Synthesis and biological evaluation of pyridin-2-one nucleosides

The synthesis of 1-(beta-D-ribofuranosyl)pyridin-2-one-3-carboxylic acid and the 3-carboxamide as well as a short series of 3N-carboxamides, prepared by TPTU/HOBt coupling of primary amines with 1-(beta-D-ribofuranosyl)pyridin-2-one-3-carboxylic acid, and their evaluation as anti-infective agents is described.     

Cryptic diversity of African tigerfish (genus Hydrocynus) reveals palaeogeographic signatures of linked neogene geotectonic events

The geobiotic history of landscapes can exhibit controls by tectonics over biotic evolution. This causal relationship positions ecologically specialized species as biotic indicators to decipher details of landscape evolution. Phylogeographic statistics that reconstruct spatio-temporal details of evolutionary histories of aquatic species, including fishes, can reveal key events of drainage evolution, notably where geochronological resolution is insufficient. Where geochronological resolution is insufficient, phylogeographic statistics that reconstruct spatio-temporal details of evolutionary histories of aquatic species, notably fishes, can reveal key events of drainage evolution. This study evaluates paleo-environmental causes of mitochondrial DNA (mtDNA) based phylogeographic records of tigerfishes, genus Hydrocynus, in order to reconstruct their evolutionary history in relation to landscape evolution across Africa. Strong geographical structuring in a cytochrome b (cyt-b) gene phylogeny confirms the established morphological diversity of Hydrocynus and reveals the existence of five previously unknown lineages, with Hydrocynus tanzaniae sister to a clade comprising three previously unknown lineages (Groups B, C and D) and H. vittatus. The dated phylogeny constrains the principal cladogenic events that have structured Hydrocynus diversity from the late Miocene to the Plio-Pleistocene (ca. 0-16 Ma). Phylogeographic tests reveal that the diversity and distribution of Hydrocynus reflects a complex history of vicariance and dispersals, whereby range expansions in particular species testify to changes to drainage basins. Principal divergence events in Hydrocynus have interfaced closely with evolving drainage systems across tropical Africa. Tigerfish evolution is attributed to dominant control by pulses of geotectonism across the African plate. Phylogenetic relationships and divergence estimates among the ten mtDNA lineages illustrates where and when local tectonic events modified Africa's Neogene drainage. Haplotypes shared amongst extant Hydrocynus populations across northern Africa testify to recent dispersals that were facilitated by late Neogene connections across the Nilo-Sahelian drainage. These events in tigerfish evolution concur broadly with available geological evidence and reveal prominent control by the African Rift System, evident in the formative events archived in phylogeographic records of tigerfish.     

The Drosophila Df31 protein interacts with histone H3 tails and promotes chromatin bridging in vitro

Df31 is a small hydrophilic protein from Drosophila melanogaster that can act as a histone chaperone in vitro. The protein is also detected as an integral component of chromatin, present at approximately the same level as histone H1. We have developed a simple assay to measure protein binding to oligonucleosomes and used it to characterise the DF31-oligonucleosome interaction. DF31 bound to chromatin in vitro at a level comparable to that observed in vivo. The DF31-chromatin interaction required the presence of core histone tails but binding was independent of the presence of H1 in the chromatin. Multiple regions of DF31 contributed to the interaction. Df31-chromatin binding still occurred on chromatin containing only H3/4, and cross-linking experiments showed that Df31 made intimate contact with H3, suggesting that this might be the primary contact site. Finally, using immobilised chromatin templates, we showed that DF31 promoted interstrand bridging between two independent oligonucleosome chains. These results provide strong evidence for a structural role of DF31 in chromatin folding and give an indication of the mechanism involved.     

Conservation of protists: is it needed at all?

Protists have scarcely been considered in traditional perspectives and strategies in environmental management and biodiversity conservation. This is a remarkable omission given that these tiny organisms are highly diverse, and have performed as key ecological players in evolutionary theatres for over a billion years of Earth history. Protists hold key roles in nearly all ecosystems, notably as participants in fluxes of energy and matter through foodwebs that centre on their predation on microbes. In spite of this, they have been largely ignored in conservation issues due to a widespread, naive belief that protists are ubiquitous and cosmopolitanously distributed. Nevertheless, recent research shows that many protists have markedly restricted distributions. These range from palaeoendemics (Gondwanan-Laurasian distribution) to local endemics. Our ignorance about the ultimate and proximate causes of such acute disparities in scale-dependent distributions of protists can be flagged as a singular reason to preserve these more cryptic participants in ecological and evolutionary dynamics. This argument is disturbing when one considers anthropogenic modifications of landscapes and the very poorly understood roles of protists in ecological processes in soils, not least in agroecolandscapes and hydrological systems. Major concerns include host specific symbiotic, symphoric and parasitic species which become extinct, unseen and largely unknown, alongside their metazoan hosts; change or loss of habitats; massive change or loss of type localities; and losses of unique genetic resources and evolutionary potential. These concerns are illustrated by examples to argue that conservation of protists should be integral to any strategy that traditionally targets vascular plants and animals. The ongoing decline in research capacity to inventory and classify protist diversity exemplifies a most acute symptom of the failures, at local, national and international levels, to support scientific responses to the biodiversity crisis. Responsible responses to these severe problems need to centre on the revival of natural history as the core discipline in biology. F. P. D. Cotterill: Formerly Principal Curator of Vertebrates, Natural History Museum of Zimbabwe, P.O. Box 240, Bulawayo, Zimbabwe Special Issue: Protist diversity and geographic distribution. Guest editor: W. Foissner     

Computer simulation of model lipid membrane dynamics

The motions of individual lipid molecules in a model membrane have been studied by computer simulation using the molecular dynamics technique. The intermolecular forces were of both the Lennard-Jones and the Coulomb type. The influence of temperature and electrical screening on the order-disorder transition was examined, and it was also found that this transition is initiated by the spontaneous generation of disclinations.     

DNA replication in cell-free extracts from Drosophila melanogaster.

We have developed an efficient in vitro replication system from 0-2 h Drosophila melanogaster embryos. Demembranated Xenopus sperm DNA when incubated in such an extract first becomes enclosed in a nucleus-like structure with a nuclear envelope and a karyoskeleton. It then undergoes one round of semiconservative replication--this replication appears completely dependent on nuclear formation. Up to 30% of input DNA is nucleated in one reaction. Efficient nuclear formation and replication are dependent on a cold treatment step, prior to disruption of the embryos. They also depend on the age of the embryos used. Extracts from older embryos (0-5 h) are capable of nuclear formation, although at a much reduced efficiency, and repair synthesis, but seem to have lost the ability to initiate DNA replication. In addition to replicating sperm DNA this system appears capable of carrying out semi-conservative replication on some plasmids. However, it cannot use these to trigger nuclear formation; replication is only seen if the plasmids are coincubated with sperm DNA. The in vitro formed nuclei have not been observed to trigger nuclear envelope breakdown and entry into mitosis. However, they can re-replicate the DNA if the nuclei are permeabilized. This system should be a useful complement to the previously isolated Xenopus in vitro replication system. In addition the amenability of Drosophila to genetic study should open up new approaches not previously possible with Xenopus.     

Further Observations on the Pathogenesis of Acne

The composition of the lipid of the forehead skin surface and the sebum excretion rate were determined in 217 subjects and controls. Acne was associated with an increase in serum excretion rate and in the squalene and wax and sterol esters in surface lipid. The changes in sebum excretion rate and squalene were statistically significant only in women, but acne in men was associated with a significant decrease in the free fatty acid content or surface lipid.The increased amounts of squalene and wax esters may lead to pilosebaceous obstruction in acne subjects. The increased sebum excretion rate in acne may ensure increased production of sebaceous triglyceride substrate available for lipolysis to irritant free fatty acids, which may then mediate the inflammatory changes of acne.     

The action of thiol reagents on the adenosine-triphosphatase activities of heavy meromyosin and L-myosin

1. The Ca²⁺-activated adenosine triphosphatase of heavy meromyosin is maximally stimulated by lower relative molar concentrations of phenylmercuric acetate than are required with myosin. 2. Stimulation of the Ca²⁺-activated adenosine triphosphatase of both heavy meromyosin and myosin by thiol reagents is markedly affected by ionic strength, the effects being greater with the former than with the latter. In particular, N-ethylmaleimide strongly inhibits the Ca²⁺-activated adenosine triphosphatase of heavy meromyosin at ionic strength below about 0·2. 3. The precise behaviour of the thiol reagents at low ionic strength is slightly modified by the age of the heavy meromyosin and myosin preparations. 4. Stimulation of the Mg²⁺-activated adenosine triphosphatase of heavy meromyosin by thiol reagents is relatively insensitive to ionic strength. 5. The adenosine triphosphatases of heavy meromyosin and myosin activated by potassium chloride in the absence of bivalent activators are inhibited by thiol reagents over the range of ionic strength at which stimulation occurs in the presence of calcium chloride as activator. 6. The modifying effects of potassium chloride and sodium chloride are qualitatively different when heavy-meromyosin adenosine triphosphatase is stimulated with phenylmercuric acetate. No such difference is observed when the enzyme is stimulated with N-ethylmaleimide.