Generation of hybrid elloramycin analogs by combinatorial biosynthesis using genes from anthracycline-type and macrolide biosynthetic pathways.

Elloramycin and oleandomycin are two polyketide compounds produced by Streptomyces olivaceus Tü2353 and Streptomyces antibioticus ATCC11891, respectively. Elloramycin is an anthracycline-like antitumor drug and oleandomycin a macrolide antibiotic. Expression in S. albus of a cosmid (cos16F4) containing part of the elloramycin biosynthetic gene cluster produced the elloramycin non-glycosylated intermediate 8-demethyl-tetracenomycin C. Several plasmid constructs harboring different gene combinations of L-oleandrose (neutral 2,6-dideoxyhexose attached to the macrolide antibiotic oleandomycin) biosynthetic genes of S. antibioticus that direct the biosynthesis of L-olivose, L-oleandrose and L-rhamnose were coexpressed with cos16F4 in S. albus. Three new hybrid elloramycin analogs were produced by these recombinant strains through combinatorial biosynthesis, containing elloramycinone or 12a-demethyl-elloramycinone (= 8-demethyl-tetracenomycin C) as aglycone moiety encoded by S. olivaceus genes and different sugar moieties, coded by the S. antibioticus genes. Among them is L-olivose, which is here described for the first time as a sugar moiety of a natural product.

[Avoidance learning in a social situation- extinction resistance and defense reaction under stress. A pilot study]. / Vermeidungslernen in einer sozialen Situation--Extinktionswiderstand und Abwehrreaktionen unter Stress. Ein Erkundungsexperiment.

Two successive experiments were conducted resulting from observations of the stability (resistance to extinction) of avoidance reactions and the manifestation of such reactions beyond the specific avoidance conditions in which they were acquired: a) 15 subjects were set the task to avoid an aversive acoustic stimulus for a helpless experimental partner. They could achieve this by reacting with contraction of either the forearm or the calf muscles in a difficult discrimination task. The stability of these avoidance reactions was assessed on different levels of forced extinction. Measures taken were HR, GSR and EMG of the avoidance reactions. Specific courses of the two autonomous measures evolved (Fig. 1,2). 14 of the 15 experimental subjects showed the avoidance behaviour during all phases of forced extinction. b) Six weeks after the experimental subjects had acquired the motor avoidance reactions all subjects were exposed to a relatively unspecific stress situation. Comparisons between experimental and control group (which consisted of the experimental partners) showed a tendency but not a significant difference as far as the reaction of the calf muscles was concerned. Contraction of the forearm muscles, however, occurred significantly more often in the experimental group. The subjects executed these reactions without being aware of it.