Single amino acid change in gp41 region of HIV-1 alters bystander apoptosis and CD4 decline in humanized mice

<p>Abstract</p> <p>Background</p> <p>The mechanism by which HIV infection leads to a selective depletion of CD4 cells leading to immunodeficiency remains highly debated. Whether the loss of CD4 cells is a direct consequence of virus infection or bystander apoptosis of uninfected cells is also uncertain.</p> <p>Results</p> <p>We have addressed this issue in the humanized mouse model of HIV infection using a HIV variant with a point mutation in the gp41 region of the Env glycoprotein that alters its fusogenic activity. We demonstrate here that a single amino acid change (V38E) altering the cell-to-cell fusion activity of the Env minimizes CD4 loss in humanized mice without altering viral replication. This differential pathogenesis was associated with a lack of bystander apoptosis induction by V38E virus even in the presence of similar levels of infected cells. Interestingly, immune activation was observed with both WT and V38E infection suggesting that the two phenomena are likely not interdependent in the mouse model.</p> <p>Conclusions</p> <p>We conclude that Env fusion activity is one of the determinants of HIV pathogenesis and it may be possible to attenuate HIV by targeting gp41.</p

Study of Leishmania pathogenesis in mice : experimental considerations

Although leishmaniases are endemic in 98 countries, they are still considered neglected tropical diseases. Leishmaniases are characterized by the emergence of new virulent and asymptomatic strains of Leishmania spp. and, as a consequence, by a very diverse clinical spectrum. To fight more efficiently these parasites, the mechanisms of host defense and of parasite virulence need to be thoroughly investigated. To this aim, animal models are widely used. However, the results obtained with these models are influenced by several experimental parameters, such as the mouse genetic background, parasite genotype, inoculation route/infection site, parasite dose and phlebotome saliva. In this review, we propose an update on their influence in the two main clinical forms of the disease: cutaneous and visceral leishmaniases

Structural Perturbations to Population Skeletons: Transient Dynamics, Coexistence of Attractors and the Rarity of Chaos

Simple models of insect populations with non-overlapping generations have been instrumental in understanding the mechanisms behind population cycles, including wild (chaotic) fluctuations. The presence of deterministic chaos in natural populations, however, has never been unequivocally accepted. Recently, it has been proposed that the application of chaos control theory can be useful in unravelling the complexity observed in real population data. This approach is based on structural perturbations to simple population models (population skeletons). The mechanism behind such perturbations to control chaotic dynamics thus far is model dependent and constant (in size and direction) through time. In addition, the outcome of such structurally perturbed models is [almost] always equilibrium type, which fails to commensurate with the patterns observed in population data.We present a proportional feedback mechanism that is independent of model formulation and capable of perturbing population skeletons in an evolutionary way, as opposed to requiring constant feedbacks. We observe the same repertoire of patterns, from equilibrium states to non-chaotic aperiodic oscillations to chaotic behaviour, across different population models, in agreement with observations in real population data. Model outputs also indicate the existence of multiple attractors in some parameter regimes and this coexistence is found to depend on initial population densities or the duration of transient dynamics. Our results suggest that such a feedback mechanism may enable a better understanding of the regulatory processes in natural populations

ccdc80-l1 Is Involved in Axon Pathfinding of Zebrafish Motoneurons

Axon pathfinding is a subfield of neural development by which neurons send out axons to reach the correct targets. In particular, motoneurons extend their axons toward skeletal muscles, leading to spontaneous motor activity. In this study, we identified the zebrafish Ccdc80 and Ccdc80-like1 (Ccdc80-l1) proteins in silico on the basis of their high aminoacidic sequence identity with the human CCDC80 (Coiled-Coil Domain Containing 80). We focused on ccdc80-l1 gene that is expressed in nervous and non-nervous tissues, in particular in territories correlated with axonal migration, such as adaxial cells and muscle pioneers. Loss of ccdc80-l1 in zebrafish embryos induced motility issues, although somitogenesis and myogenesis were not impaired. Our results strongly suggest that ccdc80-l1 is involved in axon guidance of primary and secondary motoneurons populations, but not in their proper formation. ccdc80-l1 has a differential role as regards the development of ventral and dorsal motoneurons, and this is consistent with the asymmetric distribution of the transcript. The axonal migration defects observed in ccdc80-l1 loss-of-function embryos are similar to the phenotype of several mutants with altered Hedgehog activity. Indeed, we reported that ccdc80-l1 expression is positively regulated by the Hedgehog pathway in adaxial cells and muscle pioneers. These findings strongly indicate ccdc80-l1 as a down-stream effector of the Hedgehog pathway

Working Memory Underpins Cognitive Development, Learning, and Education

Working memory is the retention of a small amount of information in a readily accessible form. It facilitates planning, comprehension, reasoning, and problem-solving. I examine the historical roots and conceptual development of the concept and the theoretical and practical implications of current debates about working memory mechanisms. Then I explore the nature of cognitive developmental improvements in working memory, the role of working memory in learning, and some potential implications of working memory and its development for the education of children and adults. The use of working memory is quite ubiquitous in human thought, but the best way to improve education using what we know about working memory is still controversial. I hope to provide some directions for research and educational practice