Elite City-Deals For Economic Growth? Cardiff Capital Region, Devolution and the Positioning of Civil Society Actors

The concept of localism and spatial delineation of the ‘city region’ have seen a renaissance as the de facto spatial political units of governance for economic development. One articulation of this has seen the creation of Cardiff Capital Region (CCR) to potentially enhance Wales’s poor economic performance and secure democratic forms of social cohesion. City regions have been vaunted as the ‘spatial imaginary’ for engendering economic development, but there are considerable state spatial restructuring tensions. The paper discusses these by following the development of city-regionalism in Wales and specifically the unfolding of the ‘elite-led’ CCR City-Deal

Substrate docking to γ-secretase allows access of γ-secretase modulators to an allosteric site

γ-Secretase generates the peptides of Alzheimer's disease, Aβ40 and Aβ42, by cleaving the amyloid precursor protein within its transmembrane domain. γ-Secretase also cleaves numerous other substrates, raising concerns about γ-secretase inhibitor off-target effects. Another important class of drugs, γ-secretase modulators, alter the cleavage site of γ-secretase on amyloid precursor protein, changing the Aβ42/Aβ40 ratio, and are thus a promising therapeutic approach for Alzheimer's disease. However, the target for γ-secretase modulators is uncertain, with some data suggesting that they function on γ-secretase, whereas others support their binding to the amyloid precursor. In this paper we address this controversy by using a fluorescence resonance energy transfer-based assay to examine whether γ-secretase modulators alter Presenilin-1/γ-secretase conformation in intact cells in the absence of its natural substrates such as amyloid precursor protein and Notch. We report that the γ-secretase allosteric site is located within the γ-secretase complex, but substrate docking is needed for γ-secretase modulators to access this site

Presenilin Is the Molecular Target of Acidic γ-Secretase Modulators in Living Cells

The intramembrane-cleaving protease γ-secretase catalyzes the last step in the generation of toxic amyloid-β (Aβ) peptides and is a principal therapeutic target in Alzheimer's disease. Both preclinical and clinical studies have demonstrated that inhibition of γ-secretase is associated with prohibitive side effects due to suppression of Notch processing and signaling. Potentially safer are γ-secretase modulators (GSMs), which are small molecules that selectively lower generation of the highly amyloidogenic Aβ42 peptides but spare Notch processing. GSMs with nanomolar potency and favorable pharmacological properties have been described, but the molecular mechanism of GSMs remains uncertain and both the substrate amyloid precursor protein (APP) and subunits of the γ-secretase complex have been proposed as the molecular target of GSMs. We have generated a potent photo-probe based on an acidic GSM that lowers Aβ42 generation with an IC50 of 290 nM in cellular assays. By combining in vivo photo-crosslinking with affinity purification, we demonstrated that this probe binds the N-terminal fragment of presenilin (PSEN), the catalytic subunit of the γ-secretase complex, in living cells. Labeling was not observed for APP or any of the other γ-secretase subunits. Binding was readily competed by structurally divergent acidic and non-acidic GSMs suggesting a shared mode of action. These findings indicate that potent acidic GSMs target presenilin to modulate the enzymatic activity of the γ-secretase complex

Perceptions and Experiences of Random Breath Testing in Queensland and the Self-Reported Deterrent Impact on Drunk Driving

ABSTRACT Objectives. The present study aimed to explore the impact of random breath testing (RBT) on the attitudes, perceptions and self-reported behaviour of motorists in the Australian state of Queensland. Particular attention was given to how exposure to RBT impacted on motorists’ perceived risk of apprehension and self-reported behaviour, relative to other variables of interest such as alcohol consumption. Methods. The study involved a telephone survey of 780 motorists drawn from throughout the state of Queensland. Participants were volunteers recruited from a random sample of all listed telephone numbers in the state, adjusted according to district population figures. The survey questionnaire collected information relating to the participants’: socio-demographic characteristics; drinking and drink driving behaviours; attitudes to drink driving and RBT; and experiences and perceptions of RBT. Results. The analysis indicated that a large proportion of the sample had both observed RBT and been breath tested within the last six months, and believed the practice served an important role in improving road safety. However, a considerable percentage also reported drink driving at least once in the last six months without being detected, with further analysis indicating that the threat of apprehension associated with RBT did not appear to greatly influence their offending behaviour. Rather, a higher frequency of alcohol consumption, combined with more favourable attitudes to drink driving and lower levels of support for RBT, appeared to be associated with offending behaviour. Conclusions. While the results confirm the high levels of exposure to RBT achieved in Queensland, the direct impact of recent exposure on drink driving behaviour appears less important than other factors such as alcohol consumption and attitudes to drink driving and RBT. Further research is required to better understand how recent and lifetime exposure to RBT impacts on motorists’ perceived risk of apprehension and subsequent drink driving behaviour

In different organisms, the mode of interaction between two signaling proteins is not necessarily conserved

Although interfaces mediating protein–protein interactions are thought to be under strong evolutionary constraints, binding of the chemotaxis histidine kinase CheA to its phosphorylation target CheY suggests otherwise. The structure of Thermotoga maritima CheA domain P2 in complex with CheY reveals a different association than that observed for the same Escherichia coli proteins. Similar regions of CheY bind CheA P2 in the two systems, but the CheA P2 domains differ by an ≈90° rotation. CheA binds CheY with identical affinity in T. maritima and E. coli at the vastly different temperatures where the respective organisms live. Distinct sets of P2 residues mediate CheY binding in the two complexes; conservation patterns of these residues in CheA and compensations in CheY delineate two families of prokaryotic chemotaxis systems. A protein complex that has the same components and general function in different organisms, but an altered structure, indicates unanticipated complexity in the evolution of protein–protein interactions and cautions against extrapolating structural data from homologs