The endoplasmic reticulum (ER) organelle is the key intracellular site of both protein and lipid biosynthesis. ER dysfunction, termed ER stress, can result in protein accretion within the ER and cell death; a pathophysiological process contributing to a range of metabolic diseases and cancers. ER stress leads to the activation of a protective signalling cascade termed the Unfolded Protein Response (UPR). However, chronic UPR activation can ultimately result in cellular apoptosis. Emerging evidence suggests that cells undergoing ER (...) class='Hi'>stress and UPR activation can release extracellular signals that can propagate UPR activation to target tissues in a cell non‐autonomous signalling mechanism. Separately, studies have determined that the UPR plays a key regulatory role in the biosynthesis of bioactive signalling lipids including sphingolipids and ceramides. Here we weigh the evidence to combine these concepts and propose that during ER stress, UPR activation drives the biosynthesis of ceramide lipids, which are exported and function as cell non‐autonomous signals to propagate UPR activation in target cells and tissues. (shrink)

Stress in health care is affected by moral factors. When people are prevented from doing ‘good’ they may feel that they have not done what they ought to or that they have erred, thus giving rise to a troubled conscience. Empirical studies show that health care personnel sometimes refer to conscience when talking about being in ethically difficult everyday care situations. This study aimed to construct and validate the Stress of Conscience Questionnaire (SCQ), a nine-item instrument for assessing (...) stressful situations and the degree to which they trouble the conscience. The items were based on situations previously documented as causing negative stress for health care workers. Content and face validity were established by expert panels and pilot studies that selected relevant items and modified or excluded ambiguous ones. A convenience sample of 444 health care personnel indicated that the SCQ had acceptable validity and internal consistency (Cronbach’s alpha exceeded 0.83 for the overall scale). Explorative factor analysis identified and labelled two factors: ‘internal demands’ and ‘external demands and restrictions’. The findings suggest that the SCQ is a concise and practical instrument for use in various health care contexts. (shrink)

Beyond protein synthesis and autophagy, emerging evidence has implicated mTORC1 in regulating protein folding and proteasomal degradation as well, highlighting its prominent role in cellular proteome homeostasis or proteostasis. In addition to growth signals, mTORC1 senses and responds to a wide array of stresses, including energetic/metabolic stress, genotoxic stress, oxidative stress, osmotic stress, ER stress, proteotoxic stress, and psychological stress. Whereas growth signals unanimously stimulate mTORC1, stresses exert complex impacts on mTORC1, most of (...) which are repressive. mTORC1 suppression, as a generic adaptive strategy, empowers cell survival under various stressful conditions. In this essay, we provide an overview of the emerging role of mTORC1 in proteostasis, the distinct molecular mechanisms through which mTORC1 reacts to diverse stresses, and the schemes exploited by cancer cells to circumvent stress‐induced mTORC1 suppression. Hence, acting as a stress sensor, mTORC1 intimately couples stresses to cellular proteostasis. (shrink)

Autophagy functions in both selective and non‐selective ways to maintain cellular homeostasis. Endoplasmic reticulum autophagy (ER‐phagy) is a subclass of autophagy responsible for the degradation of the endoplasmic reticulum through selective encapsulation into autophagosomes. ER‐phagy occurs both under physiological conditions and in response to stress cues, and plays a crucial role in maintaining the homeostatic control of the organelle. Although specific receptors that target parts of the ER membrane, as well as, internal proteins for lysosomal degradation have been identified, (...) the molecular regulation of ER‐phagy has been elusive. Recent work has uncovered novel regulators of ER‐phagy that involve post‐translational modifications of ER‐resident proteins and functional cross‐talk with other cellular processes. Herein, we discuss how morphology affects the function of the peripheral ER, and how ER‐phagy modulates the turnover of this organelle. We also address how ER‐phagy is regulated at the molecular level, considering implications relevant to human diseases. (shrink)

Professionelles Handeln bedarf moralischen Handlungsvermögens. Im Kontext pflegerischer Weiterbildungen beschreibt der Philosoph Andrew Jameton vor über drei Jahrzehnten psychologische Reaktionen auf kompromittiertes moralisches Handlungsvermögen, die er als moralischen Stress definiert. Diese Standarddefinition hat in der Pflegewissenschaft zu einer dichten Forschung geführt und zum Vorschlag einer weiten Definition. Belegt sind gravierende Folgen von moralischem Stress auf die Patientensicherheit und auf die psychische Gesundheit von Mitarbeitenden. Der Beitrag diskutiert die Rezeption des Konzepts innerhalb der Pflegewissenschaft und die jüngst vorgeschlagene weite (...) Definition von moralischem Stress als Reaktion auf Situationen wahrgenommener moralischer Unerwünschtheit. Er bezweifelt die Kongruenz der Definitionen. Gerade das Verständnis der Prävalenz von moralischem Stress in der Pflegepraxis wird durch die Ausweitung der Definition erschwert, welche den Messinstrumenten jeweils zugrunde liegt. Trotz dieser Unschärfe bleibt der Umgang mit moralischem Stress eine zentrale Herausforderung für alle Gesundheitsfachpersonen. Für die wirksame Bewältigung bedarf er aber einer Schärfung, die die Kernanliegen sowohl der „alten“ wie auch der „neuen“ Definition aufnimmt: Wahrgenommene moralische Unerwünschtheit wird als Gesamtheit an emotionalen Reaktionen auf ethisch belastende Situationen vorgeschlagen, der bei kompromittiertem moralischen Handlungsvermögen moralischer Stress folgen kann, bei erschwertem moralischen Handlungsvermögen hingegen moralisches Unbehagen. In normativer Hinsicht steht moralischer Stress für Reaktionen auf Situationen moralischer Komplizität, moralisches Unbehagen für solche auf moralischer Komplexität. Durch diese Schärfung wird moralischer Stress hinreichend klar bestimmbar und die Standarddefinition im Kern bestätigt. Aber auch das Anliegen der weiten Definition wird aufgenommen für das breite Spektrum ethischer Belastungen, die den Alltag von Gesundheitsfachpersonen prägen und spezifische Strategien zu deren Bewältigung erfordern. (shrink)

This paper presents an adaptive logic enhancement of conditional logics of normality that allows for defeasible applications of Modus Ponens to conditionals. In addition to the possibilities these logics already offer in terms of reasoning about conditionals, this way they are enriched by the ability to perform default inferencing. The idea is to apply Modus Ponens defeasibly to a conditional and a fact on the condition that it is ‘safe' to do so concerning the factual and conditional knowledge at hand. (...) It is for instance not safe if the given information describes exceptional circumstances: although birds usually fly, penguins are exceptional to this rule. The two adaptive standard strategies are shown to correspond to different intuitions, a skeptical and a credulous reasoning type, which manifest themselves in the handling of so-called floating conclusions. (shrink)

According to the received view the later Wittgenstein subscribed to the thesis that speaking a language requires being guided by rules (thesis RG). In this paper we question the received view. On its most intuitive reading, we argue, (RG) is very much at odds with central tenets of the later Wittgenstein. Giving up on this reading, however, threatens to deprive the notion of rule-following of any real substance. Consequently, the rule-following considerations cannot charitably be read as a deep and subtle (...) defense of (RG) against the threat of paradox, as proponents of the received view are wont to do. Instead, we argue, the rule-following considerations provide Wittgenstein's deep and subtle reasons for rejecting the very idea that speaking a language involves rule-guidance. Although Wittgenstein subscribed to (RG) during his middle period writings, his later remarks on rules, far from being a clarification and elaboration of his earlier views, are directed against the claim of the middle period that speaking a language is an essentially rule-guided activity. (shrink)

Donald Davidson denied convention any interesting role in the philosophical theory of meaning: Conventions are neither necessary nor sufficient to account for communication by language. This anticonventionalism is part of Davidson's more general individualism about meaning. According to Davidson, notions such as that of a shared language, shared practices of use, and the attendant notions of standard meaning and linguistic mistake, are as uninteresting to the philosophical theory of meaning as that of convention. The chapter starts with a sketch of (...) the meaning theoretical background for Davidson's anticonventionalism, arguing that Davidson ultimately motivates both anti‐conventionalism and individualism by the social or public nature of language. After quickly taking up Davidson's arguments against attempts to conventionally link semantics to nonsemantic purposes, the chapter then focuses on his attack on the idea that literal meaning is conventional meaning and the surrounding discussion. (shrink)

Donald Davidson famously held that only beliefs provide reasons for belief. Perceptual experiences, he held, are not even propositional attitudes, and thus doubly disqualified from being reason providers. John McDowell and others have tried to restore the intuitive reason-providing role of experience by suggesting that experiences do have contents. However, on McDowell’s account, experiences provide ‘reasons’ in a sense very different from the Davidsonian. In this paper, I argue that there is a better way of rescuing the reason-providing role of (...) experience: Construed as a (special) kind of belief, experience provides reasons for belief in precisely the Davidsonian sense. Moreover, the doxastic account of experience I suggest integrates naturally both with the Davidsonian picture of content determination and, consequently, with Davidsonian anti-skepticism. (shrink)

Den Bildbegriff verwendet die unterschätzte US-amerikanische Philosophin Susanne Langer argumentativ in allen drei Phasen ihres Denkens, ohne den Begriff bildtheoretisch zu fundieren. Versucht man nun diesen Bildbegriff vergleichend mit semiotischen oder phänomenologischen Bildtheorien zu diskutieren, so erlangt ihre Philosophie des Bildes nur dann die erforderliche Stringenz, wenn man die gegenwärtigen Bildtheorien einer grundlegenden Kritik unterzieht. Mit Langer erscheint u.a. Husserls Bildkonstitutionstheorie in einem neuen, aber ursprünglicheren Licht, wodurch sich eine komplementäre Bildtheorie abzeichnet, in der semiotische und phänomenologische Aspekte konstitutiv sind.

ḳunṭres 1. ʼOr ha-emunah --ḳunṭres 2. Śimḥah ṿe-hitḥazḳut, ha-derekh le-hatsalah li-nevukhim.

Lou Goble proposed powerful conditional deontic logics (CDPM) that are able to deal with deontic conflicts by means of restricting the inheritance principle. One of the central problems for dyadic deontic logics is to properly treat the restricted applicability of the principle “strengthening the antecedent”. In most cases it is desirable to derive from an obligation A under condition B, that A is also obliged under condition B and C. However, there are important counterexamples. Goble proposed a weakened rational monotonicity (...) principle to tackle this problem. This solution is suboptimal as it is for some examples counter-intuitive or even leads to explosion. The paper identifies also other problems of Goble’s systems. For instance, to make optimal use of the restricted inheritance principle, in many cases the user has to manually add certain statements to the premises. An adaptive logic framework based on CDPM is proposed which is able to tackle these problems. It allows for certain rules to be applied as much as possible. In this way counter-intuitive consequences as well as explosion can be prohibited and no user interference is required. Furthermore, for non-conflicting premise sets the adaptive logics are equivalent to Goble’s dyadic version of standard deontic logic. (shrink)

In this article, we present an argumentative approach to normative reasoning. Special attention is paid to deontic conflicts, contrary-to-duty and specificity cases, which are modelled by means of argumentative attacks. For this, we adopt a recently proposed framework for logical argumentation in which arguments are generated by a sequent calculus of a given base logic of Argument & Computation ), and use standard deontic logic as our base logic. Argumentative attacks are realized by elimination rules that allow to discharge specific (...) sequents. We demonstrate the usefulness of our approach by means of various well-known benchmark examples, and show that this approach is rich enough to capture a variety of paradigms for handling conflicting norms such as reasoning with maximally consistent sets, prioritized norms and deontic formalisms based on I/O logic. (shrink)

We translate unconstrained and constrained input/output logics as introduced by Makinson and van der Torre to modal logics, using adaptive logics for the constrained case. The resulting reformulation has some additional benefits. First, we obtain a proof-theoretic characterization of input/output logics. Second, we demonstrate that our framework naturally gives rise to useful variants and allows to express important notions that go beyond the expressive means of input/output logics, such as violations and sanctions.

The Sublime is a framework for overwhelming emotions in a neuronalphysiologic und psychological sense. And since Burke’s Enquiry it has been established as a constitutive part of the discourse of aesthetics. With Kant, his empirical exposition took a decisive transcendental turn, unfolding the dichotomy of the Mathematically and the Dynamically Sublime. Whereas in the former case, we are stunned by the incomprehensible vastness of impression, in the latter we enjoy the mighty, threatening and extinguishing power of nature once we ourselves (...) are safe. Both feelings are generated by the cinema as a dispositive of artificial experience in which it becomes sensually evident why imagination fails in its ability to comprehend the whole. But although perceiving its diminutiveness, the subject masters this failure by raising itself up in being able to think - as opposed to imagining - the Greatness. Lyotard interprets this hubris as an act of self-empowerment, tending to extinguish the experience of nature. Therefore, his interest in the Sublime bears on abstract, amorphous art and lighting installations. This article, however, argues that especially with regard to the film as mass media, the categories and concepts of the sublime as deployed in the 18. (shrink)

COVID‐19 caused an imbalance between medical resources and the number of patients in Türkiye like in many countries. There was not pandemic‐triage system, and this situation led to decision making based on experience, intuition, and judgment of allocation of scarce resources. The research explains the guiding criteria that healthcare professionals used to prioritize the distribution of scarce medical resources during the COVID‐19 pandemic. The criteria preferred by 928 healthcare professionals were evaluated when preventive measures for COVID‐19 were reduced and so (...) the number of cases increased rapidly. The results indicate that Turkish healthcare professionals largely support the utilitarian approach, which focuses on medical benefit in pandemic. The main problem was that some criteria not approved in COVID‐19 triage guidelines were considered important by healthcare professionals. These criteria, which cause discrimination by preventing the provision of fair and equal medical care to patients, are a prominent issue in the study. (shrink)

本书讨论的内容有:生存的背景、生存的误区、生存的悖谬、现实生存、社会生存、细节生存、我的境界就是我的生存等。.

H. L. A Hart complained about the ambiguity of legal positivism, and proposed a definition that refers to particular explications of the concept of law, to certain theories of legal interpretation, to particular views on the moral problem of a duty to obey the law, and to a sceptical position with regard to the meta-ethical issue of the possibility of moral knowledge. It is said to be restricted to the Thesis of Separation — the contention that there is no necessary (...) connection between law and morals. In this chapter, the Separation Thesis is discussed even further, and has three shortcomings identified: first, that it has been vacillating between object-level contentions about moral qualities of the law; that the precise logical relation between both levels has never been properly accounted for; and that the question of necessary relations between morality and law hinges crucially on the presupposition that the very concept of law itself does not unravel into different sets of convenient stipulations from different epistemological angles, each of which renders the question of such necessary relations trivial. The Separation Thesis is also identified as having two versions: the Fallibility Law and the Neutrality Law. (shrink)