bluuebunny/crossref_metadata_2025 huggingface dataset:
The Provision of Fire Services in Rural Areas
Authors: Grant Wyn
Published: March 2007

Fire services have been neglected in discussions of public service provision in rural areas. The way in which they are provided has a broader significance in terms of current debates about risk management. Fire service policy was transferred away from the Home Office, but the Bain Report provided the major stimulus to change. Early central government attempts to stimulate fire service provision in rural area were hampered by a lack of cooperation between local authorities. Rates of death from fire are influenced by attendance times and are particularly high in remote rural areas. The development of national standards of fire cover was focused on protecting property rather than saving lives with disproportionate funding being provided for urban areas. Social changes in rural areas have made it more difficult to secure sufficient numbers of retained fire fighters. It has proved particularly difficult to provide an adequate service in remote rural areas such as the Highlands and Islands of Scotland, despite recent policy initiatives there. Problems of providing fire cover are particularly acute on isolated islands. The development of integrated risk management plans should offer a more fine grained approach to providing fire cover. However, they may be too sophisticatedfor the task in rural areas and more traditional democratic mechanisms for expressing perceived community needs may have a greater relevance.
Creating Citizen-Consumers: New Labour and the Remaking of Public Services
Authors: Vidler Elizabeth , Clarke John
Published: March 2007

In this article we explore the ways in which three public services have been responding to the demand that people who use services be treated as consumers. We argue that New Labour views of modernisation and reform of public services have been organised around this principle. Drawing on a study of three services health care, policing and care we consider how senior managers interpret the pressures towards consumerism and the dilemmas that such an approach gives rise to. While each service has a distinctive trajectory through these issues, we suggest that three common dilemmas may be observed: the problematic relationship between consumerism and inequalities; the difficult intersection of rights, rationing and resources; and the ‘knowledge/power knot’ whose tangles reflect unsettled encounters between varieties of expertise, voice and authority
Tackling the Informal Economy: Towards a Co-ordinated Public Policy Approach?
Authors: Williams Colin C.
Published: March 2007

Throughout the western world, the informal economy is now a priority for action in public policy circles. This paper analyses how the UK government has sought to tackle this issue by attempting to join-up the myriad of actions being taken across government with regard to this realm, and evaluates the effectiveness of this coordinating approach. Analysing the range of departments involved in this policy realm, the finding is that although there have been numerous attempts to facilitate greater co-ordination across departments in relation to data sharing, strategy and operations, responsibility remains heavily compartmentalised and fragmented in departmental ‘silos’. It thus reveals how the development of a more comprehensive ‘data bank’, allocating overarching responsibility for strategy to one department and Minister, and the formation of an employment-place compliance unit/agency could all encourage a more fully joined up approach towards this issue. Before taking these actions, however, this paper calls for comprehensive pilot studies to be conducted in order to evaluate the marginal net benefits of such initiatives in terms of improved tax recovery and/or reduced benefit fraud since the existing joined-up actions by no means conclusively display that greater coordination between departments necessarily leads to a more effective approach
‘Shock of the New’: Complexity and Emerging Rationales for Partnership Working
Authors: Coaffee Jon
Published: March 2007

This article argues that the meta-narrative of ‘newness’ promoted by the current New Labour government embodies numerous assumptions, or theories of change, which add to, rather than reduce, the complexity of working within public sector-led regeneration partnership structures. In particular, it will argue that embedded ways of working within the public sector are also fundamental in explaining the relative success of ‘new’ partnerships and that the overall aim of governance transformation is inherently beset by conflict and hidden power-relations and is not as easy to achieve as policy guidance suggests. Using this conceptualframe, and drawing on the experiences from a number of pieces of action research in England on regeneration partnerships, this paper offers a critical assessment of the rationale behind such implicit, or explicit, claims that such policy interventions are indeed ‘new’ or innovative in terms of facilitating the transfer of knowledge or collaboration within or between partnerships.
Organisational Learning and Public Sector Management: An Alternative View
Authors: Fenwick John , McMillan Janice
Published: March 2007

The public service modernization agenda has directed attention to the problematic questions of how public sector organisations learn, what they learn, and how they fail to learn. This article considers: definitional problems of organisational learning; the critical differences between individual and organisational learning; the public organisation's capacity to learn; some of the principal sources of public sector learning; the ambivalent nature of learning networks; and the main barriers to effective learning. Drawing from a current study amongst senior public service managers, the discussion assesses the extent to which public service modernization encourages, or rather inhibits, organisational change and improvement. It is suggested that organisational learning in the public sector is not necessarily delivered through partnerships and the agenda of modernization: it may derive instead from internal processes and a focus upon the existing strengths of the organisation. The article re-evaluates the conventional wisdom of organisational learning and proposes a heretical view of learning and networks. In drawing out prospects for future research, it advocates a renewed emphasis upon effective internal learning.
Knowledge for Free? Distributed Innovation as a Source of Learning
Authors: Bowden Alistair
Published: March 2007

Distributed Innovation is an emerging framework for a novel method of new product/service development, where knowledge from within and outside the organisation is shared in an evolutionary dialogue, which consistently produces high quality results. Literature on open source software development and new product development involving ‘lead users’, are the main contributors to the discussion about the creative potential locked within service users. There is a growing thread of literature which seems to apply the underlying principles of Distributed Innovation in the public sector; this article looks at the process of learning from users in this paradigm. It aims to critically evaluate the advantages and disadvantages of Distributed Innovation within the public sector generally and local government specifically. When considering the great innovative potential held by service users, the ultimate goal of thisarticle is to answer two questions: can Distributed Innovation provide a source of learning: if so, is this knowledge for free?
‘Waking Up The Sleeping Giant’: Change Management, Policy Transfer and the Search for Collaboration
Authors: Johnston Lorraine
Published: March 2007

This article is situated within the context of the rapidpace ofpublic-sector reform since the 1970s with a focus upon the development of collaborative synergies. Such change, initially stimulated by American management gurus, set forth an ideology to create ‘lean and athletic’ organisations for the modem world - Kanter (1989) referred to these transformations as ‘When Giants Learn to Dance’. Such management principles have since become embedded in the way that we think aboutpublic-sector management, and are embodied in New Labours modernisation and new localism approaches to local government restructuring and the subsequent search for collaborative advantage. Within this context, and using a case study based upon Newcastle City Council between 1997-2005, this article analyses the adoption of a package of measures and associated policy responses, referred to collectively as ‘Waking up the Sleeping Giant’ which emerged as a reaction to the historical governance trends of clientelism, paternalism and fragmentation, which had plagued the development of intra and inter organisational partnerships. This emphasis sought to turn the council into an ‘excellent’ performing local authority, and to create an organisation that learns, continually adapts and develops more permeable internal and external boundaries. It is argued that the adoption of radical overarching management strategies can have an unsettling effect on organisational arenas with implications for the success of current modernisation policy and the successful development of collaboration and partnership working.
Partnership Overload in North West Birmingham
Authors: Coulson Andrew
Published: March 2007

The possible adverse consequences of many regeneration partnerships in a single area was raised by Peck and Tickell in 1994 and the Audit Commission in 1998 and again in 2005. This paper illustrates some of the issues through a study of four regeneration partnerships active in North West Birmingham. They operate in an area which has some of the highest unemployment in Britain, and has participated in almost every government-funded regeneration initiative since the 1980s. They work in the context also of the Birmingham Strategic Partnership charged with co-ordinating activity across the whole city, and the City Council's decentralisation to Districts, Wards and Neighbourhood Forums, with its own political and partnership structures. This article compares and contrasts the four partnerships, showing how each is the result of a separate central government initiative. In theory the resources available to the different partnerships could be pooled, and then reallocated so that there was only one regeneration partnership in each area, on a scale much smaller than those of the Regeneration Zones, Housing Market Renewal Pathfinder, or SRB6 project considered in this paper The outcome would be more on the scale of the Aston Pride New Deal for Communities. For this to happen, the Treasury would have to force central government departments to let go far more than hitherto. It is more likely that the present overlaps will continue.
Is Enabling Enough? Tensions and Dilemmas in New Labour's Strategies for Joining-up Local Governance
Authors: Sullivan Helen
Published: March 2007

Central to New Labour's ambition to transform public policy and public services was the development of joined-up government'. This article considers the experience of joining-up' at the local level, through one programme of reform, the ‘local government modernisation agenda’ (LGMA). Drawing on published research from evaluations of the LGMA this article argues that three key strategies for joining-up' locally are evident in the policies of the LGMA: empowerment, endorsement and enticement. Each strategy contains a particular vision of joined-up' local governance and what should shape it. However in practice each strategy was diluted, undermined or challenged by the existence of alternative perspectives. The article proposes that there are powerful undercurrents within the policy environment that help explain these tensions, in particular the desire of some interests to maintain prevailing central-local relations. It also highlights cross-currents that might have a greater impact on the potential for realising joined-up' local governance such as the comprehensive performance assessment. The article concludes with some reflections on which strategy is most likely to be effective in the current policy and political environment and examines the ‘fit’ of newer policy instruments such as Local Area Agreements with this proposed strategy.
Picking Winners to Define and Disseminate Best Practice
Authors: Entwistle Tom , Downe James
Published: March 2007

From 1998 the Government launched Beacon award schemes in local government, schools, the National Health Service, further education and central government. The schemes were distinctive in that they all shared the assumption that organisational learning could be advanced through a competitive process of identifying successful organisations and recruiting them to disseminate their good practices. Drawing on a number of evaluations of the different schemes, this article identifies three tensions in the operation of the Beacon model. We conclude that the relative persistence and success of the Beacon idea, in local government at least, is more a function of its effects on aspiration and morale than its concrete contribution to learning and improvement.
Charging for Public Services in the UK's Devolved Polity
Authors: Bailey Stephen James , Fingland Lisa
Published: March 2007

This article examines the impact of the UK's post-1999 system of territorial devolution on charging policy for public services. It seeks to document emerging territorial differences in charging policy and practice and explain them with reference to differences in devolution settlements and to territorially variable political, cultural and social contexts. It concludes that devolution has already led to significant territorial variations in charging policy and practice and that the Celtic territories' policies seem increasingly differentiated from those of England.
British Local Government: A Case for a New Constitutional Settlement
Authors: Copus Colin
Published: March 2007

As a creature of Statue, British local government is subject to constant change emanating from a superior constitutional source: central government. Much of the change that is imposed upon local government because of the need for governing institutions to respond to two competing sets of requirements: those that drive and are driven by either, technocracy or democracy. In all major reorganisations of local government, the attempts tofind a structuralfit between these two mutually antagonistic factors have seen the latter lose out to the former The question of local government size is part of the clash between technocracy and democracy that has been played-out in various reforms of local government in Britain. Indeed, current discussions about unitary councils and city-regions will ultimately result in larger, more remote and technocraticaly driven units of local government

The article sets out a construct for British local government that would rest on the creation of a new constitutional settlement between the centre and the localities. It explores the role newly empowered local government could play within the context of a federal UK, and addresses how the politics of these new councils should be conducted. The article also explores what new formns of political accountability would be required in this new constitutional settlement and to whom local government should be accountable. It also examines the mechanisms by which that accountability can be secured. The article sets out a radically new context for central local relationships resting on a new balance of political power; responsibility and accountability.
Performance Assessment and Wicked Problems: The Case of Health Inequalities
Authors: Blackman Tim , Greene Alexandra , Hunter David J. , McKee Lorna , Elliott Eva , Harrington Barbara , Marks Linda , Williams Gareth
Published: March 2007

This article considers the background to one of the projects in the UK Economic and Social Research Council's Public Services Programme: a major; three-year investigation of how health inequalities are being framed for intervention at a local level in post-devolution England, Scotland and Wales. A particular interest is in the difference that performance assessment makes as it engages to a greater or lesser extent with health inequalities.
(Can) Modern Local Government (be) In Touch with the People?
Authors: Brooks Josie
Published: March 2007

The recent White Paper, 'Modern Local Government: In Touch with the People' summarised Labour's project to modernise local government and to renew local democracy. Through the mediating concepts of accountability, responsiveness and representation, it is argued that the modernisation project will renew local authorities' political authority and legitimacy. However, a critical review of the White Paper and other Government's publications which discuss the modernisation of local government suggests that there are discrepancies between the claims to improve democratic local government and the role of councils in the provision of nationally decided andffunded welfare services.
Local authority anti-poverty strategies in Scotland
Authors: Higgins Vanessa , Ball Rob
Published: March 2007

This study examines the management and development of Scottish local authority anti-poverty strategies. Whilst studies of anti-poverty strategies have been carried out within England and Wales, nothing of the same depth has been conducted in Scotland. The study was carried out immediately prior to local government reorganization in order to understand key issues and gain lessons for good practice. The research involved the distribution of a postal survey to the chief executives and leaders of each of the then 65 local authorities in Scotland. In addition to the postal survey five case studies of anti-poverty strategies were carried out. This involved conducting semi-structured interviews with members and officers within five local authorities which were known to operate such strategies. The findings of the research illustrated that 25% of the responding local authorities operated anti-poverty strategies. The study identified and discussed a number of common themes generally associated with such strategies. These included the corporateness of the strategy, social inclusion, decentralization, partnerships, differences between rural and non-rural areas and differences between statutory and non-statutory services. The study also investigated and reported on, strategy development, member and office support, resource targeting and budgeting, monitoring and evaluating strategic and likely implications of local government reform.
Expanding the notion of organisational performance measurement to support joined-up government
Authors: Lovell Alan , Hand Len
Published: March 2007

This article challenges current conceptions of accounting for organisational performance in the light of moves towards joined-up government. Drawing on empirical work, the authors illustrate the tension between a desire for more inclusive policies and an emphasis on inward-looking, myopic forms of performance measurement. An expanded framework for accounting for organisational performance is offered that is compatible with notions of inclusive government.
Making a reality of community governance. Structuring government-voluntary sector relationships at the local level
Authors: Ross Kathleen , Osborne Stephen P
Published: March 2007

This article examines the emerging rhetoric of 'community governance' under the current Labour government and its import for local government-voluntary sector relationships. It explores the continuities and differences of this with that of the previous Conservative government and evaluates the extent to which this is a genuinely new perspective on these relationships. It concludes by offering a conceptual framework with which to understand these relationships and highlights the political and managerial challenges which must be faced if 'community governance' is to become more than simple rhetoric.
Stunted by Stakeholders? Limits to Collaborative Evaluation
Authors: Pollitt Christopher
Published: March 2007

Over the last five to ten years Europe has witnessed a return to fashion for evaluation. As an activity it has been expanded in most EU states and very considerably within the EU Commission. Within this broad trend there has been a strong sub-fashion for collaborative, 'pluralist' and 'partenarial' approaches to evaluation. This article comments on the nature of these approaches, notes some of the claims made on their behalf, and identifies situations in which collaboration is likely to decrease both the scientific rigour and the usefulness of an evaluation. In certain circumstances, the 'old-fashioned' model of an independent, scientific, form of evaluation is to be preferred to models of pluralism, participation and empowerment.
Joined Up Accountability: Bringing the Citizen Back In
Authors: Rowe Mike
Published: March 2007

Accountability in complex organisational networks has been identified as particularly problematic, and an issue to be addressed, both in academic and in official documents. Indeed, in launching its new public service reform agenda, the Labour government has undertaken to address accountability at a later date rather than as an integral part of its approach to reform. This article seeks to address these questions of accountability, suggesting the need to reformulate our understanding of the concept itself, placing a citizen-focused accountability at the heart of the way in which services are understood and evaluated.
Public Performance - towards a new model?
Authors: Talbot Colin
Published: March 2007

This is an article about performance in government. It considers how performance, in a variety of senses, has become a dominant theme in probably the majority of OECD countries (although not all). It asks some fundamental questions about what is 'performance' in, and of, government by reflecting on what governments do in terms of the policy instruments available to them. It looks briefly at how developments in the use and understanding of 'performance' concepts (and related issues of quality) have been changing in the private sector - especially the emergence of new holistic models of performance or 'balanced scorecards'. It discusses how far these are relevant to public services performance, concluding that while there is much to learn there are also key areas of difference between 'performance' in the private and public sectors. Drawing on the evident strengths of the more holistic models developed in the private sector, it outlines a similar approach - a balanced framework - for public services, but one which takes account of the constraints and purposes of public service - the Public Service Excellence Model.
Quality Management in Local Government - Issues and Experience
Authors: Gaster Lucy
Published: March 2007

The aim of the article is to examine key dimensions of service quality and to consider the situation within British local government. A model of public service quality is introduced. From this starting point, it is argued that local government service quality must consider the 'citizen question'. Values, objectives, definitions of quality and of standards, systems for implementation and a constructive approach to monitoring and evaluation need to be brought together in an integrated approach. Front-line staff, elected councillors and trades unions have an important part to play and all their voices also need to be heard. Local government as a whole has not yet taken on board this comprehensive approach. However, over ten years or so it has adapted to the new policy environment through a wide range of strategies. These include organisational development and quality initiatives, decentralisation, public participation and community empowerment. All help to build an environment where quality can flourish. A 'tight-loose' organisational culture is essential for success. Some tools from the private sector can be used eclectically, but the article warns against wholesale transfer, since the needs and purposes of local government are generally very different. Public service quality is not only about improving citizens' quality of life. It is also potentially a route to greater sense of citizenship, participation and democracy.
An emergent audit agenda: comparative lessons drawn from Best Value development in Local Government in Scotland compared with England
Authors: Sheffield James , Bowerman Mary
Published: March 2007

Best Value was introduced in 1997 to local governments in Scotland; in England and Wales. This article charts the introduction of the policy to local government in the two legislative domains, and compares differences in implementation between Scotland and England. Drawing on these differences, the article seeks to highlight a number of emergent issues for audit organisations. Audit will play a central role in the regulation of the Best Value Regimen. Although Best Value will change local government, and may facilitate the birth of the 'enabling authority', it will also have profound effects on the role of the auditor and the framework of local government regulation.
The Public Service Ethos: Decline and Renewal?
Authors: Carr Frank
Published: March 2007

This article examines the two principal means by which ethically based standards of conduct can be secured in public administration. The first approach, advocated by Carl Friedrich in the 1940s, places the primary emphasis on the values and self-directed willingness of the public servant to act in the public interest. This reliance on a public service ethos was to some extent the hallmark of the British Civil Service before the post-1979 managerial and organisational changes and was a product of the exemplary leadership of two great heads of the home civil service, Sir Warren Fisher and Sir Edward Bridges. It will be argued that marketization, managerialism and organisational down-sizing in the public services have created a culture whose values (risk-taking, short-term profits and efficiency gains) greatly threaten the existence of the public service ethos. Consequently, the only effective way to secure any semblance of the public interest and to deter impropriety lies in the second approach - that is to place a much greater emphasis on external monitoring and legally based sanctions and safeguards. This alternative approach was advocated by Herman Finer, a contemporary of Karl Friedrich. The legal protection given by the 1998 Public Interest Disclosure Act to ‘whistle blowers’ should be seen as a welcome step in this direction. Greater precision in the wording of the Civil Service Code and a strengthening of its inadequate enforcement mechanism would, it is argued, further help to protect endangered public service values within the Civil Service.
The Joint European Torus: an historical case study in European Public Policy
Authors: Massey Andrew
Published: March 2007

The steady integration of the European Union over many years has involved the formulation and implementation of many policies. One of the results has been the establishment of new legal and institutional structures in public administration of a supranational nature. Issues of structure are combined with those of efficiency, effectiveness and accountability. This article explores one small policy field, nuclear fusion technology research in the form of the Joint European Torus project, in order to assess some of the developments in the field and to try to understand ways in which they may be fruitfully analysed. It concludes with the contention that the success of the JET project suggests one way in which highly technical and costly projects may be structured and that in order to properly analyse and criticise the democratic deficit inherent to such policies it is necessary to adopt aflexible multi-theoretical approach.
Introducing evidence-based practice: the contrasting experiences of health care and probation service organisations in the UK
Authors: Nutley Sandra , Davies Huw T.O.
Published: March 2007

There is much interest in the UK at the present time in making public policy and practice more evidence-based. Many current initiatives focus on the creation of a systematic evidence-base for the various public policy fields. However, experience to date has shown that the fate of much research on service effectiveness is neglect. This paper looks at this issue from the point of view of changing public service practice so that it is in line with best evidence. The paper provides contextual accounts of the ways in which two public service areas (health care and the probation service) have approached the task of introducing evidence-based practice. It argues that the success of evidence-based practice initiatives is likely to depend upon the interaction between the context, content and process of these changes. Particular initiatives, such as the use of audit and feedback mechanisms to achieve practice change, are unlikely to work in all contexts.
Politics and policy evaluation
Authors: Palfrey Colin , Thomas Paul
Published: March 2007

Traditionally, the role of external evaluators has been based on the positivist paradigm of the ‘neutral’ researcher. It is, however, contestable whether evaluators can be or whether they ought to be politically impartial. ‘Fourth generation evaluation’ delineated by Guba and Lincoln represents a more stakeholder-focused approach to policy and programme evaluation while other writers have asserted the need to take an overtly ideological stance in order to represent marginalised groups. We contend in this article that in order to be methodologically sound, evaluation research has to be participative and democratic. Since policy making is inherently a political process, evaluators have to be able to live with the possibility of their democratically derived data being selectively used or even rejected.
Workplace assimilation and conflict in professional service organisations: the case of university libraries
Authors: Kirkpatrick Ian
Published: March 2007

To date, only limited attention has been given in the literature to how, in a context of work intensification, many professional service organisations have engaged in a delegation of tasks to non-professional, subordinate groups. While some studies have reported this process, little is known more generally about its wider impact. A particular concern is the extent to which delegation, as well as being a necessary response to budgetary constraint, has also become a source of conflict and tension within public organisations. Focusing on the illustrative case of university librarians, this article seeks to address these issues. Using qualitative data collected from four institutions, the article reveals how, in recent years, there has been a trend towards delegation of routine professional operations. However, while this has facilitated the extension of professional services at limited cost, it has also led to rising conflict between professional and non-professional staffs within the hierarchy. Such conflict is found not only to have some negative implications for the way services are managed, but in the long term, could also pose a limited threat to the power and status of dominant professional groups.
Social movements and email: expressions of online identity in the globalization protests
Authors: Wall Melissa A.
Published: March 2007

This study focuses on three email lists — one used by a professional organization (Friends of the Earth) and two by grass roots, street-level participants (Direct Action Network and People's Global Action) — in the Seattle World Trade Organization protests. Each list was examined in terms of how it contributed to the expression of collective identities online. Each group's list employed at least one of three processes identified here as key to collective identity: the Friends of the Earth list emphasized cognitive framing of the event; Direct Action Network focused on emotional investments among list members; and People's Global Action stressed setting boundaries among movement participants.Yet overall, none of the lists was entirely successful as a vehicle for expressing movement identities, suggesting that while the internet may facilitate certain organizational activities of social movements, it appears to have less impact on their symbolic ones.
The role of site features, user attributes, and information verification behaviors on the perceived credibility of web-based information
Authors: Flanagin Andrew J. , Metzger Miriam J.
Published: March 2007

Data from 574 participants were used to assess perceptions of message, site, and sponsor credibility across four genres of websites; to explore the extent and effects of verifying web-based information; and to measure the relative influence of sponsor familiarity and site attributes on perceived credibility.The results show that perceptions of credibility differed, such that news organization websites were rated highest and personal websites lowest, in terms of message, sponsor, and overall site credibility, with e-commerce and special interest sites rated between these, for the most part.The results also indicated that credibility assessments appear to be primarily due to website attributes (e.g. design features, depth of content, site complexity) rather than to familiarity with website sponsors. Finally, there was a negative relationship between self-reported and observed information verification behavior and a positive relationship between self-reported verification and internet/web experience.

The findings are used to inform the theoretical development of perceived web credibility.
Ubp43 regulates BCR-ABL leukemogenesis via the type 1 interferon receptor signaling
Authors: Yan Ming , Luo Jiann-Kae , Ritchie Kenneth J. , Sakai Ikuya , Takeuchi Kasuto , Ren Ruibao , Zhang Dong-Er
Published: March 2007

Interferon (IFN) signaling induces the expression of interferon-responsive genes and leads to the activation of pathways that are involved in the innate immune response. Ubp43 is an ISG15-specific isopeptidase, the expression of which is activated by IFN. Ubp43 knock-out mice are hypersensitive to IFN-α/β and have enhanced resistance to lethal viral and bacterial infections. Here we show that in addition to protection against foreign pathogens, Ubp43 deficiency increases the resistance to oncogenic transformation by BCR-ABL. BCR-ABL viral transduction/transplantation of wild-type bone marrow cells results in the rapid development of a chronic myeloid leukemia (CML)–like myeloproliferative disease; in contrast, a significantly increased latency of disease development is observed following BCR-ABL viral transduction/transplantation of Ubp43-deficient bone marrow cells. This resistance to leukemic development is dependent on type 1 IFN (IFN-α/β) signaling in Ubp43-deficient cells. Increased levels of type 1 IFN are also detected in the serum of CML mice. These results suggest that inhibition of Ubp43-negative effect on IFN signaling can potentiate the response to increased endogenous IFN levels in innate immune responses against cancer development, indicating that pharmacological inhibition of Ubp43 may be of benefit in cancers and others diseases in which interferon is currently prescribed.
Proteasome inhibitor bortezomib impairs both myelofibrosis and osteosclerosis induced by high thrombopoietin levels in mice
Authors: Wagner-Ballon Orianne , Pisani Didier F. , Gastinne Thomas , Tulliez Micheline , Chaligné Ronan , Lacout Catherine , Auradé Frédéric , Villeval Jean-Luc , Gonin Patrick , Vainchenker William , Giraudier Stéphane
Published: March 2007

Primary myelofibrosis (PMF) is the most serious myeloproliferative disorder, characterized by clonal myeloproliferation associated with cytokine-mediated bone marrow stromal reaction including fibrosis and osteosclerosis. Current drug therapy remains mainly palliative. Because the NF-κB pathway is implicated in the abnormal release of cytokines in PMF, the proteasome inhibitor bortezomib might be a potential therapy. To test its effect, we used the lethal murine model of myelofibrosis induced by thrombopoietin (TPO) overexpression. In this TPOhigh model, the development of the disease is related to a deregulated MPL signaling, as recently described in PMF patients. We first demonstrated that bortezomib was able to inhibit TPO-induced NF-κB activation in vitro in murine megakaryocytes. It also inhibited NF-κB activation in vivo in TPOhigh mice leading to decreased IL-1α plasma levels. After 4 weeks of treatment, bortezomib decreased TGF-β1 levels in marrow fluids and impaired marrow and spleen fibrosis development. After 12 weeks of treatment, bortezomib also impaired osteosclerosis development through osteoprotegerin inhibition. Moreover, this drug reduced myeloproliferation induced by high TPO level. Finally, bortezomib dramatically improved TPOhigh mouse survival (89% vs 8% at week 52). We conclude that bortezomib appears as a promising therapy for future treatment of PMF patients.
Diverging signaling events control the pathway of GPVI down-regulation in vivo
Authors: Rabie Tamer , Varga-Szabo David , Bender Markus , Pozgaj Rastislav , Lanza Francois , Saito Takashi , Watson Stephen P. , Nieswandt Bernhard
Published: March 2007

Coronary artery thrombosis is often initiated by platelet activation on collagen-rich subendothelial layers in the disrupted atherosclerotic plaque. The activating platelet collagen receptor glycoprotein VI (GPVI) noncovalently associates with the Fc receptor γ-chain (FcRγ), which signals through its immunoreceptor-tyrosine–based activation motif (ITAM) via the adaptor LAT leading to the activation of phospholipase Cγ2 (PLCγ2). GPVI is a promising antithrombotic target as anti-GPVI antibodies induce the irreversible loss of the receptor from circulating platelets by yet undefined mechanisms in humans and mice and long-term antithrombotic protection in the latter. However, the treatment is associated with transient but severe thrombocytopenia and reduced platelet reactivity to thrombin questioning its clinical usefulness. Here we show that GPVI down-regulation occurs through 2 distinct pathways, namely ectodomain shedding or internalization/intracellular clearing, and that both processes are abrogated in mice carrying a point mutation in the FcRγ-associated ITAM. In mice lacking LAT or PLCγ2, GPVI shedding is abolished, but the receptor is irreversibly down-regulated through internalization/intracellular clearing. This route of GPVI loss is not associated with thrombocytopenia or altered thrombin responses. These results reveal the existence of 2 distinct signaling pathways downstream of the FcRγ-ITAM and show that it is possible to uncouple GPVI down-regulation from undesired side effects with obvious therapeutic implications.
Keratinocyte growth factor augments immune reconstitution after autologous hematopoietic progenitor cell transplantation in rhesus macaques.
Authors: Seggewiss Ruth , Loré Karin , Guenaga F. Javier , Pittaluga Stefania , Mattapallil Joseph , Chow Catherine K. , Koup Richard A. , Camphausen Kevin , Nason Martha C. , Meier-Schellersheim Martin , Donahue Robert E. , Blazar Bruce R. , Dunbar Cynthia E. , Douek Daniel C.
Published: March 2007

Opportunistic infections contribute to morbidity and mortality after peripheral blood progenitor cell (PBPC) transplantation and are related to a deficient T-cell compartment. Accelerated T-cell reconstitution may therefore be clinically beneficent. Keratinocyte growth factor (KGF) has been shown to protect thymic epithelial cells in mice. Here, we evaluated immune reconstitution after autologous CD34+ PBPC transplantation in rhesus macaques conditioned with myeloablative total body irradiation in the absence or presence of single pretotal body irradiation or repeated peritransplant KGF administration. All KGF-treated animals exhibited a well-preserved thymic architecture 12 months after graft. In contrast, thymic atrophy was observed in the majority of animals in the control group. The KGF-treated animals showed higher frequencies of naive T cells in lymph nodes after transplantation compared with the control animals. The animals given repeated doses of KGF showed the highest levels of T-cell receptor excision circles (TRECs) and the lowest frequencies of Ki67+ T cells, which suggest increased thymic-dependent reconstitution in these animals. Of note, the humoral response to a T-cell–dependent neo-antigen was significantly higher in the KGF-treated animals compared with the control animals. Thus, our findings suggest that KGF may be a useful adjuvant therapy to augment T-cell reconstitution after human PBPC transplantation.
Large-scale dissociation and sequential reassembly of pericentric heterochromatin in dedifferentiatedArabidopsiscells
Authors: Tessadori Federico , Chupeau Marie-Christine , Chupeau Yves , Knip Marijn , Germann Sophie , van Driel Roel , Fransz Paul , Gaudin Valérie
Published: March 2007

Chromocenters in Arabidopsis thaliana are discrete nuclear domains of mainly pericentric heterochromatin. They are characterized by the presence of repetitive sequences, methylated DNA and dimethylated histone H3K9. Here we show that dedifferentiation of specialized mesophyll cells into undifferentiated protoplasts is accompanied by the disruption of chromocenter structures. The dramatic reduction of heterochromatin involves the decondensation of all major repeat regions, also including the centromeric 180 bp tandem repeats. Only the 45S rDNA repeat remained in a partly compact state in most cells. Remarkably, the epigenetic indicators for heterochromatin, DNA methylation and H3K9 dimethylation, did not change upon decondensation. Furthermore, the decondensation of pericentric heterochromatin did not result in transcriptional reactivation of silent genomic elements. The decondensation process was reversible upon prolonged culturing. Strikingly, recondensation of heterochromatin into chromocenters is a stepwise process. Compaction of the tandemly arranged 45S rDNA regions occurs first, followed by the centromeric 180 bp and the 5S rDNA repeats and finally the dispersed repeats, including transposons. The sequence of reassembly seems to be correlated to the size of the repeat domains. Our results indicate that different types of pericentromeric repeats form different types of heterochromatin, which subsequently merge to form a chromocenter.
Regulatory mechanisms governing the oocyte-specific synthesis of the karyoskeletal protein NO145
Authors: Voltmer-Irsch Susanne , Kneissel Sandra , Adenot Pierre G. , Schmidt-Zachmann Marion S.
Published: March 2007

Given the prominence and the biological importance of the nucleus it is remarkable how little is still known about structure-forming proteins in the nuclear interior. The karyoskeletal protein NO145 has been identified as a major constituent of a filamentous network surrounding the amplified nucleoli of Xenopus laevis oocytes. We now show that an orthologous protein also occurs in female germ cells of a wide range of other vertebrates, where it forms dot-like structures. Using the Xenopus oocyte system we further report a specific regulatory mechanism responsible for (1) the rapid degradation of the NO145 protein during meiotic maturation, and (2) the cell-type-dependent translation of NO145 mRNA. Microinjection experiments have revealed that NO145 is a target of proteasomes and the use of the rapid amplification of cDNA ends-polyadenylation test (RACE-PAT) has disclosed the existence of NO145 mRNAs differing in their 3′ UTRs. Reporter systems as well as polyribosome profiling experiments have revealed the regulatory importance of the 3′ UTRs, which affect the translational efficiency as well as the stability of the encoded protein. The highly conserved cell-type specificity and the extremely tight temporal regulation of NO145 synthesis suggest an important role of this protein in female meiotic prophase.
Vertebrate-specific sequences in the gephyrin E-domain regulate cytosolic aggregation and postsynaptic clustering
Authors: Lardi-Studler Barbara , Smolinsky Birthe , Petitjean Caroline M. , Koenig Franziska , Sidler Corinne , Meier Jochen C. , Fritschy Jean-Marc , Schwarz Guenter
Published: March 2007

Gephyrin is a multifunctional protein contributing to molybdenum cofactor (Moco) synthesis and postsynaptic clustering of glycine and GABAA receptors. It contains three major functional domains (G-C-E) and forms cytosolic aggregates and postsynaptic clusters by unknown mechanisms. Here, structural determinants of gephyrin aggregation and clustering were investigated by neuronal transfection of EGFP-tagged deletion and mutant gephyrin constructs. EGFP-gephyrin formed postsynaptic clusters containing endogenous gephyrin and GABAA-receptors. Isolated GC- or E-domains failed to aggregate and exerted dominant-negative effects on endogenous gephyrin clustering. A construct interfering with intermolecular E-domain dimerization readily auto-aggregated but showed impaired postsynaptic clustering. Finally, two mutant constructs with substitution of vertebrate-specific E-domain sequences with homologue bacterial MoeA sequences uncovered a region crucial for gephyrin clustering. One construct failed to aggregate, but retained Moco biosynthesis capacity, demonstrating the independence of gephyrin enzymatic activity and aggregation. Reinserting two vertebrate-specific residues restored gephyrin aggregation and increased formation of postsynaptic clusters containing GABAA receptors at the expense of PSD-95 clusters – a marker of glutamatergic synapses. These results underscore the key role of specific E-domain regions distinct from the known dimerization interface for controlling gephyrin aggregation and postsynaptic clustering and suggest that formation of gephyrin clusters influences the homeostatic balance between inhibitory and excitatory synapses.
Fertilization in mouse does not require terminal galactose or N-acetylglucosamine on the zona pellucida glycans
Authors: Williams Suzannah A. , Xia Lijun , Cummings Richard D. , McEver Rodger P. , Stanley Pamela
Published: March 2007

Fertilization in mammals requires sperm to bind to the zona pellucida (ZP) that surrounds the egg. Galactose (Gal) or N-acetylglucosamine (GlcNAc) residues on the glycans of ZP protein 3 (ZP3) have been implicated as mouse sperm receptors. However, Mgat1–/– eggs with modified N-glycans lacking terminal Gal and GlcNAc residues are fertilized. To determine if Gal and GlcNAc on O-glycans of the ZP are required for fertilization, a conditional allele of the T-synthase gene (T-synF) was generated. T-syn encodes core 1 β1,3-galactosyltransferase 1 (T-synthase), which initiates the synthesis of core-1-derived O-glycans, the only O-glycans on mouse ZP3. T-synF/F:ZP3Cre females in which T-synF was deleted at the beginning of oogenesis generated eggs lacking core-1-derived O-glycans. Nevertheless, T-synF/F:ZP3Cre females were fertile and their eggs bound sperm similarly to controls. In addition, T-syn–/– embryos generated from T-syn null eggs developed until ∼E12.5. Thus, core-1-derived O-glycans are not required for blastogenesis, implantation, or development prior to midgestation. Moreover, T-syn–/–Mgat1–/– eggs lacking complex and hybrid N-glycans as well as core-1-derived O-glycans were fertilized. The combined data show that mouse ZP3 does not require terminal Gal or GlcNAc on either N- or O-glycans for fertilization.
The AAA-ATPase p97-Ufd1-Npl4 is required for ERAD but not for spindle disassembly in Xenopus egg extracts
Authors: Heubes Simone , Stemmann Olaf
Published: March 2007

The highly abundant AAA-ATPase p97 is required for diverse cellular processes, of which ER-associated protein degradation (ERAD) is understood best. Previously, a new role of p97 in spindle disassembly at the end of mitosis has been reported. However, we show that neither addition of dominant-negative p97 mutants nor depletion of crucial p97 adaptors impairs transition of meiotic spindles into interphase arrays of microtubules. The dominant-negative approach is validated by inhibition of ERAD, which we reconstitute for the first time in the powerful biochemical system of Xenopus egg extracts. The role of p97 in spindle disassembly during meiotic exit should therefore be reconsidered.