Caspase-6 is the direct activator of caspase-8 in the cytochrome c-induced apoptosis pathway: absolute requirement for removal of caspase-6 prodomain

Caspase activation resulting from cytochrome c release from the mitochondria is an essential component of the mechanism of apoptosis initiated by a range of factors. The activation of Bid by caspase-8 in this pathway promotes further cytochrome c release, thereby completing a positive feedback loop of caspase activation. Although the identity of the caspases necessary for caspase-8 activation in this pathway are known, it is still unclear which protease directly cleaves caspase-8. In order to identify the factor responsible we undertook a biochemical purification of caspase-8 cleaving activity in cytosolic extracts to which cytochrome c had been added. Here we report that caspase-6 is the only soluble protease in cytochrome c activated Jurkat cell extracts that has significant caspase-8 cleaving activity. Furthermore the caspase-6 that we purified was sufficient to induce Bid dependent cytochrome c releasing activity in cell extracts. Inhibition of caspase-6 activity in cells significantly inhibited caspase-8 cleavage and apoptosis, therefore establishing caspase-6 as a major activator of caspase-8 in vivo and confirming that this pathway can have a critical role in promotion of apoptosis. We also show that caspase-6 is inactive until the short prodomain is removed. We suggest that the requirement for two distinct cleavage steps to activate an effector caspase may represent an effective mechanism for restriction of spontaneous caspase activation and aberrant entry into apoptosis.     

Anthranilate sulfonamide hydroxamate TACE inhibitors. Part 2: SAR of the acetylenic P1' group

The SAR of a series of potent sulfonamide hydroxamate TACE inhibitors bearing novel acetylenic P1' groups was explored. In particular, compound 4t bearing a butynyloxy P1' moiety has excellent in vitro potency against isolated TACE enzyme and in cells, good selectivity over MMP-1 and oral activity in an in vivo model of TNF-alpha production.     

Ecological and phylogenetic patterns of carbon isotope discrimination in the winter-rainfall flora of the Richtersveld,South Africa

Leaf tissues of vascular plant species from the arid Richtersveld of northern Namaqualand (Succulent Karoo), South Africa, show a great range of variation in carbon isotope discrimination. Analyses of values for species with obligate C₃ metabolism demonstrated that the water use efficiency indicated by these values varies between species and within a species population both between seedlings and mature shrubs and between sites along an aridity gradient. An expected pattern of increasing water use efficiency with greater longevity in these species was not present, however. Only among ephemerals were there taxa with high values associated with low water use efficiency, but these high values were balanced by other ephemeral species with low values comparable to those typical of moderate to long-lived shrubs. The extent to which putative CAM species in the succulent flora rely entirely on nocturnal carbon fixation is highly variable. Species of Crassulaceae and Aloe (Asphodelaceae) relied almost exclusively on CAM photosynthesis, although Crassulaceae from more mesic environments may be CAM-flexible. Succulent-leaved species of Senecio and leaves of stem-succulent Euphorbia were CAM-flexible in their values, while shrubby species of Ceraria (Portulacaceae) appeared to rely primarily on C₃ photosynthesis. Variable patterns of reliance on CAM photosynthesis were present in the ecologically dominant Mesembryanthema of the Aizoaceae. Shrubby species of the subfamily Mesembryanthemoideae, although capable of CAM-flexibility in less xeric habitats, relied largely on CAM fixation of carbon in our field sites. Within the subfamily Ruschioideae, there was a wide range of values indicating species with CAM, CAM flexibility, and primary reliance on C₃ photosynthesis. Low values indicative of typical CAM fixation were associated with species with greater longevity, suggesting that a positive correlation may exist between the degree of reliance on CAM photosynthesis and plant life span.     

Why is the Cape Peninsula so rich in plant species? An analysis of the independent diversity components

With 2285 species of higher plants crammed into 471 km², the flora of South Africa's Cape Peninsula is exceptionally rich. Similar sized areas in other Mediterranean-climate region biodiversity hot-spots support between 4.7 and 2.7 times fewer species. The high plant species richness of the Cape Peninsula is due to the exceptionally high turnover between moderately species-rich sites in different habitats (beta diversity) and between sites in similar habitats along geographical gradients (gamma diversity). Highest beta diversity, encompassing almost complete turnover, was recorded along soil fertility gradients. Although similar patterns for these independent components explain the richness of other regions in the Cape Floristic Region, it is the very long and steep habitat gradients of the Cape Peninsula that makes this region exceptionally rich. Furthermore, the flora is characterized by a high degree of rarity, a phenomenon that undoubtedly influences the turnover. Future research should focus on developing a biological and ecological understanding of the different forms of rarity and integrating this into management plans for the maintenance of biodiversity.     

Differences in the expression of the human interferon-gamma gene in fresh lymphocytes and cultured lymphoblasts

Mammalian erythrocytes have been shown to bind 125I labeled ceruloplasmin. Binding was reversible and specific. Scatchard analysis yielded linear plots with a Kd of approximately 5nM. The binding site appeared to be a protein located on the cell surface. A ceruloplasmin binding protein with a molecular weight of 60,000 daltons was isolated from human erythrocytes. Erythrocytes which were not protected by ceruloplasmin's antioxidant properties, did not bind ceruloplasmin. Our results provide evidence for the presence of ceruloplasmin receptors in the erythrocyte membrane. It is proposed that the antioxidant activity of ceruloplasmin may play a role in determining the lifespan of circulating red cells.     

Courtship songs and genetic control of their acoustic characteristics in sibling species of the Drosophila melanogaster subgroup

Six sibling species of the melanogaster subgroup differ in their wing displays and in the acoustic characteristics of their courtship songs. D. melanogaster, D. simulans and D. mauritiana have distinct but similar courtship songs. D. mauritiana, which is allopatric to the others, produces, an ambivalent song with sine song frequency and intrapulse frequency like simulans and modal interpulse interval like melanogaster. These three species appear to be behaviourally more closely similar to each other than to the three African species D. yakuba, D. teissieri and D. erecta. The acoustic characteristics of the songs of interspecific hybrids, indicate that the interpulse interval and intrapulse frequency are quantitatively controlled by genes located on the autosomes. The ability to generate sine song may be controlled by one or more genes located on the X-chromosome, but an alternative possibility, of autosomal dominant inheritance, cannot be excluded.