Trapping of palindromic ligands within native transthyretin prevents amyloid formation

Transthyretin (TTR) amyloidosis is a fatal disease for which new therapeutic approaches are urgently needed. We have designed two palindromic ligands, 2,2’-(4,4’-(heptane 1,7-diylbis(oxy))bis(3,5-dichloro-4,1-phenylene)) bis(azanediyl)dibenzoic acid (mds84) and 2,2’-(4,4’-(undecane-1,11-diylbis(oxy))bis(3,5-dichloro-4,1-phenylene)) bis(azanediyl)dibenzoic acid (4ajm15), that are rapidly bound by native wild-type TTR in whole serum and even more avidly by amyloidogenic TTR variants. One to one stoichiometry, demonstrable in solution and by MS, was confirmed by X-ray crystallographic analysis showing simultaneous occupation of both T4 binding sites in each tetrameric TTR molecule by the pair of ligand head groups. Ligand binding by native TTR was irreversible under physiological conditions, and it stabilized the tetrameric assembly and inhibited amyloidogenic aggregation more potently than other known ligands. These superstabilizers are orally bioavailable and exhibit low inhibitory activity against cyclooxygenase (COX). They offer a promising platform for development of drugs to treat and prevent TTR amyloidosis.

Mapping the human record in the British early Palaeolithic: evidence from the Solent River system

The lithic record from the Solent River and its tributaries is re-examined in the light of recent interpretations about the changing demography of Britain during the Lower and early Middle Palaeolithic. Existing models of the terrace stratigraphies in the Solent and its tributary areas are reviewed and the corresponding archaeological record (specifically handaxes) for each terrace is assessed to provide models for the relative changes in human occupation through time. The Bournemouth area is studied in detail to examine the effects of quarrying and urbanisation on collection history and on the biases it introduces to the record. In addition, the effects of reworking of artefacts from higher into lower terraces are assessed, and shown to be a significant problem. Although there is very little absolute dating available for the Solent area, a cautious interpretation of the results from these analyses would suggest a pre-Marine Isotope Stage (MIS) 12 date for the first appearance of humans, a peak in population between MIS 12 and 10, and a decline in population during MIS 9 and 8. Owing to poor contextual data and small sample sizes, it is not clear when Levallois technology was introduced. This record is compared and contrasted to that from the Thames Valley. It is suggested that changes in the palaeogeography of Britain, in particular land connections to the continent, might have contributed to differences in the archaeological records from the Solent and Thames regions.

The later Anglo-Saxon settlement at Bishopstone. A downland manor in the making

This volume reports on the excavations from 2002 to 2005 designed to investigate this transition, with the focus on the origins of Bishopstone village. Excavations adjacent to St Andrew’s churchyard revealed a dense swathe of later Anglo-Saxon (8th- to late 10th-/early 11th-century) habitation, including a planned complex of ‘timber halls’, and a unique cellared tower. The occupation encroached upon a pre-Conquest cemetery of 43 inhumations. The report provides a comprehensive analysis, interpretation and academic contextualisation of the archaeological discoveries brought to light by these excavations, the first to sample a later Anglo-Saxon rural settlement in East Sussex on an extensive scale. The inter-disciplinary approach appraises the historical and topographical evidence alongside that recovered during the excavations.

International financial centres, office market rents and volatility

Despite continuing developments in information technology and the growing economic significance of the emerging Eastern European, South American and Asian economies, international financial activity remains strongly concentrated in a relatively small number of international financial centres. That concentration of financial activity requires a critical mass of office occupation and creates demand for high specification, high cost space. The demand for that space is increasingly linked to the fortunes of global capital markets. That linkage has been emphasised by developments in real estate markets, notably the development of global real estate investment, innovation in property investment vehicles and the growth of debt securitisation. The resultant interlinking of occupier, asset, debt and development markets within and across global financial centres is a source of potential volatility and risk. The paper sets out a broad conceptual model of the linkages and their implications for systemic market risk and presents preliminary empirical results that provide support for the model proposed.

Induction of the ferritin gene (ftnA) of Escherichia coli by Fe2+–Fur is mediated by reversal of H-NS silencing and is RyhB independent

FtnA is the major iron-storage protein of Escherichia coli accounting for < or = 50% of total cellular iron. The FtnA gene (ftnA) is induced by iron in an Fe(2+)-Fur-dependent fashion. This effect is reportedly mediated by RyhB, the Fe(2+)-Fur-repressed, small, regulatory RNA. However, results presented here show that ftnA iron induction is independent of RyhB and instead involves direct interaction of Fe(2+)-Fur with an 'extended' Fur binding site (containing five tandem Fur boxes) located upstream (-83) of the ftnA promoter. In addition, H-NS acts as a direct repressor of ftnA transcription by binding at multiple sites (I-VI) within, and upstream of, the ftnA promoter. Fur directly competes with H-NS binding at upstream sites (II-IV) and consequently displaces H-NS from the ftnA promoter (sites V-VI) which in turn leads to derepression of ftnA transcription. It is proposed that H-NS binding within the ftnA promoter is facilitated by H-NS occupation of the upstream sites through H-NS oligomerization-induced DNA looping. Consequently, Fur displacement of H-NS from the upstream sites prevents cooperative H-NS binding at the downstream sites within the promoter, thus allowing access to RNA polymerase. This direct activation of ftnA transcription by Fe(2+)-Fur through H-NS antisilencing represents a new mechanism for iron-induced gene expression.

Winning and losing in the creative industries: an analysis of creative graduates' career opportunities across creative disciplines

Following earlier work looking at overall career difficulties and low economic rewards faced by graduates in creative disciplines, the paper takes a closer look into the different career patterns and economic performance of “Bohemian” graduates across different creative disciplines. While it is widely acknowledged in the literature that careers in the creative field tend to be unstructured, often relying on part-time work and low wages, our knowledge of how these characteristics differ across the creative industries and occupational sectors is very limited. The paper explores the different trajectory and career patterns experienced by graduates in different creative disciplinary fields and their ability to enter creative occupations. Data from the Higher Education Statistical Agency (HESA) are presented, articulating a complex picture of the reality of finding a creative occupation for creative graduates. While students of some disciplines struggle to find full-time work in the creative economy, for others full-time occupation is the norm. Geography plays a crucial role also in offering graduates opportunities in creative occupations and higher salaries. The findings are contextualised in the New Labour cultural policy framework and conclusions are drawn on whether the creative industries policy construct has hidden a very problematic reality of winners and losers in the creative economy.

Incorporating languages into histories of war: a research journey

This article discusses the ways in which languages can be integrated into histories of war and conflict, by exploring ongoing research in two case studies: the liberation and occupation of Western Europe (1944–47), and peacekeeping/peace building in Bosnia-Herzegovina (1995–2000). The article suggests that three methodological approaches have been of particular value in this research: adopting an historical framework; following the “translation” of languages into war situations; and contextualizing the figure of the interpreter/translator. The process of incorporating languages into histories of conflict, the article argues, has helped to uncover a broader languages landscape within the theatres of war.

Farmers' willingness to pay for agricultural extension service: evidence from Nigeria

The study was undertaken to investigate how willing would farmers be to pay for agricultural extension service in Nigeria. A multistage random sampling technique was used to select 268 respondents. Results showed that most farmers (95.1 per cent) were willing to pay for improved extension service as long as the service remained relevant to their needs. Farmers were willing to pay N1000 annually as their own share of the service cost. The most important factors that influenced farmers’ willingness to pay were states of origin, items originally paid for, major occupation, minor occupation, number of years in school and sale of farm produce.

Beyond the caves: the Palaeolithic rivers of south-west Britain

This paper introduces a new English Heritage (Aggregates Levy Sustainability Fund) project The Palaeolithic Rivers of South-West Britain (project no. 3847), and summarises the results of a first phase resource assessment. The goal of this ongoing project is to develop a new synthesis of the Lower and Middle Palaeolithic occupation of the south-west region, focusing upon river terrace-based archaeology and its implications for hominin landscape use. The resource assessment has reached two preliminary conclusions. Firstly that the region’s earliest Palaeolithic archaeological record is significantly richer than previously believed, and secondly that although find locations have been added in several areas which previously had very few or no finds (e.g.West Cornwall) the overall bias of finds to the south coast is maintained. The project has also revealed that the river terrace resource of South-West England offers potential for geochronological dating, landscape reconstruction, and improved contextualisation of the archaeological material. Some outreach components of the project are also summarised.

Analysis of the intermediate housing market mechanism in the UK

Government policies have backed intermediate housing market mechanisms like shared equity, intermediate rented and shared ownership (SO) as potential routes for some households, who are otherwise squeezed between the social housing and the private market. The rhetoric deployed around such housing has regularly contained claims about its social progressiveness and role in facilitating socio-economic mobility, centring on a claim that SO schemes can encourage people to move from rented accommodation through a shared equity phase and into full owner-occupation. SO has been justified on the grounds of it being transitional state, rather than a permanent tenure. However SO buyers may be laden with economic cost-benefit structures that do not stack up evenly and as a consequence there may be little realistic prospect of ever reaching a preferred outcome. Such behaviours have received little empirical attention as yet despite, the SO model arguably offers a sub-optimal solution towards homeownership, or in terms of wider quality of life. Given the paucity of rigorous empirical work on this issue, this paper delineates the evidence so far and sets out a research agenda. Our analysis is based on a large dataset of new shared owners, observing an information base that spans the past decade. We then set out an agenda to further examine the behaviours of the SO occupants and to examine the implications for future public policy based on existing literature and our outline findings. This paper is particularly opportune at a time of economic uncertainty and an overriding ‘austerity’ drive in public funding in the UK, through which SO schemes have enjoyed support uninterruptedly thus far.

Business parks and town centre workplaces in England: a comparative analysis of commuting-related energy consumption

To fully appreciate the environmental impact of a workplace the transport-related carbon dioxide (CO2) emissions resulting from its location should be considered in addition to the emissions that result from the occupation of the building itself. Since the first one was built in the early 1980s, business parks have become a significant workplace location for service-sector workers; a sector of the economy that grew rapidly at that time as the UK manufacturing output declined and the employment base shifted to retail services and de-regulated financial services. This paper examines the transport-related CO2 emissions associated with these workplace locations in comparison to town and city centre locations. Using 2001 Census Special Workplace Statistics which record people’s residence, usual workplace and mode of transport between them, distance travelled and mode of travel were calculated for a sample of city centre and out-of-town office locations. The results reveal the extent of the difference between transport-related CO2 emitted by commuters to out-of-town and city centre locations. The implications that these findings have for monitoring the environmental performance of workplaces are discussed.

Does short termism affect the quality of urban design in the UK?

This paper follows the report on the “Quality of Urban Design: Study of the Influence of Private Property Decision Maker in Urban Design” (RICS 1996). It focuses on one of the findings in the report, namely that decisions made in development, investment and occupation seemed overly influenced by short term considerations. In this paper, the authors review the Report and examine the concept of short termism as it affects urban design decisions. The paper concludes that although it is difficult to establish whether or not short termism exists in many decisions, there are grounds for believing that a priori short termism might particularly influence property orientated decisions. The paper ends with some implications for policy both at the economy and local level.

International investment, ownership and risk in the City of London office market: an analysis of trends 1972-1997

Office returns in the City of London are more volatile than in other UK markets. This volatility may reflect fluctuations in capital flows associated with changing patterns of ownership and the growing linkage between real estate and financial markets in the City. Using current and historical data, patterns of ownership in the City are investigated. They reveal that overseas ownership has grown markedly since 1985, that owners are predominantly FIRE sector firms and that there are strong links between ownership and occupation. This raises concerns about future volatility and systemic risk.