bluuebunny/crossref_metadata_2025 huggingface dataset:
Moderating effects of parent control on international joint ventures’ strategic objectives and performance
Authors: Whitelock Jeryl , Yang Hui
Published: July 2007

Purpose

The aim of this study is, first, to explore the moderating effects of parent control on the strategic objectives of foreign firms entering international joint ventures (IJVs) and, second, to assess performance in relation to these objectives.

Design/methodology/approach

The study integrates three major theoretical streams in the IJV field to investigate the rationale for the formation of IJVs. The primary data collection method was a web‐based survey. The ability to collect large amounts of data without interviewers, stationery or postage, makes the cost of doing web surveys very attractive. Sino‐European manufacturing IJVs (in industries such as machinery, textiles, and electronics) were investigated.

Findings

The strong empirical evidence in this study confirms the significant moderating effects of parent control on attainment of strategic objectives, suggesting that different strategic objectives of foreign partners have different performance outcomes based on the degree of control exercised by the partner and the focus on different IJV activities. The findings also indicate that market‐developing and knowledge‐acquiring objectives outperform efficiency‐seeking objectives.

Research limitations/implications

The purpose of this study was to examine satisfaction with performance from the point of view of the foreign IJV partner. Hence, data were collected from foreign senior management who represent foreign partners. Second, the single IJV host country context (China) inevitably raises the question as to whether the findings from this study can be generalised to IJVs in other emerging markets. Third, the relatively small sample size (61 IJVs), although comparable with previous studies, limits the use of more powerful statistical tools.

Practical implications

The findings of this study suggest that parent companies should formulate different control structures according to different strategic objectives. Second, and rather interestingly, different categories of objectives perform differently in joint ventures. It seems, for example, that, in joint ventures with Chinese partners, European multinational enterprises achieve better results in relation to market development and knowledge acquisition than when seeking organisational efficiency.

Originality/value

Prior research has tended to examine the IJV phenomenon from a single theoretical perspective. This study attempts to integrate three major theoretical streams in the IJV field to investigate the rationale for the formation of IJVs. As such, it potentially offers more comprehensive explanatory power. A further innovation is related to the use of a web‐based survey rather than the traditional mail survey.
Effect of line resistance and driver width on crosstalk in coupled VLSI interconnects
Authors: Kaushik Brajesh Kumar , Sarkar Sankar , Agarwal R.P. , Joshi R.C.
Published: July 2007

Purpose

This paper proposes to study the effect of line resistance and driver width on crosstalk noise for a CMOS gate driven inductively and capacitively coupled VLSI interconnects.

Design/methodology/approach

The paper considers a distributed RLC interconnect topology. The interconnect length is 4 mm and far‐end capacitive loading is 30 fF. The SPICE simulation set‐up uses an IBM 0.13 μm, 1.2 V technology model. The input falling ramp has a transition time of 50 ps. The victim line is grounded through a driver resistance of 50 Ω at near end of interconnect. While observing the effect of line resistance, the aggressor driver has PMOS and NMOS widths of 70 and 30 μm, respectively, and the line resistance is varied from 0 to 500 Ω. For capturing the effect of driver width, SPICE waveforms are generated at far end of victim line for three different line resistances (R=0, 30, and 60 Ω respectively). In each case, the aggressor PMOS driver width is swept from 20 to 100 μm. The corresponding NMOS width is half of PMOS width.

Findings

It is observed that, as line resistance increases, the noise peak reduces. This is due to the fact that with increasing resistance the incident and reflected waves traveling along the line experience increasing attenuation. Hence, the waves arriving at the far‐end of the line are of smaller magnitude and larger time durations. This causes noise pulses in the lossy lines to be smaller and wider compared with those in a lossless line. The effect of driver width on noise waveforms is further observed. It is observed that, as the PMOS (and corresponding NMOS) driver width is increased, the victim line gets more prone to crosstalk noise. The crosstalk magnitude level increases alarmingly as driver width is increased, because the driver resistance decreases, which in turn increases the current driving capability of driver.

Originality/value

While designing coupled interconnects, driver width and line resistance play an important role in deciding the crosstalk level. An interconnect designer often increases driver width and reduces line resistance for achieving lower propagation delays. This effort may result in higher crosstalk noise in coupled interconnect. Therefore, a designer should be concerned simultaneously for crosstalk noise while reducing delays.
University‐industry collaboration
Authors: Dooley Lawrence , Kirk David
Published: July 2007

Purpose

The paper aims to identify the requisite attributes and organisation to be displayed by a research university in order to engage successfully in collaborative research with industry partners.

Design/methodology/approach

The conceptual framework contrasts the traditional public funding model against the requirements of the “triple helix” model of government‐university‐industry research funding. The framework supports the exploration of a case study of a long‐standing and successful joint research partnership, the Dundee‐Kinases Consortium, which links a world‐class life sciences research centre and a group of global pharmaceutical companies.

Research limitations/implications

The case study provides a starting point, and additional case examinations will confirm the role of resource competences and organisational capabilities in facilitating performance by way of knowledge generation and transfer between partners.

Findings

The design and leadership of the consortium achieves vital performance outcomes, namely: accelerating the production of new knowledge about cell signalling processes relating to serious diseases; and faster transfer of new knowledge into drug development processes of pharmaceutical companies. The development of key enabling capabilities by the university, allied with routines for academic‐industry researcher interface, are essential elements of the partnering design.

Originality/value

The paper demonstrates that university‐industry partnerships build on government‐university funding, that university‐industry relationships foster new university capabilities, and moreover, that academic publication is not displaced by the requirements of industry partners.
Creating communities of practices to manage technological knowledge
Authors: Meeuwesen Bas , Berends Hans
Published: July 2007

Purpose

In large companies, technological knowledge lies dispersed over individual specialists, business units and locations. Communities of practice (CoPs) are a structure for sharing this dispersed knowledge. However, CoPs are usually seen as being emergent, evolving and elusive. This study aims to investigate if and how it is possible to purposefully create CoPs.

Design/methodology/approach

This study describes and evaluates the launch of four CoPs within Rolls‐Royce. A combination of quantitative and qualitative methods is used to determine and explain the activities and outcomes of the CoPs.

Findings

Each of the CoPs provided benefits to its members, but performance differences were found between the CoPs. Longer existing CoPs were more active as the structural elements and dimensions of CoPs take time to evolve and become balanced. But more active CoPs were not necessarily more beneficial to their members. This is partially explained by the degree to which a CoP focuses on local issues.

Practical implications

It is worthwhile to actively pursue the development of CoPs to manage technological knowledge. However, it takes time for CoPs to mature and become effective, and they are never fully under managerial control. Focusing on local issues increases the direct benefits for community members and therewith their commitment to the CoP.

Originality/value

This is one of the few evaluation studies of CoPs. While literature often assumes that CoPs have to emerge, this paper finds that it is also possible to purposefully create CoPs.
Science parks as knowledge organizations – the “ba” in action?
Authors: Hansson Finn
Published: July 2007

Purpose

The purpose of this study is to contribute to the understanding of the failure of science parks to become a central actor in the knowledge economy and, with the help of new organizational theory, to propose new solutions.

Design/methodology/approach

The paper reviews a number of recent studies of science parks and their effect on innovation and economic growth, measured by revenue or survival rate of new firms, but demonstrating no positive result of the parks. The paper then introduces modern organization theory, specializing in analyzing the processes of creating, managing, organizing, and transferring knowledge distributed through a number of networks and other volatile organizations in order to investigate the set‐up of science parks in the knowledge economy.

Findings

Using Nonaka's concept ofbaas a metaphor for the new tradition in organizational theory, the paper finds very few – if any – signs of these new ways of organizing in traditional science parks. The paper argues that principles from modern knowledge organizations has to be installed in science parks if the parks are to regain the initiative and become an important actor in the new regime of knowledge production. Otherwise, science parks must be viewed as an outdated institution, left over from the industrial society.

Practical implications

The paper proposes a system of certification and quality assessment that might speed up the change in science parks from organizations formed by the industrial society to organizations serving the needs of the knowledge society.

Originality/value

The paper is an original contribution to the theory of science parks and innovation policy. The use of new organizational theory on knowledge management, illustrated by Nonaka's concept ofba, presents a new solution to overcome the traditional thinking on how to organize science parks.
Theories of international production: a critical perspective
Authors: Ietto‐Gillies Grazia
Published: July 2007

Purpose

The purpose of this paper is to analyse the role that the nation‐state plays in influencing the behaviour of the transnational companies (TNCs) and how it affects one's view of TNCs as efficiency‐ versus strategy‐driven institutions.

Design/methodology/approach

The paper starts with a brief historical analysis of the main theories of international production and the TNCs, to which it then relates the role of the nation‐state and of strategic approaches.

Findings

The characteristics of the nation‐states that affect the behaviour of TNCs are linked to their regulatory regimes regarding fiscal, currency and social security regulations. These create opportunities for advantages of operating across frontiers and thus for specific strategic behaviour towards labour and governments.

Research limitations/implications

The theoretical approach presented will need to be supported by empirical findings.

Practical implications

There are policy implications specifically related to the fact that multinationalityper segives advantages and that actors other than the TNCs may have to move towards achieving a multinational organization.

Originality/value

The paper questions the international character of most current theories of the TNC, arguing about the necessity to put the nation‐states with their different characteristics at the heart of the explanations of TNCs' activities and suggests a strategic rather than efficiency approach to theories of the TNC.
Political economy of communication: a critique
Authors: Graham Phil
Published: July 2007

Purpose

This article aims to provide a critical understanding of contextual issues surrounding international business from a political economy of communication perspective.

Design/methodology/approach

The approach is based in classical dialectics and proceeds from a Marxian perspective. It includes a literature review of major theorists in political economy of communication and an analysis of present institutional relationships that frame international business in the context of corporatism.

Findings

The main argument is that current practices that dominate international business can no longer be considered as any kind of capitalism and that political economy of communication is necessary for comprehending this system. Current business practices are a form of corporatism in which ownership is separated from control, business is separated from industry, and the idea of a “going concern” is subject to “overriding concerns”. To understand the implications of these factors, political economy of communication needs new theories of value, labour, mediation, and meaning.

Research limitations/implications

The work is limited by the current pace of change, by alternative, non‐Marxist definitions of capitalism which are not taken into account here, and by the variegated nature of global business practices. The work is limited to dominant practices and definitive relationships.

Practical implications

The paper provides a useful perspective for understanding the future direction of international business, specifically in terms of communication, culture, and understandings of value.

Originality/value

This paper offers an alternative, non‐capitalistic view of “globalisation” within a Marxist framework and proposes a new theoretical and analytical synthesis for political economy of communication.
Manifesto for a post‐colonial international business and management studies
Authors: Westwood R.I. , Jack Gavin
Published: July 2007

Purpose

Submitted in the form of a manifesto, this article seeks to make a call to scholars in international management and business studies to embrace post‐colonial theory and to allow it to provide an interrogation of the ontological, epistemological, methodological and institutional resources currently dominating the field.

Design/methodology/approach

A manifesto approach is adopted in providing a series of deliberately provocative principles which it seeks to have the field adopt.

Findings

The paper finds the field to be currently imprisoned within a limited and limiting paradigmatic and institutional location and offers the resources of post‐colonial theory as a way to interrogate and reconfigure it.

Research limitations/implications

The paper points to the limitations of the field and provides the grounds for a radical reconfiguration across all aspects of its knowledge production, dissemination and research practice.

Practical implications

The paper offers practical steps which the field can take to reconfigure itself more appropriately in terms of its various research commitments and its institutional frame.

Originality/value

This article offers an original assessment of the orthodoxy currently controlling and disciplining the field, presented in the relatively novel and challenging form of a manifesto.
Application of fuzzy simulation for the evaluation of enterprise application integration in healthcare organisations
Authors: Khoumbati Khalil , Themistocleous Marinos
Published: July 2007

Purpose

This paper seeks to evaluate the adoption of enterprise application integration (EAI) in healthcare organisations. In doing so, fuzzy cognitive mapping (FCM) simulation is used to demonstrate the causal inter‐relationships between the EAI adoption factors.

Design/methodology/approach

Several factors were analysed and tested through case study strategy that supports the adoption of EAI in healthcare organisations. Using the concepts of these factors, the paper further expanded the scope of the research by exploring the area of EAI by using the FCM simulation. The computation of the node's output is based on the combination of a summing operation followed by the use of a non‐linear transformation such as threshold function.

Findings

The research findings demonstrate the application of FCM simulation that identifies casual inter‐relationships among EAI adoption factors. This enhances the quality of the evaluation process, and highlights the importance of each factor and its inter‐relationship with other factors.

Practical implications

This evaluation can be used as a decision‐making tool to support the management of the healthcare organisations when taking the decision regarding the adoption of EAI. In doing so, healthcare organisations may benefit from this evaluation process.

Originality/value

The advantages of using FCM within this study fall into two categories. One is concerned with the technique, which offers structure through symbolic and graphical representation rather than linear layout. The second is concerned with the use of results, which offers a graphical picture of rates' understanding of appraisal decisions; information obtained is clearly communicable, and insight can be gained into the structure of information.
An enterprise system component based on graph colouring for exam timetabling
Authors: Dammak Abdelaziz , Elloumi Abdelkarim , Kamoun Hichem
Published: July 2007

Purpose

This paper aims to consider the exam timetabling of the re‐sit session in the Faculty of Economics and Management Sciences of Sfax. The objective is to find a timetable which minimizes the number of timeslots for exams required by the enrolled students.

Design/methodology/approach

Two heuristic procedures based on graph colouring are developed and tested on real data to solve the exam timetabling problem at the faculty.

Findings

These heuristics were tested on a simple example which shows the out‐performance of the second heuristic compared with the first one. When tested with the real data of the faculty, exam size heuristic provides a timetable with a shorter timeframe; however, the timetable obtained from the second heuristic is of better quality.

Originality/value

The main contribution of this paper is to create an automated exam timetabling that helps the faculty to manage its own enterprise system.
The enactment of dynamic leadership
Authors: Greenfield David
Published: July 2007

Purpose

The purpose of this paper is to empirically examine how clinical team leadership can facilitate a collaborative team and, in doing so, drive change in a health service.

Design/methodology/approach

Ethnographic field work was conducted with a clinical team, comprised of 13 health professionals, in community health, in Sydney Australia. Utilising semi‐structured interviews, data were collected and then analysed using Goleman's leadership typology as an analytic lens.

Findings

Leadership can facilitate a team to realise high levels of collaboration, trust and respect. This creates an environment in which collective learning and increased responsibility thrives. Together, these elements enable front‐line staff to take ownership of their services, to integrate the organising and delivery of services, and, in doing so, improve health care practice.

Research limitations/implications

The leadership empirically observed here confirms qualities, behaviours and approaches that have been argued as important in the literature.

Practical implications

For health professionals in a clinical team leadership role Goleman's typology can be instructive. Many leaders in complex health care organisations are engaged in, and needing to respond to, unfolding situations to ensure positive improvement. At such times the typology offers a range of leadership styles to draw upon.

Originality/value

The application of the typology to health care clinical team leadership is a new development.
Logistics in hospitals: a case study of some Singapore hospitals
Authors: Pan Zhi Xiong (Thomas) , Pokharel Shaligram
Published: July 2007

Purpose

The purpose of this paper is to investigate logistics activities in Singapore hospitals. It defines various types of activities handled by a logistics division. Inventory management policy and the use of information and communication technologies (ICT) for logistics purposes are also discussed. The study identifies the nature of strategic alliances in Singapore's health care industry.

Design/methodology/approach

This study was conducted by utilizing a framework for data collection, pre‐testing the questionnaire and conducting interviews. Various relevant literature was reviewed to design the questionnaire.

Findings

This study finds that logistics division carry out many related activities and some of them also provide engineering services. The hospitals make use of ICT. The hospitals are clustered under various groups to minimize the cost of operation, including the logistics related costs. However, hospitals do not see alliances with suppliers as a strategic option; rather they focus on outsourcing of logistics services. The findings also show that Singapore hospitals have a good stocking policy for both medical and non‐medical items so that changes in patient mix can be easily handled.

Originality/value

Singapore is continuously improving its health care industry and therefore, the findings will help hospitals in other regions to adopt some of the practices, like concentrating on local vendors, outsourcing, clustering, and maximum use of information technology as competitive factors that can improve the service and reduce the cost of operation. The paper suggests motivators and barriers to the use of ICT in logistics in the health care industry.
Developing emerging leaders: a new solution to an old problem
Authors: Xavier Stephen
Published: July 2007

Purpose

This article argues that current approaches to leadership development are ineffective and proposes a new model for developing both individuals and future leadership teams concurrently.

Design/methodology/approach

The article summarizes the failures of current leadership development models and discusses five steps, with specific actions, necessary for developing future leaders and leadership teams.

Findings

With the baby boomer retirement bubble about to burst, leaders must take action now to plan for succession and create bench strength for the future success of the organization. No one is better qualified to develop a company's future leaders than its current leaders. The proposed model will enable them to do so effectively.

Practical implications

It is critical for current leaders to begin developing the next generation of leadership immediately in order to maintain continuity of leadership and to keep companies viable from generation to generation.

Originality/value

The article proposes a new model for leadership development that explores appropriate steps to identify talent, develop the talent individually, and concurrently develop future leadership teams.
The five essential practices of a talent multiplier
Authors: Cantrell Susan , Benton James M.
Published: July 2007

Purpose

The authors set out to determine which human capital processes and practices were most strongly related to company financial performance.

Design/methodology/approach

The authors surveyed more than 3,500 employees and more than 150 HR executives in 26 organizations, all of which had implemented a proprietary tool on human capital development. They used financial data from those organizations to identify 18 human‐capital management activities that are significantly correlated with financial results. They also interviewed more than 80 business and HR leaders.

Findings

Analysis of the 18 activities led the authors to derive the five practices described in this article: align people practices with business needs; implement the practices with superior execution; enlist line managers in human capital management; make policies clear, fair, and consistent; and create an information‐sharing environment.

Originality/value

The article eschews a focus of fads – “online cross‐functional team‐based brainstorming” – to realign readers on which talent management practices really lead to financial success. Although most companies will recognize the practices as fundamental, they will learn what may be preventing them from implementing the practices, and how some companies are leading the way.
Molecular plasticity of β‐catenin: New insights from single‐molecule measurements and MD simulation
Authors: Ritco‐Vonsovici Monica , Ababou Abdessamad , Horton Michael
Published: July 2007

The multifunctional protein, β‐catenin, has essential roles in cell adhesion and, through the Wnt signaling pathway, in controlling cell differentiation, development, and generation of cancer. Could distinct molecular forms of β‐catenin underlie these two functions? Our single‐molecule force spectroscopy of armadillo β‐catenin, with molecular dynamics (MD) simulation, suggests a model in which the cell generates various forms of β‐catenin, in equilibrium. We find β‐catenin and the transcriptional factor Tcf4 form two complexes with different affinities. Specific cellular response is achieved by the ligand binding to a particular matching preexisting conformer. Our MD simulation indicates that complexes derive from two conformers of the core region of the protein, whose preexisting molecular forms could arise from small variations in flexible regions of the β‐catenin main binding site. This mechanism for the generation of the various forms offers a route to tailoring future therapeutic strategies.
Sm‐like protein Hfq: Location of the ATP‐binding site and the effect of ATP on Hfq–RNA complexes
Authors: Arluison Veronique , Mutyam Shravan K. , Mura Cameron , Marco Sergio , Sukhodolets Maxim V.
Published: July 2007

Sm‐like proteins are ubiquitous ring‐shaped oligomers that exhibit a variety of nucleic acid‐binding activities. They have been linked functionally to various cellular events involving RNA, and it is generally believed that their activity is exerted via the passive binding of nucleic acids. Our earlier studies of the Sm‐like Escherichia coli protein Hfq provided the first evidence indicating that Hfq is an ATP‐binding protein. Using a combination of biochemical and genetic techniques, we have now determined a plausible ATP‐binding site in Hfq and tested Hfq's ATP‐binding affinity and stoichiometry. The results of RNA footprinting and binding analyses suggest that ATP binding by the Hfq–RNA complex results in its significant destabilization. RNA footprinting indicates deprotection of Hfq‐bound RNA tracts in the presence of ATP, suggestive of their release by the protein. The results reported herein broaden the scope of potential in vivo roles for Hfq and other Sm‐like proteins.
Theoretical study of the partial molar volume change associated with the pressure‐induced structural transition of ubiquitin
Authors: Imai Takashi , Ohyama Shusaku , Kovalenko Andriy , Hirata Fumio
Published: July 2007

The partial molar volume (PMV) change associated with the pressure‐induced structural transition of ubiquitin is analyzed by the three‐dimensional reference interaction site model (3D‐RISM) theory of molecular solvation. The theory predicts that the PMV decreases upon the structural transition, which is consistent with the experimental observation. The volume decomposition analysis demonstrates that the PMV reduction is primarily caused by the decrease in the volume of structural voids in the protein, which is partially canceled by the volume expansion due to the hydration effects. It is found from further analysis that the PMV reduction is ascribed substantially to the penetration of water molecules into a specific part of the protein. Based on the thermodynamic relation, this result implies that the water penetration causes the pressure‐induced structural transition. It supports the water penetration model of pressure denaturation of proteins proposed earlier.
Branching in the sequential folding pathway of cytochrome c
Authors: Krishna Mallela M.G. , Maity Haripada , Rumbley Jon N. , Englander S. Walter
Published: July 2007

Previous results indicate that the folding pathways of cytochrome c and other proteins progressively build the target native protein in a predetermined stepwise manner by the sequential formation and association of native‐like foldon units. The present work used native state hydrogen exchange methods to investigate a structural anomaly in cytochrome c results that suggested the concerted folding of two segments that have little structural relationship in the native protein. The results show that the two segments, an 18‐residue omega loop and a 10‐residue helix, are able to unfold and refold independently, which allows a branch point in the folding pathway. The pathway that emerges assembles native‐like foldon units in a linear sequential manner when prior native‐like structure can template a single subsequent foldon, and optional pathway branching is seen when prior structure is able to support the folding of two different foldons.
Docking and homology modeling explain inhibition of the human vesicular glutamate transporters
Authors: Almqvist Jonas , Huang Yafei , Laaksonen Aatto , Wang Da‐Neng , Hovmöller Sven
Published: July 2007

As membrane transporter proteins, VGLUT1–3 mediate the uptake of glutamate into synaptic vesicles at presynaptic nerve terminals of excitatory neural cells. This function is crucial for exocytosis and the role of glutamate as the major excitatory neurotransmitter in the central nervous system. The three transporters, sharing 76% amino acid sequence identity in humans, are highly homologous but differ in regional expression in the brain. Although little is known regarding their three‐dimensional structures, hydropathy analysis on these proteins predicts 12 transmembrane segments connected by loops, a topology similar to other members in the major facilitator superfamily, where VGLUT1–3 have been phylogenetically classified. In this work, we present a three‐dimensional model for the human VGLUT1 protein based on its distant bacterial homolog in the same superfamily, the glycerol‐3‐phosphate transporter from Escherichia coli. This structural model, stable during molecular dynamics simulations in phospholipid bilayers solvated by water, reveals amino acid residues that face its pore and are likely to affect substrate translocation. Docking of VGLUT1 substrates to this pore localizes two different binding sites, to which inhibitors also bind with an overall trend in binding affinity that is in agreement with previously published experimental data.
Biosynthesis of isoprenoids in plants: Structure of the 2C‐methyl‐d‐erithrytol 2,4‐cyclodiphosphate synthase from Arabidopsis thaliana. Comparison with the bacterial enzymes
Authors: Calisto Barbara M. , Perez‐Gil Jordi , Bergua Maria , Querol‐Audi Jordi , Fita Ignacio , Imperial Santiago
Published: July 2007

The X‐ray crystal structure of the 2C‐methyl‐d‐erythritol 2,4‐cyclodiphosphate synthase (MCS) from Arabidopsis thaliana has been solved at 2.3 Å resolution in complex with a cytidine‐5‐monophosphate (CMP) molecule. This is the first structure determined of an MCS enzyme from a plant. Major differences between the A. thaliana and bacterial MCS structures are found in the large molecular cavity that forms between subunits and involve residues that are highly conserved among plants. In some bacterial enzymes, the corresponding cavity has been shown to be an isoprenoid diphosphate‐like binding pocket, with a proposed feedback‐regulatory role. Instead, in the structure from A. thaliana the cavity is unsuited for binding a diphosphate moiety, which suggests a different regulatory mechanism of MCS enzymes between bacteria and plants.
The crystal structure of M. leprae ML2640c defines a large family of putative S‐adenosylmethionine‐dependent methyltransferases in mycobacteria
Authors: Graña Martin , Haouz Ahmed , Buschiazzo Alejandro , Miras Isabelle , Wehenkel Annemarie , Bondet Vincent , Shepard William , Schaeffer Francis , Cole Stewart T. , Alzari Pedro M.
Published: July 2007

Mycobacterium leprae protein ML2640c belongs to a large family of conserved hypothetical proteins predominantly found in mycobacteria, some of them predicted as putative S‐adenosylmethionine (AdoMet)‐dependent methyltransferases (MTase). As part of a Structural Genomics initiative on conserved hypothetical proteins in pathogenic mycobacteria, we have determined the structure of ML2640c in two distinct crystal forms. As expected, ML2640c has a typical MTase core domain and binds the methyl donor substrate AdoMet in a manner consistent with other known members of this structural family. The putative acceptor substrate‐binding site of ML2640c is a large internal cavity, mostly lined by aromatic and aliphatic side‐chain residues, suggesting that a lipid‐like molecule might be targeted for catalysis. A flap segment (residues 222–256), which isolates the binding site from the bulk solvent and is highly mobile in the crystal structures, could serve as a gateway to allow substrate entry and product release. The multiple sequence alignment of ML2640c‐like proteins revealed that the central α/β core and the AdoMet‐binding site are very well conserved within the family. However, the amino acid positions defining the binding site for the acceptor substrate display a higher variability, suggestive of distinct acceptor substrate specificities. The ML2640c crystal structures offer the first structural glimpses at this important family of mycobacterial proteins and lend strong support to their functional assignment as AdoMet‐dependent methyltransferases.
Toll‐like receptor agonists stimulate human neutrophil migration via activation of mitogen‐activated protein kinases
Authors: Aomatsu Kazuki , Kato Takayuki , Fujita Hisakazu , Hato Fumihiko , Oshitani Nobuhide , Kamata Noriko , Tamura Tomohiko , Arakawa Tetsuo , Kitagawa Seiichi
Published: July 2007

Human neutrophil migratory responses to Toll‐like receptor (TLR) agonists were studied using videomicroscopy. When challenged with lipopolysaccharide (LPS, TLR4 agonist) or N‐palmitoyl‐S‐[2,3‐bis(palmitoyloxy)‐(2RS)‐propyl]‐(R)‐cysteinyl‐seryl‐(lysyl)(3)‐lysine (P3CSK4, TLR2 agonist), neutrophils displayed enhanced motility, which was found to reflect increased random migration but not directed migration (chemotaxis). Enhanced neutrophil motility was detected within 10 min after stimulation with LPS or P3CSK4, and was sustained for more than 80 min. Stimulation of neutrophils with LPS or P3CSK4 resulted in the activation of extracellular signal‐regulated kinase (ERK) and p38 mitogen‐activated protein kinase (MAPK), which preceded neutrophil migration. TLR‐mediated neutrophil migration was strongly suppressed by pretreatment of cells with U0126 (MAPK/ERK kinase inhibitor) but not with U0124 (an inactive analogue of U0126) or SB203580 (a p38 MAPK inhibitor), and was almost completely abolished by pretreatment of cells with U0126 and SB203580 in combination. Randomly migrating neutrophils in response to LPS or P3CSK4 displayed directed migration when further challenged with gradient concentrations of N‐formyl‐methionyl‐leucyl‐phenylalanine (FMLP) or platelet‐activating factor (PAF). These findings indicate that TLR agonists stimulate human neutrophil migration via the activation of ERK and p38 MAPK, and FMLP‐ or PAF‐induced neutrophil chemotaxis is not affected by the pre‐exposure of cells to TLR agonists.
Interferon‐γ regulates chemokine expression and release in the human mast cell line HMC1: role of nitric oxide
Authors: Gilchrist M. , Befus A. D.
Published: July 2007

Mast cells (MCs) are critical immune effector cells that release cytokines and chemokines involved in both homeostasis and disease. Interferon‐γ (IFN‐γ) is a pleiotropic cytokine that regulates multiple cellular activities. IFN‐γ modulates rodent MC responsiveness via production of nitric oxide (NO), although the effects in human MC populations is unknown. We sought to investigate the effects of IFN‐γ on expression of the chemokines interleukin‐8 (IL‐8) and CCL1 (I‐309) in a human mast cell line (HMC1) and to determine the underlying regulatory mechanism. Nitric oxide synthase (NOS), IL‐8 and CCL1 expression was determined using real‐time polymerase chain reaction (PCR). NOS protein expression was analysed using western blot. NOS activity was determined using the citrulline assay. IL‐8 and CCL1 release was measured by specific enzyme‐linked immunosorbent assay (ELISA). IFN‐γ inhibited phorbol 12‐myristate 13‐acetate (PMA)‐induced release of IL‐8 and CCL1 (by 47 and 38%). Real‐time PCR analysis of IFN‐γ‐treated HMC1 showed a significant (P < 0·05) time‐dependent increase in NOS1 and NOS3 mRNA. NOS3 protein was significantly increased at 18 hr, which correlated with a significant (P < 0·05) increase in constitutive NOS (cNOS) activity. IFN‐γ‐induced inhibition of chemokine expression and release was NO dependent, as treatment with the NOS inhibitor NG‐nitro‐l‐arginine methyl ester (l‐NAME) reduced the IFN‐γ inhibitory effect on IL‐8 and CCL1 mRNA expression. NO donors mimicked the IFN‐γ effect. IFN‐γ inhibited PMA‐induced cAMP response element binding protein (CREB) phosphorylation and DNA‐binding activity. Our observations indicate for the first time that IFN‐γ enhances endogenous NO formation through NOS3 activity, and that NO regulates the transcription and release of IL‐8 and CCL1 in a human MC line.
Current practice compared with the international guidelines: endoscopic surveillance of Barrett’s esophagus
Authors: Amamra Nassira , Touzet Sandrine , Colin Cyrille , Ponchon Thierry
Published: July 2007

Rationale, aims and objectives  To describe the current practice for the surveillance of patients with Barrett’s esophagus, to compare this practice with the national guidelines published by the French Society of Digestive Endoscopy in 1998 and to identify the factors associated with the compliance to guidelines.

Method  To determine the attitudes of French hepatogastroenterologists to screening for Barrett’s oesophagus, a postal anonymous questionnaire survey was undertaken. It was sent to 246 hepatogastroenterologists in the Rhone‐Alpes area. We defined eight criteria allowed to assess the conformity of practices with the guidelines. We created three topics composed of several criterion. The topics analysed were ‘Biopsies’, ‘Surveillance’ and the diagnosis of high grade dysplasia. We studied the factors which could be associated with the compliance with the guidelines.

Results  The response rate was 81.3%. For 58.0% of the gastroenterologists, endoscopic biopsy sampling were made according to French guidelines (four‐quadrant biopsies at 2 cm intervals). Agreement was 78.0% regarding the interval of surveillance for no dysplasia (every 2 or 3 years) and 78.5% regarding the low‐grade dysplasia (every 6 or 12 months). For the management of high‐grade dysplasia, 28.6% actually confirm the diagnosis by a second anatomopathologist and 42.0% treated by proton pump inhibitor during 2 months. Concerning the biopsies, the young gastroenterologists and gastroenterologists practising in university hospitals had a better adherence to the guidelines (Relative Risk: 2.22, 95% CI 1.25–3.95 and 3.74, 95% CI 1.04–13.47, respectively). The other factors of risk were not statistically significant.

Conclusions  The endoscopic follow‐up is mostly realized in accordance with the national guidelines. However, there is a wide variability in individual current practice.
Asthma patients with low perceived burden of illness: a challenge for guideline adherence
Authors: Schneider Antonius , Biessecker Kathrin , Quinzler Renate , PharmD Petra Kaufmann‐Kolle , Meyer Franz Joachim , Wensing Michel , Szecsenyi Joachim
Published: July 2007

Rationale and aims  The reason why many patients seem to tolerate suffering from sub‐optimal treated asthma remains unclear. The aim was to evaluate the guideline adherence combined with quality of life of patients with moderate to severe asthma.

Methods  256 asthma patients from 43 primary care practices in Saxony‐Anhalt filled in a questionnaire including the Asthma Quality of Life Questionnaire (AQLQ), the Patient Health Questionnaire (PHQ‐D) and questions evaluating the asthma severity, medication and self‐management.

Results  43.4% suffered from moderate to severe asthma. Drug treatment accorded with guidelines in 36.9%, drug dosage of inhaled steroids was too low in 34.3%, and 21.5% were not treated according to guidelines. A total of 7.3% of the patients received end‐of‐dose therapy. AQLQ declined and depression rose with asthma severity and guideline non‐adherence (P < 0.001). Only 29.1% received asthma education. However, 64.5% of the patients without education did not want to receive education. They had a higher quality of life, lower depression (P < 0.001) and lower use of steroids (P = 0.016). Higher depression scores where related with hospital admission (OR 3.29; 95% CI 1.57–6.87 for each quartile of PHQ‐D) and unscheduled home visits or ambulatory care (OR 1.58; 1.07–2.33).

Conclusion  There is a large variation of asthma severity which can partly be explained by the guideline adherence of medication and deficits of patients’ management. The perceived burden of illness plays a more important role for education and self‐management than the real severity of disease. Therefore, target‐oriented interventions are needed to identify and motivate patients at risk.
Immune tolerance: mechanisms and application in clinical transplantation
Authors: Sykes M.
Published: July 2007

The achievement of immune tolerance, a state of specific unresponsiveness to the donor graft, has the potential to overcome the current major limitations to progress in organ transplantation, namely late graft loss, organ shortage and the toxicities of chronic nonspecific immumnosuppressive therapy. Advances in our understanding of immunological processes, mechanisms of rejection and tolerance have led to encouraging developments in animal models, which are just beginning to be translated into clinical pilot studies. These advances are reviewed here and the appropriate timing for clinical trials is discussed.
Salt stress responses in Arabidopsis utilize a signal transduction pathway related to endoplasmic reticulum stress signaling
Authors: Liu Jian‐Xiang , Srivastava Renu , Che Ping , Howell Stephen H.
Published: July 2007

We describe a signaling pathway that mediates salt stress responses in Arabidopsis. The response is mechanistically related to endoplasmic reticulum (ER) stress responses described in mammalian systems. Such responses involve processing and relocation to the nucleus of ER membrane‐associated transcription factors to activate stress response genes. The salt stress response in Arabidopsis requires a subtilisin‐like serine protease (AtS1P), related to mammalian S1P and a membrane‐localized b‐ZIP transcription factor, AtbZIP17, a predicted type‐II membrane protein with a canonical S1P cleavage site on its lumen‐facing side and a b‐ZIP domain on its cytoplasmic side. In response to salt stress, it was found that myc‐tagged AtbZIP17 was cleaved in an AtS1P‐dependent process. To show that AtS1P directly targets AtbZIP17, cleavage was also demonstrated in an in vitro pull‐down assay with agarose bead‐immobilized AtS1P. Under salt stress conditions, the N‐terminal fragment of AtbZIP17 tagged with GFP was translocated to the nucleus. The N‐terminal fragment bearing the bZIP DNA binding domain was also found to possess transcriptional activity that functions in yeast. In Arabidopsis, AtbZIP17 activation directly or indirectly upregulated the expression of several salt stress response genes, including the homeodomain transcription factor ATHB‐7. Upregulation of these genes by salt stress was blocked by T‐DNA insertion mutations in AtS1P and AtbZIP17. Thus, salt stress induces a signaling cascade involving the processing of AtbZIP17, its translocation to the nucleus and the upregulation of salt stress genes.
Dyskeratosis congenita: Advances in the understanding of the telomerase defect and the role of stem cell transplantation
Authors: De La Fuente Josu , Dokal Inderjeet
Published: July 2007

Abstract:  DC is a multisystem bone marrow failure syndrome exhibiting marked clinical and genetic heterogeneity. X‐linked, autosomal dominant and autosomal recessive subtypes are recognized. The gene mutated in X‐linked DC (DKC1) encodes a highly conserved nucleolar protein called dyskerin. Dyskerin associates with the H/ACA motif class of small nucleolar RNAs in small nucleolar ribonucleoprotein particles that are important in guiding the conversion of uracil to pseudouracil during the maturation of ribosomal RNA. Dyskerin also associates with the TERC, which is important in the maintenance of telomeres. Mutations in TERC have been identified in patients with autosomal dominant DC and in a subset of patients with aplastic anemia and myelodysplasia. Recently, heterozygous mutations in TERT have been found in some patients with autosomal dominant DC and aplastic anemia. Additionally, patients with the severe multisystem disorder, Hoyeraal–Hreidarsson syndrome, have been found to have DKC1 mutations. Collectively, these observations have demonstrated that classical DC, Hoyeraal–Hreidarsson syndrome and a subset of aplastic anemia are due to a primary defect in telomerase. The critical role of telomeres and telomerase in humans is seen in the multisystem abnormalities found in these patients, including the increased incidence of malignancy. As bone marrow failure is the principal cause of death, conventional allografts have been attempted with limited success due to the high rate of pulmonary and endothelial complications. However, outcomes have improved with the use of non‐myeloablative protocols, although the follow up is too short to evaluate long term toxicity and the natural course of the disease and it may be that correction of the telomerase defect is essential for the treatment of these patients.
Unrelated cord blood transplantation in children with sickle cell disease: Review of four‐center experience
Authors: Adamkiewicz Tom V. , Szabolcs Paul , Haight Ann , Baker K. Scott , Staba Susan , Kedar Amos , Chiang K. Y. , Krishnamurti Lakshmanan , Boyer Michael W. , Kurtzberg Joan , Wagner John E. , Wingard John R. , Yeager Andrew M.
Published: July 2007

Abstract:  UCBT was performed in seven children with SCD and stroke (HLA match 4/6 n = 5; 5/6 n = 2). Four received myeloablative regimens (BU, CY, ATG plus FLU in one patient). One had primary graft failure, three had sustained engraftment, two with grade III–IV GVHD (one died, one developed chronic GVHD), one with stable mixed chimerism. Three patients treated with reduced‐intensity regimens (FLU, BU or CY, ATG, TLI) failed to engraft; one engrafted after second UCBT (HU, TT, RXA, ALZ, TBI). Four patients (57%) developed viral infections. Engraftment, GVHD, and infection remain challenges.
National policies for xenotransplantation in the USA*
Authors: Bloom Eda T.
Published: July 2007

Abstract:  An overview of xenotransplantation regulatory policies in the USA was presented at the Satellite Symposium, ‘‘Xenotransplantation – Current Standards for Clinical Trials,’’ held in conjunction with the World Transplant Congress, Boston, MA, USA 2006. This article summarizes that overview.