Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain

The inhibitor-of-apoptosis proteins (IAPs) regulate programmed cell death by inhibiting members of the caspase family of enzymes. Recently, a mammalian protein called Smac (also named DIABLO) was identified that binds to the IAPs and promotes caspase activation. Although undefined in the X-ray structure, the amino-terminal residues of Smac are critical for its function. To understand the structural basis for molecular recognition between Smac and the IAPs, we determined the solution structure of the BIR3 domain of X-linked IAP (XIAP) complexed with a functionally active nine-residue peptide derived from the N terminus of Smac. The peptide binds across the third beta-strand of the BIR3 domain in an extended conformation with only the first four residues contacting the protein. The complex is stabilized by four intermolecular hydrogen bonds, an electrostatic interaction involving the N terminus of the peptide, and several hydrophobic interactions. This structural information, along with the binding data from BIR3 and Smac peptide mutants reported here, should aid in the design of small molecules that may be used for the treatment of cancers that overexpress IAPs.     

Observational defects in eighteenth-century British telescopes

Among the several remarkable properties of mercury is that it dissolves many of the metals (but not iron), forming amalgams. It was the recognition of the ready formation of gold and silver amalgams that led to the extraction of precious metals by the amalgamation method. In this article I trace some of the historical aspects associated with the development of the European amalgamation process, first devised by Ignaz von Born in the 1780s. In particular, I describe an international gathering of experts in mining and metallurgy which was held at Skleno in Slovakia in 1786, and the founding there of a society for mining sciences called ‘Die Societät der Bergbaukunde’.     

Performance Management for Social Enterprises

All organisations face the challenge of how to assess performance beyond current financial metrics. These challenges are felt especially strongly by social enterprises, organisations that use business methods to achieve social goals. Social enterprises need to evidence superior social outcomes, are normally accountable to a complex range of stakeholders and yet are often rated low to medium in terms of organisational capacity—thus whilst they have a great need for rounded measurement, they may in practice lack the ability to make use of the different approaches on offer. This paper examines the current and potential use of the conventional Balanced Scorecard model, by social enterprises. The Adventure Capital Fund provides case study evidence of extensive use of a modified Scorecard. The model used is dynamic, combining reflection on the organisation’s current position, ‘near term’ and long term issues. It aims to take a holistic and coherent view of the management of social enterprises. Experience to date suggests that the medium term snapshot provided by the Scorecard is the most valuable, allowing organisations and especially boards and senior executives to keep a ‘strategic grip’ in a period of rapid change and focus on those actions that have best chance of changing performance in the round.     

Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes

The Wellcome Trust Case Control Consortium (WTCCC) primary genome-wide association (GWA) scan on seven diseases, including the multifactorial autoimmune disease type 1 diabetes (T1D), shows associations at P < 5 x 10(-7) between T1D and six chromosome regions: 12q24, 12q13, 16p13, 18p11, 12p13 and 4q27. Here, we attempted to validate these and six other top findings in 4,000 individuals with T1D, 5,000 controls and 2,997 family trios independent of the WTCCC study. We confirmed unequivocally the associations of 12q24, 12q13, 16p13 and 18p11 (P(follow-up) 相似文献   

Under Pressure: Visioning in a Regulated Environment

This paper describes four case studies of the practice of vision development in four utilities organisations. Important observations emerge about current practice; for example, tensions can be observed in organisations struggling to satisfy the expectations of a diverse range of stakeholders. Formal methodologies for visioning are rarely adopted in vision development; rather more informal processes of debate are preferred. Difficulties with internal communication and staff buy-in to the vision are also identified. Comparisons are drawn with the results of previous work on visioning in the financial services sector.     

Process Improvement with Vision: A Financial Services Case Study

This paper reviews some of the existing models for major process improvement and puts forward an overall framework for such a project. It considers the main reasons why operational change initiatives fail. A case study of process improvement in the financial services sector is used to illustrate the conclusions drawn. The critical role of vision in successful operational change is discussed.     

Bacteria as cell surface markers on normal and malignant mammalian cells

Zusammenfassung Bakterien haften an der Oberfläche kultivierter Säugetierzellen in charakteristischer Weise. An Krebszellen haften sie nicht nur am Vorderteil, sondern auch an der Zelloberfläche und in Kernnähe.

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I thank the Royal Society for some of the equipment used in this research, the Nuffield Foundation for the award of a fellowship, and Prof.I. M. Goodbody for facilities in the Department of Zoology, University of the West Indies, Jamaica, while on sabbatical leave of absence from the University of Glasgow. I am also indebted toJ. B. Cowey, A. S. G. Curtis andD. R. Newth, of Glasgow University for their criticisms and advice, and to Miss E. Cray for assistance in the experiments.