BiP and Immunoglobulin Light Chain Cooperate to Control the Folding of Heavy Chain and Ensure the Fidelity of Immunoglobulin Assembly

The immunoglobulin (Ig) molecule is composed of two identical heavy chains and two identical light chains (H2L2). Transport of this heteromeric complex is dependent on the correct assembly of the component parts, which is controlled, in part, by the association of incompletely assembled Ig heavy chains with the endoplasmic reticulum (ER) chaperone, BiP. Although other heavy chain-constant domains interact transiently with BiP, in the absence of light chain synthesis, BiP binds stably to the first constant domain (CH1) of the heavy chain, causing it to be retained in the ER. Using a simplified two-domain Ig heavy chain (VH-CH1), we have determined why BiP remains bound to free heavy chains and how light chains facilitate their transport. We found that in the absence of light chain expression, the CH1 domain neither folds nor forms its intradomain disulfide bond and therefore remains a substrate for BiP. In vivo, light chains are required to facilitate both the folding of the CH1 domain and the release of BiP. In contrast, the addition of ATP to isolated BiP–heavy chain complexes in vitro causes the release of BiP and allows the CH1 domain to fold in the absence of light chains. Therefore, light chains are not intrinsically essential for CH1 domain folding, but play a critical role in removing BiP from the CH1 domain, thereby allowing it to fold and Ig assembly to proceed. These data suggest that the assembly of multimeric protein complexes in the ER is not strictly dependent on the proper folding of individual subunits; rather, assembly can drive the complete folding of protein subunits.

Fidelity of G protein β-subunit association by the G protein γ-subunit-like domains of RGS6, RGS7, and RGS11

Several regulators of G protein signaling (RGS) proteins contain a G protein γ-subunit-like (GGL) domain, which, as we have shown, binds to Gβ5 subunits. Here, we extend our original findings by describing another GGL-domain-containing RGS, human RGS6. When RGS6 is coexpressed with different Gβ subunits, only RGS6 and Gβ5 interact. The expression of mRNA for RGS6 and Gβ5 in human tissues overlaps. Predictions of α-helical and coiled-coil character within GGL domains, coupled with measurements of Gβ binding by GGL domain mutants, support the contention that Gγ-like regions within RGS proteins interact with Gβ5 subunits in a fashion comparable to conventional Gβ/Gγ pairings. Mutation of the highly conserved Phe-61 residue of Gγ2 to tryptophan, the residue present in all GGL domains, increases the stability of the Gβ5/Gγ2 heterodimer, highlighting the importance of this residue to GGL/Gβ5 association.

Review of implementation of the Agricultural Credit Act of 1987, Public Law 100-233 [microform] : hearing before the Subcommittee on Conservation, Credit, and Rural Development of the Committee on Agriculture, House of Representatives, One Hundredth Congress, second session, April 20, 1988.

"Serial no. 100-71."

Illinois state water plan : status of implementation /

"January 1990."

State nondiscrimination enforcement efforts in Nebraska : a review of implementation of Public Law 97-35 obligations in Health and Human Services Programs /

Includes bibliographical references.

Intensive case management: A critical re-appraisal of the scientific evidence for effectiveness

Intensive Case Management (ICM) is widely claimed to be an evidence-based and cost effective program for people with high levels of disability as a result of mental illness. However, the findings of recent randomized controlled trials comparing ICM with 'usual services' suggest that both clinical and cost effectiveness of ICM may be weakening. Possible reasons for this, including fidelity of implementation, researcher allegiance effects and changes in the wider service environment within which ICM is provided, are considered. The implications for service delivery and research are discussed.

Communities of implementation

The concept of communities of practice (CoPs) has rapidly gained ground in fields such as knowledge management and organisational learning since it was first identified by Lave and Wenger (1991) and Brown and Duguid (1991). In this article, we consider a related concept that we have entitled “communities of implementation.” Communities of implementation (CoIs) are similar to communities of practice in that they offer an opportunity for a collection of individuals to support each other and share knowledge in a dynamic environment and on a topic in which they share interest. In addition, and to differentiate them from CoPs, a community of implementation extends the responsibilities of a CoP by having as its focus the implementation of a programme of change. This may well extend to designing the change programme. Thus, whereas a main purpose of a CoP is to satisfy “a real need to know what each other knows” (Skyrme, 1999) in an informal way, we argue that a main purpose of a community of implementation is to “pool individual knowledge (including contacts and ways of getting things done) to stimulate collective enthusiasm in order to take more informed purposeful action for which the members are responsible.” Individual and collective responsibility and accountability for successfully implementing the actions/change programme is a key feature of a community of implementation. Without these pressures the members might lower the priority of implementation, allowing competing priorities to dominate their attention and resources. Without responsibility and accountability, the result is likely to be (at best) an organisation which has not begun a change programme, or (at worst) an organisation which is stuck halfway through another failing initiative. To achieve these additional objectives beyond those of a CoP, the CoI needs to provide heightened support to its members. In fact often the members will collectively strategise the development and implementation of the change programme they are leading in the organisation. Other concepts similar to CoPs have appeared in the literature, for example “communities of knowing” (Boland & Tenkasi, 1995), but none have a specific focus on implementation. Perhaps the closest example of a CoI, as suggested by our definition, is reported by Karsten, Lyytinen, Hurskainen, and Koskelainen (2001) who describe a CoP in a paper machinery manufacturer which seems to have the necessary focus on implementation. The theoretical aspects of this article will explore the relationship between CoPs and CoIs, and the needs for different arrangements for a CoI. The practical aspect of this article will consist of a report on a case study of a CoI that was successful in its implementation of a programme of change that aimed to improve its organisation’s knowledge management activities. Over two years the CoI implemented a suite of complementary actions across the organisation. These actions transformed the organisation and moved it towards achieving its ‘core values’ and overall objectives. The article will explore: the activities that formed and gelled the community, the role of the community in the implementation of actions, and experiences from key members of this community on its success and potential improvements.

Privatization : problems of implementation in Egypt

This study aims to investigate to what extent the views of the managers of the enterprises to be privatized are a barrier to smooth implementation of privatization as opposed to other problems. Accordingly, the research tackles two main issues: Identification and analysis of the major problems encountered in the implementation of the Egyptian privatization programme and at which level these problems exist while proposing different approaches to tackle them; and views of public sector top and middle-level managers regarding the main issues of privatization. The study relies upon a literature survey, interviews with stakeholders, a survey of managers' attitudes and several illustrative case studies. A model of "good practice" for the smooth and effective implementation of privatization has been designed. Practice in Egypt has then been studied and compared with the "good practice" model. Lack of strictness and firmness in implementing the announced privatization programme has been found to be a characteristic of Egyptian practice. This is partly attributable to the inadequacy of the programme and partly to the different obstacles to implementation. The main obstacles are doubtful desirability of privatization on the part of the managers at different implementation levels, resistance of stakeholders, in adequately of the legal framework governing privatization, redundant labour, lack of an efficient monitoring system allowing for accountability, inefficient marketing of privatization, ineffective communication, insufficient information at different levels and problems related to valuation and selling procedures. A large part of the thesis is concerned with SOE (State Owned Enterprise) managers' attitudes on and understanding of the privatization (appraised through surveys). Although most managers have stated their acceptance of privatization, many of their responses show that they do not accept selling SOEs. They understand privatization to include enterprise reform and restructuring, changing procedures and giving more authority to company executives, but not necessarily as selling SOEs. The majority of managers still see many issues that have to be addressed for smooth implementation of privatization e.g. insufficiency of information, incompleteness of legal framework, restructuring and labour problems. The main contribution to knowledge of this thesis is the study of problems of implementing privatization in developing countries especially managers' resistance to privatization as a major change, partly because of the threat it poses and partly because of the lack of understanding of privatization and implications of operating private businesses. A programme of persuading managers and offsetting the unfavourable effects is recommended as an outcome of the study. Five different phrases and words for the national Index to theses are: Egypt, privatization, implementation of privatization, problems of implementing privatization and managers' attitudes towards privatization.