bluuebunny/crossref_metadata_2025 huggingface dataset:
Evolutionary Learning Organization in a System Orientation of Ethico-Economics
Authors: Choudhury Masudul Alam
Published: April 2014

A new theory of learning organization bordering evolutionary economics and management is introduced. It is referred to as an evolutionary learning organizational theory of behavior, decision-making, and goals of wellbeing in the larger context of the organization in a systemic sense of organic relations. The structure, functions, and analytical features of such an organization are studied in the context of an epistemological approach in order to lay down the inherent theory. This leads to a mathematical and rigorous explanation of the theory in a comparative and contrasting light with other contributions on learning organizations. The exemplification of the unique theory of evolutionary learning organization is found to exist in Islamic epistemological context. The chapter is made for this particular case within a generalized system model of wellbeing for decision-making of the firm that overarches intra-system and inter-systems at large.
The Green 5-S Model for Organisational Learning and Development
Authors: Ho Samuel K. M.
Published: April 2014

Riding on his Total Learning Organisation (TLO), an ice-breaking paper published in The Learning Organisation, Ho (1999) has a chance to test out the model in a number of firms in HKSAR, China and Malaysia, based on his proprietary 5-S Practice, which he developed in Malaysia/HK/UK/China since the 1990s. Supported by various government bodies, Ho (2012) has used his 50-point 5-S Checklist for training and consultancy in no less than 10 countries with over 50,000 persons from over 1,000 organisations worldwide. From his observation and experience, in this chapter a powerful learning model for innovation in organizations is developed through what he defined in 1999 as the TLO. One significant finding is that in order to ensure effective knowledge transfer and organizational development, organisations should consider using a simple and useful tool such as the 5-S Practice as a seed to encourage learning and innovation. His practical experience is also shared in this chapter.
Towards Sustainable Data Centre Operations in the UK
Authors: Jones Peter , Bown Robin , Hillier David , Comfort Daphne
Published: April 2014

The purpose of this chapter is to provide an exploratory review of the sustainability agendas being addressed and publicly reported by the UK's leading data centre operators. The chapter begins with a brief discussion of the characteristics of sustainability and an outline of the origins and development of data centres within the UK. The chapter draws its empirical material from the most recent information on sustainability posted on the UK's leading data centre operators' corporate web sites. The findings reveal that all the UK's leading data centre operators provide only limited information on their commitment to sustainability with the dominant focus being on its environmental dimension and with little attention being paid to social and economic issues. More critically, the authors argue that these commitments are driven more by the search for efficiency gains, that they are couched within existing business models centred on continuing growth, and that as such the UK's leading data centre operators are pursuing a ‘weak' rather than a ‘strong' model of sustainability. The chapter suggests that the leading data centre operating companies may need to extend their sustainability reporting and to introduce external assurance procedures.
Consumerism, Market Analysis and Impact on Business Plan Definition
Authors: Ruggieri Alessandro , Silvestri Cecilia , Piccarozzi Michela
Published: April 2014

Creating a company is an event of great uncertainty and complexity. Many variables are to be considered and trying to predict the future development of the business is particularly important. A set of market and strategic analysis instruments can help entrepreneurs to define and solve problem in the start-up phase and to understand the potentialities of business. In particular, the analysis of consumerism is a particularly important factor in order to outline the development of demand and consumer behaviour. Therefore, the first instrument is certainly the business plan; it is necessary to explain and show the aspects of the market where firms will work. This chapter analyzes, through a qualitative analysis, the techniques of market analysis useful for drawing up a business plan focused on the consumer and the dynamics of consumerism. The goal is to emphasize the role the evolutionary dynamics of the consumer and his or her preferences play in leading the company planning towards specific market positioning and in determining the business volume.
Consumer Boycotts as a Consequence of Consumerism
Authors: Yener Dursun
Published: April 2014

Consumerism is not a new concept for marketing, but it has grown in importance in the recent years. Researchers have studied consumerism from within different dimensions. However, its relationship with consumer boycotts has not been dealt with accurately. A consumer boycott is a type of consumer behaviour in which consumers collectively prefer not to use their purchasing power towards a product, brand, or all products of a country. Motivations for participating in boycotts differ in accordance with various factors such as consumers' beliefs, needs, or attitudes. Being boycotted by consumers may cause economic damage and decreased amount of reputation incurred in return. Organizing a boycott and calling for people's participation is much easier today than it used to be in the past. The Internet, especially social media, is an effective tool to inform people about boycotts and free of charge. However, that does not mean all the information circulating in the Internet is always of a reliable nature. In this chapter, the case of Danone in Turkey is thoroughly analyzed. Danone has been the target of Turkey's biggest Internet smear campaign which resulted in 26% shrinkage in its whole category sales. The aim of this chapter is to examine the case of Danone in Turkey as an example of the relationship between consumerism and consumer boycotts. The research for the case of Danone, which has a special importance in Turkey, uses secondary sources such as the daily newspapers, news pages in Internet, and Danone's web page.
The Social Side of Consumerism
Authors: Tenge Marion
Published: April 2014

In the old consumerism paradigm there has been a clear cut distinction between business organizations (producers) and customers (consumers). The advent of Social Software Platforms (SSP), such as online social networks, is destabilizing this duality. SSP provide business organizations with the infrastructure to extend beyond organizational boundaries and establish network ties with their customers with the purpose to include the customer in the value creation process. The chapter reports on the findings of a mixed-methods study. The study describes how major German airports profit economically from online consumerism, i.e. collaborative conversation with passengers, while focusing on the SSP Facebook. The second purpose of the chapter is to model and test the relationship between socio-psychological human need satisfaction of passengers and their engagement level on the corporate Facebook pages of airports. Finally, the chapter offers recommendations for airport managers how to further foster passenger engagement on SSP and embrace online consumerism for economic benefit.
From Food Waste Management to a Holistic Global House
Authors: Hallier Bernd
Published: April 2014

This chapter is intended as “food for thought” for a holistic perspective on Food Waste Management, linking inductive research of an EU-project with the scope of an interdisciplinary vision combining aspects of macro-economics, ecology and ethics. The academic contribution is to demonstrate the broad variety of choices for decision-makers in different geographical and ethnic regions in a joint international effort to optimize the availability of harvested food through all the global/national food chains to the consumers; this includes those consumers who are for various reasons not able to pay the market-price at all. The original terminus “distribution” taken from the business administration literature is enlarged in this chapter by categories such as “food-recovery” and Food banks/charities.
Designing a Framework for Exchanging Partial Sets of BIM Information on a Cloud-Based Service
Authors: Redmond Alan , West Roger , Hore Alan
Published: April 2014

This paper reviews the rationale for using a partial data set in Building Information Modeling (BIM) exchanges, influenced by the recognized difficulty of exchanging data at element or object level which depends on the information requiring compatible hardware and software, in order for the data to be read and transferred freely between applications. The solution was not to introduce a new schema in contrast to the industry's existing open exchange model ‘Industry Foundation Classes' which has been in existence since the 1980's, but for the authors to re-engineer an existing Simplified Markup Language ‘BIM XML' into subsets via XML Style Sheet Transition. The language of XML was chosen because Web services, which are developed from XML data representation format and Hypertext Transfer Protocol (HTTP) communication protocol, are platform neutral, widely accepted and utilized and come with a wide range of useful technologies. Furthermore, they support Service Oriented Architecture (SOA) – the internet platform that enables interoperability between different software programs. The methodology involved developing a full hybrid research model based on mixed methods, ‘quantitative and qualitative', interlaced into two main phases. The first phase comprised of a main survey questionnaire, focus groups, two Delphi questionnaires, semi-structured interviews and a case study. The final phase, ‘product design and testing', used semantic methods and tools, such as Business Process Management Notation. The final case study (a prototype test) successfully itemized the potential of combining three applications asynchronously in real-time. The interoperable capabilities of Web services APIs for exchanging partial sets of BIM data enabled assumptions with a higher amount of detail to be reviewed at the feasibility design stage. Future services will be built upon existing Web Ontology languages such as SPARQL descriptions to be used in conjunction with several web services connecting together on a Cloud platform to produce a knowledge ‘Semantic Web'.
BIM Education for Engineers via Self-Directed, Creative Design
Authors: Kinnane Oliver , West Roger
Published: April 2014

Disruptive technologies have found traction in the construction industry, affecting long established processes and rendering old methods of design communication and construction management increasingly obsolete. Pressure is on traditional Architecture, Engineering and Construction (AEC) schools in academic institutions to respond to this paradigm shift in industry. Common among engineering schools is the necessity to maintain fundamental subjects as approved by accreditation boards. Hence it is difficult to create space for Building Information Modeling (BIM) given a curriculum already packed with established modules. This is a primary reason for the slow uptake of BIM in engineering. For engineering schools the question remains, how best to integrate BIM into the curriculum? This educational case study outlines the introduction of BIM into the curriculum of Civil and Structural Engineering students through an unobtrusive method that does not require curriculum restructuring and does not require module refocus. Two project-based modules, with inherent ‘design thinking' objectives, are adapted to enable BIM tools to be used as design, analysis and communication tools.
Re-Seeing in the Mirror of Creative Critical Reflection
Authors: Cohen Laurence Robert
Published: April 2014

This essay examines the practical application of transformative education in a vocational classroom where students learn how to write a resume. The construction of a new resume in this classroom calls on students to reexamine their previous work history in order to make connections between their past, their present, and their future. This reexamination also calls upon the student to critically reflect on the meaning and structure of their work history and, in the process, examine habits of mind and meaning perspectives which have previously defined them. When students successfully negotiate this process, they find a revised sense of identity, re-seeing themselves in their internal mirror. Their images of themselves take on new dimensions, and they feel more capable of completing their education and succeeding in their new career path.
Transformative Vocational Education
Authors: Adkisson Anthony C. , Monaghan Catherine H.
Published: April 2014

How our culture thinks about particular events as linear, normal, and expected does not always fit with the experiences of every learner, particularly underserved urban adult learners. As adult educators in this context, are there ways we might improve or change our pedagogy of instruction by developing a better understanding of transitional life moments for vocational learners. What is the role of alternative approaches to transformative learning for these learners? Specifically, what is the role of alternative approaches learning for underserved adult learners transitioning into a vocational education classroom, after years of disengagement with formal learning institutions with the need to update their technology skills? In this article, we discuss the need to use alternative conceptions of transformative learning to understand vocational learners as they make decisions to participate in vocational education programs. We explore the key issues for adult educators including implications for practice and research.
The Paradox of Transformative Learning Among Mid-Career Professionals
Authors: Agger-Gupta Niels , Etmanski Catherine
Published: April 2014

Royal Roads University (RRU) is a special purpose university in British Columbia, Canada. Since 1995, this university has focused primarily on multi-sectoral and interdisciplinary graduate education for working professionals. Most programs are offered in a blended online and face-to-face format, which enables adult learners to continue in their professions while they pursue their studies. While one might not expect a primarily distance education degree to be transformative, feedback from learners consistently points to the experience of transformative learning. This article explores the Master's of Arts in Leadership Studies (MA-L) program. It is proposed that there are at least three elements of the design of this program that contribute to experiences of transformation. First, the RRU Learning and Teaching Model creates a framework that can allow many learners to learn how to learn in a new way. Second, the MA-L program itself has its own competency framework that begins by priming learners to look inward before they seek to lead others. Third and finally, the first year two-week residency, completed after one month of online preparation, provides an embodied experience in what, for many, is a new way of being. This embodied experience creates an awareness of what is possible for human relationship and communication, not only in the context of their particular graduate learning cohort, but also with colleagues, family members, and friends. Taken together, these create an often unexpectedly, and somewhat paradoxically, transformative experience for mid-career professionals.
Application of Probabilistic Techniques for the Development of a Prognosis Model of Stroke Using Epidemiological Studies
Authors: Rodríguez-González Alejandro , Alor-Hernandez Giner , Mayer Miguel Angel , Cortes-Robles Guillermo , Perez-Gallardo Yuliana
Published: April 2014

Automated medical diagnosis systems based on knowledge-oriented descriptions have gained momentum with the emergence of recent artificial intelligence techniques. The objective of this paper is to propose a design of a probabilistic model for the prevention of stroke based on the most outstanding risk factors associated with this pathology. The authors gather probabilistic technologies to develop a new clinical support decision-making model. This development is part of a future system that aims to improve health-quality and prevent strokes. The Naïve Bayes model is proposed to calculate the probability of suffering a stroke in the future, based on epidemiological data. Due to a new design, the model is capable to determine the probability of suffering a stroke given some risk factors. The proposed model allows to calculate the final probability of suffering a specific disease for the preventive prognosis of the stroke based on risk factors. Our model enables query the probability of suffering a stroke giving as parameter the presence or absence of a specific indication, also setting if the indication can take several values with its presence, degree or value. With the obtained results the physician will be able to promote patients healthy living habits in order to prevent future stroke events.
Kansei Evaluation of Product Recommendation Based on a Partial Comparison Process
Authors: Jin Jing-Zhong , Nakamori Yoshiteru
Published: April 2014

This paper aims to find a new evaluation method for collecting Kansei and Context data, which is based on a partial comparison process; and a specification method based on customer's target, which is suitable for the special Kansei and Context data obtained from partial comparison process. For collecting Kansei and Context data, we randomly select 5 objects from all objects, and ask people to compare them on each attribute. After many times comparisons, many comparison lists will be obtained. With these lists, we map them into a directed graphic, and with using some graphic processing techniques, we combine all the comparison lists into a whole list without any contradictions, and we map the whole list into a certain range as our evaluated data. To access these special Kansei and Context data, we also discussed two specification methods based on semantic differential method. To test the new method on collecting Kansei data and the specification method, a comparison system and a recommendation system are developed.
A New Back-Propagation Neural Network Algorithm for a Big Data Environment Based on Punishing Characterized Active Learning Strategy
Authors: Zhao Qiuhong , Ye Feng , Wang Shouyang
Published: April 2014

This paper introduces the active learning strategy to the classical back-propagation neural network algorithm and proposes punishing-characterized active learning Back-Propagation (BP) Algorithm (PCAL-BP) to adapt to big data conditions. The PCAL-BP algorithm selects samples and punishments based on the absolute value of the prediction error to improve the efficiency of learning complex data. This approach involves reducing learning time and provides high precision. Numerical analysis shows that the PCAL-BP algorithm is superior to the classical BP neural network algorithm in both learning efficiency and precision. This advantage is more prominent in the case of extensive sample data. In addition, the PCAL-BP algorithm is compared with 16 types of classical classification algorithms. It performs better than 14 types of algorithms in the classification experiment used here. The experimental results also indicate that the prediction accuracy of the PCAL-BP algorithm can continue to increase with an increase in sample size.
Cutting Edge: Activation of the p38 Mitogen-Activated Protein Kinase Signaling Pathway Mediates Cytokine-Induced Hemopoietic Suppression in Aplastic Anemia
Authors: Verma Amit , Deb Dilip K. , Sassano Antonella , Kambhampati Suman , Wickrema Amittha , Uddin Shahab , Mohindru Mani , Van Besien Koen , Platanias Leonidas C.
Published: April 2014

Myelosuppressive cytokines, in particular IFN-γ and TNF-α, play an important role in the pathogenesis of idiopathic aplastic anemia in humans. It is unknown whether these negative regulators of hemopoiesis suppress stem cells by activating a common signaling cascade or via distinct nonoverlapping pathways. In this study, we provide evidence that a common element in signaling for IFN-γ and TNF-α in human hemopoietic progenitors is the p38/MapKapK-2 signaling cascade. Our studies indicate that pharmacological inhibition of p38 reverses the suppressive effects of IFN-γ and TNF-α on normal human bone marrow-derived erythroid and myeloid progenitors. Most importantly, inhibition of p38 strongly enhances hemopoietic progenitor colony formation from aplastic anemia bone marrows in vitro. Thus, p38 appears to play a critical role in the pathogenesis of aplastic anemia, suggesting that selective pharmacological inhibitors of this kinase may prove useful in the treatment of aplastic anemia and other cytokine-mediated bone marrow failure syndromes.
Cutting Edge: The Immunostimulatory Activity of the Lung Surfactant Protein-A Involves Toll-Like Receptor 4
Authors: Guillot Loïc , Balloy Viviane , McCormack Francis X. , Golenbock Douglas T. , Chignard Michel , Si-Tahar Mustapha
Published: April 2014

The collectin surfactant protein-A (SP-A) is involved in the innate host defense and the regulation of inflammatory processes in the lung. In this work we investigated the molecular mechanisms related to the immunostimulatory activity of SP-A using macrophages from C3H/HeJ mice, which carry an inactivating mutation in the Toll-like receptor (TLR)4 gene, and TLR4-transfected Chinese hamster ovary cells. We demonstrate that SP-A-induced activation of the NF-κB signaling pathway and up-regulation of cytokine synthesis such as TNF-α and IL-10 are critically dependent on the TLR4 functional complex. These findings support the concept that TLR4 is a pattern recognition receptor that signals in response to both foreign pathogens and endogenous host mediators.
Cutting Edge: Urease Release by Helicobacter pylori Stimulates Macrophage Inducible Nitric Oxide Synthase
Authors: Gobert Alain P. , Mersey Benjamin D. , Cheng Yulan , Blumberg Darren R. , Newton Jamie C. , Wilson Keith T.
Published: April 2014

Inducible NO synthase (iNOS) expression and production of NO are both up-regulated with Helicobacter pylori infection in vivo and in vitro. We determined whether major pathogenicity proteins released by H. pylori activate iNOS by coculturing macrophages with wild-type or mutant strains deficient in VacA, CagA, picB product, or urease (ureA−). When filters were used to separate H. pylori from macrophages, there was a selective and significant decrease in stimulated iNOS mRNA, protein, and NO2− production with the ureA− strain compared with wild-type and other mutants. Similarly, macrophage NO2− generation was increased by H. pylori protein water extracts of all strains except ureA−. Recombinant urease stimulated significant increases in macrophage iNOS expression and NO2− production. Taken together, these findings indicate a new role for the essential H. pylori survival factor, urease, implicating it in NO-dependent mucosal damage and carcinogenesis.
The Protein Product of the Tumor Suppressor Gene, Melanoma Differentiation-Associated Gene 7, Exhibits Immunostimulatory Activity and Is Designated IL-24
Authors: Caudell Eva G. , Mumm John B. , Poindexter Nancy , Ekmekcioglu Suhendan , Mhashilkar Abner M. , Yang Xiaohong Helena , Retter Mark W. , Hill Paul , Chada Sunil , Grimm Elizabeth A.
Published: April 2014

The melanoma differentiation-associated gene 7 (mda-7) has been studied primarily in the context of its tumor suppressor activity. Although mda-7 has been designated as IL-24 based on its gene location in the IL-10 locus and its mRNA expression in leukocytes, no functional evidence supporting this cytokine designation exists. To further characterize MDA-7/IL-24 expression patterns in the human immune system, MDA-7/IL-24 protein levels were examined in human PBMC. MDA-7/IL-24 was detected in PHA- and LPS-stimulated whole PBMC lysate by Western blot and in PHA-activated CD56 and CD19 subsets by immunohistochemistry. The biological function of MDA-7/IL-24, secreted from Ad-MDA7-transfected HEK 293 cells, was assessed by examining the effect of MDA-7/IL-24 on the cytokine secretion profile of PBMC. Within 48 h MDA-7/IL-24 induced secretion of high levels of IL-6, TNF-α, and IFN-γ and low levels of IL-1β, IL-12, and GM-CSF from human PBMC as measured by ELISA. The MDA-7/IL-24-mediated induction of these Th1-type cytokines was inhibited by the addition of IL-10 to the PBMC cultures, suggesting that these two related protein family members may provide antagonistic functions. Therefore, because human blood leukocytes can be stimulated to produce MDA-7/IL-24, as well as respond to MDA-7/IL-24 by expressing secondary cytokines, MDA-7/IL-24 has the expression profile and major functional attributes that justify its designation as an IL.
Viral Abrogation of Stem Cell Transplantation Tolerance Causes Graft Rejection and Host Death by Different Mechanisms
Authors: Forman Daron , Welsh Raymond M. , Markees Thomas G. , Woda Bruce A. , Mordes John P. , Rossini Aldo A. , Greiner Dale L.
Published: April 2014

Tolerance-based stem cell transplantation using sublethal conditioning is being considered for the treatment of human disease, but safety and efficacy remain to be established. We have shown that mouse bone marrow recipients treated with sublethal irradiation plus transient blockade of the CD40-CD154 costimulatory pathway develop permanent hematopoietic chimerism across allogeneic barriers. We now report that infection with lymphocytic choriomeningitis virus at the time of transplantation prevented engraftment of allogeneic, but not syngeneic, bone marrow in similarly treated mice. Infected allograft recipients also failed to clear the virus and died. Postmortem study revealed hypoplastic bone marrow and spleens. The cause of death was virus-induced IFN-αβ. The rejection of allogeneic bone marrow was mediated by a radioresistant CD8+TCR-αβ+NK1.1− T cell population. We conclude that a noncytopathic viral infection at the time of transplantation can prevent engraftment of allogeneic bone marrow and result in the death of sublethally irradiated mice treated with costimulation blockade. Clinical application of stem cell transplantation protocols based on costimulation blockade and tolerance induction may require patient isolation to facilitate the procedure and to protect recipients.
CD36 Is Differentially Expressed by CD8+ Splenic Dendritic Cells But Is Not Required for Cross-Presentation In Vivo
Authors: Belz Gabrielle T. , Vremec David , Febbraio Maria , Corcoran Lynn , Shortman Ken , Carbone Francis R. , Heath William R.
Published: April 2014

Cross-presentation allows the processing of Ags from donor cells into the MHC class I presentation pathway of dendritic cells (DCs). This is important for the generation of cytotoxic T cell immunity and for induction of self tolerance. Apoptotic cells are reported to be efficient targets for cross-presentation, and in vitro studies using human DCs have implicated CD36 in their capture. In support of a role for CD36 in cross-presentation, we show that this molecule is differentially expressed by CD8+ splenic DCs, which previously have been identified as responsible for cross-presentation in the mouse. Three different cross-presentation models were examined for their dependence on CD36. These included cross-priming to OVA-coated spleen cells and cross-tolerance to OVA transgenically expressed in the pancreatic islet β cells under constitutive conditions or during β cell destruction. In these models, CD36 knockout DCs were equivalent to wild-type DCs in their capacity to cross-present either foreign or self Ags, indicating that CD36 is not essential for cross-presentation of cellular Ags in vivo.
Transendothelial Migratory Pathways of Vδ1+TCRγδ+ and Vδ2+TCRγδ+ T Lymphocytes from Healthy Donors and Multiple Sclerosis Patients: Involvement of Phosphatidylinositol 3 Kinase and Calcium Calmodulin-Dependent Kinase II
Authors: Poggi Alessandro , Zocchi Maria Raffaella , Carosio Roberta , Ferrero Elisabetta , Angelini Daniela F. , Galgani Simona , Caramia Maria D. , Bernardi Giorgio , Borsellino Giovanna , Battistini Luca
Published: April 2014

We have previously reported that the Vδ2+TCRγδ+ T lymphocyte subset, expressing the NK receptor protein 1a (NKRP1a; CD161), is expanded in patients with relapsing-remitting multiple sclerosis and uses this molecule to migrate through endothelium. In this work, we show that Vδ1+ and Vδ2+ γδ T lymphocytes use distinct signal transduction pathways to accomplish this function. Indeed, we have found that Vδ1+ cells lack NKRP1a and selectively express the platelet endothelial cell adhesion molecule 1 (PECAM1; CD31), which drives transendothelial migration of this cell subset, at variance with Vδ2+ T cells, which are PECAM1 negative and use NKRP1a for transmigration. Interestingly, when Vδ2+ T cells were pretreated with two specific inhibitors of the calcium calmodulin-dependent kinase II KN62 and KN93, but not with the inactive compound KN92, the number of migrating cells and the rate of transmigration were significantly decreased. In turn, the phosphatidylinositol 3 kinase blockers wortmannin and LY294002 exerted a dose-dependent inhibition of Vδ1+ cell migration. Finally, NKRP1a and PECAM1 engagement led to activation of different signal transduction pathways: indeed, oligomerization of NKRP1a on Vδ2+ T cells activates calcium calmodulin-dependent kinase II, while occupancy of PECAM1 on Vδ1+ cells triggers the phosphatidylinositol 3 kinase-dependent Akt/protein kinase Bα activation. These findings suggest that subsets of γδ T lymphocytes may migrate to the site of lesion in multiple sclerosis using two different signaling pathways to extravasate.
Differentially Regulated Expression and Function of CD22 in Activated B-1 and B-2 Lymphocytes
Authors: Lajaunias Frédéric , Nitschke Lars , Moll Thomas , Martinez-Soria Eduardo , Semac Isabelle , Chicheportiche Yves , Parkhouse R. Michael E. , Izui Shozo
Published: April 2014

CD22 is a B cell-restricted transmembrane protein that apparently controls signal transduction thresholds initiated through the B cell Ag receptor (BCR) in response to Ag. However, it is still poorly understood how the expression of CD22 is regulated in B cells after their activation. Here we show that the expression levels of CD22 in conventional B-2 cells are markedly down-regulated after cross-linking of BCR with anti-IgM mAb but are up-regulated after stimulation with LPS, anti-CD40 mAb, or IL-4. In contrast, treatment with anti-IgM mAb barely modulated the expression levels of CD22 in CD5+ B-1 cells, consistent with a weak Ca2+ response in anti-IgM-treated CD5+ B-1 cells. Moreover, in CD22-deficient mice, anti-IgM treatment did not trigger enhanced Ca2+ influx in CD5+ B-1 cells, unlike CD22-deficient splenic B-2 cells, suggesting a relatively limited role of CD22 in BCR signaling in B-1 cells. In contrast, CD22 levels were markedly down-regulated on wild-type B-1 cells in response to LPS or unmethylated CpG-containing oligodeoxynucleotides. These data indicate that the expression and function of CD22 are differentially regulated in B-1 and conventional B-2 cells, which are apparently implicated in innate and adaptive immunity, respectively.
Vaccination with Tumor Peptide in CpG Adjuvant Protects Via IFN-γ-Dependent CD4 Cell Immunity
Authors: Stern Britta V. , Boehm Bernhard O. , Tary-Lehmann Magdalena
Published: April 2014

The low frequency of tumor Ag-specific T cells in vivo has made it challenging to directly measure their clonal sizes and cytokine signatures. We used a new generation ELISPOT approach to study the constitutive immunogenicity of the RMA tumor in syngeneic B6 mice and adjuvant-guided immunity against an MHC class II-restricted RMA peptide, H11.1. The RMA tumor was found to activate cells of the innate immune system and to induce a type 1 polarized, RMA-specific CD4 and CD8 T cell response. With clonal sizes ∼10/106, the magnitude of this constitutively induced immune response did not suffice to control the tumor cell growth. In contrast, immunization with H11.1 peptide, using an immunostimulatory CpG oligonucleotide or CFA as adjuvant, engaged ∼25- or ∼10-fold higher clonal sizes of type 1 polarized CD4 cells, respectively. Therefore, the CpG oligonucleotide functioned as a stronger type 1 adjuvant and, unlike CFA, elicited protective immunity. The protection was IFN-γ dependent, as it was not inducible in IFN-γ knockout mice. Therefore, CpG adjuvant-guided induction of type 1 immunity against tumor Ags might be a promising subunit vaccination approach.
Murine Peyer’s Patches Favor Development of an IL-10-Secreting, Regulatory T Cell Population
Authors: Jump Robin L. , Levine Alan D.
Published: April 2014

Peyer’s patches (PP) are believed to be the principal sites for induction of tolerance to Ags from food and commensal flora, yet the phenotype of T cells activated within the PP is largely unexplored. We hypothesize that exposure to Ags within the PP promotes differentiation of T cells with immunoregulatory functions. Cytokine production and cell surface marker expression of murine PP mononuclear cells (MC) are compared with those from mesenteric lymph nodes and peripheral lymph nodes (PLN). In response to stimulation through the TCR/CD3 complex, PP MC exhibit vigorous proliferation, modest production of IL-2, and significantly elevated synthesis of IL-10. Exogenous IL-12 enhances both IL-10 and IFN-γ secretion by activated PP MC. Cell surface marker analysis reveals that PP T cells consist of activated and memory subpopulations compared with the predominantly naive T cells identified in the PLN and mesenteric lymph nodes. Upon stimulation, only CD45RBlowCD4+ PP T cells produce IL-10, whereas secretion of IL-2, IL-4, and IFN-γ was not detected. Furthermore, PP MC, but not PLN MC, stimulated through the TCR/CD3 complex suppress proliferation of purified PLN T cells in vitro, evidence for a regulatory function among PP lymphocytes. We conclude that PP favor differentiation of an IL-10-producing, regulatory CD45RBlowCD4+ T cell population and that inhibition of T cell proliferation by activated PP MC may reflect regulatory activity consistent with T regulatory cells.
Catecholamines Inhibit the Antigen-Presenting Capability of Epidermal Langerhans Cells
Authors: Seiffert Kristina , Hosoi Junichi , Torii Hideshi , Ozawa Hiroaki , Ding Wanhong , Campton Kristina , Wagner John A. , Granstein Richard D.
Published: April 2014

The sympathetic nervous system modulates immune function at a number of levels. Within the epidermis, APCs (Langerhans cells (LC)) are frequently anatomically associated with peripheral nerves. Furthermore, some neuropeptides have been shown to regulate LC Ag-presenting function. We explored the expression of adrenergic receptors (AR) in murine LC and assessed their functional role on Ag presentation and modulation of cutaneous immune responses. Both purified LC and the LC-like cell lines XS52-4D and XS106 expressed mRNA for the ARs α1A and β2. XS106 cells and purified LC also expressed β1-AR mRNA. Treatment of murine epidermal cell preparations with epinephrine (EPI) or norepinephrine inhibited Ag presentation in vitro. Furthermore, pretreatment of epidermal cells with EPI or norepinephrine in vitro suppressed the ability of these cells to present Ag for elicitation of delayed-type hypersensitivity in previously immunized mice. This effect was blocked by use of the β2-adrenergic antagonist ICI 118,551 but not by the α-antagonist phentolamine. Local intradermal injection of EPI inhibited the induction of contact hypersensitivity to epicutaneously administered haptens. Surprisingly, injection of EPI at a distant site also suppressed induction of contact hypersensitivity. Thus, catecholamines may have both local and systemic effects. We conclude that specific ARs are expressed on LC and that signaling through these receptors can decrease epidermal immune reactions.
The Absence of Itk Inhibits Positive Selection Without Changing Lineage Commitment
Authors: Lucas Julie A. , Atherly Luana O. , Berg Leslie J.
Published: April 2014

The Tec family tyrosine kinase Itk is critical for efficient signaling downstream of the TCR. Biochemically, Itk is directly phosphorylated and activated by Lck. Subsequently, Itk activates phospholipase C-γ1, leading to calcium mobilization and extracellular signal-regulated kinase/mitogen-activated protein kinase activation. These observations suggested that Itk might play an important role in positive selection and CD4/CD8 lineage commitment during T cell development in the thymus. To test this, we crossed Itk-deficient mice to three lines of TCR transgenics and analyzed progeny on three different MHC backgrounds. Analysis of these mice revealed that fewer TCR transgenic T cells develop in the absence of Itk. In addition, examination of multiple T cell development markers indicates that multiple stages of positive selection are affected by the absence of Itk, but the T cells that do develop appear normal. In contrast to the defects in positive selection, CD4/CD8 lineage commitment seems to be intact in all the TCR transgenic itk−/− lines tested. Overall, these data indicate that altering TCR signals by the removal of Itk does not affect the appropriate differentiation of thymocytes based on their MHC specificity, but does impact the efficiency with which thymocytes complete their maturation process.
Down-Regulation of Monocyte Apoptosis by Phagocytosis of Platelets: Involvement of a Caspase-9, Caspase-3, and Heat Shock Protein 70-Dependent Pathway
Authors: Lang Detlef , Dohle Frank , Terstesse Martin , Bangen Philip , August Christian , Pauels Hans-Gerd , Heidenreich Stefan
Published: April 2014

Monocytes interact and cross-talk with platelets in many settings including inflammation, hemostasis, or vascular disorders. During inflammatory diseases, there is a rapid targeting of monocytes and platelets to points of inflammation and endothelial injury, where they lie side-by-side. In this in vitro study, we investigated different interactions between monocytes and platelets and elucidated whether platelets might affect monocyte apoptosis. Freshly isolated human monocytes were rendered apoptotic by serum deprivation or CD95 ligation and cocultured with platelets. Monocyte apoptosis was determined by flow cytometry, TUNEL staining, DNA electrophoresis, and transmission electron microscopy imaging. We could show that monocyte apoptosis was highly suppressed when platelets were added to the cultures. Transmission electron microscopy depicted that monocytes completely ingested thrombocytes by phagocytosis. Blocking thrombocyte uptake by the phagocytosis inhibitor cytochalasin D abrogated the enhanced monocyte survival and led to high apoptosis levels. Monocyte survival was paralleled by down-regulation of caspase-9 and -3 and up-regulation of heat shock protein 70 during uptake of platelets. Platelet supernatants and contents of platelet granules were ineffective in altering monocyte senescence. Also, ingestion of latex beads or zymosan by monocytes was ineffective to mimic platelet-dependent rescue from apoptosis. In conclusion, this study shows that platelets can suppress apoptosis of monocytes by a specific phagocytosis-dependent process with further consequences for atherosclerotic or inflammatory conditions.
Regulation of Diabetes Development by Regulatory T Cells in Pancreatic Islet Antigen-Specific TCR Transgenic Nonobese Diabetic Mice
Authors: Kanagawa Osami , Militech Ana , Vaupel Barbala A.
Published: April 2014

Nonobese diabetic (NOD) mice carrying a transgenic TCR from an islet Ag-specific CD4 T cell clone, BDC2.5, do not develop diabetes. In contrast, the same transgenic NOD mice on the SCID background develop diabetes within 4 wk after birth. Using a newly developed mAb specific for the BDC2.5 TCR, we examined the interaction between diabetogenic T cells and regulatory T cells in NOD.BDC transgenic mice. CD4 T cells from NOD.BDC mice, expressing high levels of the clonotype, transfer diabetes to NOD.SCID recipients. In contrast, CD4 T cells expressing low levels due to the expression of both transgenic and endogenous TCR α-chains inhibit diabetes transfer. The clonotype-low CD4 T cells appear late in the ontogeny in the thymus and peripheral lymphoid organs, coinciding with resistance to cyclophosphamide-induced diabetes. These results demonstrate that diabetic processes in NOD.BDC mice are regulated by a balance between diabetogenic T cells and regulatory T cells. In the absence of specific manipulation, regulatory T cell function seems to be dominant and mice remain diabetes free. Understanding of mechanisms by which regulatory T cells inhibit diabetogenic processes would provide means to prevent diabetes development in high-risk human populations.
Corticosteroids Prevent Generation of CD34+-Derived Dermal Dendritic Cells But Do Not Inhibit Langerhans Cell Development
Authors: Woltman Andrea M. , Massacrier Catherine , de Fijter Johan W. , Caux Christophe , van Kooten Cees
Published: April 2014

Corticosteroids (CS) have been shown to exert strong inhibitory effects on dendritic cell (DC) differentiation and function. Those studies were mostly performed with monocyte-derived DC, which represents only one subpopulation from the wide variety of DC types. In the present study the effects of the CS dexamethasone and prednisolone were investigated on the differentiation of CD34+ hemopoietic progenitor cells into 1) Langerhans cells (LC), which differentiate directly into CD1a+ DC; and 2) dermal/interstitial DC, which differentiate via a CD14+CD1a− phenotype into CD14−CD1a+ DC. CS present during the entire 11-day culture period, resulting in fully differentiated CD1a+ DC, increased the percentage of langerin+ DC within the CD1a+ population. In line with these data, CS treatment during the first 6 days of differentiation reduced the development of CD14+ dermal DC precursors and thereby seemed to support the generation of CD1a+ LC precursors. Addition of CS from day 6 onward specifically blocked the development of CD1a+ dermal DC by both inhibition of spontaneous and IL-4-induced differentiation of CD14+ DC precursors into CD1a+ DC as well as induction of apoptosis in CD14+ DC precursors. Apoptosis was not found in CD14+ macrophage precursors derived from the same CD34+ progenitors. The development and function of LC were not affected by CS, as demonstrated by a normal T cell stimulatory capacity and IL-12 production. These data demonstrate that CS interfere with the normal development of DC from CD34+ progenitors by specific induction of apoptosis in precursors of dermal/interstitial DC. In view of the different functional capacities of dermal/interstitial DC and Langerhans cells, this might affect the overall cellular immune response.
Overexpression of Insulin Receptor Substrate-1, But Not Insulin Receptor Substrate-2, Protects a T Cell Hybridoma from Activation-Induced Cell Death
Authors: Li Li , Qi Xiulan , Williams Mark , Shi Yufang , Keegan Achsah D.
Published: April 2014

The insulin receptor substrate (IRS) family of signaling molecules is expressed in lymphocytes, although their functions in these cells is largely unknown. To investigate the role of IRS in the protection of T cells from activation-induced cell death (AICD), we transfected the T cell hybridoma A1.1, which is IL-4 responsive but lacks expression of IRS family members with cDNA encoding IRS1 or IRS2. Stimulation of these clones with immobilized anti-CD3-induced expression of CD69 to the same level as the parental A1.1 cells. However, the A1.1 IRS1-expressing cells were markedly resistant to AICD, while the A1.1 IRS2-expressing cells were not. Inhibition of phosphatidylinositol 3′-kinase in the A1.1 IRS1-expressing cells did not abrogate their resistance to AICD. Fas mRNA was induced similarly by anti-CD3 in A1.1, A1.1 IRS1-expressing, and A1.1 IRS2-expressing cells. However, induction of Fas ligand (FasL) mRNA and functional FasL protein was delayed and decreased in IRS1-expressing cells, but not in IRS2-expressing cells. The induction of transcription from a 500-bp FasL promoter and a minimal 16-mer early growth response element linked to luciferase was also impaired in the IRS1-expressing cells. These results suggest that overexpression of IRS1, but not IRS2, protects A1.1 cells from AICD by diminishing FasL transcription through a pathway that is independent of the tyrosine phosphorylation of IRS1 and phosphatidylinositol 3′-kinase activity.
IFN-Stimulated Gene 15 Is Synergistically Activated Through Interactions Between the Myelocyte/Lymphocyte-Specific Transcription Factors, PU.1, IFN Regulatory Factor-8/IFN Consensus Sequence Binding Protein, and IFN Regulatory Factor-4: Characterization of a New Subtype of IFN-Stimulated Response Element
Authors: Meraro David , Gleit-Kielmanowicz Merav , Hauser Hansjörg , Levi Ben-Zion
Published: April 2014

Type I IFNs cause the induction of a subset of genes termed IFN-stimulated genes (ISGs), which harbor a specific DNA element, IFN-stimulated response element (ISRE). This ISRE confers the responsiveness to the IFN signal through the binding of a family of transcription factors designated IFN regulatory factors (IRFs). Some IRFs can bind to the DNA alone, such as IRF-1, which elicits transcriptional activation, or IRF-2, which leads to transcriptional repression. In addition, these factors associate with IRF-8/IFN consensus sequence binding protein (ICSBP), an immune cell-restricted IRF, and the assembled heterocomplexes lead to synergistic repression of ISRE elements. ISG15 is a prototype ISG that contains a well-characterized ISRE. Here we show that PU.1, an ETS member essential for myeloid/lymphoid cell differentiation, forms heterocomplexes with the immune-restricted IRFs, IRF-8\/ICSBP and IRF-4, which lead to transcriptional activation of ISG15. These data allowed the characterization of a subset of ISREs designated ETS/IRF response element (EIRE), which are differentially regulated in immune cells. EIREs are unique in their ability to recruit different factors to an assembled enhanceosomes. In nonimmune cells the factors will mainly include IRF members, while cell type-restricted factors, such as PU.1, IRF-8\/ICSBP, and IRF-4, will be recruited in immune cells. IRF heterocomplex formation leads to transcriptional repression, and conversely, PU.1/IRFs heterocomplex formation leads to transcriptional activation. The fact that IRF-8\/ICSBP is an IFN-γ-induced factor explains why some of the EIREs are also induced by type II IFN. Our results lay the molecular basis for the unique regulation of ISGs, harboring EIRE, in immune cells.