Cullin‐RING ligases (CRLs) are central regulators of environmental and cellular stress responses, orchestrating diverse processes through the ubiquitination of substrate proteins. As modular complexes, CRLs employ substrate‐specific adaptors to target proteins for degradation and other ubiquitin‐mediated processes, enabling dynamic adaptation to environmental cues. Recent advances have highlighted the largest CRL subfamily SCF (Skp1‐cullin‐F‐box) in environmental sensing, a role historically underappreciated for SCF ubiquitin ligases. Notably, emerging evidence suggests that the F‐box domain, a 50‐amino acid motif (...) traditionally recognized for mediating protein‐protein interactions, can act as a direct environmental sensor due to its ability to bind heavy metals. Despite these advances, the roles of many CRL components in environmental sensing remain poorly understood. This review provides an overview of CRLs in stress response regulation and emphasizes the emerging functions of F‐box proteins in environmental adaptation. (shrink)

Neddylation, a ubiquitylation‐like post‐translational modification, is catalyzed by a cascade composed of three enzymes: E1 activating enzyme, E2 conjugating enzyme, and E3 ligase with cullins as physiological substrates. Specifically, neddylation E2 UBE2M couples with E3 RBX1 to neddylate cullins 1–4, whereas neddylation E2 UBE2F couples with E3 RBX2/SAG to neddylate cullin 5, leading to activation of CRL1‐4 (Cullin‐RING ligases 1–4) and CRL5, respectively. While over‐activation of the neddylation‐CRLs axis occurs frequently in many human cancers, how neddylation‐CRLs (...) regulate the function of immune cells, particularly Treg cells was previously unknown. To this end, we recently performed Treg selective knockout of two neddylation E2s and two E3s, individually, driven by Foxp3‐Cre, and found that while the Ube2f‐Sag E2/E3 pair plays a minimal role, if any, the Ube2m‐Rbx1 pair is essential for the maintenance of Treg functionality, since their deletion triggers robust inflammatory response with autoimmune phenotypes. Milder phenotype severity upon Treg KO of upstream Ube2m than that of downstream Rbx1 strongly suggested that Rbx1 regulates Treg function in a manner dependent and independent of neddylation. (shrink)

Deciphering how DCAFs (DDB1‐CUL4 Associated Factors) modulate a broad spectrum of cellular processes, including cell cycle progression and maintenance of genomic integrity is critical to better understand cellular homeostasis and diseases. Cells contain more than 100 DCAFs that associate with the Cullin‐Ring Ubiquitin Ligase 4 (CRL4) complex that target specific protein substrates for degradation. DCAFs are thought to act as substrate receptors that dictate the specificity of the ubiquitination machinery (“catalytic DCAFs”). However, recent studies have suggested that some (...) DCAFs might play a different role by targeting CRL4 complexes to distinct cellular compartments (“structural DCAFs”). Once localized to their correct cellular domains, these CRLs dissociate from the structural DCAFs prior to their association with other, substrate‐specific catalytic DCAFs. Thus, we propose that DCAF switches can provide a mechanistic basis for the degradation of proteins that regulate cell growth and proliferation at precise points in space and time. (shrink)

Protein ubiquitination constitutes a post‐translational modification mediated by ubiquitin ligases whereby ubiquitinated substrates are degraded through the proteasomal or lysosomal pathways, or acquire novel molecular functions according to their “ubiquitin codes.” Dysfunction of the ubiquitination process in cells causes various diseases such as cancers along with neurodegenerative, auto‐immune/inflammatory, and metabolic diseases. KCTD10 functions as a substrate recognition receptor for cullin‐3 (CUL3), a scaffold protein in RING‐type ubiquitin ligase complexes. Recently, studies by ourselves and others have identified new (...) substrates that are ubiquitinated by the CUL3/KCTD10 ubiquitin ligase complex. Moreover, the type of polyubiquitination (e.g., K27‐, K48‐, or K63‐chain) of various substrates (e.g., RhoB, CEP97, EIF3D, and TRIF) mediated by KCTD10 underlies its divergent roles in endothelial barrier formation, primary cilium formation, plasma membrane dynamics, cell proliferation, and immune response. Here, the physiological functions of KCTD10 are summarized and potential mechanisms are proposed. (shrink)

The TRIM/RBCC proteins are defined by the presence of the tripartite motif composed of a RING domain, one or two B‐box motifs and a coiled‐coil region. These proteins are involved in a plethora of cellular processes such as apoptosis, cell cycle regulation and viral response. Consistently, their alteration results in many diverse pathological conditions. The highly conserved modular structure of these proteins suggests that a common biochemical function may underlie their assorted cellular roles. Here, we review recent data indicating (...) that some TRIM/RBCC proteins are implicated in ubiquitination and propose that this large protein family represents a novel class of ‘single protein RING finger’ ubiquitin E3 ligases. BioEssays 27:1147–1157, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

The RNA-binding protein, UPF1, is best known for its central role in the nonsense-mediated RNA decay pathway. Feng et al. now report a new function for UPF1—it is an E3 ubiquitin ligase that specifically promotes the decay of a key pro-muscle transcription factor: MYOD. UPF1 achieves this through its RING-like domain, which confers ubiquitin E3 ligase activity. Feng et al. provide evidence that the ability of UPF1 to destabilize MYOD represses myogenesis. In the future, it will be important to (...) define other protein substrates of UPF1-driven ubiquitination and to determine whether this biochemical activity is responsible for some of UPF1's previously defined biological functions, including in development and stress responses. The exciting findings presented by Feng et al. open up the possibility that protein turnover and RNA turnover are coupled processes. The RNA-binding protein, UPF1, is best known for its central role in the nonsense-mediated RNA decay pathway. Here we discuss a new role for UPF1—it is directly involved in protein decay. This hidden talent raises the possibility that protein turnover and RNA turnover are coupled processes. (shrink)

The pore‐forming BCL‐2 family proteins are effectors of mitochondrial poration in apoptosis initiation. Two atypical effectors—BOK and truncated BID (tBID)—join the canonical effectors BAK and BAX. Gene knockout revealed developmental phenotypes in the absence the effectors, supporting their roles in vivo. During apoptosis effectors are activated and change shape from dormant monomers to dynamic oligomers that associate with and permeabilize mitochondria. BID is activated by proteolysis, BOK accumulates on inhibition of its degradation by the E3 ligase gp78, while BAK and (...) BAX undergo direct activation by BH3‐only initiators, autoactivation, and crossactivation. Except tBID, effector oligomers on the mitochondria appear as arcs and rings in super‐resolution microscopy images. The BH3‐in‐groove dimers of BAK and BAX, the tBID monomers, and uncharacterized BOK species are the putative building blocks of apoptotic pores. Effectors interact with lipids and bilayers but the mechanism of membrane poration remains elusive. I discuss effector‐mediated mitochondrial poration. (shrink)

Sterols and the reductant nicotinamide adenine dinucleotide phosphate (NADPH), essential for eukaryotic life, arose because of, and as an adaptation to, rising levels of molecular oxygen (O2). Hence, the NADPH and O2‐intensive process of sterol biosynthesis is inextricably linked to redox status. In mammals, cholesterol biosynthesis is exquisitely regulated post‐translationally by multiple E3 ubiquitin ligases, with membrane associated Really Interesting New Gene (RING) C3HC4 finger 6 (MARCHF6) degrading at least six enzymes in the pathway. Intriguingly, all these MARCHF6‐dependent (...) enzymes require NADPH. Moreover, MARCHF6 is activated by NADPH, although what this means for control of cholesterol synthesis is unclear. Indeed, this presents a paradox for how NADPH regulates this vital pathway, since NADPH is a cofactor in cholesterol biosynthesis and yet, low levels of NADPH should spare cholesterol biosynthesis enzymes targeted by MARCHF6 by reducing its activity. We speculate MARCHF6 helps mammalian cells adapt to oxidative stress (signified by low NADPH levels) by reducing degradation of cholesterogenic enzymes, thereby maintaining synthesis of protective cholesterol. (shrink)

I welcome Enck and Condley’s (2025) emphasis on agent-regret as distinct from both moral distress and compassion fatigue, especially since it highlights a set of agential concerns that go beyond wh...

Interfirm collaboration and trust are topics currently exciting research interest. The literature treats trust as a unitary concept, providing little understanding of those processes that create trust, or are employed by parties relying on trust. I suggest that two distinct forms of trust can be observed in economic exchanges: fragile trust and resilient trust. I define these kinds of trust, speculate on processes by which economic actors learn about them, and explore contexts in which they are likely to be relied (...) upon by economic actors. I conclude with a discussion of implications for practice and scholarship. (shrink)

This paper provides evidence for the following novel insights: (1) People’s economic decisions depend on their psychological motives, which are shaped predictably by the social context. (2) In particular, the social context influences people’s other-regarding preferences, their beliefs and their perceptions. (3) The influence of the social context on psychological motives can be measured experimentally by priming two antagonistic motives—care and anger—in one player towards another by means of an observance or a violation of a fairness norm. Using a mediation (...) approach, we find that the care motive leads to higher levels of cooperation which are driven by more optimistic beliefs, a different perception of the game as well as by a shift towards more pro-social preferences. (shrink)

"Der vorliegende Band vereinigt die Beitrèage des Symposiums zur Logik der Stoiker und ihrer Vorlèaufer, das vom 1.-7.9.1991 in Bamberg stattfand"--P. [7].

This paper explores how the virtuous aesthetic cosmopolitan—one actively engaged in cultivating an authoritative appreciation for culturally unfamiliar works or traditions of art, in a manner informed by moral cosmopolitan principles—engages with the ‘exotic’ artwork in a manner that is both morally responsible and aesthetically discerning. After providing an overview of philosophical cosmopolitanism and the aesthetic cosmopolitan’s project, I consider in depth a particular example: the music of Mauritanian singer Noura Mint Seymali as encountered by an unaccustomed listener. I explore (...) potential problematic responses to the work, including both chauvinistic and exoticizing responses. I then consider possible strategies for alternative responses, informed by the aesthetic and hermeneutic theories of Hume, Gadamer, and Charles Taylor. Having revealed deficiencies with these alternatives, I go on to argue that the cosmopolitan’s best strategy is a mode of appreciation that is ‘conversational’ in nature, an open-ended approach modeled on an exchange between the appreciator and an other-cultural interlocutor. In proposing such a model, I draw on the work of Kwame Appiah and Maria Lugones, as well as Anthony Laden’s recent work on conversational norms. (shrink)

ABSTRACT Sexting has become a prominent part of adolescent culture. Under current laws, adolescents caught sexting are being arrested, facing child pornography charges, and having to register as sex offenders. State laws on child pornography and child abuse differ throughout the United States and conflict with federal laws, making the ethical obligations for psychologists unclear. The purpose of this article is to promote awareness about legal obligations regarding adolescent sexting, address the ethical dilemma that psychologists face when adolescent sexting is (...) disclosed during psychological treatment, and to provide implications and recommendations for psychologists. (shrink)

Community acts of material signification are an important form of sculpture that occur through an exchange of human and non-human agents. First these acts of sculpture are discussed in relation to extended mind, the morphogenic model of making, material engagement theory and entanglement to frame how humans shape the world as collaborators with non-humans by extending mind through material. I then discuss various acts of community material accumulation that I consider sculpture, skateboarding and clay forming as evidence of extended mind, (...) comparison of the morphogenic to the hylomorphic model of making, occurrences of materials affecting other materials absent of human intervention and my recent participatory installation Stone Fruit. These topics are used to present a lens for understanding the production of sculpture as a collaboration with opposed to dictation on systems of materials, places and people. This lens, in turn, presents community sites of material accumulation to be an important form of sculpture production. (shrink)

This paper critically examines the pervasive colonial myth that associates whiteness with cleanliness and blackness with dirtiness, a myth often perpetuated through media, especially soap advertisements. Through an analysis of Frantz Fanon’s contributions to psychoanalysis and phenomenology, the paper elucidates how racial constructs are sociogenically constructed and internalized, shaping the collective unconscious. Focusing on Fanon’s phenomenological exploration of the white gaze, the paper highlights its role in overdetermining the black man, reducing them to an object embodying racial myths. The paper (...) demonstrates the enduring influence these entrenched myths have on racialized habits of perception and advocates for their disruption. The ongoing presence of colonial mythologies in modern soap advertising demonstrates the need for a concerted effort to dismantle these sedimented habits. The conclusion focuses specifically on challenging the myth of whiwhiteness as cleanliness as it continues to operate. (shrink)

This article argues that ‘the digital’ and ‘big data’ are metaphors of obfuscation, which are used to screen the real effects of technologies on lived experiences and the planet. Now that technolog...

An introduction to Pre-Socratic philosophy. It is not intended for scholars - though the interpretation of Parmenides is wholly original. It is for students in a class on Greek Philosophy, giving a useful account of the Pre-Socratics in a course that will be dominated by Socrates, Plato and Aristotle.

In especially the Sneed-Stegmüller structuralist theory a so-called problem of theoretical terms emerges. But this problem bases on a questionable presupposition . And the structuralist solution of this problem, the so-called Ramsey-Sneed-solution, is also problematic , , ). Beyond this the structuralist assertion is problematic, that the problem of theoretical terms and his Ramsey-Sneed-solution is empirically relevant . On the basis of the discussed systematic and empirical defects of the problem of theoretical terms and its solution, the so-called non-statement view₂, (...) i. e. this solution, will be refused. (shrink)

Excerpt from Feuerbachs Straftheorie und Ihr Verhältnis zur Kantischen Philosophie Vorliegende Schrift ist der hohen juristischen Universität Jena als Dissertation angenommen und genehmigt Worden. About the Publisher Forgotten Books publishes hundreds of thousands of rare and classic books. Find more at www.forgottenbooks.com This book is a reproduction of an important historical work. Forgotten Books uses state-of-the-art technology to digitally reconstruct the work, preserving the original format whilst repairing imperfections present in the aged copy. In rare cases, an imperfection in the (...) original, such as a blemish or missing page, may be replicated in our edition. We do, however, repair the vast majority of imperfections successfully; any imperfections that remain are intentionally left to preserve the state of such historical works. (shrink)

Im Winterhalbjahr 2009/10 führte das Thomas-Mann-Archiv der ETH Zürich zusammen mit den beiden evangelisch-reformierten Gemeinden Fraumünster und Großmünster in Zürich eine Vortragsreihe durch zum Thema "Der ungläubige Thomas. Zur Religion in Thomas Manns Romanen". Im Gesamtbogen der Romane Thomas Manns wird Religion auf eine faszinierend vielschichtige Weise und in einer sich vertiefenden Denkbewegung thematisch. Die Auseinandersetzung mit Kernthemen jüdisch-christlicher wie auch mythisch-antiker Traditionen geschieht bei Thomas Mann in einer Breite und Tiefe wie bei nur wenigen seiner literarischen Zeitgenossen. Durch alle (...) Romane hindurch wird Religion nicht nur besichtigt und beschrieben, sie ist auch konstruktiv präsent in ihrer Architektur und Leitmotivik. (shrink)

Originally published in 1941. Herodicus was a Greek physician of the fifth century BC, and a native of Selymbria. The first use of therapeutic exercise for the treatment of disease and maintenance of health is credited to him, and he is believed to have been one of the tutors of Hippocates.