Substructure of the Cytoplasmic Membrane of Bacillus megaterium

The components of fractions obtained by dialyzing and differential centrifuging the “Ghost” of Bacillus megaterium were analyzed in detail. The compositions of amino acids in the main fractions (Fraction 2 and 3) of the “Ghosts”, were estimated. Fraction 2 was rich in non-polar amino acids, while Fraction 3 was scanty of them. Most of the fatty acids in Fraction 2 were 12-methyl tetradecanoic acid, while in Fraction 3 many kinds of fatty acid were detected.

As for the localization of enzymes, the three enzymes, glucose oxidase, succinic dehydrogenase and reduced nicotinamide-adenine dinucleotide oxidase, which were present in the original “Ghosts”, were mostly observed in Fraction 2, and a very little amount of them was found in the other fractions. Further, Fraction 2 could be dissolved in formic acid and dialysis of the solution brought about reaggregation to form membrane-like structure in the presence of Ca or Mg ion.     

Effect of Inositol Deficiency on Cellular Permeability of the Inositol Exacting Yeast

Inositol deficiency caused the abnormalities of permeability of the cell envelope of the inositol exacting yeasts. In the case of Schizosaccharomyces pombe, in which the marked leakage of cellular free-pool fraction was not detected, the uptake activity of glucose or methylglucoside decreased in inositol deficiency, especially in aerobic condition. Investigations on the compositions of lipids and fatty acids showed that the change in fatty acid composition was not so remarkable as that in phosphatides in inositol deficiency. One of the main causes of low transport activity may be due to the change in phosphatides, but not due to that in fatty acids, possibly. Intracellular contents of glucose was not less in inositol deficiency than in sufficiency. These results suggest that inositol deficiency caused the low activity of uptake, which might not be, however, the primary cause of low fermentative activity.

In the case of Saccharomyces cerevisiae Ino^– mutant A–21–20, the similar results about permeability and lipid analyses were obtained in inositol deficiency.     

Effects of Inositol Deficiency on Respiratory and Fermentative Activities of Inositol-exacting Yeast,Schizosaccharomyces pombe

Inositol deficiency of Schizosaccharomyces pombe did not induce significant change of contents of various cellular components except for phospholipids and inositol. The most remarkable decrease in inositol content by the deficiency occurred in the mitochondrial fraction. Electronmicroscopic observation of the inositol-deficient cells of Sch. pombe showed no remarkable thickening of cell wall as occurred in the inositol-exacting mutant of Saccharomyces cerevisiae Strain A–21–20.

Marked loss of fermentative activity under the aerobic condition was caused from inositol deficiency without significant change of activities of respiration and anaerobic fermentation. This seemed to indicate elevated regulatory control of the fermentative activity by oxygen in the inositol-deficient Sch. pombe.

Phosphorylative activities of intact cells and the isolated mitochondria coupled with oxidation was also remarkably suppressed by inositol deficiency.     

Interleukin-2 (IL-2) induces erythroid differentiation and tyrosine phosphorylation in ELM-I-1 cells transfected with a human IL-2 receptor beta chain cDNA.

The molecular mechanism of erythroid differentiation has been still ill-defined. In this study, we introduced a human interleukin-2 receptor (IL-2R) beta chain cDNA into ELM-I-1 cells which differentiated into hemoglobin-positive cells in the presence of erythropoietin (Epo), and established the transformant which expressed IL-2R beta chain. In this transformant, we revealed that IL-2 induced erythroid differentiation and the same pattern of tyrosine phosphorylation as Epo. These data suggest that tyrosine phosphorylation is involved in signal transduction pathway of erythroid differentiation. It is also implicated that the Epo and IL-2 receptor system share a common signal transduction pathway.     

Artesunate: developmental toxicity and toxicokinetics in monkeys

BACKGROUND: The developmental toxicity, toxicokinetics, and hematological effects of the antimalarial drug, artesunate, were previously studied in rats and rabbits and have now been studied in cynomolgus monkeys. METHODS: Groups of up to 15 pregnant females were dosed on Gestation Days (GD) 20–50 or for 3–7‐day intervals. RESULTS: At 30 mg/kg/day, 6 embryos died between GD30 and GD40. Histologic examination of 3 live embryos (GD26–GD36) revealed a marked reduction in embryonic erythroblasts and cardiomyopathy. At 12 mg/kg/day, 6 embryos died between GD30 and GD45. Four surviving fetuses examined on GD100 had no malformations, but long bone lengths were slightly decreased. At the developmental no‐adverse‐effect‐level (4 mg/kg/day), maternal plasma AUC was 3.68 ng.h/mL for artesunate and 6.93 ng.h/ml for its active metabolite, dihydroartemisinin (DHA). No developmental toxicity occurred with administration of 12 mg/kg/day for 3 or 7 days, GD29–31 or GD27–33 (maternal plasma AUC of 9.84 ng.h/mL artesunate and 16.4 ng.h/mL DHA). Exposures at embryotoxic doses were substantially lower than human therapeutic exposures. However, differences in monkey and human Vss for artesunate (0.5 L/kg vs. 0.18 L/kg) confound relying solely on AUC for assessing human risk. Decreases in reticulocyte count occur at therapeutic doses in humans. Changes to reticulocyte counts at embryotoxic doses in monkeys (≥12 mg/kg/day) were variable and generally minor. CONCLUSIONS: Artesunate was embryolethal at ≥12 mg/kg/day when dosed for at least 12 days at the beginning of organogenesis, but not when dosed for 3 or 7 days, indicating that developmental toxicity of artesunate is dependent upon duration of dosing in cynomologus monkeys. Birth Defects Res (Part B) 83:418–434, 2008. © 2008 Wiley‐Liss, Inc.