bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthesis of Constructs for Modeling Consumers’ Understanding and Perception of Eco-Labels
Authors: Taufique Khan , Siwar Chamhuri , Talib Basri , Sarah Farah , Chamhuri Norshamliza
Published: April 2014

The term “eco-labeling” has become a buzzword in today’s sustainable business world. The use of eco-labeling in various forms has been increasing notably for past many years, sometimes as an environmental “requirement” and sometimes merely as a marketing tool. Questions arise about how well these eco-labels are attended and understood by consumers. However, though mentionable studies are found on various aspects of eco-labels, gaps exist in exploring an inclusive set of parameters for investigating consumer perceptions of eco-labels. This paper aims at preparing a synthesis of all the possible factors to be incorporated for measuring consumer perceptions of eco-labeling of products. For making such synthesis, all major works in the field have been thoroughly reviewed. The paper comes up with a total of 10 parameters that include consumer awareness, consumer knowledge, consumer involvement, consumer trust, design and visibility, credibility of the source, type and level of information, clarity of meaning, persuasiveness, and private benefits. This tentative, yet inclusive, set of parameters is thought to be useful for designing large scale future empirical researches for developing a dependable inclusive set of parameters to test consumer understanding and perceptions of eco-label. A framework is proposed for further empirical research.
Bassins arides iraniens
Authors: Dresch Jean
Published: April 2014

Résumé. - L'Iran présente un intérêt particulier pour l'étude des bassins fermés arides. Ils occupent tout l'Iran intérieur, à l'exception du Nord-Ouest du pays. La multiplicité et la diversité des bassins s'expliquent par la structure géologique. Une typologie est proposée. Les bassins d'accumulation sont des bassins de dimensions réduites de l'Iran central ou des bassins fluviolacustres anciens ou actuels, au pied de montagnes humides. Celui de Djaz Mourian est spécialement décrit. Il fait en effet contraste avec le bassin voisin du Lut, caractérisé par des surfaces d'érosion, des glacis et les « kalut », et avec le Grand Kewir où d'immenses plaines de regradation sont modelées dans des évaporites plissées. Néotectonique, paléoclimats plus humides et morphogénèse actuelle expliquent ensemble ces différents types de bassins.
Eléments ottomans dans la physionomie géographique de la Cyrénaïque
Authors: de Planhol Xavier
Published: April 2014

Resume. - Entre la réoccupation de Tripoli (1835) et la conquête italienne (1911), le gouvernement ottoman entreprit une politique de création de postes militaires et de divisions administratives en Cyrénalque. Après une première étape qui consista en la construction de forts en 1851-1852 (Al-Marj, Al-Qayqab) le long de la principale route intérieure joignant Benghazi à Derna, un réseau cohérent de centres administratifs (muduriyet) avait été établi avant le début du vingtième siècle. On examine les conditions géographiques et politiques qui déterminèrent leurs emplacements ; on discute leurs relations avec les foyers préexistants de cristallisation du peuplement tribal, et en particulier la situation des postes ottomans par rapport aux zaouias Senoussi. Autour de Benghazi, dans une région où le réseau des muduriyet atteignait son maximum de densité et où l'autorité turque régnait sans conteste, les établissements ottomans sont strictement intercalés entre les zaouias. Dans d'autres cas, sur le haut plateau (Cyrène, Bishâra), les muduriyet étaient établies à proximité immédiate des zaouias. Typique est le cas de Al-Haniyya, dont la zaouia était un actif centre politique. Le poste ottoman était construit sur une petite colline juste en face de la zaouia, dans le dessein évident de la contrôler. Cependant d'autres établissements étaient encore fixés simplement pour des raisons stratégiques (Bumba). La seule tentative de colonisation de peuplement fut l'établissement des mou- hadjir Cretois de Marsa Susâ (1897). On étudie la structure de l'implantation primitive, ainsi que l'évolution ultérieure, caractérisée notamment par une pénétration en petits groupes sur le plateau dès avant la conquête italienne. En conclusion l'auteur tente d'évaluer le médiocre héritage de la période ottomane dans la physionomie géographique actuelle de la Cyrénaïque.
Les bandes forestières de protection dans les steppes soviétiques
Authors: Radvanyi Jean
Published: April 2014

Résumé. - La mise en culture des steppes soviétiques entraine une dégradation inquiétante des sols par érosion éolienne ou fluviatile. Les cultures, soumises aux conditions du climat continental, sont fréquemment détruites ou endommagées par les vents, la sécheresse et le gel. Depuis Dokoutchaev (1892) on cherche à résoudre ces problèmes, en particulier par la plantation de bandes forestières de protection. La période 1948-1953 fut marquée par un grand mouvement de plantations suivi d'un recul dû à un échec partiel. Actuellement, on a repris cette expérience sur une vaste échelle après avoir défini les normes optima : espèces (chêne, peuplier, érable, fruitiers...), bandes de 5 rangs ajourées, organisées en réseau dont la maille dépend de la rigueur du climat. Cette méthode est difficile à appliquer au Kazakhstan où les arbres poussent mal et l'on préconise d'y adjoindre des façons culturales originales. Le gain attendu est en moyenne de 2 à 3 qxjha de blé. Les dégâts des vents, de la sécheresse sont largement évités.
Eléments de recherche : industrialisation et hiérarchie urbaine dans le Nord des Pays-Bas
Authors: Fischer André
Published: April 2014

Résumé. - L'industrialisation régionale est-elle un facteur de renforcement ou d'éclatement de la hiérarchie urbaine préexistante ? L'exemple du Nord des Pays-Bas montre qu'en dépit d'une grande correspondance entre l'armature urbaine régionale et le choix des noyaux officiels d'industrialisation, la croissance industrielle est indépendante de la hiérarchie des villes et de leur niveau de centralité. L'industrialisation récente a provoqué un phénomène de substitution d'influence aux profits des centres de décisions extérieurs à la région.
Un espace agricole est-il un espace atone ?
Authors: Uzan-Lepagnot L.
Published: April 2014

Abstract. - Agricultural space is most often viewed as a blank space, enclosed between the edges and vertices of some central place network. - This paper deals with empirical studies predominantly performed in Southern France. Would farmers be able to constitute associations provided with an organizational power ? Could their impulse go beyond innovation diffusion processes to act as small local service centers ? Flows of information, data, new ideas should find an effective demand among other farmers of the adjacent area. If accepted, this pattern could break the classical hierarchy generally outlined in rural areas.
La terrasse holocène d'Olympie et ses équivalents méditerranéens
Authors: Dufaure Jean-Jacques
Published: April 2014

La terrasse holocène d'Olympie, sablo-limoneuse, a de nombreux équivalents autour de la Méditerranée et sa construction part de l'Empire Romain pour s'accélérer au Moyen-Age (huitième-quatorzième/quinzième siècles). Ce seul épisode de remblaiement post-wurmien, en phase avec une ablation ménagée sur les versants de roche friable, peut s'expliquer par une combinaison complexe (variant de ce fait selon les climats régionaux et le continuum historique local ?) associant des facteurs climatiques - petites fluctuations sèches agissant sur la tenue du tapis herbacé - et anthropiques - décapage néolithique des sols minces de l'optimum atlantique, puis surpâturage des sous-bois et arboriculture/viticulture collinéenne -. L'âge de la terrasse suggère des relais entre causes de déséquilibre, les raccords de quelques siècles illustrant peut-être l'inertie géomorphologique (transfert des déséquilibres des versants aux lits). La dissection coïncide avec le Petit Age Glaciaire (1500- 1850, ici fluctuation « humide ») mais la part des modes de culture et d'élevage à partir de la Renaissance reste objet de spéculation.
Les changements climatiques holocènes dans les Hautes Andes tropicales
Authors: Dollfus Olivier
Published: April 2014

Climatic changes of the late Quaternary and Holocene do not seem to have the same meaning in the Tropical Andes on both side of the equateur. In the north, after the last cold and dry episode of the Quaternary, a sequence - hot and wet interstade - cooler and dryer Lateglacial, has preceded the three periods of the Holocene. In the Fuquene basin (Colombia) : stage I : extension of oak forest, stage 2 : appearence of « cecropia », stage 3 : thinning of the oak for est in relation with land reclamation by agriculturers. - Holocene is marked by a relative thermic and pluviométrie stability with brief cooler interruption (Venezuelan Andes). South of the Equateur the to and fro movement of air masses create a different situation ; the Holocene being here on the whole stable after the last humid and cooler periods of the Quaternary. The reappearence of the seasonal contrasts correspond to the low level of the glaciers. It is necessary to refine this scheme according to regional situations : during the dryer periods on the altiplano boliviano, the rainfall is higher in the eq. Andes. - Though limited, these climatic variations have been able to have important consequences on human occupation of the Andean space in relation to its marginal ecological situation.
Glaciers alpins et chronologie holocène
Authors: Vivian Robert
Published: April 2014

Study of zones marginal to the glaciers has resulted in the discovery of tree trunks and other vegetational evidence as well as bringing to light fresh glacial land forms. C 14 dating of the organic material provides a revealing picture of Holocene. From this research work the post-wurm period appears to comprise three major events : 1. The glaciers retreated very rapidly in the Allero'd, which contained the first major post-Wurm warming trend. Snouts retreated to around 1 000 m above sea level between 12.000 and 9.000 B.P. ; 2. Since the Boreal the glaciers have oscillated within a relatively confined zone, that of the present proglacial margins, allowing the more or less continuous presence of some tree species tet the 1 500-2 300 m level ; 3. Two major advances occurred during the last 3000 years one of short duration from 1400-1300 B.C., the other longer, between 1500 and 1850 A.D.
Med1 Subunit of the Mediator Complex in Nuclear Receptor-Regulated Energy Metabolism, Liver Regeneration, and Hepatocarcinogenesis
Authors: Jia Yuzhi , Viswakarma Navin , Reddy Janardan K.
Published: April 2014

Several nuclear receptors regulate diverse metabolic functions that impact on critical biological processes, such as development, differentiation, cellular regeneration, and neoplastic conversion. In the liver, some members of the nuclear receptor family, such as peroxisome proliferator-activated
receptors (PPARs), constitutive androstane receptor (CAR), farnesoid X receptor (FXR), liver X receptor (LXR), pregnane X receptor (PXR), glucocorticoid receptor (GR), and others, regulate energy homeostasis, the formation and excretion of bile acids, and detoxification of xenobiotics. Excess
energy burning resulting from increases in fatty acid oxidation systems in liver generates reactive oxygen species, and the resulting oxidative damage influences liver regeneration and liver tumor development. These nuclear receptors are important sensors of exogenous activators as well as
receptor-specific endogenous ligands. In this regard, gene knockout mouse models revealed that some lipid-metabolizing enzymes generate PPARα-activating ligands, while others such as ACOX1 (fatty acyl-CoA oxidase1) inactivate these endogenous PPARα activators. In the absence of
ACOX1, the unmetabolized ACOX1 substrates cause sustained activation of PPARα, and the resulting increase in energy burning leads to hepatocarcinogenesis. Ligand-activated nuclear receptors recruit the multisubunit Mediator complex for RNA polymerase II-dependent gene transcription.
Evidence indicates that the Med1 subunit of the Mediator is essential for PPARα, PPARγ, CAR, and GR signaling in liver. Med1 null hepatocytes fail to respond to PPARα activators in that these cells do not show induction of peroxisome proliferation and increases in fatty acid
oxidation enzymes. Med1-deficient hepatocytes show no increase in cell proliferation and do not give rise to liver tumors. Identification of nuclear receptor-specific coactivators and Mediator subunits should further our understanding of the complexities of metabolic diseases associated with
increased energy combustion in liver.
Changes in Biomarkers in HIV-1-Infected Treatment-Naive Patients Treated with Tenofovir DF/Emtricitabine plus Atazanavir/Ritonavir or Lopinavir/Ritonavir for 96 Weeks: The CASTLE Biomarker Substudy
Authors: Moyle Graeme , Hardy Helene , Uy Jonathan , Ray Neelanjana , Jimenez-Exposito Maria Jesus , McGrath Donnie , DeJesus Edwin
Published: April 2014

Background

The impact of boosted protease inhibitor therapy on inflammatory and cardiovascular biomarker levels in treatment-naive HIV-infected patients remains unclear and may differ between agents. Unconjugated bilirubin elevation, which favourably affects vascular biomarkers and cardiovascular disease risk in Gilbert's syndrome, occurs with atazanavir.

Methods

CASTLE was a 96-week study comparing efficacy and safety in treatment-naive HIV-1-infected patients randomized to atazanavir/ritonavir (ATV/r) versus lopinavir/ritonavir (LPV/r), each in combination with tenofovir disoproxil fumarate/emtricitabine. In this substudy, fasting plasma tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), high sensitivity C-reactive protein (hs-CRP), plasminogen activator inhibitor-1 (PAI-1) and fibrinogen were assessed at baseline, week 12, 24, 48 and 96. Impact of grade 3–4 hyperbilirubinaemia on biomarkers was examined.

Results

CASTLE demonstrated similar efficacy in both treatment arms with higher rates of hyperbilirubinaemia on ATV/r and elevated lipids on LPV/r. In this substudy ( n=224), patterns of biomarker expression were similar between the ATV/r and LPV/r groups and between-group differences in biomarker percentage change from baseline were not significant at 48 and/or 96 weeks. Hyperbilirubinaemia did not influence fasting biomarker expression.

Conclusions

No significant differences were noted between ATV/r and LPV/r for biomarker percentage changes from baseline. Furthermore, no association was found between total bilirubin levels and biomarker expression.
La jouissance négativement phallique. De la belle Bouchère au rêve du cochon
Authors: Blaquière Hélène
Published: April 2014

De quoi l’hystérique jouit-elle ? L’exploration de l’insatisfaction permet de mettre au jour un mode de jouissance spécifique, ni tout à fait réduit à une jouissance phallique, ni véritablement distinct. L’hystérique se tient sur ce bord, en maintenant son désir insatisfait. L’accès à une jouissance féminine, telle est notre hypothèse, repose sur l’assomption du fantasme incestueux. Ainsi seulement, pourrait-on accéder à une jouissance Autre.
Complaisances hystériques dans la clinique actuelle
Authors: Bulat-Manenti Gorana
Published: April 2014

Grâce au travail de la cure, le matériel refoulé devant l’angoisse de castration dans le cas de paralysie a pu être analysé chez une enfant et une adolescente. L’association libre et sa mise en acte dans le transfert ont révélé les attachements œdipiens particuliers et confirmé l’importance de la fonction paternelle, hier comme aujourd’hui, dans la formation des symptômes hystériques.
Les leçons cliniques de Socrate
Authors: Zafiropoulos Markos
Published: April 2014

Cet article vise à montrer comment et en quoi la lecture de Lacan du Banquet de Platon constitue aujourd’hui la leçon inaugurale de la clinique de l’hystérie masculine et pourquoi Lacan a fait de ce texte et donc de l’amour homosexuel au masculin la référence centrale de sa recherche sur l’éminente question du transfert pour son séminaire éponyme de 1960- 1961.
The fermentation of polydextrose in the large intestine and its beneficial effects
Authors: Röytiö H. , Ouwehand A.C.
Published: April 2014

Polydextrose is a randomly bonded glucose polymer with a highly branched and complex structure. It resists digestion in the upper gastrointestinal tract and is partially fermented in the large intestine by the colonic microbes. Due to its complex structure, a plethora of microbes is required for the catabolism of polydextrose and this process occurs slowly. This gradual fermentation of polydextrose gives rise to moderate amounts of fermentation products, such as short chain fatty acids and gas. The production of these metabolites continues in the distal part of the colon, which is usually considered to be depleted of saccharolytic fermentation substrates. The fermentation of polydextrose modifies the composition of the microbiota in the colon, and has been shown to impact appetite and satiety in humans and improve the gastrointestinal function. The purpose of this short review is to summarise the in vitro, in vivo and human studies investigating the fermentation properties of polydextrose in the large intestine.
Workarounds
Authors: Nadhrah Nada , Michell Vaughan
Published: April 2014

Patient safety and the quality of clinical interventions rely on the application of best practices in clinical processes to achieve clinical and service specifications for patients. However, outcomes vary due to variations in work activity performance in terms of efficiency and quality, and variations in what is done. This chapter explores the concept of deviations from formal work processes as workarounds in health interventions. It examines workaround evolution and development, the motivation for them, and types. It identifies their positive and negative impact on patient safety and quality. The chapter is based on primary research and workaround case studies of 14 staff in three hospitals. The approach supports the work to develop a generic conceptual normative analysis model of workarounds and adopts BPMN and organisational semiotics to qualitatively and quantitatively define and compare the original work process and workaround. This chapter extends definitions of workaround types and the relationship between actors in the formal work process and informal workaround process. The authors propose a conceptual model to identify the relative safety risk of workarounds and hence their likely patient impact. The discussion focuses on the initial findings of this model on patient safety and how different workaround types impact patient safety. The chapter highlights examples of the clinical work deviations and shows that they can have both positive and negative benefits for patient safety. It emphasises how, using an informatics approach, workarounds need to be considered in detail to understand the motivation and potential impact on health activities.
Using Radio Frequency Identification Technology to Store Patients' Medical Information
Authors: Hawrylak Peter J. , Hart Chris
Published: April 2014

Radio Frequency Identification (RFID) technology enables wireless communication between a RFID reader and a RFID tag. One type, passive RFID tags, need no battery, being powered from the RFID reader's radio frequency signal. Passive RFID tags can support memories that can be used to store portions of the patient's medical history. One form factor for passive RFID tags is an employee ID (used for wireless access) or credit card form factor. This form factor allows the patient to carry their medical information with them. RFID benefits include providing information to Emergency Medical Technicians (EMTs), maintaining a patient's vaccination history and providing emergency contact information, all in a clear and unmistakable format. This simplifies information exchange during patient transfers, a cause of many preventable medical mistakes and errors. Cheap and simple systems, such as the one presented in this chapter, can reduce stress and prevent possible errors. Such systems with an intuitive human-machine interface can reduce the duration of a patient visit throughput. This system can prevent simple errors such as the administration of the wrong drug, dose, or drug omission, which is a major issue in hospitals. This requires that information be stored in a standardised manner, with limited healthcare provider access and use to protect patient privacy. This chapter explores the use of passive RFID tags to store medical information about a patient, with specific focus on storage of a child's vaccination history and safety.
Patient Safety in Community Care
Authors: Eason Ken , Waterson Patrick
Published: April 2014

The increasing number of elderly people in need of health and social care is putting pressure on current services to develop better ways of providing integrated care in the community. It is a widely held belief that e-health technologies have great potential in enabling and achieving this goal. This chapter reviews a number of technologies used for this purpose: telecare, telehealth, telemedicine, electronic patient record systems, and technologies to support mobile working. In each case, technocentric-design approaches have led to problematic implementations and failures to achieve adoption into the routine of delivering healthcare. An examination of attempts to implement major changes in the service delivery of integrated care shows that e-health technologies can be successfully implemented when they are seen as an intrinsic part of the creation of a complete system. However, the design process required for successful delivery of these services is challenging; it requires sustained and integrated development work by clinical staff and technologists coordinating their work on process changes, organisational developments, and technology implementations.
Applying Social Aspects in Home Telecare Design to Improve the Safety of Users and Quality of Service
Authors: Chidzambwa Lawrence
Published: April 2014

Telecare enables remote and cost-effective home treatment of patients, improving the safety and quality of life of frail individuals. However, despite increased availability of telecare devices, many are not fully used and often ignored due to poor social perception and experience. The research suggests the social aspects of quality and safety related to user experience have not been considered. This can lead to misuse or non-use of telecare devices, reducing patient safety and quality of life. This chapter explores the implications for the lack of social considerations in telecare and develops a series of models and methodologies to integrate the social dimension with the traditional medical intervention focus. By applying semiotics and normative behavioural theory, the authors show how a Normative Home Telecare Framework can improve telecare solution design and ensure take up and use of the devices and increase patient safety and life quality.
Healthcare Resource Sustainability
Authors: Gulliver Stephen R. , Wiafe Isaac , Grzybek Hubert , Radosavljevic Milan
Published: April 2014

Health care provision is significantly impacted by the ability of health providers to engineer a viable healthcare space to support care stakeholders needs. In this chapter, the authors discuss and propose use of organisational semiotics as a set of methods to link stakeholders to systems, which allows them to capture data about clinician activity, information transfer, and building use, which in turn allows them to define the value of specific systems in the care environment to specific stakeholders and the dependence between systems in a care space. The authors suggest use of a semantically enhanced Building Information Model (BIM) to support the linking of clinician activity to the physical resource objects and space and facilitate the capture of quantifiable data over time or in relation to key stakeholders. Finally, the authors argue for the inclusion of appropriate stakeholder feedback and persuasive mechanisms to incentivise building user behaviour to support organisational level sustainability policy.
Buffer Managed Multiple Replication Strategy Using Knapsack Policy for Intermittently Connected Mobile Networks
Authors: Poongodi C. , Natarajan A. M.
Published: April 2014

Intermittently Connected Mobile Networks (ICMNs) are a kind of wireless network where, due to mobility of nodes and lack of connectivity, there may be disconnections among the nodes for a long time. To deal with such networks, store-carry-forward method is adopted for routing. This method buffers the messages in each node for a long time until a forwarding opportunity comes. Multiple replications are made for each message. It results in an increase in network overhead and high resource consumption because of uncontrolled replications. Uncontrolled replications are done due to lack of global knowledge about the messages and the forwarding nodes. The authors introduce a new simple scheme that applies knapsack policy-based replication strategy while replicating the messages residing in a node buffer. The numbers of replications are controlled by appropriately selecting messages based on the total count on replications already made and the message size. In addition, the messages are selected for forwarding based on the relay node goodness in contacting the destination and the remaining buffer size of that relay node. Therefore, useful replications are made based on the dynamic environment of a network, and it reduces the network overhead, resource consumption, delivery delay, and in turn, increases the delivery ratio.
Performance Evaluation of GSM Traffic Transmission over Cognitive Radio Networks under Opportunistic Spectrum Sharing Collisions
Authors: Chaoub Abdelaali , Ibn-Elhaj Elhassane
Published: April 2014

Cognitive Radio networks and channel sharing are emerging as a new paradigm of communication in multimedia and wireless networks. In this chapter, the authors consider a secondary use application that consists of carrying TDMA traffic between the mobile and the base station for GSM networks over a Cognitive Radio network. Therefore, packets are not only lost by reason of Primary traffic interruptions, but the authors consider the opportunistic spectrum sharing which is the cornerstone of the Cognitive Radio concept as the major cause of collisions between several Secondary Users. The authors introduce their specific collision model, and they propose a solution consisting of the creation of many secondary user links with high reliability using a specific algorithm introduced here to alleviate traffic collisions. The authors evaluate the secondary traffic transmission performance in view of the Spectral Efficiency, and they outline the achieved gains of using the proposed solution. Finally, the authors highlight the recent trend in CR literature, which consists of leveraging the TV white spaces to deploy and enhance next generation cellular networks such as LTE.
Voice and Video over Gigabit Ethernet and ATM Backbone Networks
Authors: Sarkar Nurul I. , Dole Yash
Published: April 2014

This chapter aims to report on the performance of voice and video traffic over two popular backbone network technologies, namely Gigabit Ethernet (GbE) and Asynchronous Transfer Mode (ATM). ATM networks are being used by many universities and organizations for their unique characteristics such as scalability and guaranteed Quality of Service (QoS), especially for voice and video applications. Gigabit Ethernet matches ATM functionality by providing higher bandwidth at much lower cost, less complexity, and easier integration into the existing Ethernet technologies. It is useful to be able to compare these two technologies against various network performance metrics to find out which technology performs better for transporting voice and video conferencing. This chapter provides an in-depth performance analysis and comparison of GbE and ATM networks by extensive OPNET-based simulation. The authors measure the Quality of Service (QoS) parameters, such as voice and video throughput, end-to-end delay, and voice jitter. The analysis and simulation results reported in this chapter provide some insights into the performance of GbE and ATM backbone networks. This chapter may help network researchers and engineers in selecting the best technology for the deployment of backbone campus and corporate networks.
Computer-Aided Drug Design and Biological Evaluation of Novel Anti-Greek Goat Encephalitis Agents
Authors: Papageorgiou Louis , Vlachakis Dimitrios , Koumandou Vassiliki Lila , Papangelopoulos Nikitas , Kossida Sophia
Published: April 2014

The Flaviviridae family of viruses infects vertebrates and is primarily spread through arthropod vectors. The Greek Goat Encephalitis (GGE) flavivirus belongs to the Flaviviridae family and specifically to the genus Flavivirus. GGE virus, which is endemic in Greece, is the causative agent of tick-borne encephalitis (TBE), an infection of the central nervous system that can be transmitted from animals to humans by ticks. Although, there are very limited data regarding the GGE virus and its epidemiology in Greece, there have been few reported cases of GGE viral infection of goats in northern Greece. However, despite the severity of Flaviviridae causing diseases (e.g. Hepatitis C, Dengue fever, Yellow fever, Classical swine fever, Japanese encephalitis), currently there is not any available anti-flaviviridae therapy. Thus, there is a need for the development of effective anti-GGE viral pharmaceutical strategies. It has been shown that RNA helicases, which are involved in duplex unwinding during viral RNA replication, represent promising antiviral targets. Therefore, we suggest that inhibition of the GGE viral helicase would be an effective approach of interrupting the life cycle of the GGE virus. Our proposed research will be directed towards the computer-aided development of a series of drug-like low molecular weight compounds capable of inhibiting the helicase enzyme of GGE virus. Results derived from a repertoire of multi-disciplinary bioinformatics and statistical methods would enhance our understanding of the mechanism of action of the GGE viral helicase enzyme. Our ultimate goal is to design a series of novel anti-helicase compounds as drug candidates against the endemic GGE virus while the inhibitory activity of our novel compounds will be evaluated biologically.
Cutting Edge: Dominance by an MHC-Independent Inhibitory Receptor Compromises NK Killing of Complex Targets
Authors: Wahle Joseph A. , Paraiso Kim H. T. , Costello Amy L. , Goll Emily L. , Sentman Charles L. , Kerr William G.
Published: April 2014

Inhibitory receptors that recognize MHC class I molecules regulate NK cell responses and self-tolerance. Recent evidence indicates that self-ligands not present in the MHC locus also can modulate NK function. In this study, we show that an inhibitory receptor that recognizes an MHC-independent ligand is over expressed in SHIP−/− mice at all stages of NK development and differentiation. Overexpression of this receptor compromises key cytolytic NK functions, including killing of allogeneic, tumor, and viral targets. These results further demonstrate the critical role that SHIP plays in regulation of the NK receptor repertoire and show that regulation of MHC-independent inhibitory receptors is crucial for NK recognition and cytolysis of complex targets.
Biliary Obstruction Selectively Expands and Activates Liver Myeloid Dendritic Cells
Authors: Bleier Joshua I. , Katz Steven C. , Chaudhry Umer I. , Pillarisetty Venu G. , Kingham T. Peter , Shah Alaap B. , Raab Jesse R. , DeMatteo Ronald P.
Published: April 2014

Obstructive jaundice is associated with immunologic derangements and hepatic inflammation and fibrosis. Because dendritic cells (DCs) play a major role in immune regulation, we hypothesized that the immunosuppression associated with jaundice may result from the functional impairment of liver DCs. We found that bile duct ligation (BDL) in mice expanded the myeloid subtype of liver DCs from 20 to 80% of total DCs and increased their absolute number by >15-fold. Liver myeloid DCs following BDL, but not sham laparotomy, had increased Ag uptake in vivo, high IL-6 secretion in response to LPS, and enhanced ability to activate T cells. The effects of BDL were specific to liver DCs, as spleen DCs were not affected. Expansion of liver myeloid DCs depended on Gr-1+ cells, and we implicated monocyte chemotactic protein-1 as a potential mediator. Thus, obstructive jaundice selectively expands liver myeloid DCs that are highly functional and unlikely to be involved with impaired host immune responses.
In Situ Replication of Immediate Dendritic Cell (DC) Precursors Contributes to Conventional DC Homeostasis in Lymphoid Tissue
Authors: Diao Jun , Winter Erin , Cantin Claude , Chen Wenhao , Xu Luoling , Kelvin David , Phillips James , Cattral Mark S.
Published: April 2014

The developmental biology of dendritic cells (DC) under physiological conditions remains unclear. In this study, we show that mouse CD11c+ MHC class II−lineage− cells are immediate precursors of conventional DC and are widely distributed in both bone marrow and lymphoid tissues. These precursors have a high clonal efficiency, and when cocultured on a supportive stromal monolayer or adoptively transferred in vivo, generate a population CD11c+MHC class II+ DC that retain limited proliferation capacity. During steady state conditions, a small proportion of immediate DC precursors (DCp) and DCs are dividing actively in bone marrow and spleen. Cytokines that initiate and support proliferation of immediate DCp were defined. Collectively, our findings provide evidence of a distinct development pathway for conventional DC in both bone marrow and lymphoid tissues and highlight the importance of in situ replication of immediate DCp and DC in maintaining conventional DC populations.
Tyk2 Negatively Regulates Adaptive Th1 Immunity by Mediating IL-10 Signaling and Promoting IFN-γ-Dependent IL-10 Reactivation
Authors: Shaw Michael H. , Freeman Gordon J. , Scott Mark F. , Fox Barbara A. , Bzik David J. , Belkaid Yasmine , Yap George S.
Published: April 2014

The Jak, Tyk2, is activated in response to IL-12 and IFN-αβ and promotes IFN-γ production by Th1-type CD4 cells. Mice deficient in Tyk2 function have been previously shown to be resistant to autoimmune arthritis and septic shock but are acutely susceptible to opportunistic pathogens such as Toxoplasma gondii. In this study, we show that Tyk2, in addition to mediating the biological effects of IL-12 and IFN-αβ, is an important regulator for the signaling and expression of the immunosuppressive cytokine IL-10. In the absence of Tyk2, Ag-reactive CD4 cells exhibit impaired IL-10 synthesis following rechallenge of T. gondii vaccine-primed mice. The impaired IL-10 reactivation leads to unopposed antimicrobial effector mechanisms which results in a paradoxically superior protection of immune Tyk2−/− mice against virulent T. gondii challenge. We further demonstrate that Tyk2 indirectly controls CD4 IL-10 reactivation by signaling for maximal IFN-γ secretion. The unexpected role of IFN-γ in mediating IL-10 reactivation by Th1 cells provides compelling evidence that conditions driving Th1 responses establish a negative feedback loop, which will ultimately lead to its autoregulation. Thus, Tyk2 can be viewed as a dual-function Jak, mediating both pro and anti-inflammatory cytokine responses.
The Sialyltransferase ST3Gal-I Is Not Required for Regulation of CD8-Class I MHC Binding during T Cell Development
Authors: Kao Charlly , Sandau Michelle M. , Daniels Mark A. , Jameson Stephen C.
Published: April 2014

The CD8 coreceptor plays a crucial role in thymocyte and T cell sensitivity by binding to class I MHC and recruiting downstream signaling molecules to the TCR. Previous studies reported considerable changes in TCR-independent CD8/class I MHC binding (i.e., CD8 noncognate interactions) during T cell development, changes that correlated with altered glycosylation of surface molecules. In particular, expression of the sialyltransferase ST3Gal-I has been proposed as a critical factor regulating the attenuation of CD8 avidity during the double-positive to CD8 single-positive progression. This hypothesis is strengthened by the fact that ST3Gal-I−/− animals show a profound disregulation of CD8 T cell homeostasis. In contrast to this model, however, we report in this study that ST3Gal-I deficiency had no detectable impact on CD8 noncognate binding to multimeric peptide/MHC class I ligands at any stage of thymocyte development. We also found that the susceptibility to CD8-induced cell death is not markedly influenced by ST3Gal-I deficiency. Thus, the profound effects of ST3Gal-I on CD8 T cell survival evidently do not involve a role for this enzyme in controlling CD8-class I binding.
Diesel Exhaust Particle-Exposed Human Bronchial Epithelial Cells Induce Dendritic Cell Maturation
Authors: Bleck Bertram , Tse Doris B. , Jaspers Ilona , Curotto de Lafaille Maria A. , Reibman Joan
Published: April 2014

Increased exposure to air pollutants such as diesel exhaust particles (DEP) has been proposed as one mechanism to explain the rise in allergic disorders. However, the immunologic mechanisms by which DEP enhance allergic sensitization and asthma remain unclear. We hypothesized that DEP act as an adjuvant for immature dendritic cell (DC) maturation via its effect on airway epithelial cell-derived microenvironment for DC. Immature monocyte-derived DC (iMDDC) failed to undergo phenotypic (CD80, CD83, CD86) or functional (T cell activation) maturation in response to exposure to DEP (0.001–100 μg/ml). In contrast, primary cultures of human bronchial epithelial cells (HBEC) treated with DEP induced iMDDC phenotypic maturation (2.6 ± 0.1-fold increase in CD83 expression, n = 4, p < 0.05) and functional maturation (2.6 ± 0.2-fold increase in T cell activation, n = 4, p < 0.05). Functional maturation of iMDDC was induced by conditioned medium derived from DEP-treated HBEC, and was inhibited in cultures with DEP-treated HBEC and blocking Abs against GM-CSF, or GM-CSF-targeted small interfering RNA. These data suggest that DEP induce Ag-independent DC maturation via epithelial cell-DC interactions mediated by HBEC-derived GM-CSF. Although additional signals may be required for polarization of DC, these data suggest a novel mechanism by which environmental pollutants alter airway immune responses.
Protein Kinase C (PKC)α and PKCθ Are the Major PKC Isotypes Involved in TCR Down-Regulation
Authors: von Essen Marina , Nielsen Martin W. , Bonefeld Charlotte M. , Boding Lasse , Larsen Jeppe M. , Leitges Michael , Baier Gottfried , Ødum Niels , Geisler Carsten
Published: April 2014

It is well known that protein kinase C (PKC) plays an important role in regulation of TCR cell surface expression levels. However, eight different PKC isotypes are present in T cells, and to date the particular isotype(s) involved in TCR down-regulation remains to be identified. The aim of this study was to identify the PKC isotype(s) involved in TCR down-regulation and to elucidate the mechanism by which they induce TCR down-regulation. To accomplish this, we studied TCR down-regulation in the human T cell line Jurkat, in primary human T cells, or in the mouse T cell line DO11.10 in which we either overexpressed constitutive active or dominant-negative forms of various PKC isotypes. In addition, we studied TCR down-regulation in PKC knockout mice and by using small interfering RNA-mediated knockdown of specific PKC isotypes. We found that PKCα and PKCθ were the only PKC isotypes able to induce significant TCR down-regulation. Both isotypes mediated TCR down-regulation via the TCR recycling pathway that strictly depends on Ser126 and the di-leucine-based receptor-sorting motif of the CD3γ chain. Finally, we found that PKCθ was mainly implicated in down-regulation of directly engaged TCR, whereas PKCα was involved in down-regulation of nonengaged TCR.
TLR9 Is Required for the Gut-Associated Lymphoid Tissue Response following Oral Infection of Toxoplasma gondii
Authors: Minns Laurie A. , Menard Laurence C. , Foureau David M. , Darche Sylvie , Ronet Catherine , Mielcarz Daniel W. , Buzoni-Gatel Dominique , Kasper Lloyd H.
Published: April 2014

TLRs expressed by a variety of cells, including epithelial cells, B cells, and dendritic cells, are important initiators of the immune response following stimulation with various microbial products. Several of the TLRs require the adaptor protein, MyD88, which is an important mediator for the immune response following Toxoplasma gondii infection. Previously, TLR9-mediated innate immune responses were predominantly associated with ligation of unmethylated bacterial CpG DNA. In this study, we show that TLR9 is required for the Th1-type inflammatory response that ensues following oral infection with T. gondii. After oral infection with T. gondii, susceptible wild-type (WT; C57BL/6) but not TLR9−/− (B6 background) mice develop a Th1-dependent acute lethal ileitis; TLR9−/− mice have higher parasite burdens than control WT mice, consistent with depressed IFN-γ-dependent parasite killing. A reduction in the total T cell and IFN-γ-producing T cell frequencies was observed in the lamina propria of the TLR9−/− parasite-infected mice. TLR9 and type I IFN production was observed by cells from infected intestines in WT mice. TLR9 expression by dendritic cell populations is essential for their expansion in the mesenteric lymph nodes of infected mice. Infection of chimeric mice deleted of TLR9 in either the hemopoietic or nonhemopoietic compartments demonstrated that TLR9 expression by cells from both compartments is important for efficient T cell responses to oral infection. These observations demonstrate that TLR9 mediates the innate response to oral parasite infection and is involved in the development of an effective Th1-type immune response.
Class IA Phosphatidylinositide 3-Kinases, rather than p110γ, Regulate Formyl-Methionyl-Leucyl-Phenylalanine-Stimulated Chemotaxis and Superoxide Production in Differentiated Neutrophil-Like PLB-985 Cells
Authors: Boulven Isaline , Levasseur Sylvain , Marois Sébastien , Paré Guillaume , Rollet-Labelle Emmanuelle , Naccache Paul H.
Published: April 2014

Class I PI3Ks, through the formation of phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3), are thought of as essential elements of the neutrophil response to chemotactic factors. Moreover, the recent development of PI3K-deficient mice and isoform-specific inhibitors enabled examinations of the contribution of the distinct PI3K isoforms in neutrophil activation. However, the results of these various studies are conflicting, and the exact role of the different PI3K isoforms is not yet clearly established, particularly in human cells. In the present study, we used a different approach to assess the role of the distinct PI3K isoforms in response to the chemotactic agent fMLP. We inhibited PI3K activities by the transient expression following nucleofection of dominant negative mutants of either p85α or p110γ in the human myeloid cell line PLB-985, which can be induced to express a neutrophil-like phenotype. The data obtained with this approach showed that the production of PI(3,4,5)P3 triggered by fMLP is biphasic, with a peak of production observed in a short time period that entirely depends on p110γ activity, and a delayed phase that is mediated by class IA PI3K. We also provide evidence that the PI3K-dependent functional responses (i.e., superoxide production and chemotaxis) induced by the chemotactic factor mainly involve PI3K IA and, by implication, the delayed phase of PI(3,4,5)P3 production, whereas p110γ and the early peak of PI(3,4,5)P3 do not play major roles in the initiation or the control of these responses.
Timely DNA Vaccine Combined with Systemic IL-12 Prevents Parotid Carcinomas before a Dominant-Negative p53 Makes Their Growth Independent ofHER-2/neuExpression
Authors: Pannellini Tania , Spadaro Michela , Di Carlo Emma , Ambrosino Elena , Iezzi Manuela , Amici Augusto , Lollini Pier Luigi , Forni Guido , Cavallo Federica , Musiani Piero
Published: April 2014

Double transgenic mice overexpressing the transforming rat HER-2/neu oncogene and the mutated p53, with both dominant-negative and a gain-of-function properties, display early aggressive and metastasizing parotid tumors. Multiple acinar and ductal hyperplasia foci overexpressing the HER-2/neu gene product are evident at wk 5 and progress to poorly differentiated carcinoma by wk 7. Mice die before wk 18 with invasive carcinomas and multiple metastases that no longer express HER-2/neu. A combination of repeated electroporations of plasmids coding for the extracellular and transmembrane domains of the rat HER-2/neu receptor with systemic IL-12 administrations started when the parotids that present diffuse hyperplasia protected all female and 50% of the male mice until the close of the experiment at wk 40. This combined treatment began when multifocal in situ carcinomas that were already present cured 33% of the females and 25% of the males. The most prominent immunologic features associated with the antitumor protection were the production of high titers of anti-HER-2/neu Abs and the nonappearance of cell-mediated cytotoxic reactivity. In conclusion, anti-HER-2/neu vaccination combined with systemic IL-12 control parotid carcinomas as far as p53 mutation makes their growth independent of HER-2/neu expression.
Leptin Receptor Expression and Signaling in Lymphocytes: Kinetics During Lymphocyte Activation, Role in Lymphocyte Survival, and Response to High Fat Diet in Mice
Authors: Papathanassoglou Elizabeth , El-Haschimi Karim , Li Xian Chang , Matarese Giuseppe , Strom Terry , Mantzoros Christos
Published: April 2014

Leptin has direct effects not only on neuroendocrine function and metabolism, but also on T cell-mediated immunity. We report in this study that leptin receptor (ObR) is expressed on resting normal mouse CD4+, CD8+, B cells, and monocyte/macrophages. ObR expression is up-regulated following cell activation, but with different kinetics, in different lymphocyte subsets. Leptin binding to ObR results in increased STAT-3 activation in T cells, with a different activation pattern in resting vs anti-CD3 Ab stimulated T cells. Leptin also promotes lymphocyte survival in vitro by suppressing Fas-mediated apoptosis. B lymphocytes appear to be more susceptible to the antiapoptotic effects of leptin, and they show higher surface expression of ObR, compared with T cells. Moreover, CD4+ T cells isolated from ObR-deficient mice displayed a reduced proliferative response, compared with normal controls. Furthermore, ObR/STAT-3-mediated signaling in T lymphocytes is decreased in the diet-induced obese mouse model of obesity and leptin resistance. In summary, our findings show that the ObR is expressed on normal mouse lymphocyte subsets, that leptin plays a role in lymphocyte survival, and that leptin alters the ObR/STAT-3-mediated signaling in T cells. Taken together, our data further support the notion that nutritional status acting via leptin-dependent mechanisms may alter the nature and vigor of the immune response.