Talented suppliers? Strategic change and innovation in the UK aerospace industry

The 1990s marked the start of extensive re-structuring in the aerospace industry throughout the world. While the ensuing consolidation among prime contractors has been widely researched, the changes affecting the aerospace supply chain have received less attention. This study focuses on the re-structuring taking place within the supply chain of the UK aerospace industry. The findings point to extensive re-structuring. Unlike most earlier studies the lean supply model was found to be a powerful influence, with suppliers moving away from subcontractor status and instead taking on the mantle of ‘talented’ suppliers. While some of the implications of lean supply, in terms of the dynamics of innovation, were not apparent, there were modest signs of increased process innovation on the part of some suppliers

Metabolic Network for the Biosynthesis of Intra- and Extracellular alpha-Glucans Required for Virulence of Mycobacterium tuberculosis

Mycobacterium tuberculosis synthesizes intra- and extracellular alpha-glucans that were believed to originate from separate pathways. The extracellular glucose polymer is the main constituent of the mycobacterial capsule that is thought to be involved in immune evasion and virulence. However, the role of the alpha-glucan capsule in pathogenesis has remained enigmatic due to an incomplete understanding of alpha-glucan biosynthetic pathways preventing the generation of capsule-deficient mutants. Three separate and potentially redundant pathways had been implicated in alpha-glucan biosynthesis in mycobacteria: the GlgC-GlgA, the Rv3032 and the TreS-Pep2-GlgE pathways. We now show that alpha-glucan in mycobacteria is exclusively assembled intracellularly utilizing the building block alpha-maltose-1-phosphate as the substrate for the maltosyltransferase GlgE, with subsequent branching of the polymer by the branching enzyme GlgB. Some alpha-glucan is exported to form the alpha-glucan capsule. There is an unexpected convergence of the TreS-Pep2 and GlgC-GlgA pathways that both generate alpha-maltose-1-phosphate. While the TreS-Pep2 route from trehalose was already known, we have now established that GlgA forms this phosphosugar from ADP-glucose and glucose 1-phosphate 1000-fold more efficiently than its hitherto described glycogen synthase activity. The two routes are connected by the common precursor ADPglucose, allowing compensatory flux from one route to the other. Having elucidated this unexpected configuration of the metabolic pathways underlying alpha-glucan biosynthesis in mycobacteria, an M. tuberculosis double mutant devoid of alpha-glucan could be constructed, showing a direct link between the GlgE pathway, alpha-glucan biosynthesis and virulence in a mouse infection model

Assembly of α-Glucan by GlgE and GlgB in Mycobacteria and Streptomycetes

Actinomycetes, such as mycobacteria and streptomycetes, synthesize α-glucan with α-1,4 linkages and α-1,6 branching to help evade immune responses and to store carbon. α-Glucan is thought to resemble glycogen except for having shorter constituent linear chains. However, the fine structure of α-glucan and how it can be defined by the maltosyl transferase GlgE and branching enzyme GlgB were not known. Using a combination of enzymolysis and mass spectrometry, we compared the properties of α-glucan isolated from actinomycetes with polymer synthesized in vitro by GlgE and GlgB. We now propose the following assembly mechanism. Polymer synthesis starts with GlgE and its donor substrate, α-maltose 1-phosphate, yielding a linear oligomer with a degree of polymerization (∼16) sufficient for GlgB to introduce a branch. Branching involves strictly intrachain transfer to generate a C chain (the only constituent chain to retain its reducing end), which now bears an A chain (a nonreducing end terminal branch that does not itself bear a branch). GlgE preferentially extends A chains allowing GlgB to act iteratively to generate new A chains emanating from B chains (nonterminal branches that themselves bear a branch). Although extension and branching occur primarily with A chains, the other chain types are sometimes extended and branched such that some B chains (and possibly C chains) bear more than one branch. This occurs less frequently in α-glucans than in classical glycogens. The very similar properties of cytosolic and capsular α-glucans from Mycobacterium tuberculosis imply GlgE and GlgB are sufficient to synthesize them both

A Multi-wavelength View of the TeV Blazar Markarian 421: Correlated Variability, Flaring, and Spectral Evolution

We report results from a multi-wavelength monitoring campaign on Mrk 421 over the period of 2003-2004. The source was observed simultaneously at TeV and X-ray energies, with supporting observations frequently carried out at optical and radio wavelengths. The large amount of simultaneous data has allowed us to examine the variability of Mrk 421 in detail. The variabilities are generally correlated between the X-ray and gamma-ray bands, although the correlation appears to be fairly loose. The light curves show the presence of flares with varying amplitudes on a wide range of timescales both at X-ray and TeV energies. Of particular interest is the presence of TeV flares that have no coincident counterparts at longer wavelengths, because the phenomenon seems difficult to understand in the context of the proposed emission models for TeV blazars. We have also found that the TeV flux reached its peak days before the X-ray flux during a giant flare in 2004. Such a difference in the development of the flare presents a further challenge to the emission models. Mrk 421 varied much less at optical and radio wavelengths. Surprisingly, the normalized variability amplitude in optical seems to be comparable to that in radio, perhaps suggesting the presence of different populations of emitting electrons in the jet. The spectral energy distribution (SED) of Mrk 421 is seen to vary with flux, with the two characteristic peaks moving toward higher energies at higher fluxes. We have failed to fit the measured SEDs with a one-zone SSC model; introducing additional zones greatly improves the fits. We have derived constraints on the physical properties of the X-ray/gamma-ray flaring regions from the observed variability (and SED) of the source. The implications of the results are discussed. (Abridged)Comment: 32 pages, 12 figures, to appear in Ap

The First VERITAS Telescope

The first atmospheric Cherenkov telescope of VERITAS (the Very Energetic Radiation Imaging Telescope Array System) has been in operation since February 2005. We present here a technical description of the instrument and a summary of its performance. The calibration methods are described, along with the results of Monte Carlo simulations of the telescope and comparisons between real and simulated data. The analysis of TeV $\gamma$-ray observations of the Crab Nebula, including the reconstructed energy spectrum, is shown to give results consistent with earlier measurements. The telescope is operating as expected and has met or exceeded all design specifications.Comment: Accepted by Astroparticle Physic

A Search for TeV Gamma-Ray Emission from High-Peaked Flat Spectrum Radio Quasars Using the Whipple Air-Cherenkov Telescope

Blazars have traditionally been separated into two broad categories based upon their optical emission characteristics; BL Lacs, with faint or no emission lines, and flat spectrum radio quasars (FSRQs) with prominent, broad emission lines. The spectral energy distribution of FSRQs has generally been thought of as being more akin to the low-peaked BL Lacs, which exhibit a peak in the infrared region of the spectrum, as opposed to high-peaked BL Lacs (HBLs), which exhibit a peak in UV/X-ray region of the spectrum. All blazars currently confirmed as sources of TeV emission are HBLs. Recent surveys have found several FSRQs exhibiting spectral properties similar to HBLs, particularly the synchrotron peak frequency. These objects are potential sources of TeV emission according to several models of blazar jet emission and blazar evolution. Measurements of TeV flux or upper limits could impact existing theories explaining the links between different blazar types and could have a significant impact on our understanding of the nature of objects that are capable of TeV emission. In particular, the presence (or absence) of TeV emission from FSRQs could confirm (or cast doubt upon) recent evolutionary models that expect intermediate objects in a transitionary state between FSRQ and BL Lac. The Whipple 10 meter imaging air-Cherenkov gamma-ray telescope is well suited for TeV gamma-ray observations. Using the Whipple telescope, we have taken data on a small selection of nearby(z<0.1 in most cases), high-peaked FSRQs. Although one of the objects, B2 0321+33, showed marginal evidence of flaring, no significant emission was detected. The implications of this paucity of emission and the derived upper limits are discussed.Comment: accepted for publication in Astrophysical Journa

Trehalose-6-phosphate-mediated toxicity determines essentiality of OtsB2 in Mycobacterium tuberculosis in vitro and in mice

Trehalose biosynthesis is considered an attractive target for the development of antimicrobials against fungal, helminthic and bacterial pathogens including Mycobacterium tuberculosis. The most common biosynthetic route involves trehalose-6-phosphate (T6P) synthase OtsA and T6P phosphatase OtsB that generate trehalose from ADP/UDP-glucose and glucose-6-phosphate. In order to assess the drug target potential of T6P phosphatase, we generated a conditional mutant of M. tuberculosis allowing the regulated gene silencing of the T6P phosphatase gene otsB2. We found that otsB2 is essential for growth of M. tuberculosis in vitro as well as for the acute infection phase in mice following aerosol infection. By contrast, otsB2 is not essential for the chronic infection phase in mice, highlighting the substantial remodelling of trehalose metabolism during infection by M. tuberculosis. Blocking OtsB2 resulted in the accumulation of its substrate T6P, which appears to be toxic, leading to the self-poisoning of cells. Accordingly, blocking T6P production in a ΔotsA mutant abrogated otsB2 essentiality. T6P accumulation elicited a global upregulation of more than 800 genes, which might result from an increase in RNA stability implied by the enhanced neutralization of toxins exhibiting ribonuclease activity. Surprisingly, overlap with the stress response caused by the accumulation of another toxic sugar phosphate molecule, maltose-1-phosphate, was minimal. A genome-wide screen for synthetic lethal interactions with otsA identified numerous genes, revealing additional potential drug targets synergistic with OtsB2 suitable for combination therapies that would minimize the emergence of resistance to OtsB2 inhibitors

Dimerisation induced formation of the active site and the identification of three metal sites in EAL-phosphodiesterases

The bacterial second messenger cyclic di-3′,5′-guanosine monophosphate (c-di-GMP) is a key regulator of bacterial motility and virulence. As high levels of c-di-GMP are associated with the biofilm lifestyle, c-di-GMP hydrolysing phosphodiesterases (PDEs) have been identified as key targets to aid development of novel strategies to treat chronic infection by exploiting biofilm dispersal. We have studied the EAL signature motif-containing phosphodiesterase domains from the Pseudomonas aeruginosa proteins PA3825 (PA3825EAL) and PA1727 (MucREAL). Different dimerisation interfaces allow us to identify interface independent principles of enzyme regulation. Unlike previously characterised two-metal binding EAL-phosphodiesterases, PA3825EAL in complex with pGpG provides a model for a third metal site. The third metal is positioned to stabilise the negative charge of the 5′-phosphate, and thus three metals could be required for catalysis in analogy to other nucleases. This newly uncovered variation in metal coordination may provide a further level of bacterial PDE regulation

Prediction of uncomplicated pregnancies in obese women: A prospective multicentre study

BACKGROUND: All obese pregnant women are considered at equal high risk with respect to complications in pregnancy and birth, and are commonly managed through resource-intensive care pathways. However, the identification of maternal characteristics associated with normal pregnancy outcomes could assist in the management of these pregnancies. The present study aims to identify the factors associated with uncomplicated pregnancy and birth in obese women, and to assess their predictive performance. METHODS: Data form obese women (BMI ≥ 30 kg/m 2 ) with singleton pregnancies included in the UPBEAT trial were used in this analysis. Multivariable logistic regression was used to identify sociodemographic, clinical and biochemical factors at 15 +0 to 18 +6 weeks' gestation associated with uncomplicated pregnancy and birth, defined as delivery of a term live-born infant without antenatal or labour complications. Predictive performance was assessed using area under the receiver operating characteristic curve (AUROC). Internal validation and calibration were also performed. Women were divided into fifths of risk and pregnancy outcomes were compared between groups. Sensitivity, specificity, and positive and negative predictive values were calculated using the upper fifth as the positive screening group. RESULTS: Amongst 1409 participants (BMI 36.4, SD 4.8 kg/m 2 ), the prevalence of uncomplicated pregnancy and birth was 36% (505/1409). Multiparity and increased plasma adiponectin, maternal age, systolic blood pressure and HbA1c were independently associated with uncomplicated pregnancy and birth. These factors achieved an AUROC of 0.72 (0.68-0.76) and the model was well calibrated. Prevalence of gestational diabetes, preeclampsia and other hypertensive disorders, preterm birth, and postpartum haemorrhage decreased whereas spontaneous vaginal delivery increased across the fifths of increasing predicted risk of uncomplicated pregnancy and birth. Sensitivity, specificity, and positive and negative predictive values were 38%, 89%, 63% and 74%, respectively. A simpler model including clinical factors only (no biomarkers) achieved an AUROC of 0.68 (0.65-0.71), with sensitivity, specificity, and positive and negative predictive values of 31%, 86%, 56% and 69%, respectively. CONCLUSION: Clinical factors and biomarkers can be used to help stratify pregnancy and delivery risk amongst obese pregnant women. Further studies are needed to explore alternative pathways of care for obese women demonstrating different risk profiles for uncomplicated pregnancy and birth

Observations of the unidentified TeV gamma-ray source TeV J2032+4130 with the Whipple Observatory 10 m telescope

We report on observations of the sky region around the unidentified TeV gamma-ray source (TeV J2032+ 4130) carried out with the Whipple Observatory 10 m atmospheric Cerenkov telescope for a total of 65.5 hr between 2003 and 2005. The standard two-dimensional analysis developed by the Whipple collaboration for a stand-alone telescope reveals an excess in the field of view at a pretrial significance level of 6.1 sigma. The measured position of this excess is alpha = 20(h)32(m)27(s), delta = 41 degrees 39\u2717 (J2000.0). The estimated integral flux for this gamma-ray source is about 8% of the Crab Nebula flux. The data are consistent with a pointlike source. Here we present a detailed description of the standard two-dimensional analysis technique used for the analysis of data taken with the Whipple Observatory 10 m telescope and the results for the TeV J2032+ 4130 campaign. We include a short discussion of the physical mechanisms that may be responsible for the observed gamma-ray emission, based on possible association with known astrophysical objects, in particular, Cygnus OB2