Western views of the self as autonomous and possessed of individual rights with views that emphasize the centrality of relationship and community to the self. The essays in this collection discuss the validity of that contrast as it concerns Confucianism, the single most influential Chinese school of thought. Alasdair MacIntyre, the single most influential philosopher to articulate the need for dialogue across traditions, contributes a concluding essay of commentary. This is (...) the only consistently philosophical collection on Asia and human rights and could be used in courses on comparative ethics, political philosophy and Asian area studies. (shrink)

Through an examination of the problematic forms of pride highlighted in early texts and the traits to which they are opposed, the paper identifies three main dimensions of humility in early Confucian thought. These include a deflated self-conception, caution and fearfulness, as well as seriousness and awe. It then shows that the term jing 敬 is closely related to all three dimensions, and hence that this is the term in early Confucian thought closest to encompassing all the different aspects of (...) humility understood in a broad sense. (shrink)

The article discusses Dai Zhen's views on pattern. For Dai, pattern has to do with ensuring that the means by which one attains one's emotional propensities and satisfies one's desires will not prevent others from doing the same. The heart/mind has the capacity to know pattern on such basis and such knowledge will guide action. Ethical failure is due to a deficiency in knowledge, and self-cultivation involves developing one's capacity to know so that one can grasp the pattern in any (...) affair one encounters. (shrink)

The use of the term hsing in the Meng-tzu is discussed, along with Mencius' views on jen-hsing. It is argued that while the use of hsing need not connote something unlearned and shared, Mencius did view jen-hsing in terms of certain unlearned emotional predispositions shared by all jen. He regarded jen as a species distinguished from other animals by its capability of cultural accomplishment, and felt that it is the presence of the emotional predispositions that makes this possible.

The child objection is a major challenge for reductionism, which requires hearers to have positive reasons for testimonial justification. However, it has been pointed out that anti-reductionism, which requires only the absence of negative reasons, or defeaters, suffers from the same kind of problem. The child objection presupposes the empirical thesis that “children do not have the capacity to consider reasons,” but the plausibility of this assumption may be revealed by developmental psychology research on selective trust. This paper uses recent (...) epistemological studies as a guide to narrow down the types of defeaters that children are required to consider, and then clarifies what kind of reasons various experiments can be said to test the ability to consider, and in what sense children who pass the test can be said to be “considering” reasons. In doing so, we clarify the scope and limits of the implications that selective trust studies can have for reductionism and anti-reductionism. We then suggest what future psychological research is desired from an epistemological interest to go beyond the current limitations. (shrink)