Actinoplanic acids A and B as novel inhibitors of farnesyl-protein transferase

Actinoplanic acids A and B are macrocyclic polycarboxylic acids that are potent reversible inhibitors of farnesyl-protein transferase. Actinoplanic acids A and B were isolated from Actinoplanes sp. MA 7066 while actinoplanic acid B was isolated from both MA 7066 and Streptomyces sp. MA 7099. Actinoplanic acids A and B are competitive with respect to farnesyl diphosphate and are selective inhibitors of farnesyl-protein transferase because they do not inhibit geranylgeranyl-protein transferase type 1 or squalene synthase. MA 7066 is believed to be a novel species of actinomycetes while MA 7099 is believed to be a novel strain of Streptomyces violaceusniger on the basis of morphological, biochemical and chemotaxonomic characteristics as well as its production of actinoplanic acids.     

Multiple viral determinants contribute to pathogenicity of the acutely lethal simian immunodeficiency virus SIVsmmPBj variant.

Simian immunodeficiency virus (SIV) induces an immunodeficiency syndrome similar to human AIDS. Although the disease course of SIV-induced immunodeficiency is generally measured in months to years, a disease syndrome that results in death in 5 to 14 days has been described in pig-tailed macaques infected with the SIVsmmPBj (PBj) strain. The purpose of this study was to derive an acutely lethal PBj molecular clone in order to study viral genes involved in pathogenesis. Six infectious molecular clones were generated; acutely fatal disease was induced by experimental inoculation of pig-tailed macaques with virus stocks derived from either of two clones, PBj6.6 or PBj14.6. Molecular chimeras were constructed by exchange of regions of the genome of PBj6.6 and a nonlethal, related clone, SIVsmH4. Only a chimera expressing the PBj genome under the control of a SIVsmH4 long terminal repeat induced death soon after inoculation. These studies suggest that multiple viral genes of PBj are critical for development of acute disease. More specifically, the env gene but not the long terminal repeat PBj was required for acute disease induction; however env must act in concert with another gene(s) of the PBj genome.     

Rapid repletion of brain serotonin in malnourished corn-fed rats following L-tryptophan injection.

The concentration of tryptophan in serum, and the levels of tryptophan, serotonin (5-HT), and 5-hydroxyindole-acetic acid (5-HIAA) in brain are substantially reduced in rats that consume for 6 weeks a diet in which corn is the only source of protein. Single injections of L-tryptophan (25, 50, or 100 mg/kg) cause dose-related increases in brain tryptophan, 5-HT, and 5-HIAA in corn-fed animals. At each dose, brain tryptophan content rises to a proportionately greater extent in corn-fed rats than in well-nourished controls, even though serum tryptophan concentrations attain higher levels in controls. This difference may reflect the greatly reduced serum concentrations in corn-fed rats of other large neutral amino acids that compete with tryptophan for uptake into the brain (tyrosine, phenylalanine, leucine, isoleucine, and valine). However, the substantial decrease in serum albumin levels also diminishes the binding of tryptophan to serum albumin; thus it is not yet possible to state which of these changes is responsible for the much greater increments in brain tryptophan observed in corn-fed rats after tryptophan injection. The fact that tryptophan administration rapidly restores brain 5-hydroxyindole levels in corn-fed animals suggests that the reductions in 5-HT and 5-HIAA levels associated with this type of malnutrition may be largely caused by inadequate availability of substrate.     

Two kinds of insertions in bacterial genes

Summary Six insertion mutations in the gal operon of E. coli and two insertion mutations in the xycIIOP operon of bacteriophage lambda were tested for homology by annealing separated strands of lambda dgal DNA carrying the insertions, and inspection in the electron microscope.Class 1, consisting of the gal mutations OP 128, OP 141, T-N 116, OP 306, T-N 102 and the lambda mutation r14 are about 800 nucleotide pairs long, completely homologous and not circularly permuted. The first three insertions of class 1 are integrated in one direction with respect to the adjacent genes, the other three in the opposite direction. The DNA inserted in this class of mutations is called IS1.Class 2 consists of the gal insertion OP 308 and the lambda insertion r32. They are about 1400 nucleotide pairs long. The two are integrated in opposite direction with respect to the chromosome of dgal. The DNA in insertion mutations of class 2 will be called IS 2. IS1 and IS2 do not share any detectable homology.These data are supported by cross-hybridization experiments using RNA transcribed in vitro from lambda dgal or lambda DNA carrying one insertion and DNA carrying either the same or a different insertion.Similar results were obtained by Malamy, Fiandt, Szybalski and Fiandt, Szybalski, Malamy (accompanying papers).     

Acid hydrolases and other enzymes in secondary demyelination: a quantitative histochemical study in the wobbler mouse

Abstract— The hereditary motor neuron degeneration found in the wobbler (wr) mouse was studied as a model of secondary demyelination. Lysosomal enzymes (acid phosphatase, acid proteinase, β-glucuronidase and β-galactosidase) were found elevated about three-fold in the white matter of the affected cervical spinal cord as compared with normal controls; but they were either not increased, or increased much less, in the anterior horn. Since gliosis and influx of phagocytic cells are minimal in this model, the high hydrolase levels are believed to arise primarily from (a) the accumulations of axonal dense bodies seen in involved areas, and (b) from indigenous cells engaged in breaking down the myelin fragments. Thus, secondary demyelination may, at least in this case, be initiated by enzymes of local origin. DNA levels per unit weight of tissue in both white and gray matter of wobbler cervical cord were elevated 40-50 per cent over controls. However, this was considered to reflect the stunted growth of wobbler mice rather than proliferation or influx of cells (an altered ratio of DNA to protein was demonstrated in the brain). Wobbler mice had similar levels of lactic dehydrogenase as controls; glucose-6-phosphate dehydrogenase was moderately elevated, and glycerol-3-phosphate dehydrogenase was less active in the anterior horn but more active in the white matter of the spinal cord.     

Cellularity of rat adipose tissue: effects of growth, starvation, and obesity

The size, number, and rate of formation of mature adipocytes were studied in the epididymal pads and retroperitoneal adipose depots of the Sprague-Dawley rat. Early growth of these depots was accompanied by progressive enlargement of adipose cells as well as by increases in number. Beyond the 15th wk of life, the depot grew exclusively by the process of cellular enlargement, with no further change in cell number. Severe starvation during the 6th wk of life followed by normal feeding had no lasting effect on cell size or cell number; prolonged semistarvation beginning in the 15th wk greatly reduced cell size while cell number was unaffected. Likewise, extreme increases in depot size produced by hypothalamic lesions did not change cell number, but only cell size. The concept of a fixed number of mature adipocytes in the adult organism may be of central importance in caloric and metabolic equilibrium.