beta 2 subunit contribution to 4/7 alpha-conotoxin binding to the nicotinic acetylcholine receptor

The structures of acetylcholine-binding protein ( AChBP) and nicotinic acetylcholine receptor ( nAChR) homology models have been used to interpret data from mutagenesis experiments at the nAChR. However, little is known about AChBP-derived structures as predictive tools. Molecular surface analysis of nAChR models has revealed a conserved cleft as the likely binding site for the 4/7 alpha-conotoxins. Here, we used an alpha 3 beta 2 model to identify beta 2 subunit residues in this cleft and investigated their influence on the binding of alpha-conotoxins MII, PnIA, and GID to the alpha 3 beta 2 nAChR by two-electrode voltage clamp analysis. Although a beta 2-L119Q mutation strongly reduced the affinity of all three alpha-conotoxins, beta 2-F117A, beta 2-V109A, and beta 2-V109G mutations selectively enhanced the binding of MII and GID. An increased activity of alpha-conotoxins GID and MII was also observed when the beta 2-F117A mutant was combined with the alpha 4 instead of the alpha 3 subunit. Investigation of A10L-PnIA indicated that high affinity binding to beta 2-F117A, beta 2-V109A, and beta 2-V109G mutants was conferred by amino acids with a long side chain in position 10 (PnIA numbering). Docking simulations of 4/7 alpha-conotoxin binding to the alpha 3 beta 2 model supported a direct interaction between mutated nAChR residues and alpha-conotoxin residues 6, 7, and 10. Taken together, these data provide evidence that the beta subunit contributes to alpha-conotoxin binding and selectivity and demonstrate that a small cleft leading to the agonist binding site is targeted by alpha-conotoxins to block the nAChR.

Papillomavirus virus-like particles activate the PI3-kinase pathway via alpha-6 beta-4 integrin upon binding

We have previously shown that human papillomavirus virus-like particles (VLPs) are able to activate the Ras/MAP kinase pathway. Ras can also elicit an anti-apoptotic signal via PI3-kinase so we investigated this further. Here we show that binding of VLPs from HPV types 6b, 18, 3 1, 35 and BPV1 results in activation of PI3-kinase. Activation was achieved by either L1 or L1/L2 VLPs and was dependent on both VLP-cell interaction and correct conformation of the virus particle. VLP-induced PI3-kinase activity resulted in efficient downstream signaling to Akt and consequent phosphorylation of FKHR and GSK3 beta. We also present evidence that PV signaling is activated via the alpha 6 beta 4 integrin. These data suggest that papillomaviruses use a common receptor that is able to signal through to Ras. Combined activation of the Ras/MAP kinase and PI3-kinase pathways may be beneficial for the virus by increasing cell numbers and producing an environment more conducive to infection. (c) 2006 Elsevier Inc. All rights reserved

Foreign direct investment, transactions linkages, and the performance of the domestic sector

Using data from the UK Census of Production, including foreign ownership data, and information from UK industry input-output tables, this paper examines whether the intensity of transactions linkages between foreign and domestic firms affects productivity growth in domestic manufacturing industries. The implications of the findings for policies promoting linkages between multinational and domestic firms in the UK economy are outlined.

Foreign direct investment and local input linkages in Malaysia

This article examines variations in local input linkages in foreign transnational corporations in Malaysia. The extent to which transnational corporations foster such linkages, particularly in a developing host economy, has become an important issue for policy makers and others concerned with the long-term benefits associated with foreign direct investment. This article employs a unique data set, covering inward investors in the electrical and electronics industry, and analyzes in detail the determinants of variations in local input uses. The article develops a model of local input linkages, based on a transaction-cost framework using firm-specific factors, such as nationality of ownership, the age of the plant and its technology, and the extent to which firms employ locally recruited managers and engineers. In addition, the impacts of various policy measures on local input levels are discussed, and also the importance of the original motivation for investing in Malaysia. The article demonstrates that policy initiatives that target particular outcomes, such as stimulating exports or technology transfer, will result in a greater beneficial impact on the host country economy than more generic subsidies.

FDI, linkages and the efficiency of state-owned enterprises in China

As China seeks to consolidate its position as an emerging global economic power, reforming the largely inefficient state-owned enterprises (SOEs) presents a major challenge. Using a comprehensive micro data set, we investigate whether SOEs in China have benefited from the managerial, technical and organisational skills possessed by multinational firms operating in the economy, and conclude that the evidence in favour of positive spillovers is not overwhelming. Limited regional linkages and low level of absorptive capacity are found to be the main reasons for this disappointing performance. Policy makers involved in the reform of SOEs should ensure that managers have the right incentives to make long-term investment in absorptive capacity development.

The effects of external linkages on new product innovativeness:an examination of moderating and mediating influences

Our study of 116 new product development projects in Taiwanese Information Technology (IT) firms show that horizontal linkages more strongly impact on new product innovativeness than vertical linkages. The firm's learning ability or absorptive capacity increases new product innovativeness. It also moderates the impacts of corporate and research institute linkages on new product innovativeness. Moreover, we confirm that knowledge gains mediate the positive impacts of absorptive capacity and external linkages on new product innovativeness.

External linkages, R&D and innovation performance in US business services

This paper examines the innovation performance of 206 US business services firms. Results suggest that external linkages, particularly with customers, suppliers and strategic alliances, significantly enhance innovation performance in terms of the introduction of new services. A highly qualified workforce increases the probability of service and organizational innovation, and increases the extent of a firm's innovation, but unqualified employees also play an important role. Contrasting with some earlier research on services, the presence of formal and informal R&D significantly increases the extent of new-to-market and new-to-firm innovation.

The degradation of gel-spun poly(beta-hydroxybutyrate) fibrous matrix

Poly(β-hydroxybutyrate), (PHB), is a biologically produced, biodegradable thennoplastic with commercial potential. In this work the qualitative and quantitative investigations of the structure and degradation of a previously unstudied, novel, fibrous form of PHB, were completed. This gel-spun PHB fibrous matrix, PHB(FM), which has a similar appearance to cotton wool, possesses a relatively complex structure which combines a large volume with a low mass and has potential for use as a wound scaffolding device. As a result of the intrinsic problems presented by this novel structure, a new experimental procedure was developed to analyze the degradation of the PHB to its monomer hydroxybutyric acid, (HBA). This procedure was used in an accelerated degradation model which accurately monitored the degradation of the undegraded and degraded fractions of a fibrous matrix and the degradation of its PHB component. The in vitro degradation mechanism was also monitored using phase contrast and scanning electron microscopy, differential scanning calorimetry, fibre diameter distributions and Fourier infra-red photoacoustic spectroscopy. The accelerated degradation model was used to predict the degradation of the samples in the physiological model and this provided a clearer picture as to the samples potential biodegradation as medical implantation devices. The degradation of the matrices was characterized by an initial penetration of the degradative medium and weakening of the fibre integrity due to cleavage of the ester linkages, this then led to the physical collapse of the fibres which increased the surface area to volume ratio of the sample and facilitated its degradation. Degradation in the later stages was reduced due to the experimental kinetics, compaction and degradation resistant material, most probably the highly crystalline regions of the PHB. The in vitro degradation of the PHB(FM) was influenced by blending with various polysaccharides, copolymerizing with poly(~-hydroxyvalerate), (PHV), and changes to the manufacturing process. The degradation was also detennined to be faster than that of conventional melt processed PHB based samples. It was concluded that the material factors such as processing, sample size and shape affected the degradation of PHB based samples with the major factor of sample surface area to volume ratio being of paramount importance in determining the degradation of a sample.