bluuebunny/crossref_metadata_2025 huggingface dataset:
Developing Global Leaders
Authors: Han Pi-Chi
Published: October 2012

Although the need to develop global leaders with adequate intercultural competencies has become obvious (Morrison, 2000; Suutari, 2002), global leadership, as an emerging field, has not received a great deal of attention (Morrison, 2000). Literature of developing global leadership has been focused on partial evidence to generate simple universality with an American bias (Dickson, Hartog, & Mitchelson, 2003). This chapter attempts to propose an integrative Intercultural Effectiveness (ICE) model for Human Resource Development (HRD) professionals. The model evolves a theoretical conceptualization to link ICE and global leadership with the theory of transformative learning and the process of cross-cultural learning. It provides a series of process guidelines for HRD professionals in designing, developing, and conducting HRD programs for the development of global leadership.
Leveraging the Power of Diversity in Workplace Learning Strategies
Authors: McNeil Rita C.
Published: October 2012

Just as adult learning strategies can be categorized into three major learning strategy preference groups (Conti & Kolody, 1998), workplace learning events can also be similarly categorized into a spectrum containing three major clusters: (a) the Navigation Cluster, containing those tasks that require planning, organizing, and structuring of content; (b) the Problem-Solving Cluster, containing those tasks that require innovative creativity or critical thinking skills; and (c) the Engagement Cluster, containing those tasks that require inter- and intra-personal skills required when working in situations that involve others. The purpose of this chapter is to propose an emerging 4-step framework that can be used to guide individuals, educators, and workplace trainers through a process to assist learners in identifying their learning strategies preferences and in leveraging these individual metacognitive processes in order to achieve specific workplace learning objectives.
Global Diversity Management Programs and Strategies at CEVA Logistics
Authors: Öner Hale , Kaya Esra , Surgevil Olca , Ozbilgin Mustafa
Published: October 2012

The main Diversity and Inclusion activities of CEVA aim at increasing the participation of women at higher echelons of the management cadre, retaining diverse talent, and increasing the number of employees with disabilities. The diversity and integration understanding is the commitment to continuous improvement in every sub-region retaining the talented human capital with a focus on work and life balance initiatives and development by mentoring programs, network groups on the intranet, e-teams, and communities on gender and disability. Although diversity is integrated at CEVA at both the regional and global levels, the main motto in implementing the Diversity and Inclusion activities is “Think global, act local.”
Leveraging Workforce Diversity in Practice
Authors: Greer Bertie M. , Hill James A.
Published: October 2012

Important supply bases for buyers are those that emphasize minority-owned businesses. The increased focus on globalization, corporate social responsibility, supplier diversity, and additional benefits has established a need for buyers to develop sustainable relationships with minority-owned firms. Based on a review of the literature, and interviews with a minority supplier director, minority suppliers, and a purchasing manager, this chapter examines the relationship constructs that are important to buyer-minority-owned supplier relationships. Trust, perception of buyer’s commitment, and minority-owned supplier commitment is explored. Research propositions, implications, and directions for further research are offered.
Leveraging Workforce Diversity through Volunteerism
Authors: Joshua-Gojer Ashwini , Allen Jeff
Published: October 2012

This chapter discusses the subject of workforce diversity as it directly relates to volunteerism, using the Peace Corps as an example. The aim of the chapter is to illustrate how nonprofit institutions can draw upon the value of workforce diversity in order to obtain competitive advantages. The Peace Corps’ three-fold mission includes helping the people of interested countries in meeting their need for trained men and women, helping promote a better understanding of Americans on the part of the people served, and helping promote a better understanding of other peoples on the part of Americans (Peace Corps, 2011a). This chapter specifically discusses how the Peace Corps incorporate diversity in their volunteer program. “The agency has always reflected the diversity of America and is actively recruiting the next generation of Peace Corps Volunteers” (Peace Corps, 2011b).
Leveraging Sexual Orientation Workforce Diversity through Identity Deployment
Authors: Ghosh Apoorva
Published: October 2012

Disclosure decisions for lesbian and gay employees have been researched in organizational contexts. While the dilemmas associated, factors affecting, and situations encouraging or discouraging disclosure have been studied, the relatively unexplored area is how homosexuality can be strategically deployed at workplace to contest the associated stigma and bring positive social and political changes in the organizational climate. While scholars believe that remaining closeted may be the best strategy in a heterosexist and homophobic environment, studies report psychological strain, lack of authenticity, behavioral dilemmas, etc. experienced by closeted individuals, which, at minimum, lead to conflicts in daily situations of identity management and, at the peak, suicidal attempts due to perceived burdensomeness and failed belongingness. To address this dilemma in leveraging sexual orientation diversity in workplaces, this chapter deals with the framework of identity deployment offered by Bernstein (1997) to explore how homosexuality can be deployed in the workplace.
Utilizing a New Human Relations Framework to Leverage Workforce Diversity
Authors: Riccò Rossella
Published: October 2012

In a global society, leveraging people’s diversities is one of the major challenges faced by organizations of any size in developed countries. Factors such as demographic changes, international and national anti-discrimination measures, globalization, service-economy shifts, stakeholder pressures on organizational commitment to corporate social responsibility, and technological advances are heightening the international attention paid to the increase in people’s diversities, thereby fostering discussion on their management in organizations. Since the end of the 1980s, professionals and academics have been debating how to devise efficient, effective, and equitable ways to manage workforce diversity in organizations; however, they have produced neither a shared definition of diversity management nor a general accepted assessment on the outcomes that diversity management can deliver for organizations and persons. The aim of this chapter is to expand the understanding of diversity management by systematizing it on the basis of McGregor’s new human relations framework.
National Enterprise Architecture Framework
Authors: AlSoufi Ali , Ahmed Zakaria
Published: October 2012

Building on the belief that a positive correlation between the desired level of e-government capability and maturity and the required level of architectural maturity exists, the eGovernment Authority (eGA) of the kingdom of Bahrain embarked on a three-year eGovernment program aimed at improving service delivery to citizens through seamless integration and connected governance. In order to achieve this objective, eGA realized the need for a Kingdom-wide strategy and holistic guiding plans, and hence decided to design and develop a National Enterprise Architecture Framework (NEAF). NEAF is an aggregation of models and meta-models, governance, compliance mechanisms, technology standards, and guidelines put together to guide effective development and implementation of an Enterprise Architecture by different government entities across the Kingdom. This chapter will describe a NEAF development project success story, its objectives, and its importance to Bahrain’s economic vision 2030. It describes the NEAF development lifecycle and highlights the findings and challenges faced at each stage of the project.
A Case Study in the Emergence of Coherence through Cultural Change
Authors: Solverson Charles , Coffman Susan , Johnson David , Paralez Linda I.
Published: October 2012

The emergence of e-governance within Tacoma, WA, a progressive, midsized, U.S. city located in the Pacific Northwest, has been a process of insights and solutions. The interrelationships of e-government, Enterprise Architecture (EA), and sustainable practices as a means to e-governance are examined in the chapter thorough the case study of one Tacoma city division, Building and Land Use Services (BLUS). BLUS managers have redesigned business processes to automate service delivery by the optimization of enterprise-wide interoperable information technology. The discussion includes consideration of the influences that collective decision-making, codes, culture, and vision have on governmental transformation. The identified gap between EA and e-government systems was consistent with the emerging convergence of knowledge for developing EA maturity, developing best practices for shared information management, and expanding human potential. Internal and external stakeholders have experienced the successful emergence of BLUS into rationalized data and applications, in which the optimization of existing interoperable technology has enabled an enhanced partnership between the city government and the community.
Whole-of-Enterprise Approach to Government Architecture Applied for Implementing a Directive of EU
Authors: Velitchkov Ivo
Published: October 2012

Sustainable benefits of EA efforts could only be realised if all structures and behaviour are taken into account together with their drivers and controls. This chapter tells the story of an e-Government project in Bulgaria where a whole-of-enterprise approach was applied to identify together legal, organizational, and technological measures related to achieving compliance with a new regulation and improvement of a set of e-Government services. One of the main objectives of the project was to discover the potential for simplification of administrative procedures for authorisation of service providers in line with a new regulation in the European Union supporting realisation of a single market of services. The obtained analytical results and the defined target state were not limited to improvement of online services but included pertinent legislation harmonisation and other non-IT related changes. The applied agile EA approach helped with completing the project within 6 months and realising results exceeding its scope.
Introduction to Smart Phone Positioning
Authors: Chen Ruizhi
Published: October 2012

Ubiquitous positioning is now becoming a key technology for Location-Based Service (LBS) in smart phones. For outdoor environments, it is not a challenging task to locate mobile users using the Global Navigation Satellite System (GNSS). However, it is still difficult to locate the smart phones with a sufficient accuracy in the GNSS degraded or denied environments, such as urban canyons and indoors. Additional sensors and signals of opportunity are needed to augment the GNSS solution for such environments. The sensors include accelerometers, gyroscope, digital compass, while the signals of opportunity include the RF (Radio Frequency) signals from WLAN (Wireless Local Area Network) and Bluetooth networks. These sensors and signals of opportunity are typically available in smart phones even though most of them are not originally intended for positioning purpose. There are four positioning solutions that can be applied to smart phones: the GNSS-based positioning solution, the RAN (Radio Access Network)-based positioning solution, the positioning solution based on the signals of opportunity from short range RF technologies, and the hybrid positioning solution that utilizes multiple sensors and multiple signals of opportunity. The objective of this chapter is to give an introduction to these positioning solutions, including the positioning infrastructures, the sensors, the characteristics of the signals, and the fundamental positioning algorithms.
Assisted GNSS in Smart Phones
Authors: Chen Ruizhi
Published: October 2012

It is difficult to acquire GNSS (Global Satellite Navigation System) signals in challenging environments such as urban canyons and indoors without any assistance information. The time-to-first-fix process is extremely long for positioning in such environments, especially for the case when the user is moving. In order to speed up the time-to-first-fix process, the receiver needs assistance information from a server for quickly acquiring and tracking the GNSS signals. This chapter introduces the assisted GNSS solution. It covers the topics of acquisition assistance, sensitivity assistance, and implementation for smart phones. The objective of the chapter is to provide the readers with a general overview of the Assisted-GNSS (A-GNSS) solution from the aspects of how the A-GNSS solution speeds up the acquisition process and improves the tracking sensitivity, what kinds of assistance data are needed, and how the assistance data is delivered to the mobile users. The chapter includes sections for an introduction to the topic, acquisition assistance, sensitivity assistance, A-GNSS implementation for smart phones, future directions, and brief conclusions.
WLAN and Bluetooth Positioning in Smart Phones
Authors: Chen Ruizhi , Pei Ling , Liu Jingbin , Leppäkoski Helena
Published: October 2012

Although the short range radio frequency technologies such as WLAN (Wireless Local Area Network) and Bluetooth were originally designed for the purpose of wireless communication, they have been widely adopted as common signals of opportunity for positioning in smart phones for both indoors and outdoors. The cell identifier and radio signal strength are the most common observables used for positioning. The applicable position methods include Cell-ID, fingerprinting, and trilateration. Fingerprinting is the most common approach, which can provide a positioning accuracy of even 2-5 meters indoors using either the pattern recognition algorithm or the probabilistic algorithm; however, the obtainable accuracy depends on the positioning environment. The objective of this chapter is to present the WLAN and Bluetooth positioning methodologies and explain the related positioning algorithms. The chapter covers an introduction of the topic, descriptions of the observables, the positioning algorithms, and the implementation issues of the positioning solutions. The chapter is concluded with a short section of future research directions followed by a brief conclusion.
RFID Positioning
Authors: Retscher Guenther , Zhu Ming , Zhang Kefei
Published: October 2012

This chapter investigates the techniques and algorithms for low-cost and portable ubiquitous indoor/outdoor personal positioning systems that use Radio Frequency Identification (RFID) based multi-sensor integration. This includes, for example, integrating RFID with Micro-Electro-Mechanical Systems (MEMS), Inertial Navigation System (INS), and/or GNSS. Different positioning scenarios and technologies are discussed and assessed. Their principles of operation and the factors that affect signal strength measurements are analysed in detail. This is followed by an in-depth investigation of the achievable positioning accuracies and the corresponding application scenarios. Results of static and kinematic experiments conducted in indoor and outdoor environment show that positioning accuracies at the meter level can be achieved using RFID based integrated systems. The algorithms developed can be readily deployed in portable multi-sensor positioning systems for LBS.
Visual Positioning in a Smartphone
Authors: Ruotsalainen Laura , Kuusniemi Heidi
Published: October 2012

Numerous techniques for obtaining motion and location related information are needed for obtaining seamless positioning capability with smartphones. High-quality cameras are nowadays widely available in portable devices and can provide necessary redundant data about the user’s surroundings in addition to the other sensors usable for positioning purposes. In this chapter, after introducing methods of image processing related to feature extraction, applicable methods for visual positioning are discussed with state-of-the-art examples. Regardless whether the visual-based positioning is based on reference images in a database or using information obtained from consecutive images, the first steps of pre-processing are similar to obtain noiseless images for accurate calculations and to retrieve the required camera parameters. Smartphones have limited computational resources and that restricts the methods available for image processing. To carry out the visual positioning function, features in images are either matched to corresponding features in consecutive images, or to a database. Obtaining the location can be performed with matching the query image to a database of reference images equipped with location information. Alternatively, the attitude and position change can be resolved from consecutive images to provide localization augmentation that may be fused with other sensor information. When smartphones are concerned, the restricted resources however bring about challenges that are the focus in this chapter.
Map-Based LBSs for Hiking
Authors: Sarjakoski Tapani , Kovanen Janne , Sarjakoski L. Tiina
Published: October 2012

In a map-based location-based service, a map on a mobile device is used to visualize and communicate spatial information to the user. The objective of this chapter is to provide a review of map-based LBSs that are especially directed to outdoor activities such as hiking. Hikers as users have special information needs and requirements, which, as in any development, should provide the starting point and the goal for the LBS. The authors list the requirements and solutions such a service must address and discuss the implications of using maps for the application development. They discuss the essential components, functionality, and architectural solutions of an LBS for hiking, and describe the functionality needed for wayfinding and navigation support. Finally, the authors portray the emerging trends, such as ubiquity, adaptivity, and personal cloud solutions, that will motivate future research.
A Federated Approach to Information Management in Grids
Authors: Aktas Mehmet S. , Fox Geoffrey C. , Pierce Marlon
Published: October 2012

We propose a novel approach to managing information in grids. The proposed approach is an add-on information system that provides unification and federation of grid information services. The system interacts with local information services and assembles their metadata instances under one hybrid architecture to provide a common query/publish interface to different kinds of metadata. The system also supports interoperability of major grid information services by providing federated information management. We present the semantics and architectural design for this system. We introduce a prototype implementation and present its evaluation. As the results indicate, the proposed system achieves unification and federation of custom implementations of grid information services with negligible processing overheads.
Similarity Measures for Substituting Web Services
Authors: Bravo Maricela , Alvarado Matias
Published: October 2012

Web service substitution is one of the most advanced tasks that a composite Web service developer must achieve. Substitution occurs when, in a composite scenario, a service operation is replaced to improve the composition performance or fix a disruption caused by a failing service. To move the automation of substitution forward, a set of measures, considering structure and functionality of Web services, are provided. Most of current proposals for the discovery and matchmaking of Web services are based on the semantic perspective, which lacks the precise information that is needed toward Web service substitution. This paper describes a set of similarity measures to support this substitution. Similarity measurement accounts the differences or similarities by the syntax comparison of names and data types, followed by the comparison of input and output parameters values of Web service operations. Calculation of these measures was implemented using a filtering process. To evaluate this approach, a software architecture was implemented, and experimental tests were carried on both private and public available Web services. Additionally, as is discussed, the application of these measures can be extended to other Web services tasks, such as classification, clustering and composition.
Flexible Probabilistic QoS Management of Orchestrations
Authors: Rosario Sidney , Benveniste Albert , Jard Claude
Published: October 2012

In this paper, the authors develop a comprehensive framework for QoS management based on soft probabilistic contracts. The authors approach also encompasses general QoS parameters, with “response time” as a particular case. In addition, the authors support composite QoS parameters, for example, combining timing aspects with “quality of data” or security level. They also study contract composition (how to derive QoS contracts for an orchestration from the QoS contracts with its called services), and contract monitoring.
Optimal Fault Tolerance Strategy Selection for Web Services
Authors: Zheng Zibin , Lyu Michael R.
Published: October 2012

Service-oriented systems are usually composed by heterogeneous Web services, which are distributed across the Internet and provided by organizations. Building highly reliable service-oriented systems is a challenge due to the highly dynamic nature of Web services. In this paper, the authors apply software fault tolerance techniques for Web services, where the component failures are handled by fault tolerance strategies. In this paper, a distributed fault tolerance strategy evaluation and selection framework is proposed based on versatile fault tolerance techniques. The authors provide a systematic comparison of various fault tolerance strategies by theoretical formulas, as well as real-world experiments. This paper also presents the optimal fault tolerance strategy selection algorithm, which employs both the QoS performance of Web services and the requirements of service users for selecting optimal fault tolerance strategy. A prototype is implemented and real-world experiments are conducted to illustrate the advantages of the evaluation framework. In these experiments, users from six different locations perform evaluation of Web services distributed in six countries, where over 1,000,000 test cases are executed in a collaborative manner to demonstrate the effectiveness of this approach.
Enhancing Security Modeling for Web Services Using Delegation and Pass-On
Authors: She Wei , Yen I-Ling , Thuraisingham Bhavani
Published: October 2012

In recent years, security issues in web service environments have been widely studied and various security standards and models have been proposed. However, most of these standards and models focus on individual web services and do not consider the security issues in composite services. In this article, the authors propose an enhanced security model to control the information flow in service chains. It extends the basic web service security models by introducing the concepts of delegation and pass-on. Based on these concepts, new certificates, certificate chains, delegation and pass-on policies, and how they are used to control the information flow are discussed. The authors also introduce a case study from a healthcare information system to illustrate the protocols.
DiALog
Authors: Ringelstein Christoph , Staab Steffen
Published: October 2012

Service-oriented systems facilitate business workflows to span multiple organizations (e.g., by means of Web services). As a side effect, data may be more easily transferred over organizational boundaries. Thus, privacy issues arise. At the same time, there are personal, business and legal requirements for protecting privacy and IPR and allowing customers to request information about how and by whom their data was handled. Managing these requirements constitutes an unsolved technical and organizational problem. The authors propose to solve the information request problem by attaching meta-knowledge about how data was handled to the data itself. The authors present their solution, in form of an architecture, a formalization and an implemented prototype for logging and collecting logs in service-oriented and cross-organizational systems.
RFID Practices for Competitive Inventory Management Systems
Authors: Smith Alan D.
Published: October 2012

Although on the cutting edge of business technologies, RFID proves to be a difficult process to implement and achieve, despite recent efforts. Two Pittsburgh-based companies were showcased in this case study, namely Mobile Aspects, Inc., a recognized leader in the integration of RFID-related technologies in inventory management processes of large acute care, and Vocollect, Inc., which is especially noted for its voice-recognition software and small hardware platforms used warehousing and partially automated inventory systems. The firms’ goals for implementing inventory management, specific inventory recommendations and changes, comparison of inventory management processes, and selected measures for ensure the quality and security of data transmitted via RFID-based technologies and lessons learned were discussed.
A Hybrid Multilayer Perceptron Neural Network for Direct Marketing
Authors: Govindarajan M. , Chandrasekaran RM.
Published: October 2012

Data Mining is the use of algorithms to extract the information and patterns derived by the knowledge discovery in database process. It is often referred to as supervised learning because the classes are determined before examining the data. In many data mining applications that address classification problems, feature and model selection are considered as key tasks. That is, appropriate input features of the classifier must be selected from a given set of possible features and structure parameters of the classifier must be adapted with respect to these features and a given data set. This paper describes feature selection and model selection simultaneously for Multilayer Perceptron (MLP) classifiers. In order to reduce the optimization effort, various techniques are integrated that accelerate and improve the classifier significantly. The feasibility and the benefits of the proposed approach are demonstrated by means of data mining problem: Direct Marketing in Customer Relationship Management. It is shown that, compared to earlier MLP technique, the run time is reduced with respect to learning data and with validation data for the proposed Multilayer Perceptron (MLP) classifiers. Similarly, the error rate is relatively low with respect to learning data and with validation data in direct marketing dataset. The algorithm is independent of specific applications so that many ideas and solutions can be transferred to other classifier paradigms.
A Survey on Database Performance in Virtualized Cloud Environments
Authors: Ivanov Todor , Petrov Ilia , Buchmann Alejandro
Published: October 2012

Cloud Computing emerged as a major paradigm over the years. Major challenges it poses to computer science are related to latency, scale, and reliability issues. It leverages strong economical aspects and provides sound answers to questions like energy consumption, high availability, elasticity, or efficient computing resource utilization. Many Cloud Computing platform and solution providers resort to virtualization as key underlying technology. Properties like isolation, multi-virtual machine parallelism, load balancing, efficient resource utilization, and dynamic pre-allocation besides economic factors make it attractive. It not only legitimates the spread of several types of data stores supporting a variety of data modes, but also inherently requires different types of load: (i) analytical; (ii) Transactional/Update-intensive; and (iii) mixed real-time feed processing. The authors survey how database systems can best leverage virtualization properties in cloud scenarios. The authors show that read mostly database systems and especially column stores profit from virtualization in analytical and search scenarios. Secondly, cloud analytics virtualized database systems are efficient in transactional scenarios such as Cloud CRM virtualized database systems lag. The authors also explore how the nature of mixed cloud loads can be best reflected by virtualization properties like load balancing, migration, and high availability.
Spatial Data Mining for Highlighting Hotspots in Personal Navigation Routes
Authors: Schoier Gabriella , Borruso Giuseppe
Published: October 2012

Rapid developments in the availability and access to spatially referenced information in a variety of areas have induced the need for better analytical techniques to understand the various phenomena. In particular, the authors’ analysis is an insight into a wealth of geographical data collected by individuals as activity dairy data. The attention is drawn on point datasets corresponding to GPS traces driven along a same route in different days. In this paper, the authors explore the presence of clusters along the route, trying to understand the origins and motivations behind that to better understand the road network structure in terms of ’dense’ spaces along the network. Therefore, the attention is focused on methods to highlight such clusters and see their impact on the network structure. Spatial clustering algorithms are examined (DBSCAN) and a comparison with other non-parametric density based algorithm (Kernel Density Estimation) is performed. Different tests are performed over the urban area of Trieste (Italy), considering both multiple users and different origin/destination journeys.
The B10 Idd9.3 Locus Mediates Accumulation of Functionally Superior CD137+ Regulatory T Cells in the Nonobese Diabetic Type 1 Diabetes Model
Authors: Kachapati Kritika , Adams David E. , Wu Yuehong , Steward Charles A. , Rainbow Daniel B. , Wicker Linda S. , Mittler Robert S. , Ridgway William M.
Published: October 2012

CD137 is a T cell costimulatory molecule encoded by the prime candidate gene (designated Tnfrsf9) in NOD.B10 Idd9.3 congenic mice protected from type 1 diabetes (T1D). NOD T cells show decreased CD137-mediated T cell signaling compared with NOD.B10 Idd9.3 T cells, but it has been unclear how this decreased CD137 T cell signaling could mediate susceptibility to T1D. We and others have shown that a subset of regulatory T cells (Tregs) constitutively expresses CD137 (whereas effector T cells do not, and only express CD137 briefly after activation). In this study, we show that the B10 Idd9.3 region intrinsically contributes to accumulation of CD137+ Tregs with age. NOD.B10 Idd9.3 mice showed significantly increased percentages and numbers of CD137+ peripheral Tregs compared with NOD mice. Moreover, Tregs expressing the B10 Idd9.3 region preferentially accumulated in mixed bone marrow chimeric mice reconstituted with allotypically marked NOD and NOD.B10 Idd9.3 bone marrow. We demonstrate a possible significance of increased numbers of CD137+ Tregs by showing functional superiority of FACS-purified CD137+ Tregs in vitro compared with CD137− Tregs in T cell-suppression assays. Increased functional suppression was also associated with increased production of the alternatively spliced CD137 isoform, soluble CD137, which has been shown to suppress T cell proliferation. We show for the first time, to our knowledge, that CD137+ Tregs are the primary cellular source of soluble CD137. NOD.B10 Idd9.3 mice showed significantly increased serum soluble CD137 compared with NOD mice with age, consistent with their increased numbers of CD137+ Tregs with age. These studies demonstrate the importance of CD137+ Tregs in T1D and offer a new hypothesis for how the NOD Idd9.3 region could act to increase T1D susceptibility.
TLR15 Is Unique to Avian and Reptilian Lineages and Recognizes a Yeast-Derived Agonist
Authors: Boyd Amy C. , Peroval Marylene Y. , Hammond John A. , Prickett Michael D. , Young John R. , Smith Adrian L.
Published: October 2012

The TLRs represent a family of pattern recognition receptors critical in the induction of vertebrate immune responses. Between 10 and 13 different TLR genes can be identified in each vertebrate species, with many represented as orthologous genes in different species. The agonist specificity of orthologous TLR is also highly conserved. In contrast, TLR15 can only be identified in avian and reptilian genomes, suggesting that this receptor arose ∼320 million years ago after divergence of the bird/reptile and mammalian lineages. Transfection of a constitutively active form of chicken TLR15 led to NF-κB activation in HEK293 cells and induced cytokine mRNA upregulation in chicken cell lines. Full-length TLR15 mediated NF-κB induction in response to lysates from yeast, but not those derived from viral or bacterial pathogens, or a panel of well-characterized TLR agonists. TLR15 responses were induced by whole-cell lysates derived from Candida albicans, Saccharomyces cerevisiae, and Schizosaccharomyces pombe, but not zymosan preparations from S. cerevisiae. The ability of yeast lysate to activate TLR15-dependent NF-κB pathways (in transfection assays) or stimulate IL-1β mRNA upregulation in chicken macrophages was abrogated by heat inactivation or pre-exposure of the lysate to PMSF. Identification of yeast as an agonist source for TLR15 provides a functional framework for consideration of this TLR within the context of pattern recognition receptor evolution and may impact on the development of novel adjuvants.
p16INK4a Exerts an Anti-Inflammatory Effect through Accelerated IRAK1 Degradation in Macrophages
Authors: Murakami Yousuke , Mizoguchi Fumitaka , Saito Tetsuya , Miyasaka Nobuyuki , Kohsaka Hitoshi
Published: October 2012

Induction of cyclin-dependent kinase (CDK) inhibitor gene p16INK4a into the synovial tissues suppresses rheumatoid arthritis in animal models. In vitro studies have shown that the cell-cycle inhibitor p16INK4a also exerts anti-inflammatory effects on rheumatoid synovial fibroblasts (RSF) in CDK activity-dependent and -independent manners. The present study was conducted to discern how p16INK4a modulates macrophages, which are the major source of inflammatory cytokines in inflamed synovial tissues. We found that p16INK4a suppresses LPS-induced production of IL-6 but not of TNF-α from macrophages. This inhibition did not depend on CDK4/6 activity and was not observed in RSF. p16INK4a gene transfer accelerated LPS-triggered IL-1R–associated kinase 1 (IRAK1) degradation in macrophages but not in RSF. The degradation inhibited the AP-1 pathway without affecting the NF-κB pathway. Treatment with a proteosome inhibitor prevented the acceleration of IRAK1 degradation and downregulation of the AP-1 pathway. THP-1 macrophages with forced IRAK1 expression were resistant to the p16INK4a-induced IL-6 suppression. Senescent macrophages with physiological expression of p16INK4a upregulated IL-6 production when p16INK4a was targeted by specific small interfering RNA. These findings indicate that p16INK4a promotes ubiquitin-dependent IRAK1 degradation, impairs AP-1 activation, and suppresses IL-6 production. Thus, p16INK4a senescence gene upregulation inhibits inflammatory cytokine production in macrophages in a different way than in RSF.
IL-17 Receptor Adaptor Protein Act1/CIKS Plays an Evolutionarily Conserved Role in Antiviral Signaling
Authors: Ryzhakov Grigory , Blazek Katrina , Lai Cheryl Chuk-ke , Udalova Irina A.
Published: October 2012

Double-stranded RNA-induced antiviral gene expression in mammalian cells requires activation of IFN regulatory factor 3 (IRF3). In this study, we show that the IL-17R adaptor protein Act1/CIKS is involved in this process. Small interfering RNA-mediated knockdown of Act1 in primary human skin fibroblasts specifically attenuates expression of IFN-β and IFN-stimulated antiviral genes induced by a synthetic viral mimic, polyinosinic-polycytidylic acid. Ectopic expression of Act1 potentiates the IRF3-driven expression of a synthetic reporter construct as well as the induction of antiviral genes. We demonstrate that this effect is dependent on the ability of Act1 to functionally and physically interact with IκB kinase ε (IKKε), a known IRF3 kinase, and IRF3: 1) Act1 binds IKKε and IRF3; 2) Act1-induced IRF3 activation can be blocked specifically by coexpression of a catalytically inactive mutant of IKKε; and 3) mutants of IRF3, either lacking the C terminus or mutated at the key phosphorylation sites, important for its activation by IKKε, do not support Act1-dependent IRF3 activation. We also show that a zebrafish Act1 protein is able to trigger antiviral gene expression in human cells, which suggests an evolutionarily conserved function of vertebrate Act1 in the host defense against viruses. On the whole, our study demonstrates that Act1 is a component of antiviral signaling.
NK Cell Lytic Granules Are Highly Motile at the Immunological Synapse and Require F-Actin for Post-Degranulation Persistence
Authors: Mace Emily M. , Wu Winona W. , Ho Tina , Mann Shaina S. , Hsu Hsiang-Ting , Orange Jordan S.
Published: October 2012

The formation of a dynamic, actin-rich immunological synapse (IS) and the polarization of cytolytic granules toward target cells are essential to the cytotoxic function of NK cells. Following polarization, lytic granules navigate through the pervasive actin network at the IS to degranulate and secrete their toxic contents onto target cells. We examined lytic granule motility and persistence at the cell cortex of activated human NK cells, using high-resolution total internal reflection microscopy and highly quantitative analysis techniques. We illustrate that lytic granules are dynamic and observe substantial motility at the plane of the cell cortex prior to, but not after, degranulation. We also show that there is no significant change in granule motility in the presence of Latrunculin A (which induces actin depolymerization), when added after granule polarization, but that there is a significant decrease in lytic granule persistence subsequent to degranulation. Thus, we show that lytic granules are highly dynamic at the cytolytic human NK cell IS prior to degranulation and that the persistence of granules at the cortex following exocytosis requires the integrity of the synaptic actin network.
Mimicking an Induced Self Phenotype by Coating Lymphomas with the NKp30 Ligand B7-H6 Promotes NK Cell Cytotoxicity
Authors: Kellner Christian , Maurer Tina , Hallack Daniela , Repp Roland , van de Winkel Jan G. J. , Parren Paul W. H. I. , Valerius Thomas , Humpe Andreas , Gramatzki Martin , Peipp Matthias
Published: October 2012

Induced self expression of the NKp30 ligand B7-H6 facilitates NK cell-mediated elimination of stressed cells. A fusion protein consisting of the ectodomain of B7-H6 and the CD20 single-chain fragment variable 7D8 was generated to mimic an induced self phenotype required for NK cell-mediated target cell elimination. B7-H6:7D8 had bifunctional properties as reflected by its ability to simultaneously bind to the CD20 Ag and to the NKp30 receptor. B7-H6:7D8 bound by CD20+ lymphoma cells activated human NK cells and triggered degranulation. Consequently, the immunoligand B7-H6:7D8 induced killing of lymphoma-derived cell lines as well as fresh tumor cells from chronic lymphocytic leukemia or lymphoma patients. B7-H6:7D8 was active at nanomolar concentrations in a strictly Ag-specific manner and required interaction with both CD20 and NKp30. Remarkably, NK cell cytotoxicity was further augmented by concomitant activation of Fcγ receptor IIIa or NK group 2 member D. Thus, B7-H6:7D8 acted synergistically with the CD20 Ab rituximab and the immunoligand ULBP2:7D8, which was similarly designed as B7-H6:7D8 but engaging the NK group 2 member D receptor. In conclusion, to our knowledge, B7-H6:7D8 represents the first Ab-based molecule stimulating NKp30-mediated NK cell cytotoxicity for therapeutic purposes and provides proof of concept that Ag-specific NKp30 engagement may represent an innovative strategy to enhance antitumoral NK cell cytotoxicity.
Highly Restricted Usage of Ig H Chain VH14 Family Gene Segments in Slp65-Deficient Pre-B Cell Leukemia in Mice
Authors: Ta Van B. T. , de Bruijn Marjolein J. W. , Matheson Louise , Zoller Markus , Bach Martina P. , Wardemann Hedda , Jumaa Hassan , Corcoran Anne , Hendriks Rudi W.
Published: October 2012

Mice deficient for the adapter protein Slp65 (also known as Blnk), a key component in precursor-BCR (pre-BCR) signaling, spontaneously develop pre-B cell leukemia. In these leukemias, proliferation is thought to be driven by constitutive Jak3/Stat5 signaling, mostly due to autocrine production of IL-7, together with high surface expression of the pre-BCR. In this study, we investigated whether particular IgH specificities would predispose Slp65-deficient pre-B cells to malignant transformation. Whereas VH-D-JH junctions were diverse, we found highly restricted Ig VH gene usage: 55 out of 60 (∼92%) leukemias used a VH14/SM7-family gene, mainly VH14-1 and VH14-2. When combined with surrogate or conventional L chains, these VH14 IgH chains did not provide increased proliferative signals or exhibit enhanced poly- or autoreactivity. We therefore conclude that pre-BCR specificity per se did not contribute to oncogenic transformation. Remarkably, in a high proportion of Slp65-deficient leukemias, the nonexpressed IgH allele also harbored a VH14-family rearrangement (10 out of 50) or was in the germline configuration (10 out of 50). VH14-1 and VH14-2 gene regions differed from their neighboring VH genes in that they showed active H3K4me3 histone modification marks and germline transcription at the pro-B cell stage in Rag1-deficient mice. Taken together, these findings demonstrate that in Slp65-deficient mice, malignant transformation is largely limited to particular pre-B cells that originate from pro-B cells that had restricted IgH VH region accessibility at the time of VH-to D-JH recombination.
Trogocytosis Results in Sustained Intracellular Signaling in CD4+ T Cells
Authors: Osborne Douglas G. , Wetzel Scott A.
Published: October 2012

CD4+ T cells capture membrane and membrane-bound molecules from APCs directly from the immunological synapse in a process termed trogocytosis. The function and biological consequences of trogocytosis are largely unknown. In this study, we examine the biological significance of this phenomenon on the trogocytosis-positive T cell. We used murine fibroblasts expressing GFP-tagged I-Ek molecules loaded with a covalently attached antigenic peptide (moth cytochrome c 88–103) to present Ag to primary TCR transgenic T cells. Using a combination of high-resolution light microscopy and flow cytometry, we show that the trogocytosed molecules are retained on the surface of the T cell in association with the TCR and elevated phosphorylated ZAP-70, phosphorylated tyrosine, and phosphorylated ERK 1/2. Through the use of the Src inhibitor PP2, we demonstrate that trogocytosed molecules directly sustain TCR signaling. In addition, after removal of APC, trogocytosis-positive cells preferentially survive in culture over several days. These novel findings suggest that trogocytosed molecules continue to engage their receptors on the T cell surface and sustain intracellular signaling leading to selective survival of these cells.
The Tumor Suppressor CYLD Controls the Function of Murine Regulatory T Cells
Authors: Reissig Sonja , Hövelmeyer Nadine , Weigmann Benno , Nikolaev Alexei , Kalt Bettina , Wunderlich Thomas F. , Hahn Matthias , Neurath Marcus F. , Waisman Ari
Published: October 2012

CYLD was originally identified as a tumor suppressor gene mutated in familial cylindromatosis, an autosomal dominant predisposition to multiple benign neoplasms of the skin known as cylindromas. The CYLD protein is a deubiquitinating enzyme that acts as a negative regulator of NF-κB and JNK signaling through its interaction with NEMO and TNFR-associated factor 2. We have previously described a novel mouse strain that expresses solely and excessively a naturally occurring splice variant of CYLD (CYLDex7/8). In this study, we demonstrate that CYLD plays a critical role in Treg development and function. T cells of CYLDex7/8 mice had a hyperactive phenotype manifested by increased production of inflammatory cytokines and constitutive activation of the NF-κB pathway. Furthermore, the amount of Foxp3+ regulatory T cells in these mice was markedly enhanced in thymus and peripheral organs. Importantly, these regulatory T cells displayed decreased expression levels of CD25 and CTLA-4 associated with impaired suppressive capacity. Hence, our data emphasize an essential role of CYLD in maintaining T cell homeostasis as well as normal T regulatory cell function, thereby controlling abnormal T cell responses.
Staging and haematological abnormalities of HIV-infected persons in Mangaung in the Free State Province, South Africa
Authors: Groenewald Andries J. , Walsh Corinna M. , Van Wyk Hendrik J. , Van Zyl Sanet , Van der Merwe Lynette J.
Published: October 2012

Background: The prevalence of HIV in specific areas of South Africa and its impact on haematological parameters are largely unknown.Objectives: To (1) describe the prevalence of HIV, (2) stage HIV based on CD4 counts, and (3) determine haematological parameters amongst participants in Mangaung, Free State Province.Method: Blood specimens were obtained from 419 participants in formal and informal settlements in Mangaung. Participants were 25–64 years of age; 23.4% were male. Males and females were a mean of 45.1 and 44.3 years of age, respectively. Screening for HIV status was performed. Positive results were confirmed by a second test. Full blood counts were performed on all participants, and CD4 counts only on HIV-positive serum.Results: The overall prevalence of HIV was 40.8%. The highest prevalence occurred in the 31–40 years age group, with 38.4% of females and 39.5% of males being infected. More than 33% of HIV-uninfected participants were 51–60 years of age. No significant change in CD4 count with age was observed, probably because 19.1% of the 225 respondents who reported using medication were receiving antiretroviral (ARV) treatment. Haematological results showed that HIV-infected participants had significantly reduced values for haemoglobin, leukocytes, neutrophils and lymphocytes, compared to HIV-uninfected participants. The mean corpuscular volume (MCV) was significantly higher in HIV-infected participants.Conclusions: A high prevalence of HIV-infection was found. Anaemia and significantly reduced white blood cell counts were observed in the HIV-infected group. No significant change in CD4 counts with age was observed and could possibly be attributed to ARV therapy.
Severe Toxicity with a Generic Formulation of Zoledronic Acid: A Case Report
Authors: Sanchez Benito
Published: October 2012

Intravenous zoledronic acid (ZOL) is an integral component for the management of patients with bone metastases, but can be associated with transient flu-like symptoms, which generally occur only with the first infusion and are typically manageable with non-prescription analgesics. A 50-year-old woman with a bone metastasis secondary to breast cancer received radiation therapy, brand-name ZOL (Zometa®), and letrozole. During the first 3 cycles of Zometa (4 mg every 3–4 weeks), no acute adverse events were reported. For the next 2 cycles she was switched to generic ZOL and experienced severe toxicity (nausea, vomiting, extreme weakness, and incapacitating bone pain) that required hospitalization. Toxicity differences between generic ZOL and Zometa led the patient to pay additional costs for Zometa, and subsequent Zometa infusions were without incident. This is the first case report documenting a clinically significant difference between the safety profiles of a generic formulation of ZOL and brand-name Zometa.