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It is estimated that more than 170 million people are infected with hepatitis C virus (HCV) worldwide (1,2). Clinical trials have demonstrated that, for the first time in human history, [...]

The worldwide prevalence of chronic hepatitis C virus (HCV) infection is estimated to be approaching 200 million people (1). Current therapy relies upon a combination of pegylated interferon-a and ribavirin, a poorly tolerated regimen typically associated with less than 50% sustained virological response rate in those infected with genotype 1 virus (2,3). The development of direct-acting antiviral agents to treat HCV has focused predominantly on inhibitors of the viral enzymes NS3 protease and the RNA-dependent RNA polymerase NS5B (4). Here we describe the profile of BMS-790052, a small molecule inhibitor of the HCV NS5A protein that exhibits picomolar half-maximum effective concentrations ([EC.sub.50]) towards replicons expressing a broad range of HCV genotypes and the JFH-1 genotype 2a infectious virus in cell culture. In a phase I clinical trial in patients chronically infected with HCV, administration of a single 100-mg dose of BMS-790052 was associated with a 3.3 [log.sub.10] reduction in mean viral load measured 24 h post-dose that was sustained for an additional 120 h in two patients infected with genotype 1b virus. Genotypic analysis of samples taken at baseline, 24 and 144 h post-dose revealed that the major HCV variants observed had substitutions at amino-acid positions identified using the in vitro replicon system. These results provide the first clinical validation of an inhibitor of HCV NS5A, a protein with no known enzymatic function, as an approach to the suppression of virus replication that offers potential as part of a therapeutic regimen based on combinations of HCV inhibitors., We designed a mechanistically unbiased approach based on chemical genetics to identify chemical starting points for interfering with HCV replication. Our differentiating strategy centred on the identification of compounds functionally [...]

The Department of Health in England released a new health research strategy in 2006 with far-reaching implications for both health research and research management. The explicit policy shift is towards centres of excellence and away from historical block allocations of funding to National Health Service (NHS) healthcare organisations--with these replaced by new nationally competitive funding streams. Academic researchers wishing to access these new and rich funding sources need to work more closely with healthcare providers, as grants money will be paid through the NHS. As a result, the NHS needs to develop pre- and post- award skills in addition to its traditional governance role in research management. This has led some institutions to propose joint research support offices between themselves and the NHS. This paper explores the issues raised by these developments, concentrating on the predictors for success (or failure) of these proposed new institutional arrangements as identified in the partnership literature. Implications for research management are also discussed. Keywords: Partnerships, Structures, University/National Health Services, Research Administration, Introduction The National Health Service (NHS) Trusts in England have provided the setting in which applied health investigators conduct their research. Funding for the NHS to support this work has [...]

This paper uses literature on faculty worklife and findings from a recent study conducted by the Federal Demonstration Partnership (FDP) to shed light on the sources and extent of administrative burden experienced by faculty engaged in federal grant research. Discussion focuses on the implications for research administrators, including strategies for designing faculty support services that take into account a variety of factors that motivate academic engagement. Keywords: Research productivity, sponsored research, research administration, academic workload, Introduction Around the world, higher education institutions face significant fiscal pressure and escalating costs. At many institutions, researchers are under increased pressure to obtain funded-project revenue as a way of [...]

Introduction US Federal regulators have increased their oversight in areas that use human tissue, in particular targeting companies that remove tissue for use in medical procedures. The UK has recently [...]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.techfore.2007.05.009 Byline: J. Roland Ortt (a), David J. Langley (b), Nico Pals (b) Keywords: Market potential; Breakthrough technology; Futures research; Market research Abstract: In this article, the gap between futures research (long term) and market research (short term) is closed in two ways. Firstly, by describing methods of market exploration that can be used earlier on in the process of development and diffusion of breakthrough technologies, so market research can be applied along with futures research. Secondly, the gap is closed by actually combining futures research and market research. We start the article from the perspective of the market research discipline and describe the problems in market research that require new approaches. The validity of market research results is often low when breakthrough technologies enter the market. To investigate this problem, assumptions for valid market research results are presented. In some cases, when breakthrough technologies first enter the market, these assumptions do not hold and market research becomes problematic whereas in other cases customers' needs and preferences are not an issue at all and attention focuses on technological issues. Potential solutions to explore the market in the former cases are suggested. Four approaches are distinguished: (1) adapting existing methods; (2) combining consumer research with market structure analysis or futures research; (3) using theoretic models; and (4) probe and learn approaches. These approaches require different subsets of assumptions and are therefore applicable in different situations. Author Affiliation: (a) Associate professor of Management of Technology at Delft University of Technology, faculty of Technology, Policy, and Management, Jaffalaan 5, 2628 BZ Delft, The Netherlands (b) TNO ICT, PO Box 1416, 9701 BK Groningen, The Netherlands Article History: Received 15 October 2006; Revised 27 April 2007; Accepted 1 May 2007

PRINCE2, which stands for Projects in Controlled Environments, is a project management method covering the organisation, management, and control of projects and is widely used in both government and commercial IT and building projects in the UK, This paper describes the application of PRINCE2 to the management of large clinical trials (specifically, of a Phase III trial of a candidate microbicide to prevent vaginally acquired HIV infection). It reviews the challenge of ensuring that the project management tools add value to the project overall and are not perceived as an overly administrative burden. It reviews the requirement for high level summary reports for use by an executive committee and funding bodies, highlighting the reasons for taking this approach--in particular, not only to manage the science, but to link expenditure to activities at geographically separate trial sites and to key performance indicators, and to provide tools for monitoring risks and possible re-alignment of budgets to reflect changing activities and outputs by collaborators. The paper considers the wider costs and benefits to researchers and funders of taking this approach and explores implications for research administrators and managers at institutions involved in large, complex collaborative research projects, whether clinical or not. Key Words: Project management tools, PRINCE2, clinical trial, microbicide, Microbicides Development Programme (MDP), financial controls, Introduction Although the pharmaceutical industry has well-developed project management methodologies for research, it is unusual for academic researchers working in the education and public sectors to do so. The discipline [...]

The increasing complexity and diversity of a typical portfolio of research awards coupled with advancing technology makes successful implementation and delivery of system benefits more challenging than ever. Moreover, the role of systems in knowledge management is a fundamental issue faced by all research active organizations. One of the principal drivers for introducing better systems should be to serve the academic mission and make life easier for researchers; yet most appear to perform conversely, perhaps sacrificing potential benefits to meet the requirements of administration. The principal challenge thus is to deliver a system that meets the needs of both academic and administrative communities. This paper provides a commentary on the experience gained within a research office following implementation of two systems (one pre-award, the other post-award) and identifies key elements for successful delivery. The paper contains suggestions, based on our experience, of best practices and techniques that research administrators might adopt to ensure a well-managed project and its implementation. It concludes how, post implementation, users may begin to derive maximum benefit from systems and points to the advantages that high-quality knowledge management can offer a range of stakeholders., Introduction The research sector is rapidly changing as universities pursue academic excellence and develop more complex research strategies to drive their organisation forward. Management of the typical research portfolio of [...]

Universities operate increasingly in a global environment, and the scope and scale of sponsored research programmes have changed dramatically over the last 40 years. It is now commonplace for research programmes to involve international collaboration among researchers from multiple countries and even continents. There can be little doubt that research and its administration is an international activity that poses opportunities and challenges to those involved in its administration, support and delivery. As sponsors and regulatory frameworks have become more complex, the need for the management of research administration to move away from the principal investigator (or her/ his administrator) to resource-entities with relevant skill sets has become essential. Dedicated research support offices and professional officers are now common in the larger, research active institutions, and these have had to adapt and invariably grow as a consequence of the changes in complexity, size and scope of research programmes. Increased requirements in research administration over the last 40 years have had a global impact and there is hardly a corner of the world where we would not find colleagues striving to administer and lead research to the best of their capabilities. There can be little doubt that we truly are a global profession that offers a number of exciting opportunities to work together and move us forward even further. Key Words: Global research, international sponsored programme offices, international research collaboration, developing countries, Research administrators must ensure they are best placed to help secure and manage funding, add value to the academic mission, and continue to develop strategic alliances while ensuring risks to [...]

Molecular wires comprising a Ru(II)- or Re(I)-complex head group, an aromatic tail group, and an alkane linker reversibly inhibit the activity of the copper amine oxidase from Arthrobacterglobiformis (AGAO), with [K.sub.i] values between 6 [micro]M and 37 nM. In the crystal structure of a Ru(ll)-wire:AGAO conjugate, the wire occupies the AGAO active-site substrate access channel, the trihydroxypheny-lalanine quinone cofactor is ordered in the 'off-Cu' position with its reactive carbonyl oriented toward the inhibitor, and the 'gate' residue, Tyr-296, is in the 'open' position. Head groups, tail-group substituents, and linker lengths all influence wire-binding interactions with the enzyme. diimine | topaquinone | metalloenzyme | active site

Trimeric class I virus fusion proteins undergo a series of conformational rearrangements that leads to the association of C- and N-terminal heptad repeat domains in a 'trimer-of-hairpins' structure, facilitating the apposition of viral and cellular membranes during fusion. This final fusion hairpin structure is sustained by protein-protein interactions, associations thought initially to be refractory to small-molecule inhibition because of the large surface area involved. By using a photoaffinity analog of a potent respiratory syncytial virus fusion inhibitor, we directly probed the interaction of the inhibitor with its fusion protein target, Studies have shown that these inhibitors bind within a hydrophobic cavity formed on the surface of the N-terminal heptad-repeat trimer. In the fusogenic state, this pocket is occupied by key amino acid residues from the C-terminal heptad repeat that stabilize the trimer-of-hairpins structure. The results indicate that a low-molecular-weight fusion inhibitor can interfere with the formation or consolidation of key structures within the hairpin moiety that are essential for membrane fusion. Because analogous cavities are present in many class I viruses, including HIV, these results demonstrate the feasibility of this approach as a strategy for drug discovery.

A study of the activation of secondary metabolism due to time-dependent oxygen limitation in Amycolatopsis orientalis and Saccharopolyspora erythraea culturing by measuring dissolved oxygen levels using a miniature electrode reveals that the synthesis of erythromycin occurs under both well-aerated and oxygen-restricted conditions in inclined tube and shaken flask cultures of S. erythraea, while a novel secondary metabolite is synthesized under oxygen-restricted conditions alone. Oxygen-rich cultures of A. orientalis synthesize vancomycin and in batch bioreactor cultures. Oxygen restriction resembles substrate restriction due to dissolved nutrients in activating secondary metabolite synthesis in some cultures and suppressing it in others.

Multidimensional triple-resonance NMR spectral assignment of sequential 13C, 1H and 15N NMR values of apokedarcidin, a chromoprotein, reveals the presence of two two-stranded-, one three-stranded- and one four-stranded antiparallel beta-sheets in the solution structure of apokedarcidin. Variable target function minimization and simulated annealing programs facilitate the development of an ensemble of 15 solution structures for apokedarcidin. The overall folding topology of apokedarcidin is homologous to that of aponeocarzinostatin, apomacromomycin and apoactinonanthin, with a subdomain having two antiparallel beta-ribbons and an immunoglobin-like seven-stranded antiparallel beta-barrel.

NMR techniques, mass spectrometry, chemical degradation, derivatization and sodium borohydride reduction experiments were collectively used to determine the structure of the Kedarcidin chromophore. Stereochemistry of the aglycone was determined by NMR NOE and molecular modeling studies. The chromophore of Kedarcidin is a bioreductively activated DNA-damaging antitumor agent in which the diradical intermediate functions as the active species.

A lack of trained administrators is holding African scientists back.A lack of trained administrators is holding African scientists back., Author(s): David Langley, Therina TheronAuthor Affiliations:Discovery relies on strong support staff A researcher demonstrates the difference between two substances to a group of students in South Africa. [see PDF for [...]

The kinetics of binding of a specific HIV strand transfer inhibitor to integrase variants assembled with systematic changes to the terminal 3' adenosine is described. The results indicated that the terminal deoxyribose play a critical role to retard the rate of inhibitor dissociation, either by sterically blocking inhibitor egress or by a direct interaction with the bound inhibitor.

The article explains the phenomenon associated with the inhibition of copper amine oxidase from Arthrobacter globiformis (AGAO) by using the enantiomer-specific binding of ruthenium(II) molecular wires. The discussed inhibition is shown to exhibit a high degree of selectivity, which is not obtained by other wires.

The purification, structural characterization and kinetic and biochemical analysis of Orotidine 5'-monophosphate (OMP) decarboxylase from Plasmodium falciparum (PfODCase) is described. The structure of PfODCase solved in the absence of ligand displays a classic TIM-barrel fold characteristic of the enzyme.

A series of compounds derived from the substrate analogue of copper amine oxidases (CuAOs) are screened against six different CuAOs in order to design potent and selective inhibitors and the substrate analogues investigated were the family of 4-(aryloxy)-2-butynamines. The structural and inhibition results support the feasibility of designing selective mechanism-based inhibitors of copper amine oxidases.

Pichia pastoris lysyl oxidase (PPLO) is a copper amine oxidase, which is able to oxidize the side chain of lysine residues of polypeptides. The structural elements that are responsible for the accessibility of the active site are identified and discussed.

Research has been conducted on Porphyromonas gingivalis. The authors report that they have investigated the role of porphyrins in P. gingivalis growth recovery in heme-depleted cultures, and the results demonstrate that P. gingivalis hemoglobin receptor domain recognizes heme by a mechanism mediated by porphyrins.

A nine membered ring enediyne chromophore with powerful antibacterial and antitumor properties and a 1:1 complex of a water soluble and acidic protein constitute the maduropeptin, which is isolated from the Actinomadura madurae broth filterate. The maduropeptin apoprotein exhibits a sequence homology different from the homology of chromoproteins. A tightly bound chromophore, which is essential for the dissociation of proteins is found in the maduropeptin.

The selective interactions of cationic porphyrins with G-quadruplex structures are reported.