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Notes: The complexity of R&D projects and growing international competition are factors leading to more co-operation especially among small and medium-sized firms. But even large integrated firms are often not willing or able to perform the necessary amount of R&D and to cope with the uncertainty associated with radical innovations.In a virtual company, members form a network, thereby enabling projects to be pursued by combining member’s resources. Specific assets of a virtual company are its flexibility and ability to handle variety. Costs of co-ordination and motivation are lowered if the virtual company succeeds in building trust and commitment. On the other hand, lack of these pose severe problems.In markets with a strong scientific-technological basis and rapid rate of change the concept of a virtual organization seems appealing. High R&D costs and risks can be shared, developments and time-to-market can be accelerated and the partners can concentrate on their respective core competencies.In the paper we use an example from the biotechnology industry as a case study and discuss some of the theoretical and practical problems that are encountered in the virtual enterprise.

Notes: This paper uses a ‘knowledge-based’ approach to compare the management of R&D in two leading chemicals companies, one British (ICI plc) and one Japanese. It describes key differences in the ways they integrate the ‘near-market’ knowledge of business units and the scientific knowledge and technical expertise of R&D personnel in central R&D facilities. It shows that the same management practices that underpin superior ‘integrative capabilities’ in the Japanese firm, including central funding of R&D, job-rotation and career structures and multidisciplinary project teams, also result in significant R&D weaknesses. The comparison demonstrates that different organisational mechanisms are needed to support (1) the development and (2) the leveraging of specialist knowledge within different innovation contexts. Firms must be able to strike a balance between integrative and specialist capabilities to get the most from their R&D. Moreover, the above characteristics which underpin these capabilities are often ‘embedded’ in the broader organisation making them difficult to emulate when they represent ‘best-practice’ but also making them difficult to change in response to new threats and opportunities.

Notes: Books reviewed:D.J. Hoch, C.R. Roeding, G. Purkert and S.K. Linder, Secrets of Software Success: Management Insights from 100 Software Firms around the WorldG. Stewart, The Partnership between Science and Industry – Co-operation or Conflict of Interest?A.S. St Leger and J.P. Walsworth-Bell, Change-promoting Research for Health ServicesK.M. Weber, Innovation Diffusion and Political Control of Energy Technologies: A Comparison of Combined Heat and Power Generation in the UK and GermanyO. Grandstrand, The Economics and Management of Intellectual Property

Notes: Despite its importance to economic growth, the investment behavior of firms remains poorly understood. Existing models ignore irreversibility and the opportunity to wait for new information. Even if some recent literature accounts for these two characteristics, these models ignore information costs. This paper presents a framework for the valuation of investment opportunities accounting for information costs regarding the project cash-flows.We develop some basic models of irreversible investment to illustrate the option-like characteristics of investment opportunities under incomplete information. We show how optimal investment rules can be obtained using option pricing theory under incomplete information. It is possible to value real options and investment decisions using our approach in a context of incomplete information. Simulations are provided to illustrate our main results.

Notes: This article assumes that a firm facing technological uncertainty must decide whether to purchase R&D capital at each instant. R&D capital exhibits both irreversibility and externality through the learning-by-doing effect. The combination of irreversibility and uncertainty drives agents to be more prudent; the maxim ‘better safe than sorry’ applies. This maxim is more important if uncertainty is greater, technology progresses at a lower pace, the externality is stronger, or a catastrophic event is less likely to occur. A firm ignoring the externality will both invest later and disinvest earlier than a social planner who internalizes the externality. An equal rate of investment tax credits should be given to both costlessly reversible investments and irreversible ones, and the same rate of taxation should be imposed on disinvestment.

Notes: Some investment decisions are exposed to uncertainty over their implementation phase apart from the underlying economic uncertainty. We provide a general way of introducing implementation uncertainty, which includes prior research as a special case. The generality of our treatment stems from the fact that implementation uncertainty is allowed to affect both the level and the timing of project profitability. In a case explicitly addressed, implementation uncertainty might even cause earlier investment if the probability of uncertainty resolution exceeds the opportunity cost of delaying investment. Investment will be earlier, the higher the effect of uncertainty resolution on project profitability.

Notes: It is well known that costly reversibility complicates capital investment analysis to the point where closed form expressions for the value of a firm’s investment opportunities seldom exist. In such circumstances numerical evaluation is normally taken as the most practical (and often, the only) way of determining investment value. However, we demonstrate that power series expansions can often be used to obtain analytic expressions for the value of a firm’s investment opportunities. We use them in a research and development (R&D) setting to determine investment value when cash flows are generated by two well known stochastic processes. The first is based on the Cox, Ingersoll and Ross (1985) ‘square root’ process; the second on the Uhlenbeck and Ornstein (1930) mean reverting random walk. The criteria which lead to optimal investment decisions when the option to abandon or take up investment opportunities have the non-trivial values implied by these processes, are also briefly examined.

Notes: This article develops a real options model for valuing natural resource exploration investments (e.g. oil or copper) when there is joint price and geological-technical uncertainty. After a successful several-stage exploration phase, there is a development investment and an extraction phase. All phases are optimized contingent on price and geological-technical uncertainty.Several real options are considered. There are flexible investment schedules for all exploration stages and a timing option for the development investment. Once the mine is developed, there are closure, opening and abandonment options for the extraction phase. Our model maintains a relatively simple valuation structure by collapsing price and geological-technical uncertainty into a one-factor model.We apply the model to a copper exploration prospect and find that a significant fraction of total project value is due to the operational, development and exploration options available to project managers.

Notes: This paper examines the practicalities of applying real options theory to valuing research in the service sector, where the relationship between research and subsequent business benefit is less easily discerned than in most previous applications of options theory in, e.g. the pharmaceutical industry. The paper uses a compound options model, the Geske model, based on a three-phase lifecycle consisting of research, development and deployment. This model was applied in a case study within the e-commerce area to extract key messages for R&D managers relating to different value drivers. However, the case study emphasized the need to understand the relationship between the research activity and the subsequent revenue stream, and to be able to demonstrate the extent to which the former is necessary for the latter.

Notes: In this paper we discuss collaboration in the area of technology management. We propose the concept of collaboration profile to describe various forms of networks along key differentiating characteristics. The collaboration profile is then applied using two examples to illustrate different forms of collaboration in the biotechnology industries, the ‘virtual company’ and the ‘industrial platform’. Based on interviews with members of a virtual company as well as members of industrial platforms and drawing conclusions from theoretical insights, the advantages and disadvantages of these forms and their suitability for different stages of the technology life cycle will be discussed.Specifically, we address the following questions:What kind of collaboration profile applies to virtual companies and industrial platforms?How does the suitability of collaboration forms vary with the stage of technology development?Furthermore, we demonstrate the usefulness of the collaboration profile for analysing features and potential problems of collaborations by describing two examples. Focusing on the key characteristics of a collaboration helps to check the appropriateness of the collaboration form and to identify and manage respective problems.

Notes: In Conversational Realities (1993), John Shotter draws on social constructionist suppositions to conceptualize management as a rhetorically-responsive activity in which managers act as ‘practical authors’ of their social realities (pp. 148–59). From this perspective, organizations are reworked from permanent, independent social structures to relational landscapes continually shifting from the imaginary to the imagined in interactive moments. Managing is seen as an embodied and situated dialogical activity in which managers act as authors of organizational realities through their conversations. In this article, I take as my central premise, the constitutive and metaphorical nature of language, and explore the practical, enacted aspects of Shotter's concept of authorship. Specifically, I suggest authorship may relate to how managers attempt to construct a sense of who they are, create a shared sense of features of their organizational landscape, and how they may move others to talk or act in different ways through their dialogical practices. I draw on research conversations with managers to explore how everyday poetic talk may be crucial to the process of constructing self, realities, and meaning. This ‘reconstruction’ of management practice offers both a different way of thinking about managing and potential dialogical resources which may allow managers to author or construct organizational experiences in more deliberate ways.

Notes: This research explores managerial perceptions of organizational effectiveness and whether they have similarities with perceptions of academics, and with the competing values model of organizational effectiveness (Quinn and Rohrbaugh, 1983). The results suggest that the same values organize the patterning of effectiveness criteria in a cohesion-based solution for managers and academics. Yet, this cohesion model has inadequate explanatory power for managers’ perceptions and shows no relationship with either their experience or organizational preferences. In contrast, a conflict-based solution provides adequate explanatory power for managers and relates to their experience and to organizational preferences. If managers play any part in influencing effectiveness in organizations, then incorporating their views into models of organizational effectiveness is therefore likely to improve our understanding of organizational functioning.

Notes: Researchers have argued that top management team changes are an important force spurring change at declining firms. Yet, studies find that top executives at some firms are able to avoid being replaced even though their firms perform poorly. Also, despite support from numerous case analyses, there is little systematic evidence that replacing top managers leads to substantial organizational change at declining firms. In this study, we examine these issues by looking at levels of top management team replacement at a sample of declining firms attempting turnarounds. We find that top management team replacement levels vary with the presence of inertial or change-creating forces within firms. In particular, reduced levels of top management team replacement occur during turnaround attempts at large firms and those that have followed the same strategic orientation for a long period of time. Meanwhile, increases in outsider control of the board are associated with increased levels of replacement. We further find that higher levels of top management team replacement are associated with greater changes in firm competitive strategy and firm structure and controls during turnaround attempts. Overall, our findings show that organizational-level forces play an important role in top management and strategic change processes at declining firms.

Notes: While many researchers have fruitfully explored the patterns of adoption of product and process innovations across industries, few have studied these same patterns within individual firms. In this study we address this issue, examining the dynamics that govern the adoption of product and process innovations at the firm level over time. We examine questions such as: Which type of innovation is more readily adopted? Does the adoption of one type of innovation lead or lag the adoption of the other type? And, would the pattern of adoption of innovation types have an effect on organizational performance? Using data on the innovations introduced between 1982 and 1993 by a sample of 101 commercial banks in the United States, we find that: (1) product innovations are adopted at a greater rate and speed than process innovations; (2) a product–process pattern of adoption is more likely than a process–product pattern; (3) the adoption of product innovations is positively associated with the adoption of process innovations; and (4) high-performance banks adopt product and process innovations more evenly than low-performance banks.

Notes: The link between market orientation and performance has been claimed largely on the basis of the analysis of subjective measures of performance. Consequently, the aim of this study is to examine the links between market orientation and objectively measured financial performance. The paper begins with a brief examination of the definition and components of market orientation. Thereafter, extant research into the consequences of developing market orientation is reviewed critically, leading to the development of a number of research hypotheses. After detailing the research design and methodology adopted in this study, the findings of a survey of UK industry are presented. Briefly, the results indicate that when subjective measures of performance are adopted, market orientation is associated with company performance in certain environmental conditions. However, when objective measures of performance are adopted, we see a narrower range of environmental conditions where market orientation is positively associated with performance. The paper concludes with a series of implications for both theorists and practitioners.

Notes: Research in transition economies like China has sought and found explanations for strategic behaviour based on institutional and other social processes, leading to descriptions of China's emerging business system as ‘network capitalism’. This paper argues, however, that organizational capabilities and transaction costs are increasingly important influences on strategic choice as economic reforms proceed. An in-depth case study of one firm's behaviour in two different asset markets – R&D and distribution in the Chinese pharmaceutical industry – illustrates fundamental differences in firm strategies for securing these assets. To account for this variety and move beyond the homogeneity implied by prior research, we propose a framework for differentiating the transition trajectories for different types of complementary assets. We propose conditions under which all three perspectives – institutional and social structure, organizational capabilities and transaction costs – predict similar trajectories and firm strategies, but different decision processes, and when their predictions differ.

Notes: The subject of epistemic logic is firmly entrenched in game theory, including the analysis of common knowledge and of public announcements, such as in ‘hat problems’. How to analyse communications to subgroups of the public, and the effects of such common knowledge of a subgroup on the information state of a larger group, has only recently come into fruition. Knowledge games are introduced to provide a comfortably concrete vehicle for the study of such interactions. This paper introduces the concepts of knowledge game, deal of cards, knowledge game state, game action, and action execution. A deal of cards is a function from cards to players. A knowledge game state is represented by a pointed multiagent S5 model on the set of card deals where all players hold the same number of cards as in the actual deal. A game action combines a question with an answer, and is represented by a pointed multiagent S5 frame on the set of possible answers. The execution of a game action in a knowledge game state corresponds to the computation of a pointed multiagent S5 model that is a restriction of the direct product of the corresponding action frame and game model.

Notes: Effectivity frames are introduced as a model of what groups of agents can achieve by coordinated action in dynamic processes such as extensive games with or without simultaneous moves. Local effectivity is distinguished from different kinds of global and terminal effectivity, respectively what groups of players can maintain throughout and what they can achieve eventually. Examples are provided of how effectivity frames can be used as a tool (1) to model complex multi-agent processes such as voting procedures, (2) to investigate the interplay between local and global properties of these dynamic procedures, and (3) to examine whether a particular effectivity function can be implemented or realized by a dynamic procedure of a specific type. Finally, a modal logic for local and global coalitional effectivity is presented, and it is shown how, for example, a realization question can be translated into this logical framework yielding a satisfiability problem.

Notes: This paper considers the situation where two products are sold by the same seller, but to disjoint sets of potential buyers. Externalities may arise from each market outcome to the other. The paper examines the nature of the seller’s optimal mechanism, and, for example in the case of positive externalities, it is shown that the allocation decision in either market depends on the highest types in both markets. The optimal mechanism can be implemented by an indirect mechanism that essentially charges winning bidders for the value of their externalities. The analysis is applied to the sale of public sector franchises including exploration and development rights for oil and gas tracts.

Notes: The author argues that a government taxing a polluting monopoly by means of levies on output and inputs can implement the first-best allocation through a continuum of tax profiles. Using this degree of freedom in the tax system, the government is, in general, able to transfer income from the firm to the public sector, so that the additional tax rate acts as a non-distorting tax on profits. This transfer – and therefore public revenue – is the higher, the lower (higher) the input taxes are, and correspondingly the higher (lower) the output tax is, provided that the production function exhibits decreasing (increasing) returns to scale.

Notes: This paper extends the Stackelberg model to include any number of nonidentical firms and demonstrates significant counterintuitive results. For example, entry of an additional firm may increase the quantities and/or profits of some existing firms; it may also increase the total industry profit.

Notes: This note proposes an asymmetric information model of collective bargaining where the firm has the bargaining power and the union the private information. Results show that the firm may use lockouts to induce the union to reveal its private information.

Notes: The paper examines optimal strategic trade policy under a heterogeneous cost oligopoly. The first-best policy involves a structure of firm-specific export subsidies/taxes in which the government favours the most efficient firms only with a sufficiently low social cost of public funds.

Notes: The paper considers ‘efficient bargains’, with a union that weighs the utilities of its members unequally and negotiates over group employment levels. Such discrimination may lead to socially inefficient overemployment of the dominant group, and underemployment of the group suffering discrimination.

Notes: This article provides a nontechnical survey on recent topics in the theory of contracts. The hold-up problem is presented and the incomplete contracts approach is discussed. Emphasis is put on conceptual problems and open questions that await further research.

Notes: This paper investigates the dynamic interactions between postwar, quarterly UK consumption, investment and income within a VAR framework. Use is made of two developments which allow sets of restrictions to be tested and imposed, and which potentially make the VAR framework much more economically interpretable. One set is placed by neoclassical growth theory and involves the presence of common stochastic trends linking the secular movement of the series (i.e. the great ratios), while the other set is placed by notions of common, or more generally, codependent cycles which have their origin in ideas of comovements between growth rates. Evidence is found to support the existence of the great ratios for the UK, and evidence is also found of a codependent cycle of order one in the growth rates of consumption, investment and income, so that although the cycles are not exactly synchronized, the response of the three growth rates to a shock will be similar from two quarters after the shock has occurred. Moreover, it is lagged consumption shocks that are primarily driving the cycle.

Notes: The Standard & Poor stock market composite index is examined to determine how much of the variance in returns can be explained by monetary policy. The note employs the econometric technique of generalized forecast error variance decomposition developed by Koop et al. (Journal of Econometrics, vol. 74, 1996, pp.119–47) and Pesaran and Shin (Economics Letters, vol. 58, pp.17–29). Unlike the traditional orthogonalized decomposition, the generalized version is invariant to the ordering of the variables in the underlying vector autoregression. The results provide important information about the relationship between monetary policy and the stock market.

Notes: The paper investigates comparative statics effects of changes in uncertainty for a general family of problems that encompasses both the portfolio and saving decisions. Conditions are derived on preferences that are necessary and sufficient for unambiguous comparative statics predictions. The paper consolidates and completes the statement of restrictions on attitudes toward risk–bearing needed for determinate predictions in the portfolio and saving problems.

Notes: A prominent feature of US data is the lack of cointegration between nominal interest rates and M1 velocity. Yet, most general-equilibrium monetary models that have been used for empirical analysis have imposed cointegration between these two series. This paper presents as an alternative a money-in-the-utility function model which does not imply cointegration even though a well-defined stationary monetary equilibrium exists.

Notes: The gap between a firm’s reservoir of technical knowledge and the formation of a project to explore the commercial potential of a breakthrough technical insight or discovery is the first major discontinuity in the radical innovation lifecycle. The first step toward bridging that gap occurs when the researcher with the technical insight recognizes that it might have commercial potential and decides to alert a research manager. In our longitudinal study of eight radical innovation projects in six large, multi-national, R&D-intensive firms, the initiation of a radical innovation project was neither frequent nor routine. In fact the participants in the study indicated that the initiation of a project – in their terminology, the ‘fuzzy front end of innovation’– was the most challenging and uncertain part of the lifecycle. In this paper we explore the case data to illuminate the nature of the initiation gap. In addition we present an assessment framework that can help researchers decide whether or not to bring their technical idea to the attention of management. If the decision is positive, the assessment tool can help them prepare for the discussion with management and identify the strengths and weaknesses of the case to submitted for evaluation.

Notes: The exchange of technical personnel between organizational actors in a supply network has become known as Guest Engineering (GE). Despite increasing popularity as an inter-organisational arrangement (especially in the automotive sector) it has generated relatively little academic research and therefore this paper seeks to extend our understanding of GE by exploring how its scope is determined, what motivates the participants and how the relationships evolve. The paper draws on extant GE, supply networks and Resource-Based View (RBV) literature to derive research propositions that are used to analyse empirical work carried out with four automotive suppliers and four automotive OEMs. A number of preliminary conclusions are drawn. At a micro-project level, the criticality of the individual ‘playing the GE role’ is highlighted, as are related concerns that collaborative team structures often fail to address broader social/cultural characteristics. At a macro-project level, the study argues that difficulties and mistrust will often characterise integrated and competitively successful GE relationships. Finally, at a strategic level, GE needs to be understood as a process of resource transfer and transformation, and therefore the management of interdependency and power asymmetry are core considerations in effective adoption. The paper concludes with recommendations for further critical and practical work.

Notes: Many high-tech industries are shifting their focus from minimizing time-to-market to minimizing time-to-volume. This puts the tail end of product development, the production ramp-up, in a critical position. This article presents a case study of product transfer and production ramp-up in the hard disk drive industry. We provide a detailed description of the ramp-up period. By documenting detailed time-series of several operational measures, we also shed light on the various forces that allow an organization to increase its production volume. Finally, the setting allows us to study product transfer from development in the USA to an Asian production facility. We find that the physical distance is successfully overcome by several mechanisms.

Notes: Nowadays the public R&D laboratories have a fundamental role in countries’ development, supporting businesses as they face the technological challenges in the turbulent world scenarios. Measuring the performance of R&D organisations is crucially important to decisions about the level and direction of public funding for research and development. This research considers the public laboratories like systems and develops a mathematical model based on the measurement of R&D activities with k-indices. The score obtained from the research laboratories evaluation (relev) methodology synthesises in single value financial, scientific and technological aspects. It is an indicator, for R&D manager and policy maker, of performance in relation to other research organisations or in a time series. The method is an instrument of strategic planning and can be used for the improvement of individual activities and the overall performance of public R&D bodies.

Notes: Abstract Physical detection of antigen-specific CD4 T cells has revealed features of the in vivo immune response that were not appreciated from in vitro studies. In vivo, antigen is initially presented to naive CD4 T cells exclusively by dendritic cells within the T cell areas of secondary lymphoid tissues. Anatomic constraints make it likely that these dendritic cells acquire the antigen at the site where it enters the body. Inflammation enhances in vivo T cell activation by stimulating dendritic cells to migrate to the T cell areas and display stable peptide-MHC complexes and costimulatory ligands. Once stimulated by a dendritic cell, antigen-specific CD4 T cells produce IL-2 but proliferate in an IL-2-independent fashion. Inflammatory signals induce chemokine receptors on activated T cells that direct their migration into the B cell areas to interact with antigen-specific B cells. Most of the activated T cells then die within the lymphoid tissues. However, in the presence of inflammation, a population of memory T cells survives. This population is composed of two functional classes. One recirculates through nonlymphoid tissues and is capable of immediate effector lymphokine production. The other recirculates through lymph nodes and quickly acquires the capacity to produce effector lymphokines if stimulated. Therefore, antigenic stimulation in the presence of inflammation produces an increased number of specific T cells capable of producing effector lymphokines throughout the body.

Notes: Abstract Rheumatoid arthritis (RA), a systemic disease, is characterized by a chronic inflammatory reaction in the synovium of joints and is associated with degeneration of cartilage and erosion of juxta-articular bone. Many pro-inflammatory cytokines including TNFalpha, chemokines, and growth factors are expressed in diseased joints. The rationale that TNFalpha played a central role in regulating these molecules, and their pathophysiological potential, was initially provided by the demonstration that anti-TNFalpha antibodies added to in vitro cultures of a representative population of cells derived from diseased joints inhibited the spontaneous production of IL-1 and other pro-inflammatory cytokines. Systemic administration of anti-TNFalpha antibody or sTNFR fusion protein to mouse models of RA was shown to be anti-inflammatory and joint protective. Clinical investigations in which the activcity of TNFalpha in RA patients was blocked with intravenously administered infliximab, a chimeric anti-TNFalpha monoclonal antibody (mAB), has provided evidence that TNF regulates IL-6, IL-8, MCP-1, and VEGF production, recruitment of immune and inflammatory cells into joints, angiogenesis, and reduction of blood levels of matrix metalloproteinases-1 and -3. Randomized, placebo-controlled, multi-center clinical trials of human TNFalpha inhibitors have demonstrated their consistent and remarkable efficacy in controlling signs and symptoms, with a favorable safety profile, in approximately two thirds of patients for up to 2 years, and their ability to retard joint damage. Infliximab (a mAB), and etanercept (a sTNF-R-Fc fusion protein) have been approved by regulatory authorities in the United States and Europe for treating RA, and they represent a significant new addition to available therapeutic options.

Notes: Abstract Natural killer cells can discriminate between normal cells and cells that do not express adequate amounts of major histocompatibility complex (MHC) class I molecules. The discovery, both in mouse and in human, of MHC-specific inhibitory receptors clarified the molecular basis of this important NK cell function. However, the triggering receptors responsible for positive NK cell stimulation remained elusive until recently. Some of these receptors have now been identified in humans, thus shedding some light on the molecular mechanisms involved in NK cell activation during the process of natural cytotoxicity. Three novel, NK-specific, triggering surface molecules (NKp46, NKp30, and NKp44) have been identified. They represent the first members of a novel emerging group of receptors collectively termed natural cytotoxicity receptors (NCR). Monoclonal antibodies (mAbs) to NCR block to differing extents the NK-mediated lysis of various tumors. Moreover, lysis of certain tumors can be virtually abrogated by the simultaneous masking of the three NCRs. There is a coordinated surface expression of the three NCRs, their surface density varying in different individuals and also in the NK cells isolated from a given individual. A direct correlation exists between the surface density of NCR and the ability of NK cells to kill various tumors. NKp46 is the only NCR involved in human NK-mediated killing of murine target cells. Accordingly, a homologue of NKp46 has been detected in mouse. Molecular cloning of NCR revealed novel members of the Ig superfamily displaying a low degree of similarity to each other and to known human molecules. NCRs are coupled to different signal transducing adaptor proteins, including CD3zeta, FcRIgamma, and KARAP/DAP12. Another triggering NK receptor is NKG2D. It appears to play either a complementary or a synergistic role with NCRs. Thus, the triggering of NK cells in the process of tumor cell lysis may often depend on the concerted action of NCR and NKG2D. In some instances, however, it may uniquely depend upon the activity of NCR or NKG2D only. Strict NKG2D-dependency can be appreciated using clones that, in spite of their NCRdull phenotype, efficiently lyse certain epithelial tumors or leukemic cell lines. Other triggering surface molecules including 2B4 and the novel NKp80 appear to function as coreceptors rather than as true receptors. Indeed, they can induce natural cytotoxicity only when co-engaged with a triggering receptor. While an altered expression or function of NCR or NKG2D is being explored as a possible cause of immunological disorders, 2B4 dysfunction has already been associated with a severe form of immunodeficiency. Indeed, in patients with the X-linked lymphoproliferative disease, the inability to control Epstein-Barr virus infections may be consequent to a major dysfunction of 2B4 that exerts inhibitory instead of activating functions.

Notes: Abstract Elevation of intracellular free Ca2+ is one of the key triggering signals for T-cell activation by antigen. A remarkable variety of Ca2+ signals in T cells, ranging from infrequent spikes to sustained oscillations and plateaus, derives from the interactions of multiple Ca2+ sources and sinks in the cell. Following engagement of the T cell receptor, intracellular channels (IP3 and ryanodine receptors) release Ca2+ from intracellular stores, and by depleting the stores trigger prolonged Ca2+ influx through store-operated Ca2+ (CRAC) channels in the plasma membrane. The amplitude and dynamics of the Ca2+ signal are shaped by several mechanisms, including K+ channels and membrane potential, slow modulation of the plasma membrane Ca2+-ATPase, and mitochondria that buffer Ca2+ and prevent the inactivation of CRAC channels. Ca2+ signals have a number of downstream targets occurring on multiple time scales. At short times, Ca2+ signals help to stabilize contacts between T cells and antigen-presenting cells through changes in motility and cytoskeletal reorganization. Over periods of minutes to hours, the amplitude, duration, and kinetic signature of Ca2+ signals increase the efficiency and specificity of gene activation events. The complexity of Ca2+ signals contains a wealth of information that may help to instruct lymphocytes to choose between alternate fates in response to antigenic stimulation.

Notes: Abstract B cell development is a highly regulated process whereby functional peripheral subsets are produced from hematopoietic stem cells, in the fetal liver before birth and in the bone marrow afterward. Here we review progress in understanding some aspects of this process in the mouse bone marrow, focusing on delineation of the earliest stages of commitment, on pre-B cell receptor selection, and B cell tolerance during the immature-to-mature B cell transition. Then we note some of the distinctions in hematopoiesis and pre-B selection between fetal liver and adult bone marrow, drawing a connection from fetal development to B-1/CD5+ B cells. Finally, focusing on CD5+ cells, we consider the forces that influence the generation and maintenance of this distinctive peripheral B cell population, enriched for natural autoreactive specificities that are encoded by particular germline VH-VL combinations.

Notes: Portfolio management for product innovation – picking the right set of development projects – is critical to new product success. This article reports on the new product portfolio practices and performance of a large sample of firms in North America. Reasons why portfolio management is important are identified, followed by the relative popularity of the different portfolio techniques: financial methods are first, followed by business strategy methods, bubble diagrams and scoring models. Next, how the various portfolio methods fare in terms of six performance metrics is probed. Financial methods, although the most popular and rigorous, yield the worst results overall, while top performing firms rely more on non-financial approaches – strategic and scoring methods. The details of how some of these more popular methods are employed by firms to rate and rank development projects are also provided. Finally, managerial implications, including suggestions for making portfolio management more effective in industry, are outlined.

Notes: Managers and scholars emphasize the importance of inter-departmental integration to successful product development and emphasize the importance of product development capabilities to firm performance. Interdepartmental integration can increase shared knowledge; this in turn can reduce the severity and incidence of seemingly unnecessary and costly mistakes leading to more efficient and effective product development. This paper examines the sources of shared knowledge problems across functional and product-based groups. Using interviews, product development plans, and time-sheet data, we look at the underlying factors behind two sources of knowledge sharing problems: (1) a serial product development process (i.e. little or no face-to-face communications) and (2) ineffective use of integrating mechanisms because of sticky knowledge. For each problem source, we find two key causal factors. We discuss the problems, their factors, and the implications for management and theory.

Notes: The development of new products should be based on the needs expected to exist even several years ahead – at the moment of market introduction and during the whole lifecycle of the product. To develop successful new products in the toughening business environment, companies should be able to surpass customers’ expectations and to assess emerging customer needs proactively. Early, thorough understanding of the customer’s real needs, including the assessment of hidden and future customer needs and requirements, plays a very important role in the successful development of new products.The purpose of our paper is to study the assessment of new (hidden and future) customer needs for product development in Finnish business-to-business companies. We have carried out a survey in 93 Finnish business-to-business companies and SBUs to study their common problems in the assessment of unrecognized customer needs and potentially effective ways in clarifying new customer needs and dealing with important problems. On the basis of the results, we propose several possible ways to facilitate the assessment of unrecognized customer needs.

Notes: This study replicates prior research regarding research and development (R&D) spending by sampling R&D spending for a cross-section of firms in non-service related industries. Compustat data for 231 firms from 1992 to 1998 are used to test whether the US Federal tax credit for R&D meaningfully influenced R&D spending of the sampled firms. Firms’ (1) effective rate of R&D tax credit, (2) rate of decay in R&D capital for firms’ primary industry affiliation, (3) financial cost of capital, and (4) marginal tax rate are used to compute firms’ user-cost of capital for in-house R&D. Results show that firms that were eligible for the tax credit spent more on R&D than non-eligible firms as the user-cost of in-house R&D increased. These results add further evidence regarding the role of the tax credit in stimulating R&D activity and suggest that a tax credit for incremental research can be used to boost private-sector R&D spending.

Notes: Books reviewed:C. M. Gross, U. Reischl and P. Abercrombie, The New Ideas Factory: Expanding Technology Companies with University Intellectual CapitalP.-P. Saviotti and B. Nooteboom, (eds) Technology and Knowledge: from the Firm to Innovation SystemsW. During, R. Oakey and M. Kipling, (eds) New Technology-based Firms at the Turn of the CenturyS. J. Harryson, Managing Know-who Companies: a Multi-networked Approach to Knowledge and Innovation ManagementPeter A. Simmons, The Outsourcing R&D ToolkitG. Dosi, Innovation, Organisation and Economic Dynamics: Selected Essays

Notes: This study, carried out in 1998, aimed to develop a method of forecasting core competencies in an agricultural research organization, using the Delphi Technique. First, based on a survey of internal documents and interviews, nine organizational core competencies and their specific components (human competencies) were defined, and expert judges identified. These judges responded to a questionnaire, in which the importance of the future human competencies was assessed and the organization’s existing human capacity was evaluated. Means were calculated for both judgements and changes were made in various definitions, based on the experts’ comments. Another questionnaire was designed and sent out to an expanded panel of judges to confirm or to revise the priority mean scores obtained or to add scores in the case of competencies that entered later. Factor analysis and reliability scores have demonstrated internal and inter-competency consistencies. Technological Innovation Management and Geo-processing appeared as the top priorities and Plant Pathology as the least priority. Priorities for each human competency were also calculated and they have been helpful for decision-making concerning the selection and graduate training of researchers on the organization studied.

Notes: Most R&D management techniques to date have emphasized the immediate organizational context or the internal structure and process of the R&D project. Recently however attempts have been made at situating R&D management in a wider context of inter-organizational R&D activities. This paper presents the technique of R&D network mapping as a means of providing strategic intelligence to the R&D manager. The paper backgrounds this technique with a discussion of the general issue and significance of R&D networks. A methodology for R&D network mapping is then exemplified by outlining how a network database of cooperating projects and institutes in the telecom research sector was built by utilizing the World Wide Web. Finally a number of suggestions are made as to how and when network mapping should be applied in strategic R&D management.

Notes: There have been several studies confirming the strategic and operational importance of choosing a proper project scope. There is a lack of empirically tested managerial tools to assist in this matter, and studies with longitudinally analysed R&D projects with respect to content are scarce. This article discusses the management of advanced engineering in the automotive industry. The study presents a structured approach where individual project leaders together with top management could prepare project material, discuss, visualize, and evaluate the content around a common tool. This tool, i.e. the R&D content graphs, facilitates project content selection, both during the start-up and during the execution phase of the project. The studied project has been studied for nearly two years using an abductive case-based research design. Since the project has been longitudinally studied, it has also been possible to test the graphs’ predicting capabilities. The graphs are based on a visualization of the project content along five identified dimensions. The results reveal that the tools bring structure to project scope discussions, have some predictive value, and can also function as a vertical as well as a horizontal communication tool.

Notes: This study investigated the mutual learning process between marketing and R&D in the context of the information and communications technology industry. The relationship between product newness and role flexibility of R&D/marketing was examined via correlation analysis and multiple regression against a stratified sample of 171 new products. The results showed that different aspects of product newness are associated in a different way to role flexibility of R&D/marketing. Management should therefore be aware of such differences when planning their product development portfolio so that effective integration between R&D and marketing can be achieved.

Notes: Science parks provide an important resource network for new technology-based firms (NTBFs). To ascertain the ‘added value’ of a science park location the innovativeness of independent technology-based science park firms are compared with the levels recorded by a comparable group of firms not located on a park. The hypotheses are empirically tested on the basis of 263 new technology-based firms in Sweden located both on and off-park. The survey endeavoured to cover joint-stock firms located on the nine target science parks (163 firms). The remainder of the NTBFs were drawn from off-park locations (100 firms). The findings on science parks performance suggest that the parks milieu appear to have a positive impact on their firms growth as measured in terms of sales and jobs. However, there was no evidence of a direct relationship between science park location and profitability. While this research provided several new insights into science parks in Sweden, numerous questions remain.

Notes: This paper explores a number of variables associated with the evaluation of international R&D projects by multinational corporations (MNCs) in the electronics and IT industry of Singapore. Empirical analysis of the data collected from R&D managerial executives suggests a series of considerations in relation to their R&D investments. It is desirable if R&D can create a potential impact on the growth of their regional and international businesses. In considering the risks associated with an R&D project, a balance approach would be appropriate when demanding a return on investment. In particular, the consistence with customer demands, the achievement of time-based competitiveness, the training of R&D manpower and the development of conducive innovation environments are fundamental to the success of international R&D projects.

Notes: The science and technology (S&T) programs sponsored by the US Department of the Navy (DoN) are divided into three major budget categories:1. Basic research (6.1)2. Applied research (6.2)3. Advanced technology development (6.3)In 1999, DoN commissioned an internal review of the 6.3 program. A 31 member review panel met for 1 week to rate and comment on six evaluation criteria (military goal, military impact, technical approach/payoff, program executability, transitionability (to more advanced development/ engineering budget categories or acquisition), overall item evaluation) for each of the 55 presentation topics into which the mid-$500 million per year 6.3 program was categorized. This paper describes the review process, documents insights gained from the review, summarizes key principles for a high-quality S&T evaluation process, and presents a network-centric protocol for future large-scale S&T reviews.Insights gained from both the planning and conduct of the review should be of considerable value when conducting future large-scale 6.3-type reviews, and include the following:1. Provision of detailed programmatic descriptive material to the panelists and audience before the review is very useful; its value could be enhanced by e-mail interchange between the presenter or facilitator and the panelists before the presentations to clarify outstanding issues and allow for more effective use of actual meeting time.2. Appropriate use of group-ware could allow:• Streamlining the review process with real-time data analysis and aggregation;• Remote reviewer participation, thereby minimizing travel and logistics problems;• More reviewers to participate in the process, producing a more representative sample of the technical community;•Reviewers to be selected for expertise in specific evaluation criteria only, thereby enhancing the credibility of each rating;• Sufficient expertise on the panel such that the Jury function (fully independent decision-making) can be separated from the expert witness function (potentially conflicted technical judgement and testimony).3. When assessing and comparing quality of programs representing multiple disciplines, it is necessary to normalize. Evaluating all programs in one setting is an excellent way to accomplish this objective. Because of the realistic time constraints associated with a single-setting review, depth must be traded off for breadth. This trade-off is acceptable, as long as depth is evaluated by some means during the S&T operational management cycle.

Notes: The paper considers the product development process as a series of (real) options with reducing uncertainty over time. Criteria are developed to decide on speeding up or delaying the development process. The paper demonstrates how, in the R&D phase, any particular project may be assigned within a 2 × 2 matrix of uncertainty versus R&D option value. A similar matrix can be established for the product launch phase. The matrices support portfolio management throughout the different phases of development and enable management to decide on an appropriate point at which to abandon individual projects. The approach originates from applying real options insights into the product development process at Philips Electronics. The paper is illustrated with some actual R&D projects.

Notes: Valuation of R&D real American sequential exchange options requires specifying the pattern of R&D expenditures and the stochastic process of the eventual R&D project. We model the stages of R&D expense and then the ultimate discovery (and the development cost for the discovery) using real sequential (compound) exchange option models. We study E_Commerce R&D, so the timing is relatively short-term, with initial R&D, a second phase of R&D, and a final development phase, when the project values are realized. We use proxies from the financial markets for expected project value and cost volatilities (and correlation). Then the real option valuation is based on an approximate American sequential exchange option.

Notes: We provide a Poisson real option model of a gene-to-drug venture. First we describe a general new drug discovery programme as well as a specific secretory protein research programme. Then we model both the candidate secretory gene and the ‘hot’ gene discoveries as Poisson processes. Gene deal value sizes are modeled as lognormal distributions. Then we calculate the expected R&D value (EV) of the Poisson discoveries times the value distributions, for both stages. Finally, for generic collaborating-funding arrangements, we show the Merton (1976) standard mixed diffusion-jump option value, compared to a risk neutral ‘intrinsic’ value. Under simple assumptions, the real option value is substantial, even if there is no intrinsic value.

Notes: Using the valuation data of 421 US venture capital transactions and 176 initial public offerings, we test a simple binomial valuation model in modelling the risk-return profiles of venture capital investments. We find that the model is consistent with the previous knowledge on the risk-return profile of venture capital investments. The results also confirm the hypotheses that early-stage ventures have higher implied risk and implied volatility of the returns than more established ones.Additionally, we analyse the predictive power of the binomial pricing model and compare it to corresponding ‘traditional’ models that utilize risk-adjusted rates of return. We construct one-step ex post return forecasts for the sample ventures and compare the results to the actually realized returns. The findings indicate that the fit of the binomial model is better than the fit of the corresponding ‘traditional’ models.The results imply that option-based methods have empirical relevance in the pricing analysis of privately held companies and projects. Furthermore, practitioners can benefit from using these methods when analysing the risk-return structure of private companies and R&D projects.

Notes: The paper identifies the evolving nature of headquarters-subsidiary relations during the whole process of R&D internationalization. In-depth data on five Japanese multinationals revealed that the role of overseas laboratories actually evolved over time, from the ‘starter’ to the ‘innovator’ and then to the ‘contributor’. Such a shift in role of overseas laboratories affected the nature of headquarters-subsidiary relationship accordingly. ‘Semi-connected freedom’ was identified as an optimal condition for the overseas laboratories to reconcile the two competing pressures: need for local autonomy and need for internal information connectivity. Various managerial steps were suggested for the laboratories to reach that state: increase in process linkage, active broker’s role, short-term socialization, and project-level socialization. Some practical and theoretical implications were drawn from this research, and future research direction was suggested.

Notes: The financial value of research projects is difficult to assess because they are highly uncertain. Often, the result is either an overly conservative approach to strategic innovation, based on net present value analyses, or an overly aggressive approach based on optimistic qualitative portfolios. R&D project evaluation requires recognizing threats as well as opportunities from uncertain events, and incorporating flexibility in managerial action in response to them. Real options pricing analysis is a widely discussed tool for evaluating such managerial flexibility.The limitation of options pricing lies in its requirement for complete financial markets, in which a replicating asset can be found that reproduces (or, at least, is correlated with) the project’s payoffs in all possible states of the world. However, the major risks of research projects are typically project specific and cannot be replicated in external markets. In this situation, a decision tree is a better tool to represent managerial options during execution of the project, and to evaluate its value. A decision tree is equivalent to options pricing for risks that can be priced in the financial markets (if trading of securities is explicitly included), and moreover, it can incorporate risks and flexibility that are not traded in financial markets.Using decision trees, we demonstrate a quantitative evaluation of compound growth options from research at BestPharma, a large international pharmaceutical company. A growth option is a future opportunity that may arise from a current R&D investment. The growth option may not be related to the primary purpose of the R&D project, or not even be directly foreseeable. Kester (1984) has argued that growth options may account for a large part of project value. BestPharma faced the problem of choosing among several strategic research initiatives. They developed a decision tree representation of the projects, which helped to provide transparency about project value and strategic options. Most importantly, carefully thinking through the tree helped to identify growth options, represented by additional branches in the tree, and to quantify that they represented major sources of value.

Notes: A DELPHI Questionnaire study was completed that evaluates the relative importance of management of technology (MOT) problems and ranks 24 problems in order of importance, as perceived by MOT expert participants in industry and academia. The problem of ‘Strategic Planning for Technology Products’ ranked well above all others in terms of its evaluated importance. A follow-up DELPHI study was completed to clarify the nature and dimensions of the top problem. This second study identifies the 21 top ranked sub-problems within the Strategic Planning for Technology Products general problem and ranks these sub-problems in order of importance. The two most important of these sub-problems are ‘Linking Technology Strategic Planning to Corporate Strategic Planning’, and ‘Linking R&D Strategic Planning to Business Unit Product Development Planning’. Seen as closely related, these two problems are discussed in this article as ‘the linkage problem’. The 11 highest ranked problems of this second study are considered individually in this article. This follow-up study has important implications for both academic researchers and company managers. For researchers the results suggest specific avenues of research that can fruitfully be followed. For technology managers as well as corporate managers the study offers strong indications of areas where company planning performance may be weak, as well as steps that can be taken to deal with any planning weaknesses perceived.

Notes: This paper focuses on how process modelling and analysis using ‘light weight’ technology1 supported by focused group discussions and workshops can improve the ‘concurrence’ and integration within the New Product Development process. This enables managers to improve the management of product design and development through a better understanding of the issues. The paper argues that the traditional changes in human resource management via introduction of multifunctional/collocated teams required by Concurrent New Product Development (CNPD) can be complemented by the introduction of process management, focused on the modelling and analysis of the ‘softer’ organisational issues. A case study of a domestic appliance manufacturer, developing a new product using a collocated product development team, is described to verify the research. The paper concludes by discussing the issues that emerge from this type of approach to performance improvement in NPD management, such as involvement of all team functions, senior management commitment, standardisation of processes, and training in the process management concept including modelling and analysis techniques. The approach proposed allows one to make both tangible benefits, in terms of cost, delivery (lead times) and quality, and intangible benefits, in terms of communication, people empowerment, motivation, and collaboration.

Notes: The management of innovation requires ‘champions’ or ‘promotors’ who commit with enthusiasm to the new product or the new process idea. More complex innovations will require more than one promotor. Division of labour becomes an essential success factor. According to the promotor model, at least a dyad of a ‘power promotor’ and a ‘technology promotor’ is necessary to overcome the barriers of unwillingness and of ignorance. With growing complexity, additional problems of communication and process management will occur. This will demand a third team member, the ‘process promotor’, who is needed to overcome the barriers of non-responsibility and non-communication between the organisational units involved and to act as navigator of the process. In this article, we present an empirical investigation of 133 innovations in the German plant construction and engineering industry. The results strengthen the hypothesis that the level of success of an innovation depends on the existence of a ‘troika’ of promotors.

Notes: Career ladders are built up on the premise of employees’ interest in career mobility. The system, however, may not have the desired motivational impact when employees are hesitant or undecided to pursue them. In this paper, career issues in terms of the high-tech environment in Taiwan were explored. The relationships between engineering career choices and job attitudes were quantified. The results confirm that engineers with clear advancement aspirations in either technical or general management careers offered by organizations have better job attitudes than engineers without clear aspirations. The finding appears to be more advancement vs. non-advancement, and less technical vs. managerial. Adjustments for two types of engineers who hesitate to show their advancement aspirations are given. Other contextual implications are also discussed.

Notes: A large number of methodologies for Research and Development (R&D) project evaluation have been developed and reported in the literature over the last few decades. Almost all of this literature focused on the mechanisms and underlying theoretical foundation on which the evaluation methods are based. Very little attention has been paid to the effectiveness and suitability of the techniques, especially a comparison of the techniques. This paper presents a comparative study on a number of classes of R&D evaluation methods based on the Analytic Hierarchy Process. We look into the various factors and characteristics of R&D evaluation methods that affect their suitability. A sensitivity analysis was also carried out to determine the critical factors.

Notes: Books reviewed:P. Diederen, P. Stoneman, O. Toivanen, A. Wolters Innovation and Research Policies: An International Comparative AnalysisP.J. Buckley and P. N Ghauri The Global Challenge for Multinational Enterprises: Managing Increasing InterdependenceS. Harryson Japanese Technology and Innovation Management: From Know-how to Know-whoJohn Elkington Cannibals With Forks – the Triple Bottom Line of 21st Century Business: (Conscientious Commerce)W.L. Miller and L. Morris 4th Generation R&D: Managing Knowledge, Technology and InnovationShulin Gu China’s Industrial Technology – Market Reform and Organizational Change: VNU/INTECH Studies in New Technology and DevelopmentH.C. Marais Perspectives on Science Policy in South Africa

Notes: In this paper, we discuss the R&D process in the pharmaceutical/biotechnology industry from the viewpoint of four leading Canadian biotech startups. Based on a series of interviews with these firms, we outline the role of joint ventures and strategic alliances with university laboratories and with large established pharmaceutical firms in furthering these small firms’ ambition of themselves becoming large and established. We find that the evolution of this industry has made this goal much harder to reach and we discuss the creative ways in which these firms have adapted and thrived.

Notes: Abstract Tolerance to beta cell autoantigens represents a fragile equilibrium. Autoreactive T cells specific to these autoantigens are present in most normal individuals but are kept under control by a number of peripheral tolerance mechanisms, among which CD4+ CD25+ CD62L+ T cell-mediated regulation probably plays a central role. The equilibrium may be disrupted by inappropriate activation of autoantigen-specific T cells, notably following to local inflammation that enhances the expression of the various molecules contributing to antigen recognition by T cells. Even when T cell activation finally overrides regulation, stimulation of regulatory cells by CD3 antibodies may reset the control of autoimmunity. Other procedures may also lead to disease prevention. These procedures are essentially focused on Th2 cytokines, whether used systemically or produced by Th2 cells after specific stimulation by autoantigens. Protection can also be obtained by NK T cell stimulation. Administration of beta cell antigens or CD3 antibodies is now being tested in clinical trials in prediabetics and/or recently diagnosed diabetes.

Notes: Abstract Since the description of the first mouse knockout for an IgG Fc receptor seven years ago, considerable progress has been made in defining the in vivo functions of these receptors in diverse biological systems. The role of activating FcgammaRs in providing a critical link between ligands and effector cells in type II and type III inflammation is now well established and has led to a fundamental revision of the significance of these receptors in initiating cellular responses in host defense, in determining the efficacy of therapeutic antibodies, and in pathological autoimmune conditions. Considerable progress has been made in the last two years on the in vivo regulation of these responses, through the appreciation of the importance of balancing activation responses with inhibitory signaling. The inhibitory FcR functions in the maintenance of peripheral tolerance, in regulating the threshold of activation responses, and ultimately in terminating IgG mediated effector stimulation. The consequences of deleting the inhibitory arm of this system are thus manifested in both the afferent and efferent immune responses. The hyperresponsive state that results leads to greatly magnified effector responses by cytotoxic antibodies and immune complexes and can culminate in autoimmunity and autoimmune disease when modified by environmental or genetic factors. FcgammaRs offer a paradigm for the biological significance of balancing activation and inhibitory signaling in the expanding family of activation/inhibitory receptor pairs found in the immune system.

Notes: Abstract The adaptive immune response is initiated by the interaction of T cell antigen receptors with major histocompatibility complex molecule-peptide complexes in the nanometer scale gap between a T cell and an antigen-presenting cell, referred to as an immunological synapse. In this review we focus on the concept of immunological synapse formation as it relates to membrane structure, T cell polarity, signaling pathways, and the antigen-presenting cell. Membrane domains provide an organizational principle for compartmentalization within the immunological synapse. T cell polarization by chemokines increases T cell sensitivity to antigen. The current model is that signaling and formation of the immunological synapse are tightly interwoven in mature T cells. We also extend this model to natural killer cell activation, where the inhibitory NK synapse provides a striking example in which inhibition of signaling leaves the synapse in its nascent, inverted state. The APC may also play an active role in immunological synapse formation, particularly for activation of naive T cells.

Notes: Abstract A broad array of biological responses, including cell polarization, movement, immune and inflammatory responses, and prevention of HIV-1 infection, are triggered by the chemokines, a family of structurally related chemoattractant proteins that bind to specific seven-transmembrane receptors linked to G proteins. Here we discuss one of the early signaling pathways activated by chemokines, the JAK/STAT pathway. Through this pathway, and possibly in conjunction with other signaling pathways, the chemokines promote changes in cellular morphology, collectively known as polarization, required for chemotactic responses. The polarized cell expresses the chemokine receptors at the leading cell edge, to which they are conveyed by rafts, a cholesterol-enriched membrane fraction fundamental to the lateral organization of the plasma membrane. Finally, the mechanisms through which the chemokines promote their effect are discussed in the context of the prevention of HIV-1 infection.

Notes: Abstract The T cell compartment of adaptive immunity provides vertebrates with the potential to survey for and respond specifically to an incredible diversity of antigens. The T cell repertoire must be carefully regulated to prevent unwanted responses to self. In the periphery, one important level of regulation is the action of costimulatory signals in concert with T cell antigen-receptor (TCR) signals to promote full T cell activation. The past few years have revealed that costimulation is quite complex, involving an integration of activating signals and inhibitory signals from CD28 and CTLA-4 molecules, respectively, with TCR signals to determine the outcome of a T cell's encounter with antigen. Newly emerging data suggest that inhibitory signals mediated by CTLA-4 not only can determine whether T cells become activated, but also can play a role in regulating the clonal representation in a polyclonal response. This review primarily focuses on the cellular and molecular mechanisms of regulation by CTLA-4 and its manipulation as a strategy for tumor immunotherapy.

Notes: Abstract Interleukin-10 (IL-10), first recognized for its ability to inhibit activation and effector function of T cells, monocytes, and macrophages, is a multifunctional cytokine with diverse effects on most hemopoietic cell types. The principal routine function of IL-10 appears to be to limit and ultimately terminate inflammatory responses. In addition to these activities, IL-10 regulates growth and/or differentiation of B cells, NK cells, cytotoxic and helper T cells, mast cells, granulocytes, dendritic cells, keratinocytes, and endothelial cells. IL-10 plays a key role in differentiation and function of a newly appreciated type of T cell, the T regulatory cell, which may figure prominently in control of immune responses and tolerance in vivo. Uniquely among hemopoietic cytokines, IL-10 has closely related homologs in several virus genomes, which testify to its crucial role in regulating immune and inflammatory responses. This review highlights findings that have advanced our understanding of IL-10 and its receptor, as well as its in vivo function in health and disease.

Notes: Abstract This review describes the contribution of noncytolytic mechanisms to the control of viral infections with a particular emphasis on the role of cytokines in these processes. It has long been known that most cell types in the body respond to an incoming viral infection by rapidly secreting antiviral cytokines such as interferon alpha/beta (IFN-alpha/beta). After binding to specific receptors on the surface of infected cells, IFN-alpha/beta has the potential to trigger the activation of multiple noncytolytic intracellular antiviral pathways that can target many steps in the viral life cycle, thereby limiting the amplification and spread of the virus and attenuating the infection. Clearance of established viral infections, however, requires additional functions of the immune response. The accepted dogma is that complete clearance of intracellular viruses by the immune response depends on the destruction of infected cells by the effector cells of the innate and adaptive immune system [natural killer (NK) cells and cytotoxic T cells (CTLs)]. This notion, however, has been recently challenged by experimental evidence showing that much of the antiviral potential of these cells reflects their ability to produce antiviral cytokines such as IFN-gamma and tumor necrosis factor (TNF)-alpha at the site of the infection. Indeed, these cytokines can purge viruses from infected cells noncytopathically as long as the cell is able to activate antiviral mechanisms and the virus is sensitive to them. Importantly, the same cytokines also control viral infections indirectly, by modulating the induction, amplification, recruitment, and effector functions of the immune response and by upregulating antigen processing and display of viral epitopes at the surface of infected cells. In keeping with these concepts, it is not surprising that a number of viruses encode proteins that have the potential to inhibit the antiviral activity of cytokines.

Notes: Abstract Recent advances in the understanding of T cell activation have led to new therapeutic approaches in the treatment of immunological disorders. One attractive target of intervention has been the blockade of T cell costimulatory pathways, which result in more selective effects on only those T cells that have encountered specific antigen. In fact, in some instances, costimulatory pathway antagonists can induce antigen-specific tolerance that prevents the progression of autoimmune diseases and organ graft rejection. In this review, we summarize the current understanding of these complex costimulatory pathways including the individual roles of the CD28, CTLA-4, B7-1 (CD80), and B7-2 (CD86) molecules. We present evidence that suggests that multiple mechanisms contribute to CD28/B7-mediated T cell costimulation in disease settings that include expansion of activated pathogenic T cells, differentiation of Th1/Th2 cells, and the migration of T cells into target tissues. Additionally, the negative regulatory role of CTLA-4 in autoimmune diseases and graft rejection supports a dynamic but complex process of immune regulation that is prominent in the control of self-reactivity. This is most apparent in regulation of the CD4+CD25+CTLA-4+ immunoregulatory T cells that control multiple autoimmune diseases. The implications of these complexities and the potential for use of these therapies in clinical immune intervention are discussed.

Notes: Abstract The bare lymphocyte syndrome (BLS) is a hereditary immunodeficiency resulting from the absence of major istocompatibility complex class II (MHCII) expression. Considering the central role of MHCII molecules in the development and activation of CD4+ T cells, it is not surprising that the immune system of the patients is severely impaired. BLS is the prototype of a "disease of gene regulation." The affected genes encode RFXANK, RFX5, RFXAP, and CIITA, four regulatory factors that are highly specific and essential for MHCII genes. The first three are subunits of RFX, a trimeric complex that binds to all MHCII promoters. CIITA is a non-DNA-binding coactivator that functions as the master control factor for MHCII expression. The study of RFX and CIITA has made major contributions to our comprehension of the molecular mechanisms controlling MHCII genes and has made this system into a textbook model for the regulation of gene expression.

Notes: Abstract The human T cell leukemia virus-1 (HTLV-1) is a retrovirus that causes adult T cell leukemia (ATL) and neurological disorder, the tropical spastic paraparesis (HAM/TSP). The pathogenesis apparently results from the pleiotropic function of Tax protein, which is a key regulator of viral replication. Tax exerts (a) trans-activation and -repression of transcription of different sets of cellular genes through binding to groups of transcription factors and coactivators, (b) dysregulation of cell cycle through binding to inhibitors of CDK4/6, and (c) inhibition of some tumor suppressor proteins. These effects on a wide variety of cellular targets seem to cooperate in promoting cell proliferation. This is an effective viral strategy to amplify its proviral genome through replication of infected cells; ultimately it results in cell transformation and leukemogenesis.

Notes: Abstract Helicobacter pylori is a gram negative, spiral, microaerophylic bacterium that infects the stomach of more than 50% of the human population worldwide. It is mostly acquired during childhood and, if not treated, persists chronically, causing chronic gastritis, peptic ulcer disease, and in some individuals, gastric adenocarcinoma and gastric B cell lymphoma. The current therapy, based on the use of a proton-pump inhibitor and antibiotics, is efficacious but faces problems such as patient compliance, antibiotic resistance, and possible recurrence of infection. The development of an efficacious vaccine against H. pylori would thus offer several advantages. Various approaches have been followed in the development of vaccines against H. pylori, most of which have been based on the use of selected antigens known to be involved in the pathogenesis of the infection, such as urease, the vacuolating cytotoxin (VacA), the cytotoxin-associated antigen (CagA), the neutrophil-activating protein (NAP), and others, and intended to confer protection prophylactically and/or therapeutically in animal models of infection. However, very little is known of the natural history of H. pylori infection and of the kinetics of the induced immune responses. Several lines of evidence suggest that H. pylori infection is accompanied by a pronounced Th1-type CD4+ T cell response. It appears, however, that after immunization, the antigen-specific response is predominantly polarized toward a Th2-type response, with production of cytokines that can inhibit the activation of Th1 cells and of macrophages, and the production of proinflammatory cytokines. The exact effector mechanisms of protection induced after immunization are still poorly understood. The next couple of years will be crucial for the development of vaccines against H. pylori. Several trials are foreseen in humans, and expectations are that most of the questions being asked now on the host-microbe interactions will be answered.

Notes: Abstract Our understanding of the X-linked lymphoproliferative syndrome (XLP) has advanced significantly in the last two years. The gene that is altered in the condition (SAP/SH2D1A) has been cloned and its protein crystal structure solved. At least two sets of target molecules for this small SH2 domain-containing protein have been identified: A family of hematopoietic cell surface receptors, i.e. the SLAM family, and a second molecule, which is a phosphorylated adapter. A SAP-like protein, EAT-2, has also been found to interact with this family of surface receptors. Several lines of evidence, including structural studies and analyses of missense mutations in XLP patients, support the notion that SAP/SH2D1A is a natural inhibitor of SH2-domain-dependent interactions with members of the SLAM family. However, details of its role in signaling mechanisms are yet to be unravelled. Further analyses of the SAP/SH2D1A gene in XLP patients have made it clear that the development of dys-gammaglobulinemia and B cell lymphoma can occur without evidence of prior EBV infection. Moreover, preliminary results of virus infections of a mouse in which the SAP/SH2D1A gene has been disrupted suggest that EBV infection is not per se critical for the development of XLP phenotypes. It appears therefore that the SAP/SH2D1A gene controls signaling via the SLAM family of surface receptors and thus may play a fundamental role in T cell and APC interactions during viral infections.

Notes: Abstract There is great heterogeneity in the way humans respond to medications, often requiring empirical strategies to find the appropriate drug therapy for each patient (the "art" of medicine). Over the past 50 years, there has been great progress in understanding the molecular basis of drug action and in elucidating genetic determinants of disease pathogenesis and drug response. Pharmacogenomics is the burgeoning field of investigation that aims to further elucidate the inherited nature of interindividual differences in drug disposition and effects, with the ultimate goal of providing a stronger scientific basis for selecting the optimal drug therapy and dosages for each patient. These genetic insights should also lead to mechanism-based approaches to the discovery and development of new medications. This review highlights the current status of work in this field and addresses strategies that hold promise for future advances in pharmacogenomics.

Notes: Abstract Phenobarbital (PB) response elements are composed of various nuclear receptor (NR)-binding sites. A 51-bp distal element PB-responsive enhancer module (PBREM) conserved in the PB-inducible CYP2B genes contains two NR-binding direct repeat (DR)-4 motifs. Responding to PB exposure in liver, the NR constitutive active receptor (CAR) translocates to the nucleus, forms a dimer with the retinoid X receptor (RXR), and activates PBREM via binding to DR-4 motifs. For CYP3A genes, a common NR site [DR-3 or everted repeat (ER)-6] is present in proximal promoter regions. In addition, the distal element called the xenobiotic responsive module (XREM) is found in human CYP3A4 genes, which contain both DR-3 and ER-6 motifs. Pregnane X receptor (PXR) could bind to all of these sites and, upon PB induction, a PXR:RXR heterodimer could transactivate XREM. These response elements and NRs are functionally versatile, and capable of responding to distinct but overlapping groups of xenochemicals.

Notes: Abstract Nitric oxide (NO), a simple free radical gas, elicits a surprisingly wide range of physiological and pathophysiological effects. NO interacts with soluble guanylate cyclase to evoke many of these effects. However, NO can also interact with molecular oxygen and superoxide radicals to produce reactive nitrogen species that can modify a number of macromolecules including proteins, lipids, and nucleic acids. NO can also interact directly with transition metals. Here, we have reviewed the non-3',5'-cyclic-guanosine-monophosphate-mediated effects of NO including modifications of proteins, lipids, and nucleic acids.

Notes: Abstract L-Arginine (2-amino-5-guanidinovaleric acid) is the precursor of nitric oxide, an endogenous messenger molecule involved in a variety of endothelium-mediated physiological effects in the vascular system. Acute and chronic administration of L-arginine has been shown to improve endothelial function in animal models of hypercholesterolemia and atherosclerosis. L-Arginine also improves endothelium-dependent vasodilation in humans with hypercholesterolemia and atherosclerosis. The responsiveness to L-arginine depends on the specific cardiovascular disease studied, the vessel segment, and morphology of the artery. The pharmacokinetics of L-arginine have recently been investigated. Side effects are rare and mostly mild and dose dependent. The mechanism of action of L-arginine may involve nitric oxide synthase substrate provision, especially in patients with elevated levels of the endogenous NO synthase inhibitor asymmetric dimethylarginine. Endocrine effects and unspecific reactions may contribute to L-arginine-induced vasodilation after higher doses. Several long-term studies have been performed that show that chronic oral administration of L-arginine or intermittent infusion therapy with L-arginine can improve clinical symptoms of cardiovascular disease in man.

Notes: Abstract Cells are constantly under threat from the cytotoxic and mutagenic effects of DNA damaging agents. These agents can either be exogenous or formed within cells. Environmental DNA-damaging agents include UV light and ionizing radiation, as well as a variety of chemicals encountered in foodstuffs, or as air- and water-borne agents. Endogenous damaging agents include methylating species and the reactive oxygen species that arise during respiration. Although diverse responses are elicited in cells following DNA damage, this review focuses on three aspects: DNA repair mechanisms, cell cycle checkpoints, and apoptosis. Because the areas of nucleotide excision repair and mismatch repair have been covered extensively in recent reviews (1, 2, 3, 4, 5, 6), we restrict our coverage of the DNA repair field to base excision repair and DNA double-strand break repair.

Notes: Abstract Cytochrome P450 CYP1B1 is a relatively recently identified member of the CYP1 gene family. The purpose of this commentary is to review the regulatory mechanisms, metabolic specificity, and tissue-specific expression of this cytochrome P450 and to highlight its unique properties. The regulation of CYP1B1 involves a variety of both transcriptional and post-transcriptional mechanisms. CYP1B1 can metabolize a range of toxic and carcinogenic chemicals in vitro but in some cases with a unique stereoselectivity. Estradiol 4-hydroxylation appears to be a characteristic reaction catalyzed by human CYP1B1. However, there are considerable species differences regarding the regulation, metabolic specificity, and tissue-specific expression of this P450. In humans CYP1B1 is overexpressed in tumor cells, and this has important implications for tumor development and progression and the development of anticancer drugs specifically activated by CYP1B1.

Notes: Abstract This article reviews current knowledge of the metabolism of drugs that contain fluorine. The strategic value of fluorine substitution in drug design is discussed in terms of chemical structure and basic concepts in drug metabolism and drug toxicity.

Notes: Abstract Substantial epidemiologic data support a role for vitamin D in cancer prevention. However, dose-limiting hypercalcemic effects have proved a major obstacle to the development of natural vitamin D as a cancer chemopreventive. Structure-activity studies have sought to disassociate the toxicities and chemopreventive activities of vitamin D, and a number of synthetic deltanoids (vitamin D analogs) have shown considerable promise in this regard. Several such compounds have chemopreventive efficacy in preclinical studies, as does natural vitamin D. Data supporting further development of agents of this class include in vitro and in vivo evidence of antiproliferative, proapoptotic, prodifferentiating and antiangiogenic activities. Ongoing studies are aimed at further defining the molecular mechanisms through which vitamin D and synthetic deltanoids affect gene expression and cellular fate. Additional efforts are focused on establishing the chemopreventive index (efficacy vs toxicity) of each synthetic deltanoid.

Notes: Abstract Calmodulin (CaM) is an essential protein that serves as a ubiquitous intracellular receptor for Ca2+. The Ca2+/CaM complex initiates a plethora of signaling cascades that culminate in alteration of cellular functions. Among the many Ca2+/CaM-binding proteins to be discovered, the multifunctional protein kinases CaMKI, II, and IV play pivotal roles. Our review focuses on this class of CaM kinases to illustrate the structural and biochemical basis for Ca2+/CaM interaction with and regulation of its target enzymes. Gene transcription has been chosen as the functional endpoint to illustrate the recent advances in Ca2+/CaM-mediated signal transduction mechanisms.

Notes: Abstract Originally known for its regulation of reproductive functions, estradiol, a lipophilic hormone that can easily cross plasma membranes as well as the blood-brain barrier, maintains brain systems subserving arousal, attention, mood, and cognition. In addition, both synthetic and natural estrogens exert neurotrophic and neuroprotective effects. There is increasing evidence that estrogen actions are mediated by nongenomic as well as direct and indirect genomic pathways. Although in vitro models have provided the most extensive evidence for neurotrophic and neuroprotective actions to date, there are also in vivo studies that support these actions.

Notes: Abstract Drug interactions have always been a major concern in medicine for clinicians and patients. Inhibition and induction of cytochrome P450 (CYP) enzymes are probably the most common causes for documented drug interactions. Today, many pharmaceutical companies are predicting potential interactions of new drug candidates. Can in vivo drug interactions be predicted accurately from in vitro metabolic studies? Should the prediction be qualitative or quantitative? Although some scientists believe that quantitative prediction of drug interactions is possible, others are less optimistic and believe that quantitative prediction would be very difficult. There are many factors that contribute to our inability to quantitatively predict drug interactions. One of the major complicating factors is the large interindividual variability in response to enzyme inhibition and induction. This review examines the sources that are responsible for the interindividual variability in inhibition and induction of cytochrome P450 enzymes.

Notes: Abstract G protein-coupled receptors (GPCRs) represent a major class of proteins in the genome of many species, including humans. In addition to the mapping of a number of human disorders to regions of the genome containing GPCRs, a growing body of literature has documented frequently occurring variations (i.e. polymorphisms) in GPCR loci. In this article, we use a domain-based approach to systematically examine examples of genetic variation in the coding and noncoding regions of GPCR loci. Data to date indicate that residues in GPCRs are involved in ligand binding and coupling to G proteins and that regulation can be altered by polymorphisms. Studies of GPCR polymorphisms have also uncovered the functional importance of residues not previously implicated from other approaches that are involved in the function of GPCRs. We predict that studies of GPCR polymorphisms will have a significant impact on medicine and pharmacology, in particular, by providing new means to subclassify patients in terms of both diagnosis and treatment.

Notes: Abstract The resurgence of tuberculosis worldwide has intensified research efforts directed at examining the host defense and pathogenic mechanisms operative in Mycobacterium tuberculosis infection. This review summarizes our current understanding of the host immune response, with emphasis on the roles of macrophages, T cells, and the cytokine/chemokine network in engendering protective immunity. Specifically, we summarize studies addressing the ability of the organism to survive within macrophages by controlling phagolysosome fusion. The recent studies on Toll-like receptors and the impact on the innate response to M. tuberculosis are discussed. We also focus on the induction, specificity, and effector functions of CD4+ and CD8+ T cells, and the roles of cytokines and chemokines in the induction and effector functions of the immune response. Presentation of mycobacterial antigens by MHC class I, class II, and CD1 as well as the implications of these molecules sampling various compartments of the cell for presentation to T cells are discussed. Increased attention to this disease and the integration of animal models and human studies have afforded us a greater understanding of tuberculosis and the steps necessary to combat this infection. The pace of this research must be maintained if we are to realize an effective vaccine in the next decades.

Notes: Abstract Although interleukin-18 is structurally homologous to IL-1 and its receptor belongs to the IL-1R/Toll-like receptor (TLR) superfamily, its function is quite different from that of IL-1. IL-18 is produced not only by types of immune cells but also by non-immune cells. In collaboration with IL-12, IL-18 stimulates Th1-mediated immune responses, which play a critical role in the host defense against infection with intracellular microbes through the induction of IFN-gamma. However, the overproduction of IL-12 and IL-18 induces severe inflammatory disorders, suggesting that IL-18 is a potent proinflammatory cytokine that has pathophysiological roles in several inflammatory conditions. IL-18 mRNA is expressed in a wide range of cells including Kupffer cells, macrophages, T cells, B cells, dendritic cells, osteoblasts, keratinocytes, astrocytes, and microglias. Thus, the pathophysiological role of IL-18 has been extensively tested in the organs that contain these cells. Somewhat surprisingly, IL-18 alone can stimulate Th2 cytokine production as well as allergic inflammation. Therefore, the functions of IL-18 in vivo are very heterogeneous and complicated. In principle, IL-18 enhances the IL-12-driven Th1 immune responses, but it can also stimulate Th2 immune responses in the absence of IL-12.

Notes: Abstract Interferon regulatory factors (IRFs) constitute a family of transcription factors that commonly possess a novel helix-turn-helix DNA-binding motif. Following the initial identification of two structurally related members, IRF-1 and IRF-2, seven additional members have now been reported. In addition, virally encoded IRFs, which may interfere with cellular IRFs, have also been identified. Thus far, intensive functional analyses have been done on IRF-1, revealing a remarkable functional diversity of this transcription factor in the regulation of cellular response in host defense. Indeed, IRF-1 selectively modulates different sets of genes, depending on the cell type and/or the nature of cellular stimuli, in order to evoke appropriate responses in each. More recently, much attention has also been focused on other IRF family members. Their functional roles, through interactions with their own or other members of the family of transcription factors, are becoming clearer in the regulation of host defense, such as innate and adaptive immune responses and oncogenesis.