Selective protein degradation maintains cellular homeostasis, but this process is disrupted in many diseases. Targeted protein degradation (TPD) approaches, built upon existing cellular mechanisms, are promising methods for therapeutically regulating protein levels. Here, we review the diverse palette of tools that are now available for doing so throughout the gene expression pathway and in specific cellular compartments. These include methods for directly removing targeted proteins via the ubiquitin proteasome system with proteolysis targeting chimeras (PROTACs) or dephosphorylation targeting chimeras (DEPTACs). Similar (...) effects can also be achieved through the lysosomal system with autophagy‐targeting chimeras (AUTACs), autophagosome tethering compounds (ATTECs), and lysosome targeting chimeras (LYTACs). Other methods act upstream to degrade RNAs (ribonuclease targeting chimeras; RIBOTACs) or transcription factors (transcription factor targeting chimeras; TRAFTACs), offering control throughout the gene expression process. We highlight the evolution and function of these methods and discuss their clinical implications in diverse disease contexts. (shrink)

According to a grand narrative that long ago ceased to be told, there was a seventeenth century Scientific Revolution, during which a few heroes conquered nature thanks to mathematics. When this grand narrative was brought into question, our perspectives on the question of mathematization should have changed. It seems, however, that they were instead set aside, both because of a general distrust towards sweeping narratives that are always subject to the suspicion that they overlook the unyielding complexity of real history, (...) and because of a shift in our interests. The more obscure and idiosyncratic they are, an alchemist, a patron of the sciences or a lunatic collector is nowadays honored in journals of the history of sciences. As for the general issues involved in the question of mathematization, they are rejected as obsolete, or reserved for specialized journals in the history of mathematics. The article « Forms of mathematization » examines in general the notion of mathematization, distinguishes different forms of mathematization and defends a renewed study of the forms of mathematization in the history of the early sciences. (shrink)

In this article Sophie Haroutunian-Gordon and Megan Jane Laverty discuss Jean-Luc Nancy's conception of listening as presented in his seminal work, À l'écoute. The authors argue that Nancy uses the term “listening” to refer to the experience of coming to an idea of sound(s) initially encountered as puzzling. They illustrate Nancy's conception with teaching/learning situations involving a pianist and teacher, Deborah Sobol, and two aspiring players, Sophie Haroutunian-Gordon and Rosalie Romano. The article has four parts. In part 1, (...) the authors ask: Do we see Deborah trying to make meaning of Sophie's performance on October 2, 1998? In part 2, they ask: Do we see Sophie trying to make meaning of Deborah's words and demonstrations on the same occasion? In parts 3 and 4, they explore Sophie's and Rosalie's listening when they are coached by Deborah on January 15, 1999. In so doing, Haroutunian-Gordon and Laverty illustrate Nancy's conception of listening and demonstrate its usefulness for theorizing about and studying actual situations. (shrink)

Study 1 examined how personality and attitudes are related to daily pro-environmental behavior and whether these relationships are moderated by perceived behavioral costs and benefits. One hundred and seventy-eight participants responded to scales measuring the dark and light side of personality, as well as their pro-environmental attitude. Afterward, they were notified three times a day for 7 days in a row. Each time they reported their PEB that had occurred in the past four hours and indicated their behavioral costs and (...) benefits. Multilevel analyses showed a positive relationship between the frequency of PEB and the light triad of personality and pro-environmental attitude, while the dark tetrad was negatively related to PEB. Unexpectedly, less environmentally aware participants reported to engage in PEB with higher costs and lower benefits than did pro-environmental participants. A second study suggests that less environmentally aware people do not actually engage in PEB with high costs and low benefits, but rather that they only perceive their behavior to be costly and of little benefit. Overall, our findings suggest that the way people perceive their daily PEB is not necessarily shared by others. (shrink)

The haploid male germ cell differentiation program controls essential steps of male gametogenesis and relies partly on a significant number of sex chromosome‐linked genes. These genes need to escape chromosome‐wide transcriptional repression of sex chromosomes, which occurs during meiosis and is largely maintained in post‐meiotic cells. A newly discovered histone lysine modification, crotonylation (Kcr), marks X/Y‐linked genes that are active in post‐meiotic male germ cells. Histone Kcr, by conferring resistance to transcriptional repressors, could be a dominant element in maintaining these (...) genes active in the globally repressive environment of haploid cell sex chromosomes. Furthermore, the same mark was found associated with post‐meiotically activated genes on autosomes. Histone Kcr therefore appears to be an indicator of the male haploid cell gene expression program and a notable element of genome programming in the post‐meiotic phases of spermatogenesis. (shrink)

Cet article adopte un point de vue anthropologique pour explorer la place des individus affectés par des déficiences corporelles au sein de notre société, en s’appuyant sur une ethnographie du handi surf. En examinant ces dynamiques entre trois niveaux d’analyse : le corps, la nature et le monde, il vise à comprendre la transformation d’un corps meurtri « endormi » à un corps marin qui s’éveille à travers le contact avec la nature. Dans une perspective d’écologie corporelle, ce texte propose (...) une alternative au principe normatif qui enferme les individus dans la catégorie de « personne handicapée ». En mettant l’accent sur les capacités et sur les sensorialités maritimes, qui fondent l’identité « surfeur.se », il présentera de quelle façon l’expérience de l’immersion dans l’océan offre une autre possibilité : celle d’être au cœur du cosmos non plus dans ses limitations, mais bien dans ses capacités. (shrink)

ABSTRACTMetaphysics has a problem with plurality: in many areas of discourse, there are too many good theories, rather than just one. This embarrassment of riches is a particular problem for metaphysical realists who want metaphysics to tell us the way the world is and for whom one theory is the correct one. A recent suggestion is that we can treat the different theories as being functionally or explanatorily equivalent to each other, even though they differ in content. The aim of (...) this paper is to explore whether the notion of functionally equivalent theories can be extended and utilized in the defence of metaphysical realism, drawing upon themes from structuralism in the philosophies of mathematics and science in which the specifics of theories do not matter as long as the relations in which they stand to other theories are maintained. I argue that despite its initial attractiveness, there are significant difficulties with this proposal. Discovering these obstacles thwarts the realist structuralist project, but reveals interesting features of metaphysical systems. (shrink)

In her recent paper ‘The Epistemology of Propaganda’ Rachel McKinnon discusses what she refers to as ‘TERF propaganda’. We take issue with three points in her paper. The first is her rejection of the claim that ‘TERF’ is a misogynistic slur. The second is the examples she presents as commitments of so-called ‘TERFs’, in order to establish that radical (and gender critical) feminists rely on a flawed ideology. The third is her claim that standpoint epistemology can be used to establish (...) that such feminists are wrong to worry about a threat of male violence in relation to trans women. In Section 1 we argue that ‘TERF’ is not a merely descriptive term; that to the extent that McKinnon offers considerations in support of the claim that ‘TERF’ is not a slur, these considerations fail; and that ‘TERF’ is a slur according to several prominent accounts in the contemporary literature. In Section 2, we argue that McKinnon misrepresents the position of gender critical feminists, and in doing so fails to establish the claim that the ideology behind these positions is flawed. In Section 3 we argue that McKinnon’s criticism of Stanley fails, and one implication of this is that those she characterizes as ‘positively privileged’ cannot rely on the standpoint-relative knowledge of those she characterizes as ‘negatively privileged’. We also emphasize in this section McKinnon’s failure to understand and account for multiple axes of oppression, of which the cis/trans axis is only one. (shrink)

In this paper we propose a way to deal with natural language inference by implementing Modern Type Theoretical Semantics in the proof assistant Coq. The paper is a first attempt to deal with NLI and natural language reasoning in general by using the proof assistant technology. Valid NLIs are treated as theorems and as such the adequacy of our account is tested by trying to prove them. We use Luo’s Modern Type Theory with coercive subtyping as the formal language into (...) which we translate natural language semantics, and we further implement these semantics in the Coq proof assistant. It is shown that the use of a MTT with an adequate subtyping mechanism can give us a number of promising results as regards NLI. Specifically, it is shown that a number of inference cases, i.e. quantifiers, adjectives, conjoined noun phrases and temporal reference among other things can be successfully dealt with. It is then shown, that even though Coq is an interactive and not an automated theorem prover, automation of all of the test examples is possible by introducing user-defined automated tactics. Lastly, the paper offers a number of innovative approaches to NL phenomena like adjectives, collective predication, comparatives and factive verbs among other things, contributing in this respect to the theoretical study of formal semantics using MTTs. (shrink)

This paper contrasts two metaphysical accounts of modality and properties: Modal Realism which treats possible entities as primitive; and Strong Dispositionalism in which metaphysical possibility and necessity are determined by actually existing dispositions or powers. I argue that Strong Dispositionalism loses its initial advantages of simplicity and parsimony over Modal Realism as it is extended and amended to account for metaphysical rather than just causal necessity. Furthermore, to avoid objections to its material and formal adequacy, Strong Dispositionalism requires a richer (...) fundamental ontology which it cannot explicate without appealing either to possible worlds or to an account of counterfactual truth conditions, both of which Strong Dispositionalism was intended to replace. (shrink)

L’ouvrage de Solène Daoudal, Sirènes romanes en Poitou, xie-xiie siècles. Avatars sculptés d’une figure mythique, signale les premiers pas prometteurs d’une chercheuse dans l’univers de l’histoire de l’art médiéval. Il a été couronné en 2007 par le Prix de l’association Mnémosyne récompensant un mémoire de master en langue française consacré à l’histoire des femmes ou du genre. Dans cette étude d’histoire de l’art, Solène Daoudal se livre à une lecture décapante d’un thème bien connu de la sc...

Thought experiments play a role in science and in some central parts of contemporary philosophy. They used to play a larger role in philosophy of science, but have been largely abandoned as part of the field’s “practice turn”. This chapter discusses possible roles for thought experimentation within a practice-oriented philosophy of science. Some of these roles are uncontroversial, such as exemplification and aiding discovery. A more controversial role is the reliance on thought experiments to justify philosophical claims. It is proposed (...) that if we adopt an underlying empiricist view of concepts, then thought experiments can be seen as affording us contact with scientific practice, despite their seemingly a priori character. The advantages and drawbacks of thought experiments are discussed via comparison with case studies, on the one, and simulations on the other hand. The chapter closes with some remarks on how to combine thought experiments with other methods. (shrink)

This book presents engaging and informative analysis of three interrelated notions, namely: selfhood, the first person pronoun ‘I’ and the first person perspective. Philosophers have long debated about these notions on non-empirical grounds often focusing on the question of whether the first person pronoun ‘I’, beyond its role as a grammatical term, has an underlying implication for the ontology of selfhood. Philosophers continuously grapple with whether the first person pronoun ‘I’ is a referring expression and if it is, what its (...) referent is or could be. To give an adequate treatment of such questions, philosophers have begun working across the relevant disciplines. This book highlights some excellent examples of the complex nature of the first person thoughts as they figure in linguistics, autism, thought insertion in schizophrenia and the phenomenon of mental autonomy. In Selfhood, Autism and Thought Insertion, many of the leading philosophers working on this issue, as well as a few emerging scholars, have written 12 new essays addressing questions besetting the ontology of selfhood. The essays address topics as diverse as reflections on E. J. Lowe’s non-Cartesian substance dualism, physical determinism, the metaphysics and anti-metaphysics of the self, animalism, neo-Lockean persons, rationality and the first-person, whether the first person is essentially a linguistic concept, first-person and third-person perspectives and autism, consciousness, first person perspective and neuroimaging, thought insertion and mental autonomy. The contributors to this volume do not agree in all of the details associated with the notion of selfhood, yet they all have a common conviction that the central questions besetting it must be taken seriously. (shrink)

ABSTRACT The First British New Left formed around two journals, The New Reasoner edited by E.P.Thompson and John Saville, and the Universities and Left Review edited by Stuart Hall, Gabriel Pearson, Raphael Samuel and Charles Taylor. Both sought a ‘new’ socialism which, based on a loose concept of socialist humanism, restored the role of the individual and revitalised a popular left movement. Early commentators critiqued its lack of robust theory and organisational structure. More recently, others have proposed that, particularly amongst (...) the ULR cohort, with this ‘new’ socialism emerged a ‘new’ activist politics. Building on this, I examine the ULR’s activism as a performative politics which stressed active participation over theory and dissolved any distinction between means and ends. Whilst Thompson and Hall have tended to be considered the main protagonists in shaping this, I argue that it was Samuel, an experienced organiser, who was most responsible for shaping their early agenda. His role has been neglected because he wrote no ‘position piece’ but, appropriately for an activist politics, expressed his ideas through his actions. ‘Reading’ his performances, then, illuminates more fully both the scope and the limits of this activist politics. (shrink)

We provide insight into how firms’ trade credit decisions respond to the coevolution of business ethics practices, technological innovation, and institutional reform for firms located in pilot cities of China’s social credit reform. The reform implements an external monitoring mechanism that potentially shifts the business ethics frontier by punishing or rewarding certain (un)ethical credit behaviors. Following the reform, pilot city firms enjoy greater access to trade credit financing. Three plausible channels include reduced default risk, improved information quality, and enhanced legal (...) protection. Suppliers provide more credit to young, small, private, politically unconnected firms, and those with geographically distant suppliers. Finally, we illustrate how increased access to trade credit translates into tangible strategic and performance benefits. Overall, this study underscores the importance of aligning business ethics practices with evolving societal values and technological advancements to facilitate companies’ willingness to provide trade credit within emerging markets. (shrink)

The purpose of this study was to examine parent-child relationship as a moderator of the association between family educational involvement and the social skills of preschoolers. A total of 4,938 children were sampled from 18 preschools in Hebei province, China, and their parents completed a survey packet to collect demographic information, as well as ratings of parental involvement, relationships with their children, and child social skill development. The results of multivariate regression analysis suggested that: both home-based involvement and home-school conferencing (...) could significantly predict preschoolers’ social skills, there was stronger evidence for a relationship of home-based involvement and preschoolers’ social skills, closeness in parent-child relationship moderated the path from home-based involvement to preschoolers’ social skills, and there was no interactive effect between family educational involvement and parent-child conflict. These findings highlight the significance of the joint influences of family educational involvement and parent-child relationship in shaping children’s social skills. The impact of home-based involvement was boosted in the context of a close parent-child relationship. (shrink)

Freges Werk gilt heute als Klassiker der Philosophie und Philosophiegeschichte. Dessen Einfluss auf unterschiedlichste Bereiche der Philosophie, von der Logik und Mathematik bis hin zur Ontologie, Epistemologie und Sprachphilosophie, ist unbestritten. Vor diesem Hintergrund scheint die Annahme naheliegend, dass Freges Wirkungsgeschichte umfassend erforscht ist. Tatsächlich gilt dies nicht für die komplexe Rezeptionsgeschichte Freges, auch wenn es dazu durchaus eine Reihe von neuen, lehrreichen und detaillierten Studien gibt. 1 Der vorliegende Beitrag befasst sich mit zwei bisher kaum bekannten und unbeachtet gebliebenen (...) Frege-Rezeptionen aus den 30er und 40er Jahren des 20. Jahrhunderts. Es handelt sich dabei zum einen um Wilma Papsts Studie Gottlob Frege als Philosoph (1932), zum anderen um Editha Krenzs Doktorarbeit Der Zahlbegriff bei Frege (1942). In der Literatur werden die Namen der Autorinnen zwar wiederholt in Fußnoten oder im Literaturverzeichnis genannt, doch bis auf wenige Ausnahmen nicht diskutiert. Im Folgenden soll anhand einer problemgeschichtlichen Kontextualisierung gezeigt werden, dass beide Arbeiten interessante Aspekte zu Frege und seiner Rezeption beleuchten. (shrink)

Rawls considers the sense of justice as one of the conditions essential for the stability of a well-ordered society. This book interrogates the nature of this moral sense and tests its capacity to found a "realistic utopia", drawing on philosophical critics and the social sciences.

The article deals with the virtues of the procedural conception of justice for justifying multiculturalism. While proceduralism is at first sight poorly equipped to make democratic equality more inclusive of ethnocultural minorities, it has been supported by liberal philosophers as an efficient method to provide a principled defense of minority rights. By analysing this theoretical path and its limits, and by suggesting more particularly how Alan Patten’s “full proceduralism” fails to solve the difficulties of Will Kymicka’s “multicultural citizenship”, the article (...) raises doubts about the promise to ground multiculturalism on proceduralism. (shrink)

What is metaphysics? And what do we need it for? In this paper I argue that if we answer the first question appropriately, the second question becomes pointless. To understand what metaphysics is means to understand what it is for. I shall propose that metaphysics, as a philosophical discipline, is the addressing of reality with respect to the intelligibility of reality as a whole and, i.e., the addressing of reality's being-addressed in various contexts (everyday and scientific). Insofar as reason is (...) that which performs this ubiquitous addressing of reality, metaphysics – the addressing of the addressing of reality – turns out to be a self-addressal of reason. I shall rebut sceptical objections to this proposal, which are nourished by realist convictions, by emphasising an interesting and constructive metaphysical thesis entailed in the proposed understanding of metaphysics. At the same time, I shall oppose to idealist simplifications of the proposal by means of some reflections on the only legitimate source of a general (as opposed to special) critique of metaphysics: the questionability of the belief in a perfect intelligibility of reality. (shrink)

An Amnesty International briefing, published in July 2020, highlights the grave risks health workers are facing globally, particularly in the face of the COVID-19 pandemic.1 The report uses data from 63 countries across the world from January to June 2020 and is rich with examples. While recognising that information about the pandemic is constantly evolving, and each country is in a separate phase of the outbreak, Amnesty International draws attention to several troubling trends. By virtue of the role undertaken by (...) health workers, they face a greater exposure to COVID-19, which has contributed to many of the concerns they now deal with. The briefing notes the evidence of the higher death rate from health workers compared with the general population in countries ranging from Denmark to Argentina, while also pointing out the significantly higher death rate in BAME health workers raised by the BMA in the UK.2 PPE shortages had been reported in nearly all of the 63 countries analysed. Many health workers globally stated that they had to buy their own PPE and others described cases of ‘improvisation’, when suitable PPE was not available, such as using bin bags or raincoats. Furthermore, health workers in several countries had experienced increases in workload with formal measures to extend health workers’ contracted hours passed in some countries as well as further changes to their terms and conditions of service. There were also reports of increased mental stress, particularly from those working in ICUs; the increased work and stress is not being matched with suitable compensation or remuneration. Despite many countries passing special benefits for health workers, it was commonly stated that these benefits had not been received yet or that they did not apply to all health workers, with cleaners and other lower-paid yet vital roles excluded. Deeply concerning …. (shrink)

At the time of writing the COVID-19 pandemic was entering its ninth month, with nearly 800 000 recorded fatalities and 22 million infections in 188 countries and territories.1 In previous ethics briefings2 we raised concerns about the possibility that demand for life-sustaining treatment would overwhelm supply, with a consequent requirement for health professionals to make challenging triage decisions. Fortunately, to date, these have largely not been realised, although there is a possibility that countries in which containment measures have been less-successful, (...) such as South Africa, may still be required to triage.3 Despite the successful ‘flattening of the curve’ in many countries, there is a wide consensus that we remain firmly within the pandemic. Enormous practical challenges remain. It is unclear whether the pandemic will ultimately take the form of two or more successive waves, or whether the patchwork of global responses will lead to a sustained slow ‘burn’ with sporadic flare-ups.4 Areas of uncertainty include whether infection confers some immunity, how long any such immunity might last, whether effective vaccines can be developed and if seasonal temperature fluctuations alter the spread of the virus. The pandemic will also be fundamentally shaped by the decisions that governments make and the extent to which their diktats are complied with by citizens. With the – possibly temporary – retreat of urgent clinical ethics issues, such as triage, opportunities have arisen to reflect on some of the ethical questions that underlie and structure the demanding policy decisions that governments are wrestling with. One of the early questions was how to balance the complex constellation of costs and benefits associated with lockdown. Countries that …. (shrink)

With people’s concerns about the environment growing, the demand for organic food has increased. However, few studies have focused on organic dining intention. Therefore, this study examined generativity, which is defined as the direction and care for the growth of future generations through self-expanding forms, and its influence on attitude toward organic food, environment concern and dining intention. The moderating effect of age was also examined. A total of 418 responses were collected through a face-to-face survey from Shanghai respondents. PLS-SEM (...) was utilized to verify the model and test the relationships among the constructs. The results show that generativity directly influences environmental concerns, attitudes toward organic food and dining intentions. Furthermore, environmental concerns and attitudes toward organic food are mediating variables for generativity to affect dining intentions. The older the age group, the more likely it is for generativity to have a positive influence on attitude toward organic food and environmental concerns. Theoretical and practical implications are also discussed in this study. (shrink)

Entretien réalisé à Lyon, le 10 mai 2012, avec Martine Villelongue, directrice de l’université de la Mode. Historienne de l’Art, Martine Villelongue a soutenu une thèse sur l’œuvre de Lucien Bégule (1848-1935), maître-verrier lyonnais, à l’université de Lyon 2 en 1983, publiée en 2005. Elle a ensuite travaillé pendant une quinzaine d’années au musée des Tissus et des Arts Décoratifs de Lyon : montage d’expositions et création du service des publics de ce musée. Après avoir enseigné comme maît...