Statins: the new aspirin?

3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, have been described as the principal and the most effective class of drug to reduce serum cholesterol levels. Statin therapies have been shown to reduce cardiovascular events, including myocardial infarction, stroke, and death, significantly, by altering vascular atherosclerosis development in patients with or without coronary artery disease symptoms. Extensive use of statins has led to the increase of some undesirable effects that are heavily counterbalanced by the benefits. Indeed, pleiotropic effects extend far beyond cholesterol reduction and involve non-lipid-related mechanisms that modify endothelial functions, immunoinflammatory responses, smooth muscle cell activation, proliferation and migration, atherosclerotic plaque stability, and thrombus formation. In this review, we describe in detail the targets and mechanisms of action of statins. Received 6 June 2002; received after revision 6 September 2002; accepted 6 September 2002 RID="*" ID="*"Corresponding author.     

Axonal transport of neurofilaments in normal and disease states

Neurofilaments are among the most abundant organelles in neurones. They are synthesised in cell bodies and then transported into and through axons by a process termed 'slow axonal transport' at a rate that is distinct from that driven by conventional fast motors. Several recent studies have now demonstrated that this slow rate of transport is actually the consequence of conventional fast rates of movement that are interrupted by extended pausing. At any one time, most neurofilaments are thus stationary. Accumulations of neurofilaments are a pathological feature of several human neurodegenerative diseases suggesting that neurofilament transport is disrupted in disease states. Here, we review recent advances in our understanding of neurofilament transport in both normal and disease states. Increasing evidence suggests that phosphorylation of neurofilaments is a mechanism for regulating their transport properties, possibly by promoting their detachment from the motor(s). In some neurodegenerative diseases, signal transduction mechanisms involving neurofilament kinases and phosphatases may be perturbed leading to disruption of transport. Received 11 July 2001; received after revision 30 August 2001; accepted 31 August 2001     

Emergent excitations in a geometrically frustrated magnet

Frustrated systems are ubiquitous, and they are interesting because their behaviour is difficult to predict; frustration can lead to macroscopic degeneracies and qualitatively new states of matter. Magnetic systems offer good examples in the form of spin lattices, where all interactions between spins cannot be simultaneously satisfied. Here we report how unusual composite spin degrees of freedom can emerge from frustrated magnetic interactions in the cubic spinel ZnCr(2)O(4). Upon cooling, groups of six spins self-organize into weakly interacting antiferromagnetic loops, whose directors -- the unique direction along which the spins are aligned, parallel or antiparallel -- govern all low-temperature dynamics. The experimental evidence comes from a measurement of the magnetic form factor by inelastic neutron scattering; the data show that neutrons scatter from hexagonal spin clusters rather than individual spins. The hexagon directors are, to a first approximation, decoupled from each other, and hence their reorientations embody the long-sought local zero energy modes for the pyrochlore lattice.     

Chemical investigation of hassium (element 108)

The periodic table provides a classification of the chemical properties of the elements. But for the heaviest elements, the transactinides, this role of the periodic table reaches its limits because increasingly strong relativistic effects on the valence electron shells can induce deviations from known trends in chemical properties. In the case of the first two transactinides, elements 104 and 105, relativistic effects do indeed influence their chemical properties, whereas elements 106 and 107 both behave as expected from their position within the periodic table. Here we report the chemical separation and characterization of only seven detected atoms of element 108 (hassium, Hs), which were generated as isotopes (269)Hs (refs 8, 9) and (270)Hs (ref. 10) in the fusion reaction between (26)Mg and (248)Cm. The hassium atoms are immediately oxidized to a highly volatile oxide, presumably HsO(4), for which we determine an enthalpy of adsorption on our detector surface that is comparable to the adsorption enthalpy determined under identical conditions for the osmium oxide OsO(4). These results provide evidence that the chemical properties of hassium and its lighter homologue osmium are similar, thus confirming that hassium exhibits properties as expected from its position in group 8 of the periodic table.     

Increasing dominance of large lianas in Amazonian forests

Ecological orthodoxy suggests that old-growth forests should be close to dynamic equilibrium, but this view has been challenged by recent findings that neotropical forests are accumulating carbon and biomass, possibly in response to the increasing atmospheric concentrations of carbon dioxide. However, it is unclear whether the recent increase in tree biomass has been accompanied by a shift in community composition. Such changes could reduce or enhance the carbon storage potential of old-growth forests in the long term. Here we show that non-fragmented Amazon forests are experiencing a concerted increase in the density, basal area and mean size of woody climbing plants (lianas). Over the last two decades of the twentieth century the dominance of large lianas relative to trees has increased by 1.7-4.6% a year. Lianas enhance tree mortality and suppress tree growth, so their rapid increase implies that the tropical terrestrial carbon sink may shut down sooner than current models suggest. Predictions of future tropical carbon fluxes will need to account for the changing composition and dynamics of supposedly undisturbed forests.     

The harlequin mouse mutation downregulates apoptosis-inducing factor

Harlequin (Hq) mutant mice have progressive degeneration of terminally differentiated cerebellar and retinal neurons. We have identified the Hq mutation as a proviral insertion in the apoptosis-inducing factor (Aif) gene, causing about an 80% reduction in AIF expression. Mutant cerebellar granule cells are susceptible to exogenous and endogenous peroxide-mediated apoptosis, but can be rescued by AIF expression. Overexpression of AIF in wild-type granule cells further decreases peroxide-mediated cell death, suggesting that AIF serves as a free radical scavenger. In agreement, dying neurons in aged Hq mutant mice show oxidative stress. In addition, neurons damaged by oxidative stress in both the cerebellum and retina of Hq mutant mice re-enter the cell cycle before undergoing apoptosis. Our results provide a genetic model of oxidative stress-mediated neurodegeneration and demonstrate a direct connection between cell cycle re-entry and oxidative stress in the ageing central nervous system.     

Active genes are tri-methylated at K4 of histone H3

Lysine methylation of histones in vivo occurs in three states: mono-, di- and tri-methyl. Histone H3 has been found to be di-methylated at lysine 4 (K4) in active euchromatic regions but not in silent heterochromatic sites. Here we show that the Saccharomyces cerevisiae Set1 protein can catalyse di- and tri-methylation of K4 and stimulate the activity of many genes. Using antibodies that discriminate between the di- and tri-methylated state of K4 we show that di-methylation occurs at both inactive and active euchromatic genes, whereas tri-methylation is present exclusively at active genes. It is therefore the presence of a tri-methylated K4 that defines an active state of gene expression. These findings establish the concept of methyl status as a determinant for gene activity and thus extend considerably the complexity of histone modifications.