Alternative splicing of Bcl-2-related genes: functional consequences and potential therapeutic applications

Apoptosis is a morphologically distinct form of cell death. It is executed and regulated by several groups of proteins. Bcl-2 family proteins are the main regulators of the apoptotic process acting either to inhibit or promote it. More than 20 members of the family have been identified so far and most have two or more isoforms. Alternative splicing is one of the major mechanisms providing proteomic complexity and functional diversification of the Bcl-2 family proteins. Pro- and anti-apoptotic Bcl-2 family members should function in harmony for the regulation of the apoptosis machinery, and their relative levels are critical for cell fate. Any mechanism breaking down this harmony by changing the relative levels of these antagonistic proteins could contribute to many diseases, including cancer and neurodegenerative disorders. Recent studies have shown that manipulation of the alternative splicing mechanisms could provide an opportunity to restore the proper balance of these regulator proteins. This review summarises current knowledge on the alternative splicing products of Bcl-2-related genes and modulation of splicing mechanisms as a potential therapeutic approach.Received 5 January 2004; received after revision 31 March 2004; accepted 6 April 2004     

Wet periods in northeastern Brazil over the past 210 kyr linked to distant climate anomalies

The tropics are the main source of the atmosphere's sensible and latent heat, and water vapour, and are therefore important for reconstructions of past climate. But long, accurately dated records of southern tropical palaeoclimate, which would allow the establishment of climatic connections to distant regions, have not been available. Here we present a 210,000-year (210-kyr) record of wet periods in tropical northeastern Brazil--a region that is currently semi-arid. The record is obtained from speleothems and travertine deposits that are accurately dated using the U/Th method. We find wet periods that are synchronous with periods of weak East Asian summer monsoons, cold periods in Greenland, Heinrich events in the North Atlantic and periods of decreased river runoff to the Cariaco basin. We infer that the wet periods may be explained with a southward displacement of the Intertropical Convergence Zone. This widespread synchroneity of climate anomalies suggests a relatively rapid global reorganization of the ocean-atmosphere system. We conclude that the wet periods probably affected rainforest distribution, as plant fossils show that forest expansion occurred during these intermittent wet intervals, and opened a forest corridor between the Amazonian and Atlantic rainforests.     

The physical maps for sequencing human chromosomes 1, 6, 9, 10, 13, 20 and X

We constructed maps for eight chromosomes (1, 6, 9, 10, 13, 20, X and (previously) 22), representing one-third of the genome, by building landmark maps, isolating bacterial clones and assembling contigs. By this approach, we could establish the long-range organization of the maps early in the project, and all contig extension, gap closure and problem-solving was simplified by containment within local regions. The maps currently represent more than 94% of the euchromatic (gene-containing) regions of these chromosomes in 176 contigs, and contain 96% of the chromosome-specific markers in the human gene map. By measuring the remaining gaps, we can assess chromosome length and coverage in sequenced clones.     

Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition.

In a longitudinal study of HIV seropositive patients, there were fluctuations in the specificity of cytotoxic T cells for the virus. This was matched by variability in proviral gag DNA epitope sequences in the lymphocytes of these patients. Some of these viral variants are not recognized by autologous T cells. Accumulation of such mutations in T-cell antigenic targets would provide a mechanism for immune escape.     

Evidence for an olfactory receptor which responds to nicotine--nicotine as an odorant

The tobacco alkaloid (S)(-)-nicotine, when applied as a vapour to an in vitro head preparation, stimulates the olfactory epithelium in three strains of rats and to a lesser extent in two strains of mice. The electro-olfactogram (EOG) generated by nicotine has similar characteristics to the EOGs produced by known odorants. The nicotine EOG increases with increasing concentration of nicotine vapour (1-100 nM) applied to the olfactory epithelium. Differential reduction of the nicotine EOG by the lectin concanavalin A is seen in Wistar and Lister Hooded rats. The reduction of the nicotine EOG by concanavalin A is prevented by adding alpha-methyl-D-mannoside to the lectin superfusion medium. This suggests that there is a glyco-moiety associated with at least one olfactory receptor responding to nicotine. Our results suggest that rat olfactory epithelium has receptor sites for nicotine. Nicotine is an unusual compound because it shows both odorant and pharmacological properties.     

Spatial variation in response to odorants on the rat olfactory epithelium

We have measured the electro-olfactogram produced by four odorants, nicotine, i-pentyl acetate, i-pentanoic acid and cineole from twelve positions on an in vitro preparation of rat olfactory tissue. Each odorant shows a different pattern of response over the twelve positions which can be explained by differences in olfactory receptor populations between regions of the rat olfactory epithelium. The result for nicotine is further evidence that there are olfactory receptors which are stimulated by nicotine when it is presented as a vapour.