Analog Computer Research

Contains reports on three research projects

UK construction companies’ strategies in the face of business cycles

Firms in the construction industry have always had to deal with the challenges of the economic cycle and develop strategies to deal with the resulting fluctuations in their business environment. In the context of the 2008–2011 double-dip recession in the UK, the results of a survey targeting the top one hundred construction companies in the UK are reported here. This research is particularly intended to assess whether the strategies of large companies in the construction sector, when faced with the issues associated with the variation in the economic cycle, have changed since the previous business cycle (i.e. the 1986–1990 boom followed by the 1990–1991 recession). The survey reveals the challenges that companies have faced, reports on company behaviour and on the policies adopted. While there are many similarities between policies adopted during the recessionary periods of the two cycles, the research found notable changes in attitudes towards diversification, human resource management and price bidding

The uses and functions of ageing celebrity war reporters

This article starts from the premise that recognition of professional authority and celebrity status depends on the embodiment and performance of field-specific dispositional practices: there’s no such thing as a natural, though we often talk about journalistic instinct as something someone simply has or doesn’t have. Next, we have little control over how we are perceived by peers and publics, and what we think are active positioning or subjectifying practices are in fact, after Bourdieu, revelations of already-determined delegation. The upshot is that two journalists can arrive at diametrically opposed judgements on the basis of observation of the same actions of a colleague, and as individuals we are blithely hypocritical in forming (or reciting) evaluations of the professional identity of celebrities. Nowhere is this starker than in the discourse of age-appropriate behaviour, which this paper addresses using the examples of ‘star’ war reporters John Simpson, Kate Adie and Martin Bell. A certain rough-around-the-edges irreverence is central to dispositional authenticity amongst war correspondents, and for ageing hacks this incorporates gendered attitudes to sex and alcohol as well as indifference to protocol. And yet perceived age-inappropriate sexual behaviour is also used to undermine professional integrity, and the paper ends by outlining the phenomenological context that makes possible this effortless switching between amoral and moralising recognition by peers and audiences alike

Protein disulfide-isomerase interacts with a substrate protein at all stages along its folding pathway

In contrast to molecular chaperones that couple protein folding to ATP hydrolysis, protein disulfide-isomerase (PDI) catalyzes protein folding coupled to formation of disulfide bonds (oxidative folding). However, we do not know how PDI distinguishes folded, partly-folded and unfolded protein substrates. As a model intermediate in an oxidative folding pathway, we prepared a two-disulfide mutant of basic pancreatic trypsin inhibitor (BPTI) and showed by NMR that it is partly-folded and highly dynamic. NMR studies show that it binds to PDI at the same site that binds peptide ligands, with rapid binding and dissociation kinetics; surface plasmon resonance shows its interaction with PDI has a Kd of ca. 10−5 M. For comparison, we characterized the interactions of PDI with native BPTI and fully-unfolded BPTI. Interestingly, PDI does bind native BPTI, but binding is quantitatively weaker than with partly-folded and unfolded BPTI. Hence PDI recognizes and binds substrates via permanently or transiently unfolded regions. This is the first study of PDI's interaction with a partly-folded protein, and the first to analyze this folding catalyst's changing interactions with substrates along an oxidative folding pathway. We have identified key features that make PDI an effective catalyst of oxidative protein folding – differential affinity, rapid ligand exchange and conformational flexibility

The TRACTISS protocol: a randomised double blind placebo controlled clinical trial of anti-B-cell therapy in patients with primary Sjögren's Syndrome.

Background: Primary Sjögren's Syndrome (PSS) mainly affects women (9:1 female:male ratio) and is one of the commonest autoimmune diseases with a prevalence of 0.1 - 0.6% of adult women. For patients with PSS there is currently no effective therapy that can alter the progression of the disease. The aim of the TRACTISS study is to establish whether in patients with PSS, treatment with rituximab improves clinical outcomes. Methods/design: TRACTISS is a UK multi-centre, double-blind, randomised, controlled, parallel group trial of 110 patients with PSS. Patients will be randomised on a 1:1 basis to receive two courses of either rituximab or placebo infusion in addition to standard therapy, and will be followed up for up to 48 weeks. The primary objective is to assess the extent to which rituximab improves symptoms of fatigue and oral dryness. Secondary outcomes include ocular dryness, salivary flow rates, lacrimal flow, patient quality of life, measures of disease damage and disease activity, serological and peripheral blood biomarkers, and glandular histology and composition. Discussion: The TRACTISS trial will provide direct evidence as to whether rituximab in patients with PSS leads to an improvement in patient symptoms and a reduction in disease damage and activity. Trial registration: UKCRN Portfolio ID: 9809 ISRCTN65360827

Borrelia valaisiana resist complement-mediated killing independently of the recruitment of immune regulators and inactivation of complement components

Spirochetes belonging to the Borrelia (B.) burgdorferi sensu lato complex differ in their resistance to complement-mediated killing, particularly in regard to human serum. In the present study, we elucidate the serum and complement susceptibility of B. valaisiana, a genospecies with the potential to cause Lyme disease in Europe as well as in Asia. Among the investigated isolates, growth of ZWU3 Ny3 was not affected while growth of VS116 and Bv9 was strongly inhibited in the presence of 50% human serum. Analyzing complement activation, complement components C3, C4 and C6 were deposited on the surface of isolates VS116 and Bv9, and similarly the membrane attack complex was formed on their surface. In contrast, no surface-deposited components and no aberrations in cell morphology were detected for serum-resistant ZWU3 Ny3. While further investigating the protective role of bound complement regulators in mediating complement resistance, we discovered that none of the B. valaisiana isolates analyzed bound complement regulators Factor H, Factor H-like protein 1, C4b binding protein or C1 esterase inhibitor. In addition, B. valaisiana also lacked intrinsic proteolytic activity to degrade complement components C3, C3b, C4, C4b, and C5. Taken together, these findings suggest that certain B. valaisiana isolates differ in their capability to resist complement-mediating killing by human serum. The molecular mechanism utilized by B. valaisiana to inhibit bacteriolysis appears not to involve binding of the key host complement regulators of the alternative, classical, and lectin pathways as already known for serum-resistant Lyme disease or relapsing fever borreliae

Intoxicating entertainment? The influence of "Star Music Trek" on the drinking practices of Nigerian students

Sophisticated marketing strategies are increasingly used by transnational alcohol companies in Nigeria. While this facilitates alcohol availability and encourages alcohol consumption, there are no effective policies to regulate alcohol marketing. This study draws on qualitative interviews with 31 Nigerian university students (aged 19–23 years) to explore some of the ways in which “Star Music Trek” (SMT, a brewer-sponsored music concert) establishes spaces that facilitate alcohol consumption among Nigerian youths. The data were analyzed to generate themes with the aid of NVivo 10 software. The article argues that although the rationale for attending the SMT event is to be entertained by famous artists for a reduced entrance fee, the event creates conditions that influence young people to use alcohol in diverse ways. Among nondrinkers, SMT establishes conditions that influence alcohol initiation because purchasing “Star beer,” the brand that sponsors SMT, not only serves as a ticket or gate pass to some of the concerts, but it is also the only brand sold at the event. Among those who use alcohol, SMT creates spaces that encourage a culture of intoxication because of the easy availability and accessibility of Star beer and promotional activities in the form of price reductions, raffle draws, and free drinks. The participants also discussed the ways in which the sponsor uses its marketing representatives to promote brand allegiance by encouraging attendees to favor Star beer after the concert. Overall, the findings reveal that SMT is a sophisticated marketing strategy to promote the Star brand. The study discusses the implications of the findings and concludes that effective national alcohol control policies should be formulated and implemented in Nigeria.The doctoral research, from which this article was taken was funded by the Tertiary Education Trust Fund (TETFUND)

Crystal structure of a tripartite complex between C3dg, C-terminal domains of factor H and OspE of Borrelia burgdorferi

Complement is an important part of innate immunity. The alternative pathway of complement is activated when the main opsonin, C3b coats non-protected surfaces leading to opsonisation, phagocytosis and cell lysis. The alternative pathway is tightly controlled to prevent autoactivation towards host cells. The main regulator of the alternative pathway is factor H (FH), a soluble glycoprotein that terminates complement activation in multiple ways. FH recognizes host cell surfaces via domains 19–20 (FH19-20). All microbes including Borrelia burgdorferi, the causative agent of Lyme borreliosis, must evade complement activation to allow the infectious agent to survive in its host. One major mechanism that Borrelia uses is to recruit FH from host. Several outer surface proteins (Osp) have been described to bind FH via the C-terminus, and OspE is one of them. Here we report the structure of the tripartite complex formed by OspE, FH19-20 and C3dg at 3.18 Å, showing that OspE and C3dg can bind simultaneously to FH19-20. This verifies that FH19-20 interacts via the “common microbial binding site” on domain 20 with OspE and simultaneously and independently via domain 19 with C3dg. The spatial organization of the tripartite complex explains how OspE on the bacterial surface binds FH19-20, leaving FH fully available to protect the bacteria against complement. Additionally, formation of tripartite complex between FH, microbial protein and C3dg might enable enhanced protection, particularly on those regions on the bacteria where previous complement activation led to deposition of C3d. This might be especially important for slow-growing bacteria that cause chronic disease like Borrelia burgdorferi.Peer reviewe