Enzymes of Sphingolipid metabolism in Drosophila melanogaster

Sphingolipids are important structural components of membranes that delimit the boundaries of cellular compartments, cells and organisms. They play an equally important role as second messengers, and transduce signals across or within the compartments they define to initiate physiological changes during development, differentiation and a host of other cellular events. For well over a century Drosophila melanogaster has served as a useful model organism to understand some of the fundamental tenets of development, differentiation and signaling in eukaryotic organisms. Directed approaches to study sphingolipid biology in Drosophila have been initiated only recently. Nevertheless, earlier phenotypic studies conducted on genes of unknown biochemical function have recently been recognized as mutants of enzymes of sphingolipid metabolism. Genome sequencing and annotation have aided the identification of homologs of recently discovered genes. Here we present an overview of studies on enzymes of the de novo sphingolipid biosynthetic pathway, known mutants and their phenotypic characterization in Drosophila.Received 14 June 2004; received after revision 15 August 2004; accepted 21 August 2004     

Solving the membrane protein folding problem

One of the great challenges for molecular biologists is to learn how a protein sequence defines its three-dimensional structure. For many years, the problem was even more difficult for membrane proteins because so little was known about what they looked like. The situation has improved markedly in recent years, and we now know over 90 unique structures. Our enhanced view of the structure universe, combined with an increasingly quantitative understanding of fold determination, engenders optimism that a solution to the folding problem for membrane proteins can be achieved.     

Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans

The functional interaction of BAFF and APRIL with TNF receptor superfamily members BAFFR, TACI and BCMA is crucial for development and maintenance of humoral immunity in mice and humans. Using a candidate gene approach, we identified homozygous and heterozygous mutations in TNFRSF13B, encoding TACI, in 13 individuals with common variable immunodeficiency. Homozygosity with respect to mutations causing the amino acid substitutions S144X and C104R abrogated APRIL binding and resulted in loss of TACI function, as evidenced by impaired proliferative response to IgM-APRIL costimulation and defective class switch recombination induced by IL-10 and APRIL or BAFF. Family members heterozygous with respect to the C104R mutation and individuals with sporadic common variable immunodeficiency who were heterozygous with respect to the amino acid substitutions A181E, S194X and R202H had humoral immunodeficiency. Although signs of autoimmunity and lymphoproliferation are evident, the human phenotype differs from that of the Tnfrsf13b-/- mouse model.     

Acetylcholine receptors in the gastrulating chick embryo

Summary Muscarinic acetylcholine receptors are present in the gastrulating chick embryo.     

Protein synthesis inhibition induced by dimethylnitrosamine and diethylnitrosamine on isolated rat hepatocytes.

Time- and dose-dependent protein synthesis inhibition takes place following exposure to high doses of dimethylnitrosamine (DMN) or diethylnitrosamine (DENA) in isolated rat hepatocytes. The ability of DENA to depress protein synthesis is 5-fold higher than that of DMN. Cells inhibited by 60 min exposure to DMN or DENA, and then incubated in a nitrosamine-free medium, regain their initial rate of protein synthesis. This recovery is faster and more complete for DENA-treated cells.     

Reduction of acute toxicity of cyclophosphamide and X-rays by the new immunomodulating compound BM 12.531.

BM 12.531, the 2-[2-cyanaziridinyl-(1)]-2-[2-carbamoylaziridinyl-(1)]-propane, (prop. INN Azimexon), reduces significantly the acute toxicity of cyclophosphamide and X-rays in rats and mice, respectively. The leucopenia induced by X-rays was partially compensated by BM 12.531 in rats.     

Comparison of the in vitro effects of colchicine and its derivative colchiceine on chondrocyte morphology and function

Colchiceine is a colchicine-metabolite which has been reported to inhibit axonal transport although not binding to brain tubulin. In the present study, colchiceine was shown not to depolymerize cytoplasmic microtubules, nor to mimic other effects of colchicine on the ultrastructure of cultured chondrocytes. In addition, the synthesis of proteoglycans was inhibited by colchicine but slightly stimulated by colchiceine. These results support the idea that the disturbances in cultured chondrocytes caused by colchicine are specifically related to a loss of cytoplasmic microtubules.     

Liver vitamin A stores in chronic alcoholism in rats: effect of propylthiouracil treatment

Administration of alcohol to rats through drinking water for 8 weeks produced a significant decrease in the liver vitamin A stores without causing any change in the plasma vitamin A levels. Treatment of the alcoholic rats with propylthiouracil for 2 weeks restored the liver vitamin A reserves to control levels.     

Effects of cadmium on the immune system of mice

Summary Chronic oral exposure of mice to Cd⁺⁺ inhibits cell-mediated immunity of delayed type hypersensitivity induced by sheep red blood cells (SRBC). No effect was detected on humoral immune response to SRBC. Spleen cells derived from mice exposed to Cd⁺⁺ showed in vitro enhanced response to T and B cell mitogens. These results demonstrate that Cd⁺⁺ exposure alters the immune system of mice.Dedicated to Prof. Georg Henneberg on the occasion of his 70th anniversary on 12.10.1978.Acknowledgments. Supported by a grant from the Umweltbundesamt. We thank Ms Odenwald, Ms Schulz, Klinikum Steglitz, and Ms Emeis, Robert Koch-Institut Abt. Immunologie, for the excellent technical assistance.