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)

Traditionally, discussions of moral participation – and in particular moral agency – have focused on fully formed human actors. There has been some interest in the development of morality in humans, as well as interest in cultural differences when it comes to moral practices, commitments, and actions. However, until relatively recently, there has been little focus on the possibility that nonhuman animals have any role to play in morality, save being the objects of moral concern. Moreover, when nonhuman cases are (...) considered as evidence of moral agency or subjecthood, there has been an anthropocentric tendency to focus on those behaviors that inform our attributions of moral agency to humans. For example, some argue that the ability to evaluate the principles upon which a moral norm is grounded is required for full moral agency. Certainly, if a moral agent must understand what makes an action right or wrong, then most nonhuman animals would not qualify (and perhaps some humans too). However, if we are to understand the evolution of moral psychology and moral practice, we need to turn our attention to the foundations of full moral agency. We must first pay attention to the more broadly normative practices of other animals. Here, we begin that project by considering evidence that great apes and cetaceans participate in normative practices. (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].

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)

v. 1. General moral theology -- v. 2. The truth will set you free.

1. Das Fundament aus Schrift und Tradition -- 2. Der Weg des Menschen zur Wahrheit und Liebe -- 3. Die Verantwortung des Menschen für das Leben.

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)

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)

Die pseudoplatonischen Dialoge Ã_ber die Tugend und Alkyon Hubertus Neuhausen: Der pseudo-platonische Alkibiades II und die sokratischen Alkibiadesdialoge Rosa Maria Piccione: Gli Pseudoplatonica nella tradizione dei florilegi Christopher ...

Study on Budhist Pramāṇa-vāda (doctrine of proof: an epistemological study of the nature of knowledge) and Hetu-vidya (science of causes: a system of logic).

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)

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.