Self-tolerance eliminates T cells specific for Mls-modified products of the major histocompatibility complex

In mice the product of the Mlsa locus is an unusual antigen capable of interaction with certain products of the major histocompatibility locus (MHC) to form a ligand for a large portion of the T-cell alpha/beta receptor repertoire, including nearly all receptors that use V beta 8.1. The presence of Mlsa/MHC during T-cell development results in the deletion of T cells that express V beta 8.1, documenting the importance of clonal deletion in establishing tolerance to self antigens.     

Sequence of Plasmodium falciparum chromosomes 2, 10, 11 and 14

The mosquito-borne malaria parasite Plasmodium falciparum kills an estimated 0.7-2.7 million people every year, primarily children in sub-Saharan Africa. Without effective interventions, a variety of factors-including the spread of parasites resistant to antimalarial drugs and the increasing insecticide resistance of mosquitoes-may cause the number of malaria cases to double over the next two decades. To stimulate basic research and facilitate the development of new drugs and vaccines, the genome of Plasmodium falciparum clone 3D7 has been sequenced using a chromosome-by-chromosome shotgun strategy. We report here the nucleotide sequences of chromosomes 10, 11 and 14, and a re-analysis of the chromosome 2 sequence. These chromosomes represent about 35% of the 23-megabase P. falciparum genome.     

Human infection by genetically diverse SIVSM-related HIV-2 in west Africa.

Our understanding of the biology and origins of human immunodeficiency virus type 2 (HIV-2) derives from studies of cultured isolates from urban populations experiencing epidemic infection and disease. To test the hypothesis that such isolates might represent only a subset of a larger, genetically more diverse group of viruses, we used nested polymerase chain reactions to characterize HIV-2 sequences in uncultured mononuclear blood cells of two healthy Liberian agricultural workers, from whom virus isolation was repeatedly unsuccessful, and from a culture-positive symptomatic urban dweller. Analysis of pol, env and long terminal repeat regions revealed the presence of three highly divergent HIV-2 strains, one of which (from one of the healthy subjects) was significantly more closely related to simian immunodeficiency viruses infecting sooty mangabeys and rhesus macaques (SIVSM/SIVMAC) than to any virus of human derivation. This subject also harboured multiply defective viral genotypes that resulted from hypermutation of G to A bases. Our results indicate that HIV-2, SIVSM and SIVMAC comprise a single, highly diverse group of lentiviruses which cannot be separated into distinct phylogenetic lineages according to species of origin.     

Thymosin beta4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair

Heart disease is a leading cause of death in newborn children and in adults. Efforts to promote cardiac repair through the use of stem cells hold promise but typically involve isolation and introduction of progenitor cells. Here, we show that the G-actin sequestering peptide thymosin beta4 promotes myocardial and endothelial cell migration in the embryonic heart and retains this property in postnatal cardiomyocytes. Survival of embryonic and postnatal cardiomyocytes in culture was also enhanced by thymosin beta4. We found that thymosin beta4 formed a functional complex with PINCH and integrin-linked kinase (ILK), resulting in activation of the survival kinase Akt (also known as protein kinase B). After coronary artery ligation in mice, thymosin beta4 treatment resulted in upregulation of ILK and Akt activity in the heart, enhanced early myocyte survival and improved cardiac function. These findings suggest that thymosin beta4 promotes cardiomyocyte migration, survival and repair and the pathway it regulates may be a new therapeutic target in the setting of acute myocardial damage.     

Identification of genes involved in Drosophila melanogaster geotaxis,a complex behavioral trait

Identifying the genes involved in polygenic traits has been difficult. In the 1950s and 1960s, laboratory selection experiments for extreme geotaxic behavior in fruit flies established for the first time that a complex behavioral trait has a genetic basis. But the specific genes responsible for the behavior have never been identified using this classical model. To identify the individual genes involved in geotaxic response, we used cDNA microarrays to identify candidate genes and assessed fly lines mutant in these genes for behavioral confirmation. We have thus determined the identities of several genes that contribute to the complex, polygenic behavior of geotaxis.     

Chromatic sensitivity of ganglion cells in the peripheral primate retina

Visual abilities change over the visual field. For example, our ability to detect movement is better in peripheral vision than in foveal vision, but colour discrimination is markedly worse. The deterioration of colour vision has been attributed to reduced colour specificity in cells of the midget, parvocellular (PC) visual pathway in the peripheral retina. We have measured the colour specificity (red-green chromatic modulation sensitivity) of PC cells at eccentricities between 20 and 50 degrees in the macaque retina. Here we show that most peripheral PC cells have red-green modulation sensitivity close to that of foveal PC cells. This result is incompatible with the view that PC pathway cells in peripheral retina make indiscriminate connections ('random wiring') with retinal circuits devoted to different spectral types of cone photoreceptors. We show that selective cone connections can be maintained by dendritic field anisotropy, consistent with the morphology of PC cell dendritic fields in peripheral retina. Our results also imply that postretinal mechanisms contribute to the psychophysically demonstrated deterioration of colour discrimination in the peripheral visual field.     

Understanding the thermal evolution of deep-water continental margins

Areas of exploration for new hydrocarbons are changing as the hydrocarbon industry seeks new resources for economic and political reasons. Attention has turned from easily accessible onshore regions such as the Middle East to offshore continental shelves. Over the past ten years, there has been a marked shift towards deep-water continental margins (500-2,500 m below sea level). In these more hostile regions, the risk and cost of exploration is higher, but the prize is potentially enormous. The key to these endeavours is a quantitative understanding of the structure and evolution of the thinned crust and lithosphere that underlie these margins.