Promotion of purine nucleotide binding to thymidylate synthase by a potent folate analogue inhibitor, 1843U89.

A folate analogue, 1843U89 (U89), with potential as a chemotherapeutic agent due to its potent and specific inhibition of thymidylate synthase (TS; EC 2.1.1.45), greatly enhances not only the binding of 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) and dUMP to Escherichia coli TS but also that of dGMP, GMP, dIMP, and IMP. Guanine nucleotide binding was first detected by CD analysis, which revealed a unique spectrum for the TS-dGMP-U89 ternary complex. The quantitative binding of dGMP relative to GMP, FdUMP, and dUMP was determined in the presence and absence of U89 by ultrafiltration analysis, which revealed that although the binding of GMP and dGMP could not be detected in the absence of U89 both were bound in its presence. The Kd for dGMP was about the same as that for dUMP and FdUMP, with binding of the latter two nucleotides being increased by two orders of magnitude by U89. An explanation for the binding of dGMP was provided by x-ray diffraction studies that revealed an extensive stacking interaction between the guanine of dGMP and the benzoquinazoline ring of U89 and hydrogen bonds similar to those involved in dUMP binding. In addition, binding energy was provided through a water molecule that formed hydrogen bonds to both N7 of dGMP and the hydroxyl of Tyr-94. Accommodation of the larger dGMP molecule was accomplished through a distortion of the active site and a shift of the deoxyribose moiety to a new position. These rearrangements also enabled the binding of GMP to occur by creating a pocket for the ribose 2' hydroxyl group, overcoming the normal TS discrimination against nucleotides containing the 2' hydroxyl.

Chroniques de J. Froissart,

Vol. 8, pt. II, to vol. 11, edited by Gaston Raynaud; vol. 12- by Léon Mirot.

Breve de beatificacion del ... siervo ... Nicolas Factor... del orden de Menores Observantes y relación de la solemnidad conque se celebró en Roma ... el dia 27 de agosto de ... 1786 : acompaña la carta del R.P. Postulador de la causa.

Mode of access: Internet.

Geology of parts of the upper Mississippi Valley zinc-lead district.

Issued as separate chapters A-I.

Esquisses critiques.

Includes index.

Idea ortodoxa de la divina institucion del estado religioso contra los errores de los liberales y pistoyanos monacómacos.

Mode of access: Internet.

Guerra de Granada, que hizo el rei D.Felipe II. contra los moriscos de aquel reino, sus rebeldes.

Mode of access: Internet.

Joannis Ludovici Vivis Valentini Opera omnia /

Includes indexes.

Legitimidad de las monedas hebreo-samaritanas; confutacin̤ de la Diatribe.

Mode of access: Internet.

Colección de documentos inéditos del Archivo General de la Corona de Aragón.

Editors: t. 1-17, Próspero de Bofarull y Mascaró.--t. 18-40, Manuel de Bofarull y de Sartorio.--t. 41, Francisco de Bofarull y Sans.

Sermons : Preached before the University of Oxford /

Mode of access: Internet.

The missing ingredient:inter-municipal cooperation and central-local relations in the UK

The thrust of the argument presented in this chapter is that inter-municipal cooperation (IMC) in the United Kingdom reflects local government's constitutional position and its exposure to the exigencies of Westminster (elected central government) and Whitehall (centre of the professional civil service that services central government). For the most part councils are without general powers of competence and are restricted in what they can do by Parliament. This suggests that the capacity for locally driven IMC is restricted and operates principally within a framework constructed by central government's policy objectives and legislation and the political expediencies of the governing political party. In practice, however, recent examples of IMC demonstrate that the practices are more complex than this initial analysis suggests. Central government may exert top-down pressures and impose hierarchical directives, but there are important countervailing forces. Constitutional changes in Scotland and Wales have shifted the locus of central- local relations away from Westminster and Whitehall. In England, the seeding of English government regional offices in 1994 has evolved into an important structural arrangement that encourages councils to work together. Within the local government community there is now widespread acknowledgement that to achieve the ambitious targets set by central government, councils are, by necessity, bound to cooperate and work with other agencies. In recent years, the fragmentation of public service delivery has affected the scope of IMC. Elected local government in the UK is now only one piece of a complex jigsaw of agencies that provides services to the public; whether it is with non-elected bodies, such as health authorities, public protection authorities (police and fire), voluntary nonprofit organisations or for-profit bodies, councils are expected to cooperate widely with agencies in their localities. Indeed, for projects such as regeneration and community renewal, councils may act as the coordinating agency but the success of such projects is measured by collaboration and partnership working (Davies 2002). To place these developments in context, IMC is an example of how, in spite of the fragmentation of traditional forms of government, councils work with other public service agencies and other councils through the medium of interagency partnerships, collaboration between organisations and a mixed economy of service providers. Such an analysis suggests that, following changes to the system of local government, contemporary forms of IMC are less dependent on vertical arrangements (top-down direction from central government) as they are replaced by horizontal modes (expansion of networks and partnership arrangements). Evidence suggests, however that central government continues to steer local authorities through the agency of inspectorates and regulatory bodies, and through policy initiatives, such as local strategic partnerships and local area agreements (Kelly 2006), thus questioning whether, in the case of UK local government, the shift from hierarchy to network and market solutions is less differentiated and transformation less complete than some literature suggests. Vertical or horizontal pressures may promote IMC, yet similar drivers may deter collaboration between local authorities. An example of negative vertical pressure was central government's change of the systems of local taxation during the 1980s. The new taxation regime replaced a tax on property with a tax on individual residency. Although the community charge lasted only a few years, it was a highpoint of the then Conservative government policy that encouraged councils to compete with each other on the basis of the level of local taxation. In practice, however, the complexity of local government funding in the UK rendered worthless any meaningful ambition of councils competing with each other, especially as central government granting to local authorities is predicated (however imperfectly) on at least notional equalisation between those areas with lower tax yields and the more prosperous locations. Horizontal pressures comprise factors such as planning decisions. Over the last quarter century, councils have competed on the granting of permission to out-of-town retail and leisure complexes, now recognised as detrimental to neighbouring authorities because economic forces prevail and local, independent shops are unable to compete with multiple companies. These examples illustrate tensions at the core of the UK polity of whether IMC is feasible when competition between local authorities heightened by local differences reduces opportunities for collaboration. An alternative perspective on IMC is to explore whether specific purposes or functions promote or restrict it. Whether in the principle areas of local government responsibilities relating to social welfare, development and maintenance of the local infrastructure or environmental matters, there are examples of IMC. But opportunities have diminished considerably as councils lost responsibility for services provision as a result of privatisation and transfer of powers to new government agencies or to central government. Over the last twenty years councils have lost their role in the provision of further-or higher-education, public transport and water/sewage. Councils have commissioning power but only a limited presence in providing housing needs, social care and waste management. In other words, as a result of central government policy, there are, in practice, currently far fewer opportunities for councils to cooperate. Since 1997, the New Labour government has promoted IMC through vertical drivers and the development; the operation of these policy initiatives is discussed following the framework of the editors. Current examples of IMC are notable for being driven by higher tiers of government, working with subordinate authorities in principal-agent relations. Collaboration between local authorities and intra-interand cross-sectoral partnerships are initiated by central government. In other words, IMC is shaped by hierarchical drivers from higher levels of government but, in practice, is locally varied and determined less by formula than by necessity and function. © 2007 Springer.

Institutional shifts in inter-municipal service delivery:an analysis of developments in eight Western European countries

Comparative research on inter-municipal cooperation in eight European countries shows that there is a great variety of institutional arrangements for cooperation across the different countries. Also, these arrangements tend to change over time in terms of the scope of cooperation among partners, their composition and the degree of organizational integration. This article describes and analyzes the variety of and shifts in institutional arrangements for a specific class of inter-municipal cooperation arrangements: those that are set up to provide for the joint delivery of public services. It is argued that specific arrangements are typically the outcomes of interaction between national institutional contexts,?environmental factors and local preferences.

A systems methodology for analysing and simulating manufacturing systems

The Systems Engineering Group (SEG) at De Montfort University are developing the Boardman Soft Systems Methodology (BSSM) which allows complex human systems to be modelled, this work builds upon Checkland's Soft Systems Methodology (1981). The BSSM has been applied to the modelling of the systems engineering process as used in design and manufacturing companies. The BSSM is used to solicit information from a company and this data is then transformed into systemic diagrams (systemigrams). These systemigrams are posited to be accurate and concise representations of the system which has been modelled. This paper describes the collaboration between SEG and a manufacturing company (MC) in Leicester, England. The purpose of this collaboration was twofold. First, it was to create an objective view of the MC's processes, in the form of systemigrams. It was important to get this modelled by a source outside of the company, as it is difficult for people within a system being modelled to be unbiased. Secondly, it allowed a series of systemigrams to be produced which can then be subjected to simulation, for the purpose of aiding risk management decisions and to reduce the project cycle time