Analgesia and hyperalgesia from GABA-mediated modulation of the cerebral cortex

It is known that pain perception can be altered by mood, attention and cognition, or by direct stimulation of the cerebral cortex, but we know little of the neural mechanisms underlying the cortical modulation of pain. One of the few cortical areas consistently activated by painful stimuli is the rostral agranular insular cortex (RAIC) where, as in other parts of the cortex, the neurotransmitter gamma-aminobutyric acid (GABA) robustly inhibits neuronal activity. Here we show that changes in GABA neurotransmission in the RAIC can raise or lower the pain threshold--producing analgesia or hyperalgesia, respectively--in freely moving rats. Locally increasing GABA, by using an enzyme inhibitor or gene transfer mediated by a viral vector, produces lasting analgesia by enhancing the descending inhibition of spinal nociceptive neurons. Selectively activating GABA(B)-receptor-bearing RAIC neurons produces hyperalgesia through projections to the amygdala, an area involved in pain and fear. Whereas most studies focus on the role of the cerebral cortex as the end point of nociceptive processing, we suggest that cerebral cortex activity can change the set-point of pain threshold in a top-down manner.     

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 Bacillus anthracis Ames and comparison to closely related bacteria

Bacillus anthracis is an endospore-forming bacterium that causes inhalational anthrax. Key virulence genes are found on plasmids (extra-chromosomal, circular, double-stranded DNA molecules) pXO1 (ref. 2) and pXO2 (ref. 3). To identify additional genes that might contribute to virulence, we analysed the complete sequence of the chromosome of B. anthracis Ames (about 5.23 megabases). We found several chromosomally encoded proteins that may contribute to pathogenicity--including haemolysins, phospholipases and iron acquisition functions--and identified numerous surface proteins that might be important targets for vaccines and drugs. Almost all these putative chromosomal virulence and surface proteins have homologues in Bacillus cereus, highlighting the similarity of B. anthracis to near-neighbours that are not associated with anthrax. By performing a comparative genome hybridization of 19 B. cereus and Bacillus thuringiensis strains against a B. anthracis DNA microarray, we confirmed the general similarity of chromosomal genes among this group of close relatives. However, we found that the gene sequences of pXO1 and pXO2 were more variable between strains, suggesting plasmid mobility in the group. The complete sequence of B. anthracis is a step towards a better understanding of anthrax pathogenesis.     

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.     

Polyamine-dependent gene expression

The polyamines spermidine and spermine along with the diamine putrescine are involved in many cellular processes, including chromatin condensation, maintenance of DNA structure, RNA processing, translation and protein activation. The polyamines influence the formation of compacted chromatin and have a well-established role in DNA aggregation. Polyamines are used in the posttranslational modification of eukaryotic initiation factor 5A, which regulates the transport and processing of specific RNA. The polyamines also participate in a novel RNA-decoding mechanism, a translational frameshift, of at least two known genes, the TY1 transposon and mammalian antizyme. Polyamines are crucial for their own regulation and are involved in feedback mechanisms affecting both polyamine synthesis and catabolism. Recently, it has become apparent that the polyamines are able to influence the action of the protein kinase casein kinase 2. Here we address several roles of polyamines in gene expression.Received 27 November 2002; received after revision 9 January 2003; accepted 31 January 2003     

Killing cancer by targeting genes that cancer cells have lost: allele-specific inhibition,a novel approach to the treatment of genetic disorders

Oligonucleotide-based drugs are now rapidly establishing themselves as an important tool in both research and treatment of genetic disorders. In the past many problems were encountered in using antisense oligonucleotides. Our expanding knowledge and new oligonucleotide chemistries are giving us the chance to treat serious genetic disorders such as cancer in novel, elegant and effective ways not previously possible. In addition, recent knowledge about RNA interference may add to these new approaches for disease treatment with oligonucleotide-based drugs. In this review we discuss one such novel therapeutic strategy against cancer called allele-specific inhibition (ASI). ASI is an approach where cancer cells are attacked at one of the few widely occurring and consistently weak points: the loss of large segments of DNA. Oligonucleotide-based drugs may provide the required selectivity for this therapeutic approach.     

Interaction of reelin signaling and Lis1 in brain development

Loss-of-function mutations in RELN (encoding reelin) or PAFAH1B1 (encoding LIS1) cause lissencephaly, a human neuronal migration disorder. In the mouse, homozygous mutations in Reln result in the reeler phenotype, characterized by ataxia and disrupted cortical layers. Pafah1b1(+/-) mice have hippocampal layering defects, whereas homozygous mutants are embryonic lethal. Reln encodes an extracellular protein that regulates layer formation by interacting with VLDLR and ApoER2 (Lrp8) receptors, thereby phosphorylating the Dab1 signaling molecule. Lis1 associates with microtubules and modulates neuronal migration. We investigated interactions between the reelin signaling pathway and Lis1 in brain development. Compound mutant mice with disruptions in the Reln pathway and heterozygous Pafah1b1 mutations had a higher incidence of hydrocephalus and enhanced cortical and hippocampal layering defects. Dab1 and Lis1 bound in a reelin-induced phosphorylation-dependent manner. These data indicate genetic and biochemical interaction between the reelin signaling pathway and Lis1.     

Volcanically emitted sodium chloride as a source for Io's neutral clouds and plasma torus

The atmosphere of Jupiter's satellite Io is extremely tenuous, time variable and spatially heterogeneous. Only a few molecules--SO2, SO and S2--have previously been identified as constituents of this atmosphere, and possible sources include frost sublimation, surface sputtering and active volcanism. Io has been known for almost 30 years to be surrounded by a cloud of Na, which requires an as yet unidentified atmospheric source of sodium. Sodium chloride has been recently proposed as an important atmospheric constituent, based on the detection of chlorine in Io's plasma torus and models of Io's volcanic gases. Here we report the detection of NaCl in Io's atmosphere; it constitutes only approximately 0.3% when averaged over the entire disk, but is probably restricted to smaller regions than SO2 because of its rapid photolysis and surface condensation. Although the inferred abundance of NaCl in volcanic gases is lower than predicted, those volcanic emissions provide an important source of Na and Cl in Io's neutral clouds and plasma torus.