Hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) mediates post-endocytic trafficking of protease-activated receptor 2 and calcitonin receptor-like receptor

The E3 ligase c-Cbl ubiquitinates protease-activated receptor 2 (PAR(2)), which is required for post-endocytic sorting of PAR(2) to lysosomes, where degradation arrests signaling. The mechanisms of post-endocytic sorting of ubiquitinated receptors are incompletely understood. Here, we investigated the role of hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), in post-endocytic sorting and signaling of PAR(2). In HEK-PAR(2) cells, PAR(2) activating peptide (PAR(2)-AP) induced PAR(2) trafficking from the cell surface to early endosomes containing endogenous HRS, and then to lysosomes. HRS overexpression or knockdown with small interfering RNA caused formation of enlarged HRS-positive endosomes, where activated PAR(2) and c-Cbl accumulated, and PAR(2) failed to traffic to lysosomes. Overexpression of HRS prevented PAR(2)-AP-induced degradation of PAR(2), as determined by Western blotting. Overexpression of HRS mutant lacking an ubiquitin-binding motif similarly caused retention of PAR(2) in enlarged endosomes. Moreover, HRS overexpression or knockdown caused retention of ubiquitin-resistant PAR(2)Delta14K/R in enlarged HRS-containing endosomes, preventing recycling and resensitization of PAR(2)Delta14K/R. HRS overexpression or knockdown similarly prevented lysosomal trafficking and recycling of calcitonin receptor-like receptor, a non-ubiquitinated receptor that traffics to lysosomes after sustained activation and recycles after transient activation. Thus, HRS plays a critically important role in the post-endocytic sorting of single receptors, PAR(2) and CLR, to both degradative and recycling pathways. This sorting role for HRS is independent of its ubiquitin-interacting motif, and it can regulate trafficking of both ubiquitinated and non-ubiquitinated PAR(2) and non-ubiquitinated CLR. The ultimate sorting decision to degradative or recycling pathways appears to occur downstream from HRS.

Animal disease and the limits of local knowledge: dealing with ticks and tick-borne diseases in South Africa

Some proponents of local knowledge, such as Sillitoe (2010), have expressed second thoughts about its capacity to effect development on the ‘revolutionary’ scale once predicted. Our argument in this article follows a similar route. Recent research into the management of livestock in South Africa makes clear that rural African livestock farmers experience uncertainty in relation to the control of stock diseases. State provision of veterinary services has been significantly reduced over the past decade. Both white and African livestock owners are to a greater extent left to their own devices. In some areas of animal disease management, African livestock owners have recourse to tried-and-tested local remedies, which are largely plant-based. But especially in the critical sphere of tick control, efficacious treatments are less evident, and livestock owners struggle to find adequate solutions to high tickloads. This is particularly important in South Africa in the early twenty-first century because land reform and the freedom to purchase land in the post-apartheid context affords African stockowners opportunities to expand livestock holdings. Our research suggests that the limits of local knowledge in dealing with ticks is one of the central problems faced by African livestock owners. We judge this not only in relation to efficacy but also the perceptions of livestock owners themselves. While confidence and practice varies, and there is increasing resort of chemical acaricides we were struck by the uncertainty of livestock owners over the best strategies.

Listening behind the Curtain: BBC broadcasting to East Germany and its Cold War echo

This article considers the BBC External Service's East German wing, which broadcast from 1949 on, focusing on the continuities in broadcast techniques between wartime anti-Nazi programming and slots such as 'Two Comrades' and 'The Bewildered Newspaper Reader', both of which replicated pre-1945 formats. The role of the Foreign Office, both as cold warrior in the 1940s and force for detente in the 1970s is included. The article also investigates the response from German listeners to the BBC's external service broadcasting in the 1950s and 1960s. The BBC paid special attention to its German listeners, and has preserved a large number of original letters at the Written Archive at Caversham, as well as conducting regular listener surveys. These considered whether Britain's democratic agenda was getting across in the late 1940s and 50s, but the author also considers to what extent German listeners were pressing for a harder stance in the Cold War or were urging caution on the great powers deciding their fate.

Boots Book-lovers' Library and the novel: The impact of a circulating library market on twentieth-century fiction

In a Report for the Society of Bookmen in 1928, British publishers estimated that between a quarter to two thirds of all the books they published went to four circulating libraries: Boots, Smith’s, Mudie’s, and The Times bookclub. This essay examines the literary impact of one of the largest of these, Boots Book-lovers’ Library (1899-66), which by 1935 had around 400 libraries attached to their high-street pharmacies catering for the tastes of over one million subscribers a year. Compared to the wealth of studies examining the influence of the library market in the Victorian period, the significance of the subscription libraries as key distributors of fiction in the twentieth century is not well known. But private libraries expanded rapidly in the early twentieth century to cater for what Sidney Dark termed a ‘new reading public’, and records in publishers’ archives indicate that authors routinely adapted their unpublished manuscripts in order to meet the perceived demands of this library reader. This article examines the impact of the Boots Book-lovers’ Library market on authors’ practices of writing and revision, and on literary marketing and censorship. It focuses in particular on the author James Hanley (1897-1985), using unpublished correspondence in the Chatto & Windus archive at the University of Reading to demonstrate how the publisher’s sense of the tastes and expectations of the Boots library reader influenced the editorial process.

A police state? The Nyasaland emergency and colonial intelligence.

The Nyasaland Emergency in 1959 proved a decisive turning point in the history of the Federation of Rhodesia and Nyasaland, which from 1953 to 1963 brought together the territories of Northern Rhodesia (Zambia), Southern Rhodesia (Zambia) and Nyasaland (Malawi) under a settler-dominated federal government. The British and Nyasaland governments defended the emergency by claiming to have gathered intelligence which showed that the Nyasaland African Congress was preparing a campaign of sabotage and murder. The Devlin Commission, appointed to investigate the emergency, dismissed the evidence of a ‘murder plot’, criticised the Nyasaland government's handling of the Emergency and, notoriously, described Nyasaland as a ‘police state’. This article has two principal aims. First, using the recently declassified papers of the Intelligence and Security Department (ISD) of the Colonial Office, it seeks to provide the first detailed account of what the British government knew of the intelligence relating to the ‘murder plot’ and how they assessed it, prior to the outbreak of the emergency. It demonstrates that officials in the ISD and members of the Security Service adopted a far more cautious attitude towards the intelligence than did Conservative ministers, and had greater qualms about allowing it into the public domain to justify government policy. Second, the article examines the implications of Devlin's use of the phrase ‘police state’ for Nyasaland and for the late colonial state in general. It contrasts Devlin's use of the term with that of security experts in the ISD, who routinely applied it to policing systems that diverged from their own preferred model. Hence, whereas Devlin compared policing in Nyasaland unfavourably with that in Southern Rhodesia, implying, ironically, that Nyasaland was ‘under-policed’ (because there were fewer police per head of population in Nyasaland than in Southern Rhodesia), the ISD regarded the intensive system of policing operated by the British South Africa Police in Southern Rhodesia as characteristic of a ‘police state’. The article suggests that the frequent use of the term ‘police state’ was indicative of broader anxieties about what Britain's legacy would be for the post-independence African state.

The trilogy of John of God

Monteiro’s assertion of the almighty auteur, after the post-structuralist and post-modern experiences, which had shattered the author and his work in theory and practice, reinstates an authority aimed at organising the chaos caused by the lack of narrative. In a way, therefore, Monteiro’s output is conservative, displaying a peculiar atemporal style, which seems entirely immune to fashion. On the other hand, however, few contemporary films could be more radical than his. Authorship, in his case, means the absence of limits and total freedom of expressing his obsessive world.

IS capabilities for supporting post crisis regulatory compliance

The financial crisis of 2007-2009, has precipitated large scale regulatory change. Financial organizations are faced with implementing new regulations of considerable breadth and depth. Firms are faced with engaging in complex and costly change management programs at a time when profits are diminished. Furthermore, investors are becoming increasingly focused on compliance are seeking to ensure that organizations can demonstrate robust compliance practices as part of their due diligence process .The role of IS in underpinning stable, is paramount. IS allows the stable and consistent controls for meeting regulations in order to ensure long term effective compliance. Consequently, our study explores the IS capabilities which support the post crisis regulatory landscape. We identify eight key capabilities: Managing Internal Controls, Measuring Monitoring and Reporting Transactions, IS Development and Procurement, Managing Third Parties, Sharing and Selecting Best Practice, IS Leadership, Data Management and Enabling Cultural Change.

Access and excess in The Texas Chain Saw Massacre

Much is made of the viscerally disturbing qualities embedded in The Texas Chain Saw Massacre - human bodies are traumatised, mutilated and distorted – and the way these are matched by close and often intense access to the performers involved. Graphic violence focused on the body specifically indicates the film as a key contemporary horror text. Yet, for all this closeness to the performers, it soon becomes clear in undertaking close-analysis of the film that access to them is equally characterised by extreme distance, both spatially and cognitively. The issue of distance is particularly striking, not least because of its ramifications on engagement, which throws up various aesthetic and methodological questions concerning performers’ expressive authenticity. This article considers the lack of access to performance in The Texas Chain Saw Massacre, paying particular attention to how this fits in with contemporaneous presentations of performance more generally, as seen in films such as Junior Bonner (Sam Peckinpah, 1972). As part of this investigation I consider the affect of such a severe disruption to access on engagement with, and discussion of, performance. At the heart of this investigation lie methodological considerations of the place of performance analysis in the post-studio period. How can we perceive anything of a character’s interior life, and therefore engage with performers who we fundamentally lack access to? Does such an apparently significant difference in the way performers and their embodiment is treated mean that they can even be thought of as delivering a performance?

Institutional pressures on financial services firms: the role of information systems in regulatory compliance

The financial crisis of 2008 led to new international regulatory controls for the governance, risk and compliance of financial services firms. Information systems play a critical role here as political, functional and social pressures may lead to the deinstitutionalization of existing structures, processes and practices. This research examines how an investment management system is introduced by a leading IT vendor across eight client sites in the post-crisis era. Using institutional theory, it examines changes in working practices occurring at the environmental and organizational levels and the ways in which technological interventions are used to apply disciplinary effects in order to prevent inappropriate behaviors. The results extend the constructs of deinstitutionalization and identify empirical predictors for the deinstitutionalization of compliance and trading practices within financial organizations.

New animals, new landscapes and new worldviews: the Iron Age to Roman transition at Fishbourne

Anthropologists and cultural geographers have long accepted that animals play an important role in the creation of human cultures. However, such beliefs are yet to be embraced by archaeologists, who seldom give zooarchaeological data much consideration beyond the occasional economic or environmental reconstruction. In an attempt to highlight animal remains as a source of cultural information, this paper examines the evidence for the changing relationship between people and wild animals in Iron Age and Roman southern England. Special attention is given to ‘exotic’ species — in particular fallow deer, domestic fowl and the hare — whose management increased around AD 43. In Iron Age Britain the concept of wild game reserves was seemingly absent, but the post-Conquest appearance of new landscape features such as vivaria, leporaria and piscinae indicates a change in worldview from a situation where people seemingly negotiated with the ‘wilderness’ and ‘wild things’ to one where people felt they had the right or the responsibility to bring them to order. Using Fishbourne Roman Palace as a case study, we argue that wild and exotic animals represented far more than gastronomic treats or symbols of Roman identity, instead influencing the way in which people engaged with, traversed and experienced their surroundings.

Stakeholder interpretations of design: Semiotic insights into the briefing process

Briefing phase interactions between clients and designers are recognized as social engagements, characterized by communicative sign use, where conceptual ideas are gradually transformed into potential design solutions. A semiotic analysis of briefing communications between client stakeholders and designers provides evidence of the significance and importance of stakeholder interpretation and understanding of design, empirical data being drawn from a qualitative study of NHS hospital construction projects in the UK. It is contended that stakeholders engage with a project through communicative signs and artefacts of design, referencing personal cognitive knowledge in acts of interpretation that may be different from those of designers and externally appointed client advisers. Such interpretations occur in addition to NHS client and design team efforts to ‘engage’ with and ‘understand’ stakeholders using a variety of methods. Social semiotic theorizations indicate how narrative strategies motivate the formulation of signs and artefacts in briefing work, the role of sign authors and sign readers being elucidated as a result. Findings are contextualized against current understandings of briefing communications and stakeholder management practices, a more socially attuned understanding of briefing countering some of the process-led improvement models that have characterized much of the post-Egan report literature. A stakeholder interpretation model is presented as one potential method to safeguard against unforeseen interpretations occurring, the model aligning with the proposal for a more measured recognition of how designs can trigger interpretations among client stakeholders.

The influence of anisotropic F region ion velocity distributions on ionospheric ion outflows into the magnetosphere

The contribution to the field-aligned ionospheric ion momentum equation, due to coupling between pressure anisotropy and the inhomogeneous geomagnetic field, is investigated. We term this contribution the “hydrodynamic mirror force” and investigate its dependence on the ion drift and the resulting deformations of the ion velocity distribution function from an isotropic form. It is shown that this extra upforce increases rapidly with ion drift relative to the neutral gas but is not highly dependent on the ion-neutral collision model employed. An example of a burst of flow observed by EISCAT, thought to be the ionospheric signature of a flux transfer event at the magnetopause, is studied in detail and it is shown that the nonthermal plasma which results is subject to a hydrodynamic mirror force which is roughly 10% of the gravitational downforce. In addition, predictions by the coupled University College London-Sheffield University model of the ionosphere and thermosphere show that the hydrodynamic mirror force in the auroral oval is up to 3% of the gravitational force for Kp of about 3, rising to 10% following a sudden increase in cross-cap potential. The spatial distribution of the upforce shows peaks in the cusp region and in the post-midnight auroral oval, similar to that of observed low-energy heavy ion flows from the ionosphere into the magnetosphere. We suggest the hydrodynamic mirror force may modulate these outflows by controlling the supply of heavy ions to regions of ion acceleration and that future simulations of the effects of Joule heating on ion outflows should make allowance for it.

Changes in fire regimes since the Last Glacial Maximum: an assessment based on a global synthesis and analysis of charcoal data

Fire activity has varied globally and continuously since the last glacial maximum (LGM) in response to long-term changes in global climate and shorter-term regional changes in climate, vegetation, and human land use. We have synthesized sedimentary charcoal records of biomass burning since the LGM and present global maps showing changes in fire activity for time slices during the past 21,000 years (as differences in charcoal accumulation values compared to pre-industrial). There is strong broad-scale coherence in fire activity after the LGM, but spatial heterogeneity in the signals increases thereafter. In North America, Europe and southern South America, charcoal records indicate less-than-present fire activity during the deglacial period, from 21,000 to ∼11,000 cal yr BP. In contrast, the tropical latitudes of South America and Africa show greater-than-present fire activity from ∼19,000 to ∼17,000 cal yr BP and most sites from Indochina and Australia show greater-than-present fire activity from 16,000 to ∼13,000 cal yr BP. Many sites indicate greater-than-present or near-present activity during the Holocene with the exception of eastern North America and eastern Asia from 8,000 to ∼3,000 cal yr BP, Indonesia and Australia from 11,000 to 4,000 cal yr BP, and southern South America from 6,000 to 3,000 cal yr BP where fire activity was less than present. Regional coherence in the patterns of change in fire activity was evident throughout the post-glacial period. These complex patterns can largely be explained in terms of large-scale climate controls modulated by local changes in vegetation and fuel load