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Recent findings suggest that Notch-1 signaling contributes to neuronal death in ischemic stroke, but the underlying mechanisms are unknown. Hypoxia inducible factor-1α (HIF-1α), a global regulator of cellular responses to hypoxia, can interact with Notch and modulate its signaling during hypoxic stress. Here we show that Notch signaling interacts with the HIF-1α pathway in the process of ischemic neuronal death. We found that a chemical inhibitor of the Notch-activating enzyme, γ-secretase, and a HIF-1α inhibitor, protect cultured cortical neurons against ischemic stress, and combined inhibition of Notch-1 and HIF-1α further decreased neuronal death. HIF-1α and Notch intracellular domain (NICD) are co-expressed in the neuronal nucleus, and co-immunoprecipitated in cultured neurons and in brain tissue from mice subjected to focal ischemic stroke. Overexpression of NICD and HIF-1α in cultured human neural cells enhanced cell death under ischemia-like conditions, and a HIF-1α inhibitor rescued the cells. RNA interference-mediated depletion of endogenous NICD and HIF-1α also decreased cell death under ischemia-like conditions. Finally, mice treated with inhibitors of γ-secretase and HIF-1α exhibited improved outcome after focal ischemic stroke, with combined treatment being superior to individual treatments. Additional findings suggest that the NICD and HIF-1α collaborate to engage pro-inflammatory and apoptotic signaling pathways in stroke.

The infection of bacterial organisms generally causes cell death to facilitate microbial invasion and immune escape, both of which are involved in the pathogenesis of infectious diseases. In addition to the intercellular infectious processes, pathogen-produced/secreted enterotoxins (mostly exotoxins) are the major weapons that kill host cells and cause diseases by inducing different types of cell death, particularly apoptosis and necrosis. Blocking these enterotoxins with synthetic drugs and vaccines is important for treating patients with infectious diseases. Studies of enterotoxin-induced apoptotic and necrotic mechanisms have helped us to create efficient strategies to use against these well-characterized cytopathic toxins. In this article, we review the induction of the different types of cell death from various bacterial enterotoxins, such as staphylococcal enterotoxin B, staphylococcal alpha-toxin, Panton-Valentine leukocidin, alpha-hemolysin of Escherichia coli, Shiga toxins, cytotoxic necrotizing factor 1, heat-labile enterotoxins, and the cholera toxin, Vibrio cholerae. In addition, necrosis caused by pore-forming toxins, apoptotic signaling through cross-talk pathways involving mitochondrial damage, endoplasmic reticulum stress, and lysosomal injury is discussed.

Infection with dengue virus (DENV) causes an increase in proinflammatory responses, such as nitric oxide (NO) generation and TNF-α expression; however, the molecular mechanism underlying this inflammatory activation remains undefined, although the activation of the transcription factor NF-κB is generally involved. In addition to TNF-α production in DENV-infected murine macrophage RAW264.7 cells, inducible NO synthase was transcriptionally and posttranslationally elevated and accompanied by NO generation. NF-κB is known to be activated by DENV infection. Pharmacologically inhibiting NF-κB activation abolishes iNOS/NO biosynthesis and TNF-α production. With inhibition, the potential role of NF-κB in oxidative signaling regulation was prevented during DENV infection. Heat-inactivated DENV failed to cause the identified inflammatory responses. Pharmacological inhibition of TLR3 partly decreased NF-κB activation; however, it effectively abolished inducible iNOS/NO biosynthesis but did not inhibit TNF-α production. In contrast to TLR3, viral protein NS2B3 also independently contributed to NF-κB activation to regulate TNF-α production. These results show the distinct pathways for NF-κB activation caused by DENV infection individually for the regulation of iNOS/NO and TNF-α expression.

BACKGROUND: Anesthetic propofol has immunomodulatory effects, particularly in the area of anti-inflammation. Bacterial endotoxin lipopolysaccharide (LPS) induces inflammation through toll-like receptor (TLR) 4 signaling. We investigated the molecular actions of propofol against LPS/TLR4-induced inflammatory activation in murine RAW264.7 macrophages. METHODOLOGY/PRINCIPAL FINDINGS: Non-cytotoxic levels of propofol reduced LPS-induced inducible nitric oxide synthase (iNOS) and NO as determined by western blotting and the Griess reaction, respectively. Propofol also reduced the production of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-10 as detected by enzyme-linked immunosorbent assays. Western blot analysis showed propofol inhibited LPS-induced activation and phosphorylation of IKKβ (Ser180) and nuclear factor (NF)-κB (Ser536); the subsequent nuclear translocation of NF-κB p65 was also reduced. Additionally, propofol inhibited LPS-induced Akt activation and phosphorylation (Ser473) partly by reducing reactive oxygen species (ROS) generation; inter-regulation that ROS regulated Akt followed by NF-κB activation was found to be crucial for LPS-induced inflammatory responses in macrophages. An in vivo study using C57BL/6 mice also demonstrated the anti-inflammatory properties against LPS in peritoneal macrophages. CONCLUSIONS/SIGNIFICANCE: These results suggest that propofol reduces LPS-induced inflammatory responses in macrophages by inhibiting the interconnected ROS/Akt/IKKβ/NF-κB signaling pathways.

朋友如何發揮輔助彼此品德修養的功能？以友輔仁的確實機制為何？本文旨在探討 Aristotle觀點下羞恥的德育價值以及「在朋友面前感到羞恥」的積極意涵。首先指明羞恥是對不名譽的恐懼，若稱具有羞恥心的人則表示其已經內化一套社會的是非善惡觀。因此，羞恥是值得在德育上培養的可欲的道德情緒。就Aristotle發展論的德育觀而言，羞恥扮演個體道德發展上承先啟後的樞紐角色。本文嘗試闡明「以友輔仁」的具體機制之一便是藉由「在朋友面前感到羞恥」彰顯出來的，這是透過與德行之友的安穩交心對話，將先前經由習慣養成的德行付諸理性檢驗，此即「德行重估」，透過雙方實踐智慧的運用將習俗性羞恥轉變為真羞恥，若然，原先他人眼中的不光彩便轉換為個人眼中的不光彩，他律性的羞恥轉變為自律的羞恥。此課題的探討有望回應R. S. Peters提出的「道德教育的弔詭」，釋明從道德他律到自律的「過渡」如何可能。實務性價值在於闡明羞恥的德育價值，以及以友輔仁的運作機制。 This study focuses on addressing the following questions: How do friends help each other to improve character? What is the exact mechanism by which virtue is fostered through character friendship? From an Aristotelian perspective, this study investigates the moral value of shame. Shame is argued to be a desirable moral emotion worth developing. As a distinctive type of fear, shame reflects the fear of dishonor and disgrace caused mostly by one’s own voluntary actions as well as those of significant others. Aristotle analyzed shame in detail in terms of its eliciting causes, intentional objects, and personal feelings. Different from other emotions that are aroused directly by the confronting situation, shame is normally felt in front of other people. As the proverb goes, “Shame dwells in the eyes.” Specifically, the eyes literally refer to the witnessing by the surrounding people and figuratively signify the negative judgment made by other people on an individual’s actions. Thus, shame is not a moral virtue in itself. Precisely, shame is an intermediate emotional state between two extremes (i.e., bashfulness and shamelessness) and can be regarded, at best, as a quasi-virtue, in that it helps to constrain the actions of modest people. Therefore, shame is considered to be conditionally good, but not good without qualification. After clarifying the nature of shame, Aristotle emphasizes that the development of shame as a moral emotion is worthwhile among young people because shame symbolizes a watershed and a critical turning point in one’s virtue development. From an Aristotelian developmental perspective of the inculcation of virtues, a young child is incapable of listening to and understanding rational argument and teaching; therefore, virtue education must begin with cultivating their “noble joy” and “noble hatred” through proper habituation of both virtuous emotions and actions. In so doing, their inborn, primitive, basic pleasures, and pains are gradually transformed and broadened, and by being led to attend to certain morally significant information and read it properly, more sophisticated and appropriate joys and hatred come into being. Among the various emotions, shame is a noble hatred, especially for one’s voluntary disgraceful bad behavior. As soon as an individual develops shame, it indicates that they have successfully internalized a social measure of differentiating right from wrong. At this juncture, the conventional concept of good and evil is established in their mind. The standard of social honor and the moral emotion of shame can be perceived as being two sides of the same coin. According to Colby and Kohlberg’s characterization of Aristotle’s stage theory of virtue development, “shame ethics” goes above and beyond the previous “fear ethics,” in that as a distinctive species of the main genus of fear, shame is not a fear of personal corporal pain but a fear of disgrace resulting from the transgression of social order. Nevertheless, for Aristotle, the goal of virtue development is full virtue interwoven with practical wisdom. The issue of concern is how the habituated virtue could be converted into full virtue. This question reflects R. S. Peters’s well-known “the paradox of moral education” to the effect that the goal of moral education is to develop an individual conducting themself rationally, intelligently, and autonomously, but the brutal fact of human psychology is that a young child is impervious to this form of education and instead the child must be raised through habituation, namely by following conventional behavior and tradition. In brief, in Peters’s famous words, “they can and must enter the palace of Reason through the courtyard of Habit and Tradition.” Are reason and habit compatible? How can the goal of rational morality be accomplished through habituation? In addition to the interpretation by N. Sherman of the very nature of habituation as a type of “critical practice, which dispels the misgiving that habituation and reason are incompatible, this study argues that Aristotle’s detailed analysis of shame in general and his notion of “shame before character friendship” in particular explains how the “habituated virtue” can be converted into full virtue through the critical examination of character friends’ practical wisdom. Specifically, this study describes the significant and positive meaning of “feeling shame before character friendship.” “Shame before character friendship” is argued to play a pivotal role in converting conventional shame into real shame. Conventional shame refers to feelings about bad things or evils defined by social conventions; real shame refers to feelings about genuine faults recognized by one’s practical wisdom. The mechanism by which full virtue is fostered through character friendship involves people feeling free to talk to each other, exchange ideas, and critically scrutinize their respective habituated virtues. Specifically, character friendship is developed between two virtuous people who love each other and wish well for each other’s virtue development. They enjoy living together by spending time on performing virtuous actions and having rational dialogues. In this manner, the so-called “virtue reassessment” occurs. That is, two virtuous friends freely and critically scrutinize the reasonableness and rational ground of their habituated virtues and their associated conventional shame. Thus, shame stops a person from dwelling in the eyes of others but dwelling in their own eyes. That is, bad things and evils are now measured by one’s own standard of value rather than the previously internalized traditional social standard of honor. This discussion on Aristotle’s distinction of two types of shame and his elaboration on the special meaning of “shame before character friendship” can hopefully be a response to Peters’s “the paradox of moral education,” elaborating how the transition from moral heteronomy and habituated virtue to moral autonomy and full virtue is possible. That is, the long-standing paradox of moral education is resolvable from Aristotelian perspective. In addition, the discussion has practical educational implications for explaining the moral value of cultivating the moral emotion of shame and developing character friendship.

本研究從反省當前品格教育常見的「德行陶養」作法著手，指出「化整為零」作法的可能緣由，分就學理依據與實務可行性兩方面立論，繼而指出這種「化整為零」作法可能的弊病在於忽略品格的完整性與個殊性。受到新近興起的道德楷模教育的啟發，筆者認為遠端道 德楷模所體現的高度「道德認同」適可作為突破現行困境的解方。筆者於是轉而闡述A. Blasi的道德認同理論。道德認同指的是道德在個人自我認同中的重要程度，當道德構成本質性自我不可或缺的環節時，代表個體有高度的道德認同。此理論非但可以解釋長久以來備受討論 的「知而不行」與「明知故犯」等道德認知與行動落差的現象，並可從道德自我、整體品格的觀點來為個人發展迄今的品格樣態提供整全的視角─認識到「我是誰」，並凸顯每個人品格的殊異性。這種後設認知可謂提供了道德行動者一種自我知識。最終，道德認同發揮了「化零為整」的作用，可與「化整為零」的德行陶養工作相互補足。 Background Since character education re-emerged in the United States in the 1990s, it has been a crucial educational policy in many countries worldwide. Character education is generally described as an educational enterprise aimed at the inculcation of virtues, and Aristotelian ethics is generally acknowledged as the major philosophical foundation of character education. The burgeoning domain of positive psychology emphasizes broadening the types of virtues, and the Jubilee Centre for Character and Virtues in the United Kingdom proposed four “building blocks of character,” namely, intellectual virtues, moral virtues, civic virtues, and performance virtues. However, I argue that this description follows the same line of thought, that is, that character is divided into various traits. Besides, it helps to explain why character education is usually characterized as aiming at the inculcation of virtues. Research Questions and Purpose This paper discusses two major questions: (1) Why does character education focus its attention on the inculcation of “virtues” rather than on the straightforward formation of “character”? (2) Furthermore, why is this common line of thought problematic? What is wrong with the commonplace description of character as the aggregate of character traits? In responding to these two questions, I attempt to show that, although the common practice of dividing character into traits, and thus good character into virtues, is theoretically and practically feasible, it presents the risk of not seeing the forest for the trees. Findings The aforementioned common practice of conceiving of character education as an educational enterprise aimed at the inculcation of virtues is explainable on two main grounds. First, the major theoretical foundation of character education, that is, Aristotelian ethics, focuses on the cultivation of various virtues. The shifting of the focus of discourse from character to virtue is understandable. Second, as noted by Cunningham, character is difficult, or even nearly impossible, to operationalize. A feasible alternative is to focus on the specific traits of character. An application of such an approach is trait theory within personality study. Furthermore, although positive psychology aims to establish a “new science of character” and thus investigate the formation of good character, its proponents state that character is manifold in that it is composed of various strengths and virtues. Therefore, dividing character into traits and conceptualizing the intent of character education as the inculcation of virtues are expected. However, a severe shortcoming of the common practice of dividing character into traits or virtues is that it neglects the integrity of character as a whole and the individual nature of each person’s character. By referring to the literature on moral exemplar education, I highlight the idea of moral identity. The moral identities of moral exemplars explain their subjectively experienced personal responsibility and subsequent moral commitment and moral action. Moreover, exemplars’ distinct moral personalities and character are clearly reflected in their moral identities. Therefore, moral identity must be further investigated. According to Blasi, moral (self) identity is one of the various dimensions of one’s self-identity and is paramount because it relates to one’s real self. More specifically, moral identity is related to the degree to which specific moral ideals and concerns are incorporated into the sense of self. First, moral identity symbolizes the extent to which morality is incorporated into one’s identity and therefore it is a matter of degrees and characteristic of individual differences. It symbolizes the degree to which moral concerns are appropriated and internalized. Moral identity is also related to what Kupperman calls the “strength of character.” When confronted by temptations or dangers, a person with strong strength of character is resolute in behaving consistently with their moral concerns. By contrast, a person with weak character is more likely to succumb to temptations or dangers. Second, moral identity is related not only to moral cognition but also moral motivation and moral action. The stronger an individual identifies with certain morals, the more eager they are to put those morals into practice because their moral agency compels them to assume personal responsibility for that with which they identify and accordingly imbues them with a strict obligation to act. The self is the main source of moral compulsion. Moral obligation and compulsion are internal feelings and thus not imposed externally. Finally, a person’s moral identity is distinct from those of others. Thus, although Mother Teresa and Martin Luther King Jr. are both moral exemplars, their character is distinct, as depicted by their differing moral identities. The individualization of character is therefore manifest. Moreover, moral identity encourages individuals to step back and consider which moral concerns are integral to their self-identity and thus inseparable from their real self. The aforementioned notion of moral identity provides an opportunity to examine the various traits composing character from a holistic viewpoint. Implications for Educational Practice The proposed idea of “assembling parts into a whole” is not meant to replace the notion of inculcating virtues, which is characteristic of character education. These two notions of character education are complementary. This study has several implications. First, the cultivation of individual virtues should be considered the starting point and primary mission of character education, and the secondary goals should be the integration of character and development of moral identity. Thus, the missing piece of the moral identity puzzle ─ namely, how the inculcation of virtues paves the way for moral identity development ─ should be considered in the study of character education. Second, moral identity is the key to explaining the research gap related to moral cognition and moral action. To convert the “should” (the head) into the “must” (the heart), one’s identification with moral concerns must be strengthened. In this regard, moral exemplars may inspire and touch the hearts of individuals. However, because of the induvial nature of moral personality and character, presenting as many moral models as possible and encouraging educated individuals to select their own moral exemplars may help them to successfully identify with various moral ideals.

In this study, a novel polymer electrolyte composite membrane is successfully fabricated using electrospinning and solution casting. The composite membrane comprises two microporous poly(vinylidene fluoride-hexafluoropropylene) (PVDF-HFP) layers plus an intermediate quaternary ammonium-containing SiO2 nanoparticles modified polyethylene terephthalate (PET) nanofibrous nonwoven to form a sandwiched PVDF-HFP/PET/PVDF-HFP composite, which is employed as a separator for lithium-ion batteries (LIBs). The properties of the PET composite membrane are compared with those of commercial PE separator, such as the morphologies, physical properties, and electrochemical performances. According to our results, the composite membrane demonstrates superior thermal stability (thermal shrinkage ∼8%), electrolyte-philicity (contact angle ∼2.9°), electrolyte uptake and retention (282%, 74%), and ionic conductivity (∼10−3 S cm−1). The separators are assembled into Li/LiFePO4 cells for electrochemical tests, showing that the PET composite membrane cells exhibit higher capacities than those with the PE separator at 0.2–10C both at 25 °C and 55 °C. The discharge capacity retention and coulombic efficiency of the PET composite membrane cells at 1C/1C for 200 cycles can be respectively enhanced about 20% and 2% at 55 °C as compared to the PE separator cells. These results demonstrate that our prepared PET composite membrane is highly promising for LIB applications. [ABSTRACT FROM AUTHOR]