Evidence for a Direct and Functional Interaction between the Regulators of G Protein Signaling-2 and Phosphorylated C Terminus of Cholecystokinin-2 Receptor

Signaling of G protein-coupled receptors (GPCRs) is regulated by different mechanisms. One of these involves regulators of G protein signaling (RGS), which are diverse and multifunctional proteins that bind to active G alpha subunits of G proteins and act as GTPase-activating proteins. Little is known about the molecular mechanisms that govern the selective use of RGS proteins in living cells. We first demonstrated that CCK2R-mediated inositol phosphate production, known to be G(q-)dependent, is more sensitive to RGS2 than to RGS4 and is insensitive to RGS8. Both basal and agonist-stimulated activities of the CCK2R are regulated by RGS2. By combining biochemical functional, and in silico structural approaches, we demonstrate that a direct and functional interaction occurs between RGS2 and agonist-stimulated cholecystokinin receptor-2 (CCK2R) and identified the precise residues involved: phosphorylated Ser434 and Thr439 located in the C-terminal tail of CCK2R and Lys62, Lys63, and Gln67, located in the N-terminal domain of RGS2. These findings confirm previous reports that RGS proteins can interact with GPCRs to modulate their signaling and provide a molecular basis for RGS2 recognition by the CCK2R.

Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease

We undertook a two-stage genome-wide association study (GWAS) of Alzheimer's disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 x 10(-157)) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ) gene (rs11136000, P = 1.4 x 10(-9)) and 5. to the PICALM gene (rs3851179, P = 1.9 x 10(-8)). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimer's disease in the combined dataset (rs11136000, P = 8.5 x 10(-10), odds ratio = 0.86; rs3851179, P = 1.3 x 10(-9), odds ratio = 0.86).

Early crime writing and the state: Jonathan Wild, Daniel Defoe and Bernard Mandeville in 1720s London

This article argues that the early development of crime writing needs to be understood in relation to the consolidation of the modern state. It demonstrates that London in the 1720s constitutes a significant moment in this early development for three main reasons. First, the period witnessed a crime epidemic which reached its climax in the 1720s and which precipitated a set of particularly aggressive counter-measures by the state; second, it saw the rise and eventual fall of the infamous Jonathan Wild who acted as both thief and surrogate policeman; and third, it was also marked by a surge in interests on the part of writers like Daniel Defoe and Bernard Mandeville in the related matters of crime and punishment. This article explores the ways in which accounts of crime and punishment in this period deployed and in some instances interrogated the rhetoric of social contract theory and writings on statecraft, particularly by Thomas Hobbes and Mandeville. But while the criminal biographies and gallows sermons produced by the Newgate prison’s ‘ordinaries’ provided crude and reductive accounts of the efficacy of the state, the article shows how two accounts of the life of Jonathan Wild (by Defoe and H.D) responded in highly complex ways to the issues of crime and policing and provided a consistently and self-consciously ambivalent reading of the state and state power. To conclude, I suggest that this ambivalence can be read as a critique of the impartial or neutral state and that it constitutes one of the key features of what we would later understand to be crime writing as a dedicated literary genre.

The Fraternity of Metaphors: Jean-Luc Godard's Film Socialisme

Since the 'completion' of Histoire(s) du cinema (1988-1998), Jean-Luc Godard's work has become increasingly mosaic-like in its forms and configurations, and markedly elegiac in its ruminations on history, cinema, art, and thought. While his associative aesthetic and citational method –including his choice of ‘actors’, and the fragmentariness of his ‘soundtracks’ – can combine to create a distinctive cinematic event, the films themselves refuse to cohere around a unifying concern, or yield to a thematic schema. Not surprisingly, Film Socialisme does not offer us the illusion of narrative or structural integrity anymore than it contributes to the quotidian rhetoric of political and moral argument. It is, however, a political film in the sense that it alters something more fundamental than opinions and points of view. It transforms a way of seeing and understanding reality and history, fiction and documentary, images, and images of images. If anything, it belongs to that dissident or ‘dissensual’ category of artwork capable of ‘emancipating the spectator’ by disturbing what Jacques Rancière terms ‘the distribution of the sensible’ in that it generates gaps, openings, and spaces, poses questions, invites associations without positing a fixed position, imposing an interpretation, or allowing itself to invest in the illusion of expressive objectivity and the stability of meaning. The myriad citations and fragments that comprise the film are never intended to culminate into anything cohesive, never mind conclusive. In one sense, they have no source and no context beyond their moment in the film itself, and what we make of that moment. This article studies the degree to which Godard allows these images and sounds to combine and collide, associate and dissolve in this film, arguing that Film Socialisme is both an important intervention in the history of contemporary cinema, and necessary point of reference in any serious discussion of the relations between that cinema and political reality.