A new class of anthelmintics effective against drug-resistant nematodes

Anthelmintic resistance in human and animal pathogenic helminths has been spreading in prevalence and severity to a point where multidrug resistance against the three major classes of anthelmintics--the benzimidazoles, imidazothiazoles and macrocyclic lactones--has become a global phenomenon in gastrointestinal nematodes of farm animals. Hence, there is an urgent need for an anthelmintic with a new mode of action. Here we report the discovery of the amino-acetonitrile derivatives (AADs) as a new chemical class of synthetic anthelmintics and describe the development of drug candidates that are efficacious against various species of livestock-pathogenic nematodes. These drug candidates seem to have a novel mode of action involving a unique, nematode-specific clade of acetylcholine receptor subunits. The AADs are well tolerated and of low toxicity to mammals, and overcome existing resistances to the currently available anthelmintics.     

Deficiency of glutaredoxin 5 reveals Fe-S clusters are required for vertebrate haem synthesis

Iron is required to produce haem and iron-sulphur (Fe-S) clusters, processes thought to occur independently. Here we show that the hypochromic anaemia in shiraz (sir) zebrafish mutants is caused by deficiency of glutaredoxin 5 (grx5), a gene required in yeast for Fe-S cluster assembly. We found that grx5 was expressed in erythroid cells of zebrafish and mice. Zebrafish grx5 rescued the assembly of grx5 yeast Fe-S, showing that the biochemical function of grx5 is evolutionarily conserved. In contrast to yeast, vertebrates use iron regulatory protein 1 (IRP1) to sense intracellular iron and regulate mRNA stability or the translation of iron metabolism genes. We found that loss of Fe-S cluster assembly in sir animals activated IRP1 and blocked haem biosynthesis catalysed by aminolaevulinate synthase 2 (ALAS2). Overexpression of ALAS2 RNA without the 5' iron response element that binds IRP1 rescued sir embryos, whereas overexpression of ALAS2 including the iron response element did not. Further, antisense knockdown of IRP1 restored sir embryo haemoglobin synthesis. These findings uncover a connection between haem biosynthesis and Fe-S clusters, indicating that haemoglobin production in the differentiating red cell is regulated through Fe-S cluster assembly.     

Observation of spin Coulomb drag in a two-dimensional electron gas

An electron propagating through a solid carries spin angular momentum in addition to its mass and charge. Of late there has been considerable interest in developing electronic devices based on the transport of spin that offer potential advantages in dissipation, size and speed over charge-based devices. However, these advantages bring with them additional complexity. Because each electron carries a single, fixed value (- e) of charge, the electrical current carried by a gas of electrons is simply proportional to its total momentum. A fundamental consequence is that the charge current is not affected by interactions that conserve total momentum, notably collisions among the electrons themselves. In contrast, the electron's spin along a given spatial direction can take on two values, +/- [planck]/2 (conventionally upward arrow, downward arrow), so that the spin current and momentum need not be proportional. Although the transport of spin polarization is not protected by momentum conservation, it has been widely assumed that, like the charge current, spin current is unaffected by electron-electron (e-e) interactions. Here we demonstrate experimentally not only that this assumption is invalid, but also that over a broad range of temperature and electron density, the flow of spin polarization in a two-dimensional gas of electrons is controlled by the rate of e-e collisions.     

X-irradiation of mice in early fetal period influences dose-dependently sex ratio of offspring until weaning.

Fractionated X-irradiation of mouse fetuses on gestation days 11-13 resulted in a significantly increased postnatal mortality of female litters. This occurred only at 3 x 110 rad, which was the threshold for the formation of typical neuroepithelial, rosette-like malformations.     

Prostaglandin I3 is formed in vivo in man after dietary eicosapentaenoic acid

Greenland Eskimos who live on a traditional marine diet rich in long chain omega 3-polyunsaturated fatty acids have a low incidence of cardiovascular disease and myocardial infarction. In their plasma and platelet lipids, arachidonic acid, the precursor of dienoic prostanoids, is partly replaced by eicosapentaenoic acid (C20:5, omega 3; EPA), the precursor of trienoic prostanoids. Studies with an Eskimo diet or a Western diet supplemented with sea fish or fish oil rich in EPA resulted in an 'Eskimo-like' pattern of plasma and platelet lipids. Moreover, less reactive platelets, a reduced ex vivo formation of proaggregatory thromboxane A2 and a blunted circulatory response to pressor hormones were reported. These favourable functional effects may be induced by a shift of prostanoid formation from the dienoic to the trienoic series. We show here that the major urinary metabolite of endogenous prostaglandin I3 is present in subjects that have ingested either cod liver oil (approximately 4 g EPA per day) or mackerel (approximately 10-15 g EPA per day). Our studies provide the first direct evidence for in vivo formation of prostaglandin I3 in man.     

Sex-dependent action of prenatal fractionated X-irradiation in the mouse. Biochemical findings.

X-irradiation of pregnant NMRI-mice on gestational days 11-13 with 3 x 10.5 Gy increased postnatal mortality of the female offspring only. Weights, protein content and acetylcholinesterase, as well as Na,K-ATPase activities in the brains of all treated offspring, were changed. There were, however, no differences between females and males with respect to these parameters.