bluuebunny/crossref_metadata_2025 huggingface dataset:
André Mazon et les études slaves : Introduction
Authors: Gonneau Pierre
Published: April 2014

André Mazon et les études slaves

Introduction

André Mazon passed away on july 13th 1967. This issue of the Revue des études slaves takes a look back at a distinguished man who actively studied and traveled the Slavic world for more than sixty years, through wars, revolutions and academic turmoils. In France, he was instrumental to the development of Slavic studies with his teaching first at Strasbourg University, then at the Collège de France, and with his many publications. He was also as an organizer, a long-time head of the Institut d’études slaves, a pillar of the redaction of the Revue des études slaves, and an untiring defender of scientific relations with other slavists. Jean Breuillard draws a complete picture of Mazon’s legacy as a linguist. Robert Roudet revisits the famous controversy Mazon raised by his skepticism about the authenticity of the Slovo o Polku Igoreve, uniting against himself Roman Jakobson and Dmitrij Lixačev. Antoine Marès shows us Mazon practising his ‘religion of exchanges’ and maintaining or restoring scientific ties with the Slavic countries, in spite of their ideological transformations. Vladislav Rjéoutski studies the particular case of relations with Soviet Russia. Finally, Edward L. Keenan gives us the point of view of a disciple of Roman Jakobson who nevertheless shares Mazon’s views about the Slovo.
André Mazon, un slaviste au XXe siècle : profil politique d’un savant
Authors: Marès Antoine
Published: April 2014

André Mazon, a 20th Century Slavist Political Profile of a Scholar

More than other fields, Slavic Studies are marked by a strong ideological bias, even if denied by its scholars. The work of André Mazon (1881-1967), the ‘leader’ of French Slavic Studies for several decades, proves to be a good example. From 1918 on, he is marked by two fundamental influences: the ‘religion’ of scientific exchange, and a deep interest in Russian and Czech intellectual spaces. At the same time, he sees the Slavic world as a whole. This article tries to show the political commitments of a scholar and his evolution when confronted with the great events of his time. The aim is also to be a starting point for a wider research on French Slavists.
Enjeux actuels des thérapies à l'adolescence
Authors: Jeammet Philippe
Published: April 2014

Les enjeux actuels des thérapies à l’adolescence sont fonction des enjeux de l’adolescence elle-même. La quête objectale et identificatoire propre à cet âge fait peser une menace sur le narcissisme de l’adolescent et le sentiment d’unité et de maîtrise du Moi. Plus le narcissisme est défaillant plus l’objet est perçu comme aliénant et menaçant. Dans ces conditions le thérapeute a potentiellement un rôle traumatique. Les données de la réalité interne étant ce qu’elles sont, les processus de dégagement proviendront essentiellement de la possibilité de trouver dans la réalité externe des supports efficaces aptes à entrer dans une résonance positive avec les données internes et à les soutenir dans leur fonction narcissique comme dans leur quête objectale. Ce constat nous a conduits à mettre l’accent sur l’importance des aménagements de cette réalité externe et le rôle de celle-ci comme auxiliaire de l’appareil psychique favorisant ou empêchant le jeu des investissements et des contre-investissements. Le modèle psychanalytique du fonctionnement mental et de l’appareil psychique autorise ainsi une utilisation de l’espace externe et donc du dispositif de soin dans une perspective de restauration de la fonctionnalité de l’espace psychique interne. Il est alors possible d’y parvenir, soit par la relation duelle si le sujet peut à la fois contenir et mobiliser suffisamment ses conflits au niveau de son espace psychique interne, soit par l’adjonction d’un cadre externe de soin, plus ou moins extensif et sophistiqué selon les cas.
Sur le pas de la porte
Authors: Tuset Annabelle
Published: April 2014

A travers l’histoire clinique de Soufiane, adolescent issu de migrants présentant des troubles du comportement graves, l’auteur tentera d’établir un lien entre un investissement particulier de l’espace géographique (espace où le corps prend nécessairement place) : appréhension de l’espace de la ville, de la consultation ou de l’école mais aussi de la maison, et une impossibilité d’investissement de l’espace interne. La notion de la formation de l’identité, élaboration fondamentale à l’adolescence, apparaissant en arrière-plan tout au long du trajet de Soufiane.
Les beaux enfants, les belles moissons
Authors: Cotinat Danièle
Published: April 2014

L’adolescence masculine en Grèce Ancienne fait l’objet d’un traitement particulier. Nous en percevons des éléments éclatés, à Athènes à l’époque classique, dans des rites, des mythes et des institutions modifiées au fil du temps. Le travail de l’historien est de rechercher la cohérence qu’il y a derrière. Depuis les travaux sur les rites d’initiation, la reconnaissance et l’utilisation des apports de l’ethnologie et l’anthropologie comparées, on admet l’existence de rites de passage qui ponctuent la vie des jeunes, de la naissance à l’âge adulte, destinés à intégrer ces vies nouvelles. Dans une société patrilinéaire c’est le père qui est le médiateur de cette intégration ouverte sur le monde extérieur. Elle culmine à l’âge extrême où il faut sortir définitivement de l’enfance pour entrer dans une vie d’homme, sans retour. Le jeune devient alors le Même, après un détour dans la différence totale, une inversion par rapport à sa vie future. La folie des jeunes années est ainsi canalisée. Tant qu’il est jeune le Grec connaît une vie où rien n’est véritablement en place, à la limite de l’animalité. Le seuil franchi, les rôles sont tracés et tranchés, l’adolescence est terminée.
The SHEEP Model
Authors: Rosenorn-Lanng Deborah J. , Michell Vaughan A.
Published: April 2014

This chapter explains the development of a model, titled “SHEEP,” to identify quality and safety factors relating to near misses. The model allows frequency of risk factors and their impact to be analysed at departmental or institutional levels, which enables a structured focusing of resources at an organisational level.
A Pharmaco-Cybernetics Approach to Patient Safety
Authors: Yap Kevin Yi-Lwern
Published: April 2014

Pharmaco-cybernetics is an upcoming interdisciplinary field that supports our use of medicines and drugs through the combined use of computational technologies and techniques with human-computer-environment interactions to reduce or prevent drug-related problems. The advent of pharmaco-cybernetics has led to the development of various software, tools, and Internet applications that can be used by healthcare practitioners to deliver optimum pharmaceutical care and health-related outcomes. Patients are becoming more informed through health information on the Internet, which empowers them to better participate in the management of their own conditions. Focusing on patients with cancer, this chapter describes the use of a pharmaco-cybernetics approach to identify clinically relevant predictors of two debilitating adverse drug reactions, which are a cause of patient safety – chemotherapy-induced nausea and vomiting and febrile neutropenia. The early identification of such clinical predictors enables clinicians to prevent or reduce the occurrence of adverse drug reactions in cancer patients undergoing chemotherapy through appropriate management strategies. The computational methods used in this approach involve two unsupervised machine-learning techniques – principal component and multiple correspondence analyses. Using two case examples, this chapter shows the potential of machine-learning techniques for identifying patients who are at greater risks of these adverse drug reactions, thus enhancing patient safety. This chapter also aims to increase the awareness among healthcare professionals and clinician-scientists about the usefulness of such techniques in clinical patient populations, so that these can be considered as part of clinical care pathways to enhance patient safety and effectively manage cancer patients on chemotherapy.
Customer Strategy Definition in Elderly Care
Authors: Khashab Basel , Joshi Uday , Gulliver Stephen R.
Published: April 2014

With an aging global population, it is important that clinicians empower their patients. Empowering the patient-physician interaction leads to a more positive health outcome. This chapter discusses the potential of adopting Customer Relationship Management (CRM) as a way of guiding non-critical care services (i.e. linking the problems of customer-focused care expectation and resource allocation management). Implementation of CRM solutions would create value for patients by supporting trust and service creation; however, the chapter highlights a need for a common and systematic way to implement CRM solutions in the healthcare domain.
Technology Acceptance and Care Self-Management
Authors: Wannatawee Patcharin , Alhammad Muna , Gulliver Stephen R.
Published: April 2014

With an aging global population, the number of people living with a chronic illness is expected to increase significantly by 2050. If left unmanaged, chronic care leads to serious health complications, resulting in poor patient quality of life and a costly time bomb for care providers. If effectively managed, patients with chronic care tend to live a richer and more healthy life, resulting in a less costly total care solution. This chapter considers literature from the areas of technology acceptance and care self-management, which aims to alleviate symptoms and/or reason for non-acceptance of care, and thus minimise the risk of long-term complications, which in turn reduces the chance of spiralling health expenditure. By bringing together these areas, the chapter highlights areas where self-management is failing so that changes can be made in care in advance of health deterioration.
Information Architecture for Pervasive Healthcare Information Provision with Technological Implementation
Authors: Tan Chekfoung , Liu Shixiong
Published: April 2014

The Pervasive Healthcare Information Provision (PHIP) is a concept that ensures patients are covered with healthcare services with the appropriate information provision together with the technical infrastructure when needed. Clinicians can obtain the real-time information by accessing the electronic patient record that supports decision-making in providing health services. PHIP aims to provide comprehensive healthcare services to its stakeholders covering the social and technical aspect. Information architecture is a high-level map of information requirements of an organisation that possesses business processes and information flows. Organisational semiotics, a fundamental theory for information and communication, helps in understanding the nature of information. It deals with information and information systems in a balanced way, taking account of both the physical space (when physical actions take place) and the information space (which are mainly characterised by information and communication using signs, symbols, and data). Information sharing among multi-stakeholders in decision-making is essential for pervasive healthcare. The information architecture can be reflected in information systems implementation such as Electronic Patient Record (EPR) and other forms. The aim of this chapter is to derive a conceptual model of information architecture for PHIP, including technological implementation via wireless technology. The information architecture serves as requirement engine that covers social and technical needs from both patients and clinicians. The contribution of this research is two fold: 1) establishing the theoretical perspective of information architecture, which serves as backbone to support PHIP, and 2) implementing PHIP via wireless technology and agent-based system.
The Role of Business Model Innovation on the Disruptive Potential of PWLAN in the Western European Hotspot Markets
Authors: Hüsig Stefan
Published: April 2014

In this chapter, the authors describe and analyze the impact of Wireless Local Area Network (WLAN) technologies on mobile data communications in the Western European hotspot markets. To do this, they use the disruptive innovation theory and the business model perspective as a basis. The main proposition to be analyzed is whether or not WLAN has developed disruptive potential for the incumbents in this market so far. The results imply that incumbents and new entrants have taken advantage of the opportunity provided by WLAN technologies and the public hotspot market in Western Europe. Although the market success of both types of players varies amongst the countries analyzed, in most Western European countries the incumbents dominate the public hotspot market. This result suggests a predominantly sustaining impact of public WLAN on the incumbents. However, the sustaining impact of public WLAN is weaker if alternative business models such as free or community network hotspots are taken into account. These findings support the view that incumbents frame new technological opportunities or threats in their established business model. In contrast, new entrants tend to use a more flexible approach and innovate the business model around the new technology as well. However, if the underlying technology lacks disruptiveness, the effect remains sustaining for the industry structure. After all, business model innovation is no panacea in disrupting the incumbents if the underlying technology lacks sufficient intrinsic disruptive potential and the established business model fits with the new technological opportunities or threats.
A Causal Model Analysis of Spectrum Management Policies
Authors: Sridhar Varadharajan , Casey Thomas , Hämmäinen Heikki
Published: April 2014

Demand for wireless data and Internet services are expected to grow exponentially, worldwide, in the near future. While regulators of advanced countries have often used centralized planning and coordination approach to forecast and allocate the associated spectrum blocks to wireless operators for meeting the demand, it is often ad-hoc in emerging markets dictated by market forces. In this chapter, the authors construct a casual model to represent the different variables that affect spectrum management practices. The authors discuss possible policy options including release of digital dividend spectrum, spectrum refarming, and secondary markets consisting of spectrum leasing, sharing, and trading. Using the causal model structure, the authors trace paths of evolution of spectrum policies, taking an example each for developed and emerging countries. The authors further hypothesize that emerging countries with their unique market structure, legacy of spectrum management, and ex-poste regulation are better suited to create active secondary markets compared to developed markets.
Emerging Trends in Digital Libraries
Authors: Holland Barbara
Published: April 2014

New Technologies pose new challenges when libraries build their virtual collections. With the growth and popularity of e-books and other portable devices, collections can no longer be evaluated purely on the bases of content. Today, there is a growing trend in seeking information using mobile devices. Libraries can extend new types of services to users of mobile devices and develop, license, or otherwise make available scholarly content configured for mobile devices. Libraries will soon become part of an institutional planning process for the development of services for mobile devices. Only users can indicate how these platforms will be used as mobile tools for study or entertainment devices. The University of Technology Library (now a part of Aalto University) 2009-2010, in collaboration with the Usability Research Group, surveyed various e-book readers. Furthermore, the California Lutheran University ran a two-semester pilot to explore how course use of e-readers affects student learning from 2009-2010. To improve access to digital assets at the Norwegian National Library, an Android App was created and tested for mobile use. In addition, two military educational schools conducted a study of current mobile device ownership and use by their students. Survey results revealed that a majority of students say they would engage in mobile learning if it were available. This chapter examines surveys and emerging trends in Digital Libraries, mobile devices, and mobile learning.
Wind Farm Layout Optimization Using a Viral Systems Algorithm
Authors: Espiritu Jose F. , Ituarte-Villarreal Carlos M.
Published: April 2014

In the present research a new viral systems optimization algorithm is developed to find the optimal number and position of wind turbines in large wind farms with the main objective of minimizing the cost per unit power produced from the wind park. The developed algorithm is applied to three well known problems in literature which are: 1) constant wind speed and unidirectional uniform wind, 2) constant wind speed with variable direction, and 3) non-uniform variable wind speed with variable direction. In the final results, the distance between two wind turbines is reduced to one meter, compared to 5 rotor diameters in previous studies.
Frequency Modulation Sound Parameter Identification using Shuffled Particle Swarm Optimization
Authors: Ahandan Morteza Alinia , Alavi-Rad Hosein , Jafari Nooreddin
Published: April 2014

The frequency modulation sound parameter identification is a complex multimodal optimization problem. This problem is modeled in the form of a cost function that is the sum-squared error between the samples of estimated wave and the samples of real wave. In this research, the authors propose a shuffled particle swarm optimization algorithm to solve this problem. In the shuffled particle swam optimization proposed here, population such as shuffled frog leaping algorithm is divided to several memeplexes and each memeplex is improved by the particle swam optimization algorithm. A comparison among the obtained results of the authors' proposed algorithm with the results reported in the literature confirms a better performance of the authors' proposed algorithm.
A New Radial Basis Function Artificial Neural Network based Recognition for Kurdish Manuscript
Authors: Zebardast Behnam , Maleki Isa
Published: April 2014

During recent decades, recognizing letters was a considerable discussion for artificial intelligence researchers and recognize letters due to the variety of languages and different approaches have many challenges. The Artificial Neural Networks (ANNs) are framed based on particular application such as recognition pattern and data classification through learning process is configured. So, it is a proper approach to recognize letters. Kurdish language has two popular handwritings based on Arabic and Latin. In this paper, Radial Basis Function (RBF) of ANNs is used to recognize Kurdish-Latin manuscripts. Although, the authors' proposed method is also used to recognize the letters of all Latin languages which include English, Turkish and etc. are used. The authors implement RBF of ANNs in MATLAB environment. In this paper, the efficiency criteria is supposed to minimize the Mean Square Error (MSE) to recognize Kurdish letters and maximize recognition accuracy of Kurdish letters in training and testing stage of RBF of ANNs. The recognition accuracy in training and testing stages are 100% and 96.7742%, respectively.
Cutting Edge: Allogeneic CD4+CD25+Foxp3+ T Regulatory Cells Suppress Autoimmunity while Establishing Transplantation Tolerance
Authors: Adeegbe Dennis , Bayer Allison L. , Levy Robert B. , Malek Thomas R.
Published: April 2014

An important unresolved question with regard to T regulatory (Treg) cell specificity and suppressive activity is whether allogeneic Treg cells inhibit self-reactive T cells. In the present study, this issue was addressed using IL-2Rβ-deficient mice that develop rapid lethal autoimmunity due to impaired production of Treg cells. We show that adoptive transfer of completely MHC-mismatched Treg cells into IL-2Rβ−/− mice resulted in life-long engraftment of the donor cells, which exhibited skewed reactivity toward host alloantigens, and prevented autoimmunity. Thus, Treg cells that underwent thymic selection by peptide/MHC class II complexes distinct from those recognized by autoreactive T cells, still effectively suppress autoimmunity. Remarkably, when such animals were skin grafted, they exhibited dominant tolerance to those grafts bearing MHC molecules that were shared with donor Treg cells. Collectively, these data demonstrate that effective engraftment by allogeneic Treg cells controls autoimmunity and results in permissive conditions for long-term acceptance of allografts.
Transgenic Galectin-1 Induces Maturation of Dendritic Cells That Elicit Contrasting Responses in Naive and Activated T Cells
Authors: Perone Marcelo J. , Larregina Adriana T. , Shufesky William J. , Papworth Glenn D. , Sullivan Mara L. G. , Zahorchak Alan F. , Stolz Donna Beer , Baum Linda G. , Watkins Simon C. , Thomson Angus W. , Morelli Adrian E.
Published: April 2014

Dendritic cells (DC) are professional APC that control the balance between T cell immunity and tolerance. Genetic engineering of DC to regulate the outcome of the immune response is an area of intense research. Galectin (gal)-1 is an endogenous lectin that binds to glycoproteins and exerts potent regulatory effects on T cells. Consequently, gal-1 participates in central deletion of thymocytes and exerts therapeutic effects on experimental models of T cell-mediated autoimmune disorders and graft-vs-host disease. Together, these observations strongly indicate that engineering DC to express transgenic (tg) gal-1 may be beneficial to treat T cell-mediated disorders. In this study, we have investigated the impact of the expression of high levels of tg gal-1 on maturation/activation of DC and on their T cell stimulatory function. Murine DC were transduced with a recombinant adenovirus encoding hu gal-1 (gal-1-DC). Tg gal-1 was exported by a nonclassical pathway through exosomes and was retained on the DC surface inducing segregation of its ligand CD43. Expression of tg gal-1 triggered activation of DC determined by induction of a more mature phenotype, increased levels of mRNA for proinflammatory cytokines, and enhanced ability to stimulate naive T cells. Conversely, gal-1-DC induced rapid apoptosis of activated T cells. In vivo, gal-1-DC increased significantly the sensitization phase of contact hypersensitivity assays while inducing a drastic inhibition of the elicitation phase by triggering apoptosis of activated T cells in the dermis. Gal-1-DC represent a novel tool to control differentially the afferent and efferent arms of the T cell response.
IL-2 Is Required for the Activation of Memory CD8+ T Cells via Antigen Cross-Presentation
Authors: Blachère Nathalie E. , Morris Heather K. , Braun Deborah , Saklani Hélène , Di Santo James P. , Darnell Robert B. , Albert Matthew L.
Published: April 2014

Dendritic cells (DCs) are capable of capturing exogenous Ag for the generation of MHC class I/peptide complexes. For efficient activation of memory CD8+ T cells to occur via a cross-presentation pathway, DCs must receive helper signals from CD4+ T cells. Using an in vitro system that reflects physiologic recall memory responses, we have evaluated signals that influence helper-dependent cross-priming, while focusing on the source and cellular target of such effector molecules. Concerning the interaction between CD4+ T cells and DCs, we tested the hypothesis that CD40 engagement on DCs is critical for IL-12p70 (IL-12) production and subsequent stimulation of IFN-γ release by CD8+ T cells. Although CD40 engagement on DCs, or addition of exogenous IL-12 are both sufficient to overcome the lack of help, neither is essential. We next evaluated cytokines and chemokines produced during CD4+ T cell/DC cross talk and observed high levels of IL-2 produced within the first 18–24 h of Ag-specific T cell engagement. Functional studies using blocking Abs to CD25 completely abrogated IFN-γ production by the CD8+ T cells. Although required, addition of exogenous IL-2 did not itself confer signals sufficient to overcome the lack of CD4+ T cell help. Thus, these data support a combined role for Ag-specific, cognate interactions at the CD4+ T cell/DC as well as the DC/CD8+ T cell interface, with the helper effect mediated by soluble noncognate signals.
Chronic Immune Therapy Induces a Progressive Increase in Intratumoral T Suppressor Activity and a Concurrent Loss of Tumor-Specific CD8+ T Effectors in her-2/neu Transgenic Mice Bearing Advanced Spontaneous Tumors
Authors: Nair Raji E. , Kilinc Mehmet O. , Jones Stacy A. , Egilmez Nejat K.
Published: April 2014

A single intratumoral injection of IL-12 and GM-CSF-encapsulated microspheres induces the complete regression of advanced spontaneous tumors in her-2/neu transgenic mice. However, tumor regression in this model is transient and long-term cure is not achieved due to recurrence. Posttherapy molecular analysis of immune activation/suppression markers within the tumor microenvironment demonstrated a dramatic up-regulation of IFN-γ and a concomitant down-regulation of Forkhead/winged-helix protein 3 (Foxp3), TGFβ, and IL-10 expression. Therapy-induced reversion of immune suppression was transient since all three markers of suppression recovered rapidly and surpassed pretherapy levels by day 7 after treatment, resulting in tumor resurgence. Repeated treatment enhanced short-term tumor regression, but did not augment long-term survival. Serial long-term analysis demonstrated that although chronic stimulation enhanced the IFN-γ response, this was countered by a parallel increase in Foxp3, TGFβ, and IL-10 expression. Analysis of tumor-infiltrating T lymphocyte populations showed that the expression of Foxp3 and IL-10 was associated with CD4+CD25+ T cells. Repeated treatment resulted in a progressive increase in tumor-infiltrating CD4+CD25+Foxp3+ T suppressor cells establishing their role in long-term neutralization of antitumor activity. Analysis of tumor-infiltrating CD8+ T cells demonstrated that although treatment enhanced IFN-γ production, antitumor cytotoxicity was diminished. Monitoring of CD8+ T cells that specifically recognized a dominant MHC class I her-2/neu peptide showed a dramatic increase in tetramer-specific CD8+ T cells after the first treatment; however, continuous therapy resulted in the loss of this population. These results demonstrate that both enhanced suppressor activity and deletion of tumor-specific T cells are responsible for the progressive loss of efficacy that is associated with chronic immune therapy.
Opposing Effects of ICOS on Graft-versus-Host Disease Mediated by CD4 and CD8 T Cells
Authors: Yu Xue-Zhong , Liang Yaming , Nurieva Roza I. , Guo Fei , Anasetti Claudio , Dong Chen
Published: April 2014

ICOS, a CD28 family member expressed on activated CD4+ and CD8+ T cells, plays important roles in T cell activation and effector function. Here we studied the role of ICOS in graft-vs-host disease (GVHD) mediated by CD4+ or CD8+ T cells in allogeneic bone marrow transplantation. In comparison of wild-type and ICOS-deficient T cells, we found that recipients of ICOS−/− CD4+ T cells exhibited significantly less GVHD morbidity and delayed mortality. ICOS−/− CD4+ T cells had no defect in expansion, but expressed significantly less Fas ligand and produced significantly lower levels of IFN-γ and TNF-α. Thus, ICOS−/− CD4+ T cells were impaired in effector functions that lead to GVHD. In contrast, recipients of ICOS−/− CD8+ T cells exhibited significantly enhanced GVHD morbidity and accelerated mortality. In the absence of ICOS signaling, either using ICOS-deficient donors or ICOS ligand-deficient recipients, the levels of expansion and Tc1 cytokine production of CD8+ T cells were significantly increased. The level of expansion was inversely correlated with the level of apoptosis, suggesting that increased ability of ICOS−/− CD8+ T cells to induce GVHD resulted from the enhanced survival and expansion of those cells. Our findings indicate that ICOS has paradoxical effects on the regulation of alloreactive CD4+ and CD8+ T cells in GVHD.
The CC Chemokine MCP-1 Stimulates Surface Expression of CX3CR1 and Enhances the Adhesion of Monocytes to Fractalkine/CX3CL1 via p38 MAPK
Authors: Green Simone R. , Han Ki Hoon , Chen Yiming , Almazan Felicidad , Charo Israel F. , Miller Yury I. , Quehenberger Oswald
Published: April 2014

The membrane-anchored form of CX3CL1 has been proposed as a novel adhesion protein for leukocytes. This functional property of CX3CL1 is mediated through CX3CR1, a chemokine receptor expressed predominantly on circulating white blood cells. Thus far, it is still uncertain at what stage of the trafficking process CX3CR1 becomes importantly involved and how the CX3CR1-dependent adhesion of leukocytes is regulated during inflammation. The objective of this study was to examine the functional effects of chemokine stimulation on CX3CR1-mediated adhesion of human monocytes. Consistent with previous reports, our data indicate that the activity of CX3CR1 on resting monocytes is sufficient to mediate cell adhesion to CX3CL1. However, the basal, nonstimulated adhesion activity is low, and we hypothesized that like the integrins, CX3CR1 may require a preceding activation step to trigger firm leukocyte adhesion. Compatible with this hypothesis, stimulation of monocytes with MCP-1 significantly increased their adhesion to immobilized CX3CL1, under both static and physiological flow conditions. The increase of the adhesion activity was mediated through CCR2-dependent signaling and obligatory activation of the p38 MAPK pathway. Stimulation with MCP-1 also induced a rapid increase of CX3CR1 protein on the cell surface. Inhibition of the p38 MAPK pathway prevented this increase of CX3CR1 surface expression and blunted the effect of MCP-1 on cell adhesion, indicating a causal link between receptor surface density and adhesion activity. Together, our data suggest that a chemokine signal is required for firm CX3CR1-dependent adhesion and demonstrate that CCR2 is an important regulator of CX3CL1-dependent leukocyte adhesion.
The Complementarity Determining Region 2 of BV8S2 (Vβ8.2) Contributes to Antigen Recognition by Rat Invariant NKT Cell TCR
Authors: Pyż Elwira , Naidenko Olga , Miyake Sachiko , Yamamura Takashi , Berberich Ingolf , Cardell Susanna , Kronenberg Mitchell , Herrmann Thomas
Published: April 2014

Invariant NKT cells (iNKT cells) are characterized by a semi-invariant TCR comprising an invariant α-chain paired with β-chains with limited BV gene usage which are specific for complexes of CD1d and glycolipid Ags like α-galactosylceramide (α-GalCer). iNKT cells can be visualized with α-GalCer-loaded CD1d tetramers, and the binding of mouse CD1d tetramers to mouse as well as to human iNKT cells suggests a high degree of conservation in recognition of glycolipid Ags between species. Surprisingly, mouse CD1d tetramers failed to stain a discrete cell population among F344/Crl rat liver lymphocytes, although comprised iNKT cells are indicated by IL-4 and IFN-γ secretion after α-GalCer stimulation. The arising hypothesis that rat iNKT TCR recognizes α-GalCer only if presented by syngeneic CD1d was then tested with the help of newly generated rat and mouse iNKT TCR-transduced cell lines. Cells expressing mouse iNKT TCR reacted to α-GalCer presented by rat or mouse CD1d and efficiently bound α-GalCer-loaded mouse CD1d tetramers. In contrast, cells expressing rat iNKT TCR responded only to α-GalCer presented by syngeneic CD1d and bound mouse CD1d tetramers only poorly or not at all. Finally, CD1d-dependent α-GalCer reactivity and binding of mouse CD1d tetramers was tested for cells expressing iNKT TCR comprising either rat or mouse AV14 (Vα14) α-chains and wild-type or mutated BV8S2 (Vβ8.2) β-chains. The results confirmed the need of syngeneic CD1d as restriction element for rat iNKT TCR and identified the CDR2 of BV8S2 as an essential site for ligand recognition by iNKT TCR.
Local Amplification of Glucocorticoids by 11β-Hydroxysteroid Dehydrogenase Type 1 Promotes Macrophage Phagocytosis of Apoptotic Leukocytes
Authors: Gilmour James S. , Coutinho Agnes E. , Cailhier Jean-François , Man Tak Yung , Clay Michael , Thomas Graham , Harris Hayley J. , Mullins John J. , Seckl Jonathan R. , Savill John S. , Chapman Karen E.
Published: April 2014

Glucocorticoids promote macrophage phagocytosis of leukocytes undergoing apoptosis. Prereceptor metabolism of glucocorticoids by 11β-hydroxysteroid dehydrogenases (11β-HSDs) modulates cellular steroid action. 11β-HSD type 1 amplifies intracellular levels of active glucocorticoids in mice by reactivating corticosterone from inert 11-dehydrocorticosterone in cells expressing the enzyme. In this study we describe the rapid (within 3 h) induction of 11β-HSD activity in cells elicited in the peritoneum by a single thioglycolate injection in mice. Levels remained high in peritoneal cells until resolution. In vitro experiments on mouse macrophages demonstrated that treatment with inert 11-dehydrocorticosterone for 24 h increased phagocytosis of apoptotic neutrophils to the same extent as corticosterone. This effect was dependent upon 11β-HSD1, as 11β-HSD1 mRNA, but not 11β-HSD2 mRNA, was expressed in these cells; 11-dehydrocorticosterone was ineffective in promoting phagocytosis by Hsd11b1−/− macrophages, and carbenoxolone, an 11β-HSD inhibitor, prevented the increase in phagocytosis elicited in wild-type macrophages by 11-dehydrocorticosterone. Importantly, as experimental peritonitis progressed, clearance of apoptotic neutrophils was delayed in Hsd11b1−/− mice. These data point to an early role for 11β-HSD1 in promoting the rapid clearance of apoptotic cells during the resolution of inflammation and indicate a novel target for therapy.
Differential Binding of Cross-Reactive Anti-DNA Antibodies to Mesangial Cells: The Role of α-Actinin
Authors: Zhao Zeguo , Deocharan Bisram , Scherer Philipp E. , Ozelius Laurie J. , Putterman Chaim
Published: April 2014

Target Ag display is a necessary requirement for the expression of certain immune-mediated kidney diseases. We previously had shown that anti-DNA Abs that cross-react with α-actinin may be important in the pathogenesis of murine and human lupus nephritis; in murine models, we had found that a significant proportion of pathogenic serum and kidney-deposited Igs are α-actinin reactive. Furthermore, a pathogenic anti-DNA/α-actinin Ab showed enhanced binding to immortalized mesangial cells (MCs) derived from a lupus prone MRL-lpr/lpr mouse as compared with MCs from BALB/c mice which are not susceptible to spontaneous lupus, suggesting that kidney α-actinin expression may be contributing to nephritis. In the current study, we established that two isoforms of α-actinin that are present in the kidney, α-actinin 1 and α-actinin 4, can both be targeted by anti-α-actinin Abs. We found novel sequence polymorphisms between MRL-lpr/lpr and BALB/c in the gene for α-actinin 4. Moreover, α-actinin 4 and a splice variant of α-actinin 1 were both expressed at significantly higher levels (mRNA and protein) in MCs from the lupus prone MRL-lpr/lpr strain. Significantly, we were able to confirm these differences in intact kidney by examining glomerular Ig deposition of anti-α-actinin Abs. We conclude that enhanced α-actinin expression may determine the extent of Ig deposition in the Ab-mediated kidney disease in lupus. Modulation of Ag expression may be a promising approach to down-regulate immune complex formation in the target organ in individuals with circulating pathogenic Abs.
Peripheral Blood Neutrophil Activation Patterns Are Associated with Pulmonary Inflammatory Responses to Lipopolysaccharide in Humans
Authors: Abraham Edward , Nick Jerry A. , Azam Tania , Kim Soo Hyun , Mira Jean-Paul , Svetkauskaite Daiva , He Qianbin , Zamora Marty , Murphy James , Park Jong Sung , Overdier Katherine , Dinarello Charles A.
Published: April 2014

Increased nuclear accumulation of NF-κB in LPS-stimulated peripheral blood neutrophils has been shown to be associated with more severe clinical course in patients with infection associated acute lung injury. Such observations suggest that differences in neutrophil response may contribute to the pulmonary inflammation induced by bacterial infection. To examine this question, we sequentially measured LPS-induced DNA binding of NF-κB in neutrophils collected from healthy humans on at least three occasions, each separated by at least 2 wk, and then determined pulmonary inflammatory responses after instillation of LPS into the lungs. Consistent patterns of peripheral blood neutrophil responses, as determined by LPS-induced NF-κB DNA binding, were present in volunteers, with a >80-fold difference between individuals in the mean area under the curve for NF-κB activation. The number of neutrophils recovered from bronchoalveolar lavage after exposure to pulmonary LPS was significantly correlated with NF-κB activation in peripheral blood neutrophils obtained over the pre-LPS exposure period (r = 0.65, p = 0.009). DNA binding of NF-κB in pulmonary neutrophils also was associated with the mean NF-κB area under the curve for LPS-stimulated peripheral blood neutrophils (r = 0.63, p = 0.01). Bronchoalveolar lavage levels of IL-6 and TNFRII were significantly correlated with peripheral blood neutrophil activation patterns (r = 0.75, p = 0.001 for IL-6; and r = 0.48, p = 0.049 for TNFRII. These results demonstrate that stable patterns in the response of peripheral blood neutrophils to LPS exist in the human population and correlate with inflammatory response following direct exposure to LPS in the lung.
Secreted Proteins fromMycobacterium tuberculosisGain Access to the Cytosolic MHC Class-I Antigen-Processing Pathway
Authors: Lewinsohn David M. , Grotzke Jeff E. , Heinzel Amy S. , Zhu LiQing , Ovendale Pamela J. , Johnson Mark , Alderson Mark R.
Published: April 2014

CD8+ T cells play an important role in the host response to infection with Mycobacterium tuberculosis (Mtb). Mtb resides in an arrested phagosome that is phenotypically similar to an early endosome. The mechanisms by which Mtb-derived Ags gain access to the HLA-I-processing pathway are incompletely characterized. Studies with CD8+ T cell lines have suggested that Mtb Ags gain access to the HLA-I pathway in an alternate vacuolar pathway that is both brefeldin A (BFA) and TAP independent. To define the requirements of entry of Ag into the HLA-I pathway, we have used human CD8+ T cell clones specific for the secreted Mtb Ag CFP10. Human monocyte-derived dendritic cells were pulsed with CFP10 expressed in a recombinant adenovirus, surface adsorbed to microspheres, or in its native form by Mtb. When delivered by adenovirus, processing and presentation of CFP10 were blocked by both BFA and the proteasomal blocker lactacystin. In contrast, processing of CFP10 adsorbed to the surface of microspheres was not affected by either of these Ag-processing inhibitors. BFA, lactacystin, and TAP inhibition blocked the recognition of Mtb-infected dendritic cells, suggesting that processing was via a cytosolic pathway for this secreted protein Ag. We conclude that secreted proteins from Mtb can be processed in a BFA- and proteasome-dependent manner, consistent with egress of Ag into the cytosol and subsequent loading of proteasomally derived peptides.
PneumocystisCell Wall β-Glucans Induce Dendritic Cell Costimulatory Molecule Expression and Inflammatory Activation through a Fas-Fas Ligand Mechanism
Authors: Carmona Eva M. , Vassallo Robert , Vuk-Pavlovic Zvezdana , Standing Joseph E. , Kottom Theodore J. , Limper Andrew H.
Published: April 2014

Respiratory failure during Pneumocystis pneumonia is mainly a consequence of exaggerated inflammatory responses to the organism. Dendritic cells (DCs) are the most potent APCs in the lung and are key to the regulation of innate and adaptive immune responses. However, their participation in the inflammatory response directed against Pneumocystis infection has not been fully elucidated. Therefore, we studied the role of Pneumocystis carinii, as well as Saccharomyces cerevisiae, cell wall-derived β-glucans, in DC costimulatory molecule expression. We further studied the impact of β-glucans on subsequent T cell activation. Because cytokine secretion by DCs has recently been shown to be regulated by Fas ligand (FasL), its role in β-glucan activation of DCs was also investigated. β-Glucan-induced DC activation occurred in part through dectin-1 receptors. We demonstrated that DC activation by β-glucans elicits T cell activation and polarization into a Th1 patterned response, but with the conspicuous absence of IL-12. These observations differed from LPS-driven T cell polarization, suggesting that β-glucans and LPS signal DC activation through different mechanisms. We additionally determined that IL-1β and TNF-α secretion by β-glucan-stimulated DCs was partially regulated by Fas-FasL. This suggests that dysregulation of FasL could further enhance exuberant and prolonged cytokine production by DCs following DC-T cell interactions, further promoting lung inflammation typical of Pneumocystis pneumonia.
Transcellular Secretion of Group V Phospholipase A2 from Epithelium Induces β2-Integrin-Mediated Adhesion and Synthesis of Leukotriene C4 in Eosinophils
Authors: Muñoz Nilda M. , Meliton Angelo Y. , Lambertino Anissa , Boetticher Evan , Learoyd Jonathan , Sultan Faraz , Zhu Xiangdong , Cho Wonhwa , Leff Alan R.
Published: April 2014

We examined the mechanism by which secretory group V phospholipase A2 (gVPLA2) secreted from stimulated epithelial cells activates eosinophil adhesion to ICAM-1 surrogate protein and secretion of leukotriene (LT)C4. Exogenous human group V PLA2 (hVPLA2) caused an increase in surface CD11b expression and focal clustering of this integrin, which corresponded to increased β2 integrin-mediated adhesion. Human IIaPLA2, a close homolog of hVPLA2, or W31A, an inactive mutant of hVPLA2, did not affect these responses. Exogenous lysophosphatidylcholine but not arachidonic acid mimicked the β2 integrin-mediated adhesion caused by hVPLA2 activation. Inhibition of hVPLA2 with MCL-3G1, a mAb against gVPLA2, or with LY311727, a global secretory phospholipase A2 (PLA2) inhibitor, attenuated the activity of hVPLA2; trifluoromethylketone, an inhibitor of cytosolic group IVA PLA2 (gIVA-PLA2), had no inhibitory effect on hVPLA2-mediated adhesion. Activation of β2 integrin-dependent adhesion by hVPLA2 did not cause ERK1/2 activation and was independent of gIVA-PLA2 phosphorylation. In other studies, eosinophils cocultured with epithelial cells were stimulated with FMLP/cytochalasin B (FMLP/B) and/or endothelin-1 (ET-1) before LTC4 assay. FMLP/B alone caused release of LTC4 from eosinophils, which was augmented by coculture with epithelial cells activated with ET-1. Addition of MCL-3G1 to cocultured cells caused ∼50% inhibition of LTC4 secretion elicited by ET-1, which was blocked further by trifluoromethylketone. Our data indicate that hVPLA2 causes focal clustering of CD11b and β2 integrin adhesion by a novel mechanism that is independent of arachidonic acid synthesis and gIVA-PLA2 activation. We also demonstrate that gVPLA2, endogenously secreted from activated epithelial cells, promotes secretion of LTC4 in cocultured eosinophils.
Proinflammatory Role of Glucocorticoid-Induced TNF Receptor-Related Gene in Acute Lung Inflammation
Authors: Cuzzocrea Salvatore , Nocentini Giuseppe , Di Paola Rosanna , Agostini Massimiliano , Mazzon Emanuela , Ronchetti Simona , Crisafulli Concetta , Esposito Emanuela , Caputi Achille P. , Riccardi Carlo
Published: April 2014

Glucocorticoid-induced TNFR-related gene (GITR) participates in the immune/inflammatory response. Because GITR expression has been described in cells other than T lymphocytes, we investigated whether it also modulates acute inflammatory response. Using GITR-deficient (GITR−/−) mice, we analyzed the role of GITR in the development of carrageenan-induced lung inflammation (pleurisy) by studying several proinflammatory markers 2–8 h after carrageenan injection. When compared with GITR+/+, GITR−/− mice exhibited decreased production of turbid exudate containing a lower number of leukocytes. This was correlated with the reduction of inflammatory markers (including TNF-α, IL-1β, myeloperoxidase, inducible NO synthase, and cyclooxygenase 2) in the pleural exudate and/or in the lung. Moreover, endothelial cells expressed lower levels of adhesion molecules. In lungs of GITR+/+ mice, GITR ligand expression was not modulated during pleurisy, while that of GITR increased, as a consequence of increased infiltration by GITR-expressing cells and of GITR up-regulation in macrophages and endothelial cells. Finally, cotreatment of GITR+/+ mice with carrageenan and Fc-GITR fusion protein decreased the number of inflammatory cells (pleural macrophages and lung neutrophils) as compared with carrageenan treatment alone, confirming that GITR plays a role in the modulation of pleurisy.
Homozygosity for the IgG2 Subclass Allotype G2M(n) Protects against Severe Infection in Hereditary C2 Deficiency
Authors: Jönsson Göran , Oxelius Vivi-Anne , Truedsson Lennart , Braconier Jean Henrik , Sturfelt Gunnar , Sjöholm Anders G.
Published: April 2014

Homozygous C2 deficiency (C2D) is the most common deficiency of the classical complement pathway in Western countries. It is mostly found in patients with autoimmune disease or susceptibility to bacterial infections and in healthy persons. We wished to assess to what extent other immunological factors might explain differences of susceptibility to infections in C2D. For this reason, 44 Swedish patients with C2D were stratified with regard to the severity of documented infections. Investigations of IgG subclass levels, IgG subclass-specific GM allotypes, concentrations of factor B, properdin, and factor H, and polymorphisms of mannan-binding lectin and the Fc receptors FcγRIIa and FcγRIIIb were performed. Homozygosity for the G2M*n allele, which is known to promote Ab responses to polysaccharide Ags, was strongly associated with the absence of severe infections (p < 0.001) in the patients, suggesting a major protective role. The combination of mannan (or mannose)-binding lectin and C2 deficiency was found to be a minor susceptibility factor for invasive infection (p = 0.03). Low concentrations of IgG2 and factor B might sometimes contribute to susceptibility to infection. Other factors investigated did not appear to be important. In conclusion, the findings indicated that efficient Ab responses to polysaccharides are protective against severe infection in C2D. Implications with regard to vaccination should be considered.