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In studies exploring the effects of HCMV infection on immune system ageing ('immunosenescence'), after organ transplantation or in other settings, HCMV-specific T-cell responses are often assessed with respect to purportedly 'immunodominant' protein subunits. However, the response structure in terms of recognized antigens and response hierarchies (architecture) is not well understood and actual correlates of immune protection are not known.We explored the distribution of T-cell response sizes and dominance hierarchies as well as response breadth in 33HCMV responders with respect to>200HCMV proteins.At the individual responder level HCMV-specific T-cell responses were generally arranged in clear dominance hierarchies; interestingly, the number of proteins recognized by an individual correlated closely with the size of their biggest response. Target-specificity varied considerably between donors and across hierarchy levels with the presence, size, and hierarchy position of responses to purportedly 'immunodominant' targets being unpredictable.Predicting protective immunity based on isolated HCMV subunit-specific T-cell response is questionable in light of the complex architecture of this response. Our findings have important implications for T-cell monitoring, intervention strategies, as well as the application animal models to the understanding of human infection.

The epidermis is the outermost layer of the body and protects it from environmental insults. This crucial function is sustained by a continuous process of self-renewal involving the carefully balanced proliferation and differentiation of progenitor cells constantly replacing the mature cells at the surface of the epidermis. Genetic changes in the signalling pathways controlling keratinocyte proliferation and differentiation disrupt this balance and lead to pathological changes including carcinogenesis. This review discusses the role of Ras, an oncogene critically involved in the development of skin neoplasia, and its downstream effector Raf in epidermal homeostasis and tumourigenesis. In particular, we will focus on the recently established role of Raf-1 as the decisive element that, by restraining keratinocyte differentiation, allows the development and maintenance of Ras-driven tumours.

Item does not contain fulltext BACKGROUND: HLA class I peptide tetramers represent powerful diagnostic tools for detection and monitoring of antigen-specific CD8(+) T cells. The impetus for the current multicenter study is the critical need to standardize tetramer flow cytometry if it is to be implemented as a routine diagnostic assay. Hence, the European Working Group on Clinical Cell Analysis set out to develop and evaluate a single-platform tetramer-based method that used cytomegalovirus (CMV) as the antigenic model. METHODS: Absolute numbers of CMV-specific CD8(+) T cells were obtained by combining the percentage of tetramer-binding cells with the absolute CD8(+) T-cell count. Six send-outs of stabilized blood from healthy individuals or CMV-carrying donors with CMV-specific CD8(+) T-cell counts of 3 to 10 cells/microl were distributed to 7 to 16 clinical sites. These sites were requested to enumerate CD8(+) T cells and, in the case of CMV-positive donors, CMV-specific subsets on three separate occasions using the standard method. RESULTS: Between-site coefficients of variation of less than 10% (absolute CD8(+) T-cell counts) and approximately 30% (percentage and absolute numbers of CMV-specific CD8(+) T cells) were achieved. Within-site coefficients of variation were approximately 5% (absolute CD8(+) T-cell counts), approximately 9% (percentage CMV-specific CD8(+) T cells), and approximately 17% (absolute CMV-specific CD8(+) T-cell counts). The degree of variation tended to correlate inversely with the proportion of CMV-specific CD8(+) T-cell subsets. CONCLUSIONS: The single-platform MHC tetramer-based method for antigen-specific CD8(+) T-cell counting has been evaluated by a European group of laboratories and can be considered a reproducible assay for routine enumeration of antigen-specific CD8(+) T cells.

Background\ud \ud Improved diagnostic tests for tuberculosis in children are needed. We hypothesized that transcriptional signatures of host blood could be used to distinguish tuberculosis from other diseases in African children who either were or were not infected with the human immunodeficiency virus (HIV).\ud \ud Methods\ud \ud The study population comprised prospective cohorts of children who were undergoing evaluation for suspected tuberculosis in South Africa (655 children), Malawi (701 children), and Kenya (1599 children). Patients were assigned to groups according to whether the diagnosis was culture-confirmed tuberculosis, culture-negative tuberculosis, diseases other than tuberculosis, or latent tuberculosis infection. Diagnostic signatures distinguishing tuberculosis from other diseases and from latent tuberculosis infection were identified from genomewide analysis of RNA expression in host blood.\ud \ud Results\ud \ud We identified a 51-transcript signature distinguishing tuberculosis from other diseases in the South African and Malawian children (the discovery cohort). In the Kenyan children (the validation cohort), a risk score based on the signature for tuberculosis and for diseases other than tuberculosis showed a sensitivity of 82.9% (95% confidence interval [CI], 68.6 to 94.3) and a specificity of 83.6% (95% CI, 74.6 to 92.7) for the diagnosis of culture-confirmed tuberculosis. Among patients with cultures negative for Mycobacterium tuberculosis who were treated for tuberculosis (those with highly probable, probable, or possible cases of tuberculosis), the estimated sensitivity was 62.5 to 82.3%, 42.1 to 80.8%, and 35.3 to 79.6%, respectively, for different estimates of actual tuberculosis in the groups. In comparison, the sensitivity of the Xpert MTB/RIF assay for molecular detection of M. tuberculosis DNA in cases of culture-confirmed tuberculosis was 54.3% (95% CI, 37.1 to 68.6), and the sensitivity in highly probable, probable, or possible cases was an estimated 25.0 to 35.7%, 5.3 to 13.3%, and 0%, respectively; the specificity of the assay was 100%.\ud \ud Conclusions\ud \ud RNA expression signatures provided data that helped distinguish tuberculosis from other diseases in African children with and those without HIV infection. (Funded by the European Union Action for Diseases of Poverty Program and others).

Das radioaktive Wasserstoffisotop Tritium (³H) entsteht auf natürliche Weise in der oberen Atmosphäre und wird über den Niederschlag in den hydrologischen Kreislauf eingeführt. Seit den 1950er Jahren gelangt zudem anthropogen produziertes Tritium durch oberirdische Nuklearwaffentests, Emissionen aus Kernkraftanlagen und Industriebetrieben in den Wasserkreislauf. Tritium verhält sich identisch zum Wasserstoffisotop 1H, wodurch es sich als nahezu idealer Tracer für Untersuchungen von Fließ- und Speicherprozessen eignet. Die hier vorgestellten Untersuchungen und Ergebnisse zur Tritiummodellierung bauen auf früheren Arbeiten im Wesergebiet auf. Durch die Verwendung der Ergebnisse flächendifferenzierter Wasserhaushaltsmodelle WaSiM-ETH, TACD) wird das Tritiumbilanzmodell TRIBIL mit detaillierten, qualitativ besseren Eingangsdaten versorgt. In diesem Zusammenhang erfolgen eine Separation der Abflusskomponenten sowie eine Analyse der Wasserbilanz- und Speichergrößen. Die verbesserte Datengrundlage und die Kombination der Modelle erlauben eine sicherere Abschätzung der Tritiumbilanz. Die Ergebnisse zeigen, dass durch die Kopplung von Wasserhaushalts- und Tritiumbilanzmodell bessere Modellanpassungen der Tritiumkonzentrationen im Oberflächenwasser des Wesergebietes erreicht werden. Dadurch können die Gebietsspeicher und die Abflusskomponenten im Wesergebiet schärfer gefasst werden.

Transitions theory emphasizes the important role of niches as sources of sustainable innovation. A defining niche characteristic is the provision of ‘protective space’. It is surprising that the concept of ‘niche protection’ has received little systematic attention to date. Drawing upon UK and Netherlands solar photovoltaic histories, this paper explores protection as having three functional properties: 1) shielding the niche innovation from mainstream selection pressures. 2) nurturing the development of the niche innovation, and 3) empowering niche advocates to influence mainstream selection environments. We develop ideas about how empowerment evolves. We distinguish between 1) empowerment concerned with removing protections as the niche innovation adapts and becomes competitive under prevailing regime selection pressures (fit and conform) and 2) empowerment concerned with transforming selection environments; protection become institutionalized as part of a new regime (stretch and transform). The analysis develops further by focusing on the political dynamics of empowerment. We conclude that niche advocates seeking empowerment employ narratives with three distinctive features: 1) articulating sociotechnical expectations in a positive, socio-political way; 2) making claims for niche-friendly institutional reforms; 3) critical statements about the regime in ways that emphasize opportunities for the niche innovation

Hurricane Isabel made landfall as a Category 2 Hurricane on 18 September 2003, on the North Carolina Outer Banks between Cape Lookout and Cape Hatteras, then coursed northwestward through Pamlico Sound and west of Chesapeake Bay where it downgraded to a tropical storm. Wind damage on the west and southwest shores of Pamlico Sound and the western shore of Chesapeake Bay was moderate, but major damage resulted from the storm tide. The NOAA, National Ocean Service, National Centers for Coastal Ocean Sciences, Center for Coastal Fisheries and Habitat Research at Beaufort, North Carolina and the Center for Coastal Environmental Health and Biomedical Research Branch at Oxford, Maryland have hurricane preparedness plans in place. These plans call for tropical storms and hurricanes to be tracked carefully through NOAA National Weather Service (NWS) watches, warnings, and advisories. When a hurricane watch changes to a hurricane warning for the areas of Beaufort or Oxford, documented hurricane preparation plans are activated. Isabel exacted some wind damage at both Beaufort and Oxford. Storm tide caused damage at Oxford, where area-wide flooding isolated the laboratory for many hours. Storm tide also caused damage at Beaufort. Because of their geographic locations on or near the open ocean (Beaufort) or on or near large estuaries (Beaufort and Oxford), storm tide poses a major threat to these NOAA facilities and the safety of federal employees. Damage from storm surge and windblown water depends on the track and intensity of a storm. One tool used to predict storm surge is the Sea, Lake, and Overland Surges from Hurricanes (SLOSH) model of the NWS, which provides valuable surge forecasts that aid in hurricane preparation.

Documents CEREQ ; 134; L'enseignement supérieur préoccupe de manière croissante l'Etat et les acteurs socio-économiques locaux. Les effectifs de l'enseignement supérieur ont augmenté très rapidement depuis le début des années 90. Le développement des poursuites d'études aboutit à une hausse rapide des moyens financiers et humains nécessaires au fonctionnement de l'enseignement supérieur. Par ailleurs, l'élévation du niveau des sortants du système éducatif modifie en profondeur les liens entre la formation et l'emploi. A tous les niveaux institutionnels des politiques ont été mises en place, afin de favoriser le développement d'enquêtes de cheminement, et de disposer de certains indicateurs de référence. La multiplication des enquêtes a entraîné une demande accrue d'aide méthodologique. Par ailleurs, les structures nationales et locales qui réalisent les enquêtes ont ressenti le besoin de coopérer pour coordonner leurs méthodes. Le CEREQ (Centre d'Etudes et de Recherches sur les qualifications) a donc créé, avec ses centres associés et les universités, un groupe de travail composé de spécialistes des enquêtes de cheminement. Le groupe a tout d'abord réalisé l'inventaire des études portant sur le devenir des étudiants. Il a ensuite travaillé sur la méthodologie des enquêtes longitudinales, fort de l'expérience acquise par ses membres. Ce document synthétise les résultats de ses travaux. Il constitue à la fois un guide méthodologique et une réflexion sur l'exploitation et l'analyse des résultats.