Mutations in Rab3a alter circadian period and homeostatic response to sleep loss in the mouse

Rab3a is the most abundant Rab (ras-associated binding) protein in the brain and has a regulatory role in synaptic vesicle trafficking. Mice with a targeted loss-of-function mutation in Rab3a have defects in Ca(2+)-dependent synaptic transmission: the number of vesicles released in response to an action potential is greater than in wildtype mice, resulting in greater synaptic depression and the abolishment of CA3 mossy-fiber long term potentiation. The effect of these changes on behavior is unknown. In a screen for mouse mutants with abnormal rest-activity and sleep patterns, we identified a semidominant mutation, called earlybird, that shortens the circadian period of locomotor activity. Sequence analysis of Rab3a identified a point mutation in the conserved amino acid (Asp77Gly) within the GTP-binding domain of this protein in earlybird mutants, resulting in significantly reduced levels of Rab3a protein. Phenotypic assessment of earlybird mice and a null allele of Rab3a revealed anomalies in circadian period and sleep homeostasis, providing evidence that Rab3a-mediated synaptic transmission is involved in these behaviors.     

Microfabrication technology: organized assembly of carbon nanotubes

Nanoscale structures need to be arranged into well-defined configurations in order to build integrated systems. Here we use a chemical-vapour deposition method with gas-phase catalyst delivery to direct the assembly of carbon nanotubes in a variety of predetermined orientations onto silicon/silica substrates, building them into one-, two- and three-dimensional arrangements. The preference of nanotubes to grow selectively on and normal to silica surfaces forces them to inherit the lithographically machined template topography of their substrates, allowing the sites of nucleation and the direction of growth to be controlled.     

Normal faulting in central Tibet since at least 13.5 Myr ago

Tectonic models for the evolution of the Tibetan plateau interpret observed east-west thinning of the upper crust to be the result of either increased potential energy of elevated crust or geodynamic processes that may be unrelated to plateau formation. A key piece of information needed to evaluate these models is the timing of deformation within the plateau. The onset of normal faulting has been estimated to have commenced in southern Tibet between about 14 Myr ago and about 8 Myr ago and, in central Tibet, about 4 Myr ago. Here, however, we report a minimum age of approximately 13.5 Myr for the onset of graben formation in central Tibet, based on mineralization ages determined with Rb-Sr and 40Ar-39Ar data that post-date a major graben-bounding normal fault. These data, along with evidence for prolonged activity of normal faulting in this and other Tibetan grabens, support models that relate normal faulting to processes occurring beneath the plateau. Thinning of the upper crust is most plausibly the result of potential-energy increases resulting from spatially and temporally heterogeneous changes in thermal structure and density distribution within the crust and upper mantle beneath Tibet. This is supported by recent geophysical and geological data, which indicate that spatial heterogeneity exists in both the Tibetan crust and lithospheric mantle.     

Pathogenic enterococci: new developments in the 21st century

Enterococci, traditionally viewed as Gram-positive commensal bacteria inhabiting the alimentary canals of humans and animals, are now acknowledged to be organisms capable of causing life-threatening infections in humans, especially in the nosocomial environment. The existence of enterococci in such a dual role is facilitated, at least in part, by its intrinsic and acquired resistance to virtually all antibiotics currently in use. Beginning with the initial identification of a streptococci of fecal origin in the late 19th century, enterococci have been studied for over a century now. A number of comprehensive reviews during this time have addressed various aspects of enterococci, including classification, biology, virulence, antibiotic resistance and so on. This review specifically addresses the important advances in the field of enterococcal research that have occurred since the beginning of the 21st century. Most notable among these developments have been the insights into enterococcal genomes and pathogenicity.Received 10 April 2003; received after revision 31 May 2003; accepted 3 June 2003     

An exceptionally preserved Lower Cretaceous ecosystem

Fieldwork in the Early Cretaceous Jehol Group, northeastern China has revealed a plethora of extraordinarily well-preserved fossils that are shaping some of the most contentious debates in palaeontology and evolutionary biology. These discoveries include feathered theropod dinosaurs and early birds, which provide additional, indisputable support for the dinosaurian ancestry of birds, and much new evidence on the evolution of feathers and flight. Specimens of putative basal angiosperms and primitive mammals are clarifying details of the early radiations of these major clades. Detailed soft-tissue preservation of the organisms from the Jehol Biota is providing palaeobiological insights that would not normally be accessible from the fossil record.     

Artemisinins target the SERCA of Plasmodium falciparum

Artemisinins are extracted from sweet wormwood (Artemisia annua) and are the most potent antimalarials available, rapidly killing all asexual stages of Plasmodium falciparum. Artemisinins are sesquiterpene lactones widely used to treat multidrug-resistant malaria, a disease that annually claims 1 million lives. Despite extensive clinical and laboratory experience their molecular target is not yet identified. Activated artemisinins form adducts with a variety of biological macromolecules, including haem, translationally controlled tumour protein (TCTP) and other higher-molecular-weight proteins. Here we show that artemisinins, but not quinine or chloroquine, inhibit the SERCA orthologue (PfATP6) of Plasmodium falciparum in Xenopus oocytes with similar potency to thapsigargin (another sesquiterpene lactone and highly specific SERCA inhibitor). As predicted, thapsigargin also antagonizes the parasiticidal activity of artemisinin. Desoxyartemisinin lacks an endoperoxide bridge and is ineffective both as an inhibitor of PfATP6 and as an antimalarial. Chelation of iron by desferrioxamine abrogates the antiparasitic activity of artemisinins and correspondingly attenuates inhibition of PfATP6. Imaging of parasites with BODIPY-thapsigargin labels the cytosolic compartment and is competed by artemisinin. Fluorescent artemisinin labels parasites similarly and irreversibly in an Fe2+-dependent manner. These data provide compelling evidence that artemisinins act by inhibiting PfATP6 outside the food vacuole after activation by iron.