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.     

A uniquely specialized ear in a very early tetrapod

The Late Devonian genus Ichthyostega was for many decades the earliest known tetrapod, and the sole representative of a transitional form between a fish and a land vertebrate. However, despite being known since 1932 (ref. 1) from a large collection of specimens, its morphology remained enigmatic and not what was expected of a very primitive tetrapod. Its apparent specializations led it to be considered as a "blind offshoot" or "sidebranch" off the tetrapod family tree, and recent cladistic analyses have disagreed about its exact phylogenetic position within the tetrapod stem group. In particular, its braincase and ear region defied interpretation, such that conventional anatomical terms seemed inapplicable. Using new material collected in 1998 (ref. 9), preparation of earlier-collected material, and high-resolution computed tomography scanning, here we identify and interpret these problematic anatomical structures. They can now be seen to form part of a highly specialized ear, probably a hearing device for use in water. This represents a structurally and functionally unique modification of the tetrapod otic region, unlike anything seen in subsequent tetrapod evolution. The presence of deeply grooved gill bars as in its contemporary Acanthostega suggest that Ichthyostega may have been more aquatically adapted than previously believed.     

The recent expansion of Pluto's atmosphere

Stellar occultations--the passing of a relatively nearby body in front of a background star--can be used to probe the atmosphere of the closer body with a spatial resolution of a few kilometres (ref. 1). Such observations can yield the scale height, temperature profile, and other information about the structure of the occulting atmosphere. Occultation data acquired for Pluto's atmosphere in 1988 revealed a nearly isothermal atmosphere above a radius of approximately 1,215 km. Below this level, the data could be interpreted as indicating either an extinction layer or the onset of a large thermal gradient, calling into question the fundamental structure of this atmosphere. Another question is to what extent Pluto's atmosphere might be collapsing as it recedes from the Sun (passing perihelion in 1989 in its 248-year orbital period), owing to the extreme sensitivity of the equilibrium surface pressure to the surface temperature. Here we report observations at a variety of visible and infrared wavelengths of an occultation of a star by Pluto in August 2002. These data reveal evidence for extinction in Pluto's atmosphere and show that it has indeed changed, having expanded rather than collapsed, since 1988.     

The genome sequence of the filamentous fungus Neurospora crassa

Neurospora crassa is a central organism in the history of twentieth-century genetics, biochemistry and molecular biology. Here, we report a high-quality draft sequence of the N. crassa genome. The approximately 40-megabase genome encodes about 10,000 protein-coding genes--more than twice as many as in the fission yeast Schizosaccharomyces pombe and only about 25% fewer than in the fruitfly Drosophila melanogaster. Analysis of the gene set yields insights into unexpected aspects of Neurospora biology including the identification of genes potentially associated with red light photobiology, genes implicated in secondary metabolism, and important differences in Ca2+ signalling as compared with plants and animals. Neurospora possesses the widest array of genome defence mechanisms known for any eukaryotic organism, including a process unique to fungi called repeat-induced point mutation (RIP). Genome analysis suggests that RIP has had a profound impact on genome evolution, greatly slowing the creation of new genes through genomic duplication and resulting in a genome with an unusually low proportion of closely related genes.     

The mosaic that is our genome

The discovery of the basis of genetic variation has opened inroads to understanding our history as a species. It has revealed the remarkable genetic similarity we share with other individuals as well as with our closest primate relatives. To understand what make us unique, both as individuals and as a species, we need to consider the genome as a mosaic of discrete segments, each with its own unique history and relatedness to different contemporary and ancestral individuals.     

Human mitochondrial tRNAs in health and disease

The human mitochondrial genome encodes 13 proteins, all subunits of the respiratory chain complexes and thus involved in energy metabolism. These genes are translated by 22 transfer RNAs (tRNAs), also encoded by the mitochondrial genome, which form the minimal set required for reading all codons. Human mitochondrial tRNAs gained interest with the rapid discovery of correlations between point mutations in their genes and various neuromuscular and neurodegenerative disorders. In this review, emerging fundamental knowledge on the structure/function relationships of these particular tRNAs and an overview of the large variety of mechanisms within translation, affected by mutations, are summarized. Also, initial results on wide-ranging molecular consequences of mutations outside the frame of mitochondrial translation are highlighted. While knowledge of mitochondrial tRNAs in both health and disease increases, deciphering the intricate network of events leading different genotypes to the variety of phenotypes requires further investigation using adapted model systems.Received 3 December 2002; received after revision 14 January 2003; accepted 27 January 2003