Decreasing population selection rates of resistance mutation K65R over time in HIV-1 patients receiving combination therapy including tenofovir.

OBJECTIVES: The use of tenofovir is highly associated with the emergence of mutation K65R, which confers broad resistance to nucleoside/nucleotide analogue reverse transcriptase inhibitors (NRTIs), especially when tenofovir is combined with other NRTIs also selecting for K65R. Although recent HIV-1 treatment guidelines discouraging these combinations resulted in reduced K65R selection with tenofovir, updated information on the impact of currently recommended regimens on the population selection rate of K65R is presently lacking. METHODS: In this study, we evaluated changes over time in the selection rate of resistance mutation K65R in a large population of 2736 HIV-1-infected patients failing combination antiretroviral treatment between 2002 and 2010. RESULTS: The K65R resistance mutation was detected in 144 patients, a prevalence of 5.3%. A large majority of observed K65R cases were explained by the use of tenofovir, reflecting its wide use in clinical practice. However, changing patterns over time in NRTIs accompanying tenofovir resulted in a persistent decreasing probability of K65R selection by tenofovir-based therapy. The currently recommended NRTI combination tenofovir/emtricitabine was associated with a low probability of K65R emergence. For any given dual NRTI combination including tenofovir, higher selection rates of K65R were consistently observed with a non-nucleoside reverse transcriptase inhibitor than with a protease inhibitor as the third agent. DISCUSSION: Our finding of a stable time trend of K65R despite elevated use of tenofovir illustrates increased potency of current HIV-1 therapy including tenofovir.

Characterization of Melan-A reactive memory CD8+ T cells in a healthy donor.

Melan-A specific CD8+ T cells are thought to play an important role against the development of melanoma. Their in vivo expansion is often observed with advanced disease. In recent years, low levels of Melan-A reactive CD8+ T cells have also been found in HLA-A2 healthy donors, but these cells harbor naive characteristics and are thought to be mostly cross-reactive for the Melan-A antigen. Here, we report on a large population of CD8+ T cells reactive for the Melan-A antigen, identified in one donor with no evidence of melanoma. Interestingly, this population is oligoclonal and displays a clear memory phenotype. However, a detailed study of these cells indicated that they are unlikely to be directly specific for melanoma, so that their in vivo expansion may have been driven by an exogenous antigen. Screening of a Melan-A cross-reactive peptide library suggested that these cells may be specific for an epitope derived from a Mycobacterium protein, which would provide a further example of CD8+ T cell cross-reactivity between a pathogen antigen and a tumor antigen. Finally, we discuss potential perspectives regarding the role of such cells in heterologous immunity, by influencing the balance between protective immunity and pathology, e.g. in the case of melanoma development.

Cultural transmission can inhibit the evolution of altruistic helping.

The study of culturally inherited traits has led to the suggestion that the evolution of helping behaviors is more likely with cultural transmission than without. Here we evaluate this idea through a comparative analysis of selection on helping under both genetic and cultural inheritance. We develop two simple models for the evolution of helping through cultural group selection: one in which selection on the trait depends solely on Darwinian fitness effects and one in which selection is driven by nonreproductive factors, specifically imitation of strategies achieving higher payoffs. We show that when cultural variants affect Darwinian fitness, the selection pressure on helping can be markedly increased relative to that under genetic transmission. By contrast, when variants are driven by nonreproductive factors, the selection pressure on helping may be reduced relative to that under genetic inheritance. This occurs because, unlike biological offspring, the spread of cultural variants from one group to another through imitation does not reduce the number of these variants in the source group. As a consequence, there is increased within-group competition associated with traits increasing group productivity, which reduces the benefits of helping. In these cases, selection for harming behavior (decreasing the payoff to neighbors) may occur rather than selection for helping.

RNA-driven cyclin-dependent kinase regulation: when CDK9/cyclin T subunits of P-TEFb meet their ribonucleoprotein partners.

The positive transcription elongation factor (P-TEFb) consists of CDK9, a cyclin-dependent kinase and its cyclin T partner. It is required for transcription of most class II genes. Its activity is regulated by non-coding RNAs. The 7SK cellular RNA turns the HEXIM cellular protein into a P-TEFb inhibitor that binds its cyclin T subunit. Thus, P-TEFb activity responds to variations in global cellular transcriptional activity and to physiological conditions linked to cell differentiation, proliferation or cardiac hypertrophy. In contrast, the Tat activation region RNA plays an activating role. This feature at the 5' end of the human immunodeficiency (HIV) viral transcript associates with the viral protein Tat that in turn binds cyclin T1 and recruits active P-TEFb to the HIV promoter. This results in enhanced P-TEFb activity, which is critical for an efficient production of viral transcripts. Although discovered recently, the regulation of P-TEFb becomes a paradigm for non-coding RNAs that regulate transcription factors. It is also a unique example of RNA-driven regulation of a cyclindependent kinase.

Parasite and egg burden, hepatic collagen and histologic pattern of liver granulomas in selection III high and low antibody responder mice infected with Schistosoma mansoni

Selection III mice have particular immunological characteristics: they are high (H III) or low (L III) antibody producer animals, yet both lines display similar T cell responses and macrophage activities. We submittedthese mice to infection with Schistosoma mansoni to assess in vivo parasite and egg burden, hepatic collagen and cellular composition of granulomas in both lines. Titration of anti-Schistosoma IgG by ELISA showed remarkably higher values inH III line, at both studied periods (8th and 12th weeks post-infection). Nevertheless, the number of adult worms recovered from the portal system was similar inboth lines, being not associated with anti-Schistosoma antibody levels. There isan increase in hepatic collagen from the 8th to the 12th weeks post-infection, which is paralleled by an increase in the number of eggs in the liver. This association apparently occurs at the same radio in H III and L III animals. The most important difference found between the two lines was the outstanding contrast interms of volume and eosinophil counts in the granulomas, with lesions from H IIImice clearly being larger and containing more of these cells than LIII lesions.

Protein recovery, separation and purification: selection of optimal techniques using an expert system

The paper discusses the utilization of new techniques ot select processes for protein recovery, separation and purification. It describesa rational approach that uses fundamental databases of proteins molecules to simplify the complex problem of choosing high resolution separation methods for multi component mixtures. It examines the role of modern computer techniques to help solving these questions.

Are parties domocratizing themselves? the evolution of leardership selection in Spain (1977-2008)

The aim of this paper is to verify, for the Spanish case, whether between 1977 and 2008 has increased the internal democracy of the major political parties (PSOE, AP / PP, PCE / IU, PNV and CDC). To do this, we will focus on their leadership selection processes, one of the key elements associated with intra-party democracy. The paper is going to introduce data on four different dimensions of leadership selection: the certification process, the voting procedure, the inclusiveness of the selectorate and, finally, the degree of competitiveness. The results will show that have been few changes in the leadership selection processes of the Spanish political parties since 1977. However, the results of the Spanish case will also be used to suggest some preliminary links between the four dimensions.

Knowledge of Catalan, public/private sector choice and earnings: Evidence from a double sample selection model

This paper explores the earnings return to Catalan knowledge for public and private workers in Catalonia. In doing so, we allow for a double simultaneous selection process. We consider, on the one hand, the non-random allocation of workers into one sector or another, and on the other, the potential self-selection into Catalan proficiency. In addition, when correcting the earnings equations, we take into account the correlation between the two selectivity rules. Our findings suggest that the apparent higher language return for public sector workers is entirely accounted for by selection effects, whereas knowledge of Catalan has a significant positive return in the private sector, which is somewhat higher when the selection processes are taken into account.

Development and selection of NKT cells.

NKT cells utilize a restricted alphabeta TCR repertoire that recognizes glycolipids in association with CD1d. The recent development of fluorescent CD1d tetramers loaded with the synthetic glycolipid alpha-galactosyl-ceramide has led to a clearer definition of NKT-cell subsets as well as important insights into their developmental origin. As many as four subsets may exist, differing in NK1.1 expression, TCR repertoire and dependence on CD1d and various glycolipids for development. Two different lineage-commitment models have been proposed, with most evidence favoring a byproduct of conventional-T-cell development.

Sequencing and identification of expressed Schistosoma mansoni genes by random selection of cDNA clones from a directional library

We have initiated a gene discovery program in Schistosoma mansoni based on the technique of Expressed Sequence Tags (ESTs), i.e. partial sequences of cDNAs obtained from single passes in automatic DNA sequencers. ESTs can be used to identify genese onf the basis of their homology whith sequences from other species deposited in DNA or protein databases. Trasncripts with sequences without matches in teh databases may represent novel parasite-specific genes. This approach has shown to be very efficient and in less than two years a broad range of novel genes has already been ascertained, more than doubling the number of known S. mansoni genes.

On the maintenance of sex-chromosome polymorphism by sex-antagonistic selection

Complex sex-determination systems are a priori unstable and require specific selective forces for their maintenance. Analytical derivations have suggested that sex-antagonistic selection may play such a role, but this assumed absence of recombination between the sex-determining and sex-antagonistic genes. Using individual-based simulations, and focusing on the sex chromosome and coloration polymorphisms of platy fishes as a case study, we show that the conditions for polymorphism maintenance induce female-biases in primary sex ratios, so that sex-ratio selection makes the system collapse towards male- or female heterogamety as soon as recombinant genotypes appear. However, a polymorphism can still be maintained under scenarios comprising strong sexual selection against dull males, mild natural selection against bright females, and low recombination rates. Though such conditions are plausibly met in natural populations of fishes harbouring such polymorphisms, quantitative empirical evaluations are required to properly test whether sex-antagonistic selection is a causal agent, or if other selective processes are required (such as local mate competition favouring female biased sex ratios).

Perspectives de l'inactivation des pathogènes: quand la fiction dépasse la réalité [Back to the future: a fiction dealing with pathogen inactivation of blood products].

AIM OF THE PAPER: Arouse the reflection with a fiction having a scientific appearance, presenting a late and unexpected complication of the universal inactivation of pathogens. CONCLUSION: Such a fiction story opens the debate on a series of fundamental questions that could be addressed during the paradigm shift that is expected by introducing universal pathogen inactivation of blood products.

Multi-level SLA-driven resource management on Cloud Providers

Nowadays, service providers in the Cloud offer complex services ready to be used as it was a commodity like water or electricity to their customers with any other extra effort for them. However, providing these services implies a high management effort which requires a lot of human interaction. Furthermore, an efficient resource management mechanism considering only provider's resources is, though necessary, not enough, because the provider's profit is limited by the amount of resources it owns. Dynamically outsourcing resources to other providers in response to demand variation avoids this problem and makes the provider to get more profit. A key technology for achieving these goals is virtualization which facilitates provider's management and provides on-demand virtual environments, which are isolated and consolidated in order to achieve a better utilization of the provider's resources. Nevertheless, dealing with some virtualization capabilities implies an effort for the user in order to take benefit from them. In order to avoid this problem, we are contributing the research community with a virtualized environment manager which aims to provide virtual machines that fulfils with the user requirements. Another challenge is sharing resources among different federated Cloud providers while exploiting the features of virtualization in a new approach for facilitating providers' management. This project aims for reducing provider's costs and at the same time fulfilling the quality of service agreed with the customers while maximizing the provider's revenue. It considers resource management at several layers, namely locally to each node in the provider, among different nodes in the provider, and among different federated providers. This latter layer supports the novel capabilities of outsourcing when the local resources are not enough to fulfil the users demand, and offering resources to other providers when the local resources are underused.