In vitro expansion of CD4+CD25highFOXP3+CD127low/- regulatory T cells from peripheral blood lymphocytes of healthy Mycobacterium tuberculosis-infected humans.

CD4+CD25highFOXP3+ regulatory T (Treg) cells have recently been found at elevated levels in the peripheral blood of tuberculosis patients, compared to Mycobacterium tuberculosis latently infected (LTBI) healthy individuals and non-infected controls. Here, we show that CD4+CD25highFOXP3+ T lymphocytes can be expanded in vitro from peripheral blood mononuclear cells (PBMC) of LTBI individuals, but not of uninfected controls by incubating them with BCG in the presence of TGF-beta. These expanded cells from the PBMC of LTBI subjects expressed CTLA-4, GITR and OX-40, but were CD127low/- and have therefore the phenotype of Treg cells. In addition, they inhibited in a dose-dependant manner the proliferation of freshly isolated mononuclear cells in response to polyclonal stimulation, indicating that they are functional Treg lymphocytes. In contrast, incubation of the PBMC with BCG alone preferentially induced activated CD4+ T cells, expressing CD25 and/or CD69 and secreting IFN-gamma. These results show that CD4+CD25highFOXP3+ Treg cells can be expanded or induced in the peripheral blood of LTBI individuals in conditions known to predispose to progression towards active tuberculosis and may therefore play an important role in the pathogenesis of the disease.

Regulatory T cells depress immune responses to protective antigens in active tuberculosis.

RATIONALE: Tuberculosis (TB) remains a leading cause of death, and the role of T-cell responses to control Mycobacterium tuberculosis infections is well recognized. Patients with latent TB infection develop strong IFN-gamma responses to the protective antigen heparin-binding hemagglutinin (HBHA), whereas patients with active TB do not. OBJECTIVES: We investigated the mechanism of this difference and evaluated the possible involvement of regulatory T (Treg) cells and/or cytokines in the low HBHA T-cell responses of patients with active TB. METHODS: The impact of anti-transforming growth factor (TGF)-beta and anti-IL-10 antibodies and of Treg cell depletion on the HBHA-induced IFN-gamma secretion was analyzed, and the Treg cell phenotype was characterized by flow cytometry. MEASUREMENTS AND MAIN RESULTS: Although the addition of anti-TGF-beta or anti-IL-10 antibodies had no effect on the HBHA-induced IFN-gamma secretion in patients with active TB, depletion of CD4(+)CD25(high)FOXP3(+) T lymphocytes resulted in the induction by HBHA of IFN-gamma concentrations that reached levels similar to those obtained for latent TB infection. No effect was noted on the early-secreted antigen target-6 or candidin T-cell responses. CONCLUSIONS: Specific CD4(+)CD25(high)FOXP3(+) T cells depress the T-cell-mediated immune responses to the protective mycobacterial antigen HBHA during active TB in humans.

Cell-to-cell contact-independent regulatory T cells in human tuberculosis

info:eu-repo/semantics/nonPublished

CD4+CD25+FOXP3+ regulatory T-cells and the development of active tuberculosis in humans

info:eu-repo/semantics/published

Emergence: a paradigm for robust and scalable distributed applications

Natural distributed systems are adaptive, scalable and fault-tolerant. Emergence science describes how higher-level self-regulatory behaviour arises in natural systems from many participants following simple rulesets. Emergence advocates simple communication models, autonomy and independence, enhancing robustness and self-stabilization. High-quality distributed applications such as autonomic systems must satisfy the appropriate nonfunctional requirements which include scalability, efficiency, robustness, low-latency and stability. However the traditional design of distributed applications, especially in terms of the communication strategies employed, can introduce compromises between these characteristics. This paper discusses ways in which emergence science can be applied to distributed computing, avoiding some of the compromises associated with traditionally-designed applications. To demonstrate the effectiveness of this paradigm, an emergent election algorithm is described and its performance evaluated. The design incorporates nondeterministic behaviour. The resulting algorithm has very low communication complexity, and is simultaneously very stable, scalable and robust.

Maximising heat transfer efficiency in the cold crucible induction melting process

Induction heating is an efficient method used to melt electrically conductive materials, particularly if melting takes place in a ceramic crucible. This form of melting is particularly good for alloys, as electromagnetic forces set up by the induction coil lead to vigorous stirring of the melt ensuring homogeneity and uniformity in temperature. However, for certain reactive alloys, or where high purity is required, ceramic crucibles cannot be used, but a water-cooled segmented copper crucible is employed instead. Water cooling prevents meltdown or distortion of the metal wall, but much of the energy goes into the coolant. To reduce this loss, the electromagnetic force generated by the coil is used to push the melt away from the walls and so minimise contact with water-cooled surfaces. Even then, heat is lost through the crucible base where contact is inevitable. In a collaborative programme between Greenwich and Birmingham Universities, computer modelling has been used in conjunction with experiments to improve the superheat attainable in the melt for a,number of alloys, especially for y-TiAl intermetallics to cast aeroengine turbine blades. The model solves the discretised form of the turbulent Navier-Stokes, thermal energy conservation and Maxwell equations using a Spectral Collocation technique. The time-varying melt envelope is followed explicitly during the computation using an adaptive mesh. This paper briefly describes the mathematical model used to represent the interaction between the magnetic field, fluid flow, heat transfer and change of phase in the crucible and identifies the proportions of energy used in the melt, lost in the crucible base and in the crucible walls. The role of turbulence is highlighted as important in controlling heat losses and turbulence damping is introduced as a means of improving superheat. Model validation is against experimental results and shows good agreement with measured temperatures and energy losses in the cooling fluid throughout the melting cycle.

Water privatisation

The article examines the expansion of private water companies since 1989 the withdrawal from developing countries from 2003 onwards, and the economic impact of privatisation. The analysis is set in the context of the historical development of water services in the north and the south, showing that the role of private water companies since the start of the 20th century has been historically limited and exceptional. The impact of water privatisation is considered in relation to the issues of investment, prices, and efficiency, drawing on empirical evidence from the north and developing countries in Asia, Africa and Latin America. Particular attention is given to France and the UK, where private water companies, for different reasons, are most established. The evidence from both north and south shows systematic underinvestment, monopoly pricing, regulatory gaming, and no significant efficiency differences between public and private sector operators. In conclusion, the article identifies institutional policies including fiscal constraints and lending conditionalities as key drivers of privatisation, and questions whether these can sustain privatisation in the water sector where historical experience indicates it is an inappropriate solution.

Competition Relatedness And Efficiency

Seger has argued that, if a law of diminishing returns of personal fitness with increasing consumption of a limiting resource applies, a greater increment to inclusive fitness3 may accrue to an individual by sharing the resource with its relatives than by excluding them. That is, from the point of view of an individual's inclusive fitness, there will exist an optimal relation between resource abundance, conversion efficiency (in terms of increment in personal fitness per resource unit consumed) and competitor abundance and relatedness to the subject. Here, this is rendered more concrete by deriving expressions for the optimum consumption rate for any one of a number of related individuals competing for a finite resource.