bluuebunny/crossref_metadata_2025 huggingface dataset:
Emergent Knowledge Artifacts for Supporting Trialogical E-Learning
Authors: Tzitzikas Yannis , Christophides Vassilis , Flouris Giorgos , Kotzinos Dimitris , Markkanen Hannu , Plexousakis Dimitris , Spyratos Nicolas
Published: February 2011

This article elaborates on scenarios for collaborative knowledge creation in the spirit of the trialogical learning paradigm. According to these scenarios, the group knowledge base is formed by combining the knowledge bases of the participants, according to various methods. The provision of flexible methods for defining various aspects of the group knowledge is expected to enhance synergy in the knowledge creation process and could lead to the development of tools that overcome the inelasticities of the current knowledge creation practices. Subsequently, these scenarios are projected to various knowledge representation frameworks and for each one of them, we analyze and discuss related techniques and identify issues that are worth further research.
CAT-MD
Authors: Triantafillou Evangelos , Georgiadou Elissavet , Economides Anastasios A.
Published: February 2011

In the last decade, the use of different mobile products such as mobile phones and personal digital assistant (PDA) devices has increased rapidly. In parallel, the use of computerized adaptive testing (CAT) has expanded mainly due to the advancements in communication and information technology. The introduction of mobiles devices into the learning pedagogy can complement e-learning and e-testing by creating an additional channel of assessment with mobile devices. Although mobile computing has become an important and interesting research issue, little research has been done on the implementation of CAT using mobile devices. The current study describes the design issues that were considered for the development and the implementation of a CAT on mobile devices, CAT-MD (computerized adaptive testing on mobile devices).
EVAWEB V2
Authors: Gonzalez-Tablas A.I. , Ramos A. Orfila , Ribagorda A.
Published: February 2011

Security is one of the main problems in Web-based assessment systems, particularly in guaranteeing the non-repudiation of test submissions. The authors have developed EVAWEB, a Web-based assessment system that addresses this issue by using digital signatures. Moreover, the use of this technology in EVAWEB provides a real context to students for learning how digital signatures work. This article focuses on the enhancements that have been incorporated into EVAWEB in order to develop an improved second version of the system.
An Application of the LS-Plan System to an Educational Hypermedia
Authors: Limongelli Carla , Sciarrone Filippo , Vaste Giulia
Published: February 2011

LS-Plan is a system capable to provide educational hypermedia with adaptivity. During the student’s navigation in hyperspace, the system, by means of a suitable interface, receives in input, for each visited learning node, a behavioral pattern, containing the student’s knowledge acquired or not acquired in that node and measured by a post-test questionnaire. Then, by means of the adaptation algorithms, the system returns a Learning Object Sequence to the hypermedia, just to be recommended to the student. In this work we investigate in detail the adaptation algorithms together with the didactic strategies behind them, through an application to a real learning domain, subdivided in five case studies. Moreover, we show in detail how the automated planner, embedded into the system, allows consistency checks during the arrangement of the pool of Learning Nodes, allowing the teacher to define possible didactic strategies during automatic course personalization. Finally, the performance of the system is evaluated by means of an experimental design with positive results.
A Case-Based Approach to Adaptive Hypermedia Navigation
Authors: Micarelli Alessandro , Sciarrone Filippo , Gasparetti Fabio
Published: February 2011

Hypermedia, with its combination of multimedia and non-linear organization of links among informative nodes, provides a highly interactive environment. In structured domains such as Web-based Educational Systems, the complexity of the learning domain often requires a large set of learning nodes and conceptual interrelationships that can cause several issues, e.g.: lack of comprehension, disorientation and inefficacious learning strategies. In this article we propose a new approach to guided navigation in hypermedia-based domains, suitable for helping users in structured and complex learning environments such as cultural heritage domains. Our proposal draws inspiration from the Case-Based Reasoning paradigm associated with a hypermedia structural analysis. In particular, our presentation highlights the use of a hybrid architecture for Adaptive Navigation Support, where the indexing problem of the case-based reasoner is solved by way of a sub-symbolic approach. A case study in the Neo-Realist Italian Cinema domain is discussed along with a formal and controlled evaluation that proves the advantages of the proposed approach.
Minimal Functionalities of Course Management Systems
Authors: Adlakha V. G. , Aggarwal A. K.
Published: February 2011

In this article the authors offer a faculty perspective on desirable features of a Course Management System (CMS). This article is the result of our Web teaching experiences over a period of eight years using three different CMS platforms. The authors anticipate that this article could help guide software developers in developing appropriate CMS tools and would help institutions to gain greater insight into the selection of an appropriate CMS for effective Web-based or web-enhanced education (WBE). We develop a list of necessary functionalities that a CMS must provide for web-based education. The discussion could also assist current and future Web course instructors by increasing their awareness to take advantage of many features that might exist in their CMS.
Practitioner Case Study
Authors: Brewer Daniel , Adamson Greg
Published: February 2011

This interview-based case study describes current portal project practices based on a diverse set of projects, including B2B, B2C, B2E, E2E and mobile. Since 2000 portals have increased their functionality, and widespread availability of portal software has encouraged organisations to install and experiment with them. Portals are adding value by drawing applications together, particularly through search, and assembling existing tools for a user in a way that enhances their value. Operational challenges include support and security. Success has depended on beginning with support and security frameworks based on similar industry experience. Performance has been the key project success factor, and project sponsors are beginning to understand non-functional requirements: portability, scalability, availability, reliability and security. SOA principles are only partially applied, due to investment in existing systems. A recent trend is Microsoft SharePoint’s rapid market growth through ease of implementation.
SOA Implementation Challenges for Medium Sized Corporations
Authors: Worley Brenton , Adamson Greg
Published: February 2011

In the commercial world, SOA implementation practitioners are finding a gulf between tools, whether vendor-based or open source, and the practical first needs of customers. Future-facing tool developers are addressing problems of orchestration to achieve the SOA promise. Most corporations, however, have not yet established either the services to be abstracted, or the governance requirements around exposing those services, such as the right level of service granularity. This case study is based on recent experience in the utility and retail sectors. The drivers for each are compelling: a business-driven need for IT flexibility. Examples are provided to show that customers in both sectors need to develop their architecture and governance before attempting to choose the right tools. Confusion also exists between tools and off-the-shelf solutions in the SOA environment. The challenge of agile approach for SOA development is also examined.
Using the Building Blocks
Authors: Lamantia Joe
Published: February 2011

This article is a case study that explores the use of the Building Blocks portal design framework over a series of enterprise portal projects spanning several years. This article describes the business contexts that shaped each portal as it was designed, showing the use and reuse of design and development elements based on the Building Blocks. This article discusses the changes and adaptations that shaped the elements of the Building Blocks design framework over time.
The Philosophy of Software Architecture
Authors: Goel Amit
Published: February 2011

Computer Software Intensive systems have become ingrained in our daily life. Apart from obvious scientific and business applications, various embedded devices are empowered with computer software. Such a diverse application of Computer Software has led to inherent complexity in building such systems. As civilizations moved forward, the concept of architectural thinking and practice was introduced to grapple with the complexity and other challenges of creating buildings, skyscrapers, townships, and cities. The Practice of Software Architecture is an attempt to understand and handle similar challenges in Software Intensive Systems. This paper introduces software architecture and the underlying philosophy thereof. This paper provokes a discussion around the present and future of Software Architecture. The authors discuss skills and roles of Software Architect.
Security System for Distributed Business Applications
Authors: Schmidt Thomas , Wippel Gerald , Glanzer Klaus , Furst Karl
Published: February 2011

Internet-focused application components of cooperating enterprises need comprehensive security technologies that go far beyond simple Internet authentication and authorization mechanisms. Basically, authentication is the process of determining the identity of a user or system, whereas authorization is the process of specifying who is allowed to access which resources. XML-based Web services is an upcoming and very promising technology. It enables the communication among Internet application components regardless of their implementation language. A major drawback of existing Web service approaches is the missing security conventions. Therefore, we concentrated all our effort on developing a holistic extended enterprise authentication and authorization system to facilitate agile and secure enterprise-spanning business processes with Web service-enabled application components.
The Deployment of Protocol Stack Components Using Web Services
Authors: Curran Kevin , Gallagher Brendan
Published: February 2011

Multimedia has varying optimal transport methods. The traditional methods employed by transport protocols are to ship all data through identical protocol stacks. An ideal method would transport each media through an optimized stack constructed solely for that medium, allowing improved multimedia QoS to be achieved even at runtime. Dynamically composable protocol stacks overcome the limitations imposed by generic protocol stacks. A dynamically composable protocol stack allows optimization for particular traffic. Here, protocol layers such as real-time G.711 or PCM conversion capabilities could be deployed to address the impedance matching across heterogeneous receivers. Protocol layers are created by the protocol stack (using a Protocol Profiler) according to a properties argument defined when creating an instance of Stack. The SOAP is a lightweight remote procedure calling protocol for the exchange of structured data in a decentralized environment. SOAP enables programs to run and interoperate with other SOAP applications (called Web services) in a distributed environment. The SOAP protocol is based on eXtensible Markup Language (XML) and Hypertext Transmission Protocol (HTTP), which, it is claimed, makes it a language- and platform-neutral vehicle for RPC over the Internet and through firewalls. This paper describes a SOAP Web service deployed on an apache Tomcat server that enables clients to download protocol stack components as MIME attachments. The deployment middleware framework is named Webber. Webber provides additional flexibility that can be extremely useful for environments that have not been considered by standard generic protocols.
Model-Based Development of Web Services Descriptions Enabling a Precise Matching Concept
Authors: Hausmann Jan Hendrik , Heckel Reiko , Lohmann Marc
Published: February 2011

Web services are software components that can be discovered and employed at runtime using the Internet. Conflicting requirements towards the nature of these services can be identified. From a business perspective, Web services promise to enable the formation of ad-hoc cooperations on a global scale. From a technical perspective, a high degree of standardization and rigorous specifications are required to enable the automated integration of Web services. A suitable technology for Web services has to mediate these needs for flexibility and stability. To be usable in practice, this technology has to be aligned to standard software engineering practice to allow for a seamless development of Web service enabled components. In this paper, we introduce a new approach to the description of Web services. It is a visual approach based on the use of software models and graph transformations and allows for the flexible description of innovative services while providing a precise matching concept. A methodology enabling the seamless development of such Web service descriptions in the context of a standard model-based development approach is presented.
Realizability of Conversation Protocols with Message Contents
Authors: Fu Xiang , Bultan Tevfik , Su Jianwen
Published: February 2011

A promising way to model the global behavior of a Web Service composition is to characterize the set of conversations among the participating Web Services. A conversation protocol specifies the desired global behaviors of a Web Service composition. The realizability problem is to decide whether, given a conversation protocol, a Web Service composition can be synthesized that generates exactly the same set of conversations specified by the protocol. This is a key problem in the top-down specification of the Web Service compositions. In our earlier work, we developed sufficient conditions for realizability of conversation protocols based on a model that abstracts the contents of the messages. The present paper extends our earlier work by allowing message contents to be used in the realizability analysis. We show that taking the message contents into account yields more accurate analysis. To overcome the state-space explosion caused by the message contents, we propose symbolic analysis techniques for the realizability conditions. In addition, we show that the analysis of one of the realizability conditions — the autonomy condition — can be done using an iterative refinement approach.
XWRAPComposer
Authors: Liu Ling , Zhang Jianjun , Han Wei , Pu Carlton , Caverlee James , Park Sungkeun , Critchlow Terence , Buttler David , Coleman Matthew
Published: February 2011

We present a service-oriented architecture and a set of techniques for developing wrapper code generators, including the methodology of designing an effective wrapper program construction facility and a concrete implementation, called XWRAPComposer. Our wrapper generation framework has two unique design goals. First, we explicitly separate tasks of building wrappers that are specific to a Web service from the tasks that are repetitive for any service, thus the code can be generated as a wrapper library component and reused automatically by the wrapper generator system. Second, we use inductive learning algorithms that derive information flow and data extraction patterns by reasoning about sample pages or sample specifications. More importantly, we design a declarative rule-based script language for multi-page information extraction, encouraging a clean separation of the information extraction semantics from the information flow control and execution logic of wrapper programs. We implement these design principles with the development of the XWRAPComposer toolkit, which can semi-automatically generate WSDL-enabled wrapper programs. We illustrate the problems and challenges of multi-page data extraction in the context of bioinformatics applications and evaluate the design and development of XWRAPComposer through our experiences of integrating various BLAST services.
Auction-Based Pricing Model for Web Service Providers
Authors: Zhang Jia , Zhang Ning , Zhang Liang-Jie
Published: February 2011

Applying auctions to Web services selection and invocation calls for examination due to the unique features of Web services, such as interoperable machine-to machine interactions and re-enterable bargaining services. In this paper, we propose a formal model for Web services-based auctions. Examining a one sided sealed auction type, we prove mathematically that service requestors’ risk preferences could lead to different pricing strategies for service providers towards higher profit. We argue that Service Level Agreement (SLA) documents can be used to analyze service requestors’ preferences. On top of WS Agreement, we propose a basic service requestor risk preference elicitation algorithm, as well as a historical data-based service requestor risk preference prediction model. Guidelines are provided to iteratively approach the learning rate of the proposed risk preference prediction model. The methods and techniques presented in this paper can be reused to investigate and examine more facades of services-oriented auctions towards establishing a new research realm on comprehensive services-oriented auctions.
A Service-Oriented Composition Framework with QoS Management
Authors: Fung Casey K. , Hung Patrick C.K. , Linger Richard C. , Wang Guijun , Walton Gwendolyn H.
Published: February 2011

Quality of Services (QoS) management in compositions of services requires careful consideration of QoS characteristics of the services and effective QoS management in their execution. This paper describes an approach to implementation of QoS management in compositions of Web services in the context of Computational Quality Attributes and Service Level Agreements. Building on prior research work of others in the use of Message Detail Records, this paper integrates the results from several research threads to propose a QoS Management Architecture to support dynamic processing of service- and flow level quality attributes to support QoS requests and analyses in Web-service-oriented architectures. The study of QoS management in a Web service composition framework was motivated by the evolution of the composition framework for a toolkit for integration and experimentation of distributed system applications. A message tracking model is proposed for supporting QoS end-to-end management by applying the Computational Quality Attribute (CQA) concepts of Flow-Service-Quality engineering. Quality attributes are defined, computed and acted upon as dynamic characteristics of systems, with values constantly changing in operation. A CQA provision is illustrated, with a simple Web Services travel reservation example. The example is elaborated to illustrate QoS end-to-end management using the Simple Object Access Protocol (SOAP) message tracking model.
Web Service Architectures for Text Mining
Authors: Davis Neil , Demetriou George , Gaizauskas Robert , Guo Yikun , Roberts Ian
Published: February 2011

Text mining technology can be used to assist in finding relevant or novel information in large volumes of unstructured data, such as that which is increasingly available in the electronic scientific literature. However, publishers are not text mining specialists, nor typically are the end user scientists who consume their products. This situation suggests a web services based solution, where text mining specialists process the literature obtained from publishers and make their results available to remote consumers (research scientists). In this paper we discuss the integration of web services and text mining within the domain of scientific publishing and explore the strengths and weaknesses of three generic architectural designs for delivering text mining web services. We argue for the superiority of one of these and demonstrate its viability by reference to an application designed to provide access to the results of text mining over the PubMed database of scientific abstracts.
Web Service Discovery and Composition for Virtual Enterprises
Authors: Dorn Jürgen , Hrastnik Peter , Rainer Albert
Published: February 2011

One main characteristic of virtual enterprises are short-term collaborations between business partners to provide efficient and individualized services to customers. The MOVE project targets at a methodology and a software framework to support such flexible collaborations based on process oriented design and communication by Web services. MOVE’s framework supports the graphical design and verification of business processes, the execution and supervision of processes in transaction-oriented environment, and the dynamic composition and optimization of processes. A business process may be composed from a set of Web services, deployed itself as Web service and executed in the framework. The composition of processes from Web services is implemented with methods from AI-planning. We apply answer set programming (ASP) and map Web service descriptions and customer requests into the input language of the ASP software DLV. Composition goals and constraints guide a composition challenge. We show the performance of our program and give some implementation details. Finally we conclude with some insights.
WSMoD
Authors: Comerio M. , De Paoli F. , Grega S. , Maurino A. , Batini Carlo
Published: February 2011

Web services are increasingly used as an effective means to create and streamline processes and collaborations among governments, businesses, and citizens. As the number of available Web services is steadily increasing, there is a growing interest in providing methodologies that address the design of Web services according to specific qualities of service (QoS) rather than functional descriptions only. In this paper, we present WSMoD (Web Services MOdeling Design), a methodology that explicitly addresses this issue. Furthermore, we exploit general knowledge available on services, expressed by ontologies describing services, their qualities, and the context of use, to help the designer in expressing service requirements. Ontologies are used to acquire knowledge among the entities involved in service design and to check the consistency of the Web service. The discussion of a QoS-based Web service design within a real case study bears evidence of the potentials of WSMoD.
Pricing Utility Computing Services
Authors: Denne Mark
Published: February 2011

Utility computing is the emerging term for the delivery of information technology in a “payas-you go” model. It has attracted considerable attention as a means of delivering lower total cost of ownership (TCO) and more predictable service levels for in-house IT. At its heart, utility transformation allows IT consumers to switch from capital-based procurement of IT assets to operational cost procurement of IT services. Unsurprisingly, the change is closely linked with the adoption of service oriented architectures (SOA) and service oriented infrastructures (SOI). In fact, utility transformation often provides the overarching business and financial framework for driving a move to SOA. It defines the IT chargeback environment and the resulting compelling business context.Key to the success of utility transformation is the implementation of appropriate service pricing models. A variety of innovative pricing models can be used to improve service predictability, to create incentives for certain behaviors, and to manage the flow of notional revenue to the IT organization (ITO). They are invaluable to the SOA business case. This article examines several such models.
Ubiquitous Provision of Context-Aware Web Services
Authors: Yang Stephen J.H. , Zhang Jia , Chen Irene Y.L.
Published: February 2011

Providing context-aware Web services refers to an adaptive process of delivering contextually matched Web services to meet service requesters’ needs at the moment. This article presents an ontology-based context model that enables formal description and acquisition of contextual information pertaining to both service requesters and services. The context model is supported by context query and phased acquisition techniques. We also report two context-aware Web services built on top of our context model to demonstrate how the model can be used to facilitate Web services discovery and Web content adaptation. Implementation details of the context elicitation system and the evaluation results of context-aware services provision are also reported.
Pattern-Based Translation of BPMN Process Models to BPEL Web Services
Authors: Ouyang Chun , Dumas Marlon , H.M. Arthur , van der Aalst Wil M.P.
Published: February 2011

The business process modeling notation (BPMN) is a graph-oriented language primarily targeted at domain analysts and supported by many modeling tools. The business process execution language for Web services (BPEL) on the other hand is a mainly block-structured language targeted at software developers and supported by several execution platforms. Translating BPMN models into BPEL code is a necessary step towards standards-based business process development environments. This translation is challenging since BPMN and BPEL represent two fundamentally different classes of languages. Existing BPMN-to-BPEL translations rely on the identification of block-structured patterns in BPMN models that are mapped onto structured BPEL constructs. This article advances the state of the art in BPMN-to-BPEL translation by defining methods for identifying not only perfectly block-structured fragments in BPMN models, but quasi-structured fragments that can be turned into perfectly structured ones and flow-based acyclic fragments that can be mapped onto a combination of structured constructs and control links. Beyond its direct relevance in the context of BPMN and BPEL, this article addresses issues that arise generally when translating between graph-oriented and block-structured flow definition languages.
Constructing Home Network Systems and Integrated Services Using Legacy Home Appliances and Web Services
Authors: Nakamura Masahide , Tanaka Akihiro , Igaki Hiroshi , Tamada Haruaki , Matsumoto Ken-ichi
Published: February 2011

This article presents a framework that adapts the conventional home electric appliances with the infrared remote controls (legacy appliances) to the emerging home network system (HNS). The proposed method extensively uses the concept of service-oriented architecture to improve programmatic interoperability among multi-vendor appliances. We first prepare APIs that assist a PC to send infrared signals to the appliances. We then aggregate the APIs within self-contained service components, so that each of the components achieves a logical feature independent of device/vendor-specific operations. The service components are finally exhibited to the HNS as Web services. As a result, the legacy appliances can be used as distributed components with open interfaces. To demonstrate the effectiveness, we implement an actual HNS and integrated services with multi-vendor legacy appliances.
XML Compression for Web Services on Resource-Constrained Devices
Authors: Werner Christian , Buschmann Carsten , Brandt Ylva , Fischer Stefan
Published: February 2011

Compared to other middleware approaches like CORBA or Java RMI the protocol overhead of SOAP is very high. This fact is not only disadvantageous for several performance-critical applications, but especially in environments with limited network bandwidth or resource-constrained computing devices. Although recent research work concentrated on more compact, binary representations of XML data only very few approaches account for the special characteristics of SOAP communication. In this article we will discuss the most relevant state-of-the-art technologies for compressing XML data. Furthermore, we will present a novel solution for compacting SOAP messages. In order to achieve significantly better compression rates than current approaches, our compressor utilizes structure information from an XML Schema or WSDL document. With this additional knowledge on the “grammar” of the exchanged messages, our compressor generates a single custom pushdown automaton, which can be used as a highly efficient validating parser as well as a highly efficient compressor. The main idea is to tag the transitions of the automaton with short binary identifiers that are then used to encode the path trough the automaton during parsing. Our approach leads to extremely compact data representations and is also usable in environments with very limited CPU and memory resources.
A Model-Driven Development Framework for Non-Functional Aspects in Service Oriented Architecture
Authors: Wada Hiroshi , Suzuki Junichi , Oba Katsuya
Published: February 2011

Service oriented architecture (SOA) is an emerging style of software architectures to reuse and integrate existing systems for designing new applications. Each application is designed in an implementation independent manner using two major abstract concepts: services and connections between services. In SOA, non-functional aspects (e.g., security and fault tolerance) of services and connections should be described separately from their functional aspects (i.e., business logic) because different applications use services and connections in different non-functional contexts. This paper proposes a model-driven development (MDD) framework for non-functional aspects in SOA. The proposed MDD framework consists of (1) a Unified Modeling Language (UML) profile to model non-functional aspects in SOA, and (2) an MDD tool that transforms a UML model defined with the proposed profile to application code. Empirical evaluation results show that the proposed MDD framework improves the reusability and maintainability of service-oriented applications by hiding low-level implementation technologies in SOA.
Early Capacity Testing of an Enterprise Service Bus
Authors: Ueno Ken , Tatsubori Michiaki
Published: February 2011

An enterprise service-oriented architecture is typically done with a messaging infrastructure called an Enterprise Service Bus (ESB). An ESB is a bus which delivers messages from service requesters to service providers. Since it sits between the service requesters and providers, it is not appropriate to use any of the existing capacity planning methodologies for servers, such as modeling, to estimate the capacity of an ESB. There are programs that run on an ESB called mediation modules. Their functionalities vary and depend on how people use the ESB. This creates difficulties for capacity planning and performance evaluation. This article proposes a capacity planning methodology and performance evaluation techniques for ESBs, to be used in the early stages of the system development life cycle. The authors actually run the ESB on a real machine while providing a pseudo-environment around it. In order to simplify setting up the environment they provide ultra-light service requestors and service providers for the ESB under test. The authors show that the proposed mock environment can be set up with practical hardware resources available at the time of hardware resource assessment. Their experimental results showed that the testing results with our mock environment correspond well with the results in the real environment.
Automatic Determination of Compatibility in Evolving Services
Authors: Becker Karin , Pruyne Jim , Singhal Sharad , Lopes Andre , Milojicic Dejan
Published: February 2011

A major advantage of Service-Oriented Architectures (SOA) is composition and coordination of loosely coupled services. Because the development lifecycles of services and clients are de-coupled, multiple service versions must be maintained to support older clients. Typically versions are managed within the SOA by updating service descriptions using conventions on version numbers and namespaces. In all cases, the compatibility among services descriptions must be evaluated, which can be hard, error-prone and costly if performed manually, particularly for complex descriptions. In this paper, the authors describe a method to automatically determine when two service descriptions are backward compatible. The authors describe a case study to illustrate version compatibility information in a SOA environment and present initial performance overheads. By automatically exploring compatibility information, a) service developers can assess the impact of proposed changes; b) proper versioning requirements can be put in client implementations guaranteeing that incompatibilities will not occur during run-time; and c) messages exchanged in the SOA can be validated to ensure that only expected messages or compatible ones are exchanged.
Uridine 5′-Diphosphate Induces Chemokine Expression in Microglia and Astrocytes through Activation of the P2Y6 Receptor
Authors: Kim Beomsue , Jeong Hey-kyeong , Kim Jong-hyeon , Lee Sang Yoon , Jou Ilo , Joe Eun-hye
Published: February 2011

Chemokines play critical roles in inflammation by recruiting inflammatory cells to injury sites. In this study, we found that UDP induced expression of chemokines CCL2 (MCP-1) and CCL3 (MIP-1α) in microglia, astrocytes, and slice cultures by activation of P2Y6. Interestingly, CCL2 was more highly expressed than CCL3. However, CCL2 synthesis kinetics in response to UDP differed in microglia and astrocytes; microglia rapidly produced small amounts of CCL2, whereas astrocytes continuously synthesized large amounts of CCL2, resulting in a high ultimate level of the chemokine. UDP-induced chemokine expression was reduced in the presence of a specific antagonist of P2Y6 (MRS2578) or small interfering RNA directed against the P2Y6 gene. Inhibition of phospholipase C and calcium increase, downstream signaling pathways of Gq-coupled P2Y6, reduced UDP-induced chemokine expression. UDP activated two calcium-activated transcription factors, NFATc1 and c2. Furthermore, inhibitors of calcineurin (a phosphatase activating NFAT) and NFAT reduced UDP-induced chemokine synthesis. We also found, using a transmigration assay, that UDP-treated astrocytes recruited monocytes. These results suggest that UDP induces chemokine expression in microglia and astrocytes of the injured brain by activation of P2Y6 receptors.
IL-12 Enhances the Antitumor Actions of Trastuzumab via NK Cell IFN-γ Production
Authors: Jaime-Ramirez Alena Cristina , Mundy-Bosse Bethany L. , Kondadasula SriVidya , Jones Natalie B. , Roda Julie M. , Mani Aruna , Parihar Robin , Karpa Volodymyr , Papenfuss Tracey L. , LaPerle Krista M. , Biller Elizabeth , Lehman Amy , Ray Chaudhury Abhik , Jarjoura David , Burry Richard W. , Carson William E.
Published: February 2011

The antitumor effects of therapeutic mAbs may depend on immune effector cells that express FcRs for IgG. IL-12 is a cytokine that stimulates IFN-γ production from NK cells and T cells. We hypothesized that coadministration of IL-12 with a murine anti-HER2/neu mAb (4D5) would enhance the FcR-dependent immune mechanisms that contribute to its antitumor activity. Thrice-weekly therapy with IL-12 (1 μg) and 4D5 (1 mg/kg) significantly suppressed the growth of a murine colon adenocarcinoma that was engineered to express human HER2 (CT-26HER2/neu) in BALB/c mice compared with the result of therapy with IL-12, 4D5, or PBS alone. Combination therapy was associated with increased circulating levels of IFN-γ, monokine induced by IFN-γ, and RANTES. Experiments with IFN-γ–deficient mice demonstrated that this cytokine was necessary for the observed antitumor effects of therapy with IL-12 plus 4D5. Immune cell depletion experiments showed that NK cells (but not CD4+ or CD8+ T cells) mediated the antitumor effects of this treatment combination. Therapy of HER2/neu-positive tumors with trastuzumab plus IL-12 induced tumor necrosis but did not affect tumor proliferation, apoptosis, vascularity, or lymphocyte infiltration. In vitro experiments with CT-26HER2/neu tumor cells revealed that IFN-γ induced an intracellular signal but did not inhibit cellular proliferation or induce apoptosis. Taken together, these data suggest that tumor regression in response to trastuzumab plus IL-12 is mediated through NK cell IFN-γ production and provide a rationale for the coadministration of NK cell-activating cytokines with therapeutic mAbs.
Estriol Generates Tolerogenic Dendritic Cells In Vivo That Protect against Autoimmunity
Authors: Papenfuss Tracey L. , Powell Nicole D. , McClain Melanie A. , Bedarf Ashley , Singh Amber , Gienapp Ingrid E. , Shawler Todd , Whitacre Caroline C.
Published: February 2011

Chronic inflammation contributes to numerous diseases, and regulation of inflammation is crucial for disease control and resolution. Sex hormones have potent immunoregulatory abilities. Specifically, estrogen influences immune cells and inflammation, which contributes to the sexual dimorphism of autoimmunity and protection against disease seen during pregnancy in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Although long thought to act primarily on T cells, recent evidence demonstrated that myeloid cells, such as dendritic cells (DCs), are essential in mediating estrogen’s protective effects. Estriol (E3), a pregnancy-specific estrogen, has therapeutic efficacy in MS and EAE, and we evaluated whether E3 could act exclusively through DCs to protect against the inflammatory autoimmune disease EAE. Levels of activation markers (CD80 and CD86) and inhibitory costimulatory markers (PD-L1, PD-L2, B7-H3, and B7-H4) were increased in E3 DCs. E3 DCs had decreased proinflammatory IL-12, IL-23, and IL-6 mRNA expression, increased immunoregulatory IL-10 and TGF-β mRNA expression, and a decreased ratio of IL-12/IL-10 protein production. Importantly, transfer of E3 DCs to mice prior to active induction of EAE protected them from developing EAE through immune deviation to a Th2 response. This protection was apparent, even in the face of in vitro and in vivo inflammatory challenge. In summary, our results showed that E3 generates tolerogenic DCs, which protect against the inflammatory autoimmune disease EAE. Targeted generation of tolerogenic DCs with immunomodulatory therapeutics, such as E3, has potential applications in the treatment of numerous autoimmune and chronic inflammatory diseases.
Inhibition of Type 1 Diabetes Correlated to a Lactobacillus johnsonii N6.2-Mediated Th17 Bias
Authors: Lau Kenneth , Benitez Patrick , Ardissone Alexandria , Wilson Tenisha D. , Collins Erin L. , Lorca Graciela , Li Nan , Sankar Dhyana , Wasserfall Clive , Neu Josef , Atkinson Mark A. , Shatz Desmond , Triplett Eric W. , Larkin Joseph
Published: February 2011

Although it is known that resident gut flora contribute to immune system function and homeostasis, their role in the progression of the autoimmune disease type 1 diabetes (T1D) is poorly understood. Comparison of stool samples isolated from Bio-Breeding rats, a classic model of T1D, shows that distinct bacterial populations reside in spontaneous Bio-Breeding diabetes-prone (BBDP) and Bio-Breeding diabetes-resistant animals. We have previously shown that the oral transfer of Lactobacillus johnsonii strain N6.2 (LjN6.2) from Bio-Breeding diabetes-resistant to BBDP rodents conferred T1D resistance to BBDP rodents, whereas Lactobacillus reuteri strain TD1 did not. In this study, we show that diabetes resistance in LjN6.2-fed BBDP rodents was correlated to a Th17 cell bias within the mesenteric lymph nodes. The Th17 bias was not observed in the non-gut–draining axillary lymph nodes, suggesting that the Th17 bias was because of immune system interactions with LjN6.2 within the mesenteric lymph node. LjN6.2 interactions with the immune system were observed in the spleens of diabetes-resistant, LjN6.2-fed BBDP rats, as they also possessed a Th17 bias in comparison with control or Lactobacillus reuteri strain TD1–fed rats. Using C57BL/6 mouse in vitro assays, we show that LjN6.2 directly mediated enhanced Th17 differentiation of lymphocytes in the presence of TCR stimulation, which required APCs. Finally, we show that footpad vaccination of NOD mice with LjN6.2-pulsed dendritic cells was sufficient to mediate a Th17 bias in vivo. Together, these data suggest an interesting paradigm whereby T1D induction can be circumvented by gut flora-mediated Th17 differentiation.
T Cell Development Critically Depends on Prethymic Stromal Patched Expression
Authors: Uhmann Anja , van den Brandt Jens , Dittmann Kai , Heß Ina , Dressel Ralf , Binder Claudia , Lühder Fred , Christiansen Hans , Fassnacht Martin , Bhandoola Avinash , Wienands Jürgen , Reichardt Holger M. , Hahn Heidi
Published: February 2011

We recently described that T cell specification in mice deficient in the Hedgehog (Hh) receptor Patched (Ptch) is blocked at the level of the common lymphoid progenitor in the bone marrow (BM). Adoptive transfer of wild-type BM in Ptch-deficient mice provides evidence that T cell development strictly depends on Ptch expression in the nonhematopoietic compartment. Transplantation experiments using BM deficient in the glucocorticoid receptor exclude any involvement of the stress hormone corticosterone in our model. Using cell-type–specific knockout mice, we show that T cell development is independent of T cell-intrinsic Ptch expression. Furthermore, Ptch expression by the thymus stroma is dispensable, as revealed by fetal thymus organ culture and thymus transplantation. In contrast, analysis of the earliest thymic progenitors in Ptch-deficient mice indicated that Ptch is required for the development or supply of thymic homing progenitors that give rise to earliest thymic progenitors. Collectively, our findings identified Ptch as an exclusive T cell-extrinsic factor necessary for proper development of T cells at their prethymic stage. This observation may be important for current considerations using Hh inhibitors upstream of Ptch in diseases accompanied by aberrant Hh signaling.
Long-Term Control of Simian Immunodeficiency Virusmac251 Viremia to Undetectable Levels in Half of Infected Female Rhesus Macaques Nasally Vaccinated with Simian Immunodeficiency Virus DNA/Recombinant Modified Vaccinia Virus Ankara
Authors: Manrique Mariana , Kozlowski Pamela A. , Cobo-Molinos Antonio , Wang Shainn-Wei , Wilson Robert L. , Montefiori David C. , Mansfield Keith G. , Carville Angela , Aldovini Anna
Published: February 2011

The efficacy of two SIV DNA plus recombinant modified vaccinia virus Ankara nasal vaccine regimens, one combined with plasmids expressing IL-2 and IL-15, the other with plasmids expressing GM-CSF, IL-12, and TNF-α, which may better stimulate humoral responses, was evaluated in two female rhesus macaque groups. Vaccination stimulated significant SIV-specific mucosal and systemic cell-mediated immunity in both groups, whereas SIV-specific IgA titers were sporadic and IgG titers negative. All vaccinated animals, except one, became infected after intravaginal SIVmac251 low-dose challenge. Half of the vaccinated, infected animals (7/13) promptly controlled virus replication to undetectable viremia for the duration of the trial (130 wk) and displayed virological and immunological phenotypes similar to those of exposed, uninfected individuals. When all vaccinated animals were considered, a 3-log viremia reduction was observed, compared with controls. The excellent viral replication containment achieved in vaccinated animals translated into significant preservation of circulating α4β7high+/CD4+ T cells and of circulating and mucosal CD4+/CM T cells and in reduced immune activation. A more significant long-term survival was also observed in these animals. Median survival was 72 wk for the control group, whereas >50% of the vaccinated animals were still disease free 130 wk postchallenge, when the trial was closed. There was a statistically significant correlation between levels of CD4+/IFN-γ+ and CD8+/IFN-γ+ T cell percentages on the day of challenge and the control of viremia at week 60 postchallenge or survival. Postchallenge immunological correlates of protection were systemic anti-SIV Gag + Env CD4+/IL-2+, CD4+/IFN-γ+, and CD8+/TNF-α+ T cells and vaginal anti-SIV Gag + Env CD8+ T cell total monofunctional responses.
Impaired Wound Healing with Defective Expression of Chemokines and Recruitment of Myeloid Cells in TLR3-Deficient Mice
Authors: Lin Qing , Fang Dan , Fang Jiazhu , Ren Xiangrong , Yang Xiaoping , Wen Feng , Su Shao Bo
Published: February 2011

Skin injury evokes both innate and adaptive immune responses to restore tissue integrity. TLRs play a critical role in host responses to injurious insults. Previous studies demonstrated that RNAs released from damaged tissues served as endogenous ligands for TLR3. In this study, we investigated the involvement of TLR3 in skin restoration after injury. Full excisional wounds were created on the skin of mice with TLR3 deficiency. We found that skin wound closure in TLR3−/− mice was significantly delayed compared with control littermates. Wound healing parameters, including re-epithelialization, granulation formation, and neovascularization, were decreased in TLR3−/− mice. Further studies revealed that the absence of TLR3 led to defective recruitment of neutrophils and macrophages, in association with decreased expression of the chemokines, MIP-2/CXCL2, MIP-1α/CCL3, and MCP-1/CCL2, in the wound. Moreover, in wild type mice, the mRNA level and protein content of TLR3 was significantly upregulated in wounded skins and silencing of TLR3 signal adaptor Toll/IL-1R domain-containing adapter inducing IFN-β with small interfering RNA retarded wound closure. These results indicate an essential role for TLR3 and Toll/IL-1R domain-containing adapter inducing IFN-β in wound healing by regulating chemokine production and recruitment of myeloid cells to wound for tissue repair.
Supplemental and Highly Elevated Tocopherol Doses Differentially Regulate Allergic Inflammation: Reversibility of α-Tocopherol and γ-Tocopherol’s Effects
Authors: McCary Christine A. , Abdala-Valencia Hiam , Berdnikovs Sergejs , Cook-Mills Joan M.
Published: February 2011

We have reported that supplemental doses of the α- and γ-tocopherol isoforms of vitamin E decrease and increase, respectively, allergic lung inflammation. We have now assessed whether these effects of tocopherols are reversible. For these studies, mice were treated with Ag and supplemental tocopherols in a first phase of treatment followed by a 4-wk clearance phase, and then the mice received a second phase of Ag and tocopherol treatments. The proinflammatory effects of supplemental levels of γ-tocopherol in phase 1 were only partially reversed by supplemental α-tocopherol in phase 2, but were completely reversed by raising α-tocopherol levels 10-fold in phase 2. When γ-tocopherol levels were increased 10-fold (highly elevated tocopherol) so that the lung tissue γ-tocopherol levels were equal to the lung tissue levels of supplemental α-tocopherol, γ-tocopherol reduced leukocyte numbers in the lung lavage fluid. In contrast to the lung lavage fluid, highly elevated levels of γ-tocopherol increased inflammation in the lung tissue. These regulatory effects of highly elevated tocopherols on tissue inflammation and lung lavage fluid were reversible in a second phase of Ag challenge without tocopherols. In summary, the proinflammatory effects of supplemental γ-tocopherol on lung inflammation were partially reversed by supplemental levels of α-tocopherol but were completely reversed by highly elevated levels of α-tocopherol. Also, highly elevated levels of γ-tocopherol were inhibitory and reversible in lung lavage but, importantly, were proinflammatory in lung tissue sections. These results have implications for future studies with tocopherols and provide a new context in which to review vitamin E studies in the literature.