Effects of modification of the hydrophobic C-1-C-16 segment of tautomycin on its affinity to type-1 and type-2A protein phosphatases.

Among the naturally occurring toxins that are known to have specific inhibitory effects on type-1 and type-2A protein phosphatases (PP1 and PP2A), tautomycin (TM) is unique in that it exhibits significantly higher affinity to PP1 than to PP2A. The ratio of the dissociation constant for the PP1-TM interaction to that for the PP2A-TM interaction (the PP1/PP2A ratio) is 0.01-0.03. The aim of the present study was to evaluate the possible contributions of the C-1-C-16 segment of TM to the affinity characteristics of the toxin. The relatively hydrophobic segment contains a spiroketal motif whose enantiomeric form is present in okadaic acid (OA), which exhibits exceedingly higher affinity to PP2A than to PP1. We therefore synthesized two TM analogues: TM1 in which the side chains of the spiroketal motif of TM were removed but its absolute configuration was retained, and TM2 in which the spiroketal motif of TM1 was replaced with its enantiomeric form. The effects of TM, TM1 and TM2 on the activities of the native catalytic subunits of PP1 (PP1C) and PP2A and a recombinant gamma isoform of PP1 (PP1gamma) were examined. The PP1/PP2A ratio determined thereby was 0.2-0.5 for TM1 and 5-10 for TM2. Both the presence of the side chains and the stereochemistry of the spiroketal moieties may be major determining factors for the affinity characteristics of TM. We also show that a monoclonal antibody raised against OA binds to TM2 albeit with much lower affinity than to OA, whereas it exhibits no measurable affinities to TM and TM1.

Beliefs about overcoming psychological problems among British and Japanese students.

This study was part of a series investigating lay attributions for the cure of psychological problems. Three groups of students--Japanese students in Japan, Japanese students studying in England, and British students--completed a questionnaire and rated the perceived efficacy of 24 different strategies for overcoming each of 5 psychological problems: agoraphobia, depression, smoking cessation, lack of confidence, and obesity. Factor analysis of the curative strategies revealed 5 interpretable factors, the first 3 of which were Professional Help, Inner Control, and Understanding. There were numerous cultural differences between the British group and both Japanese groups in their written ratings of strategies, particularly professional help, for each psychological problem.

[Review of the research on "theory of mind"].

The concept "theory of mind", first proposed by Premack and Woodruff (1978), has drastically changed our view of the mind. In the first half of this paper, the concept's history and recent developments were reviewed. Included were studies of non-human primates, normal children, and autistic children, in addition to some philosophical discussions. The "false belief" paradigm has been successful in understanding children older than 4 years and in characterizing children with high-functioning autism. But with the paradigm alone, it is difficult to explain the "mind" of most non-human primates, younger children, and a large part of autistic children. In the second half, a theoretical discussion was made to understand early developments of mind. The theory theory and competing theories of modularity, simulation, and intersubjectivity were compared concerning the observability of mind (of self and others), the basic mechanisms for understanding the mind, the indispensability of theorizing the mind, and the need for metarepresentation in pretend plays.

Efficacy of Cafon gel on cutaneous infection with herpes simplex virus (HSV)-2 and acyclovir-resistant HSV in mice.

Caffeine is known to inhibit replication of herpes simplex virus (HSV)-1 and the therapeutic efficacy of caffeine (Cafon) gel has been shown in a mouse model cutaneously infected with HSV-1. In this study we examined the inhibitory effect of caffeine on infection with HSV-2 and acyclovir-resistant HSV-1 strains, thymidine kinase (TK)-deficient and phosphonoacetic acid (PAA)-resistant HSV-1 in vitro and in vivo. Caffeine inhibited plaque formation of HSV-2 and acyclovir-resistant HSV-1 strains and their EC50 values ranged from 0.42 to 1.11 mg/ml. Topical treatment with Cafon gel was significantly effective in retarding the development of skin lesions caused by cutaneous infection with HSV-2 and PAA-resistant HSV-1 and in reducing the virus yield of the skin infected with TK-deficient HSV-1. The results suggested that Cafon gel would be useful for the topical treatment of cutaneous infection with HSV-2 and acyclovir-resistant HSV strains.

Topical treatment of cutaneous herpes simplex virus-1 infection in mice with a specially formulated caffeine gel (Cafon).

Caffeine, although not a nucleoside analog, is known to inhibit the replication of herpes simplex virus-1 (HSV-1) and has been shown to significantly limit the spread of HSV infection in vitro. The therapeutic efficacy of caffeine was examined in a murine cutaneous infection model. The midflanks of 6-week-old BALB/c mice were infected with HSV cutaneously after application of 10% caffeine (Cafon) gel, and was reapplied to the midflank 5 times daily thereafter. Treatment with Cafon gel significantly retarded the development of skin lesions. Both midflanks were cutaneously infected, and a placebo and active gel were applied to the right and left midflanks respectively. Cafon gel significantly retarded the appearance of vesiculation and reduced the number of vesicles compared with the placebo gel. Cafon gel was as effective as 5% acyclovir ointment, and no significant difference was observed in the development of local lesions between these two topical preparations. The efficacy of Cafon gel also corresponded to that of oral treatment with 5 mg/kg or more of acyclovir in our cutaneous infection system. These results suggest that Cafon gel can be useful for the topical treatment of cutaneous HSV infection.

Posttransfusion fulminant hepatitis B associated with precore-defective HBV mutants.

Fulminant hepatitis B developed in 8 recipients of blood units without detectable hepatitis B surface antigen on routine screening. All 124 hepatitis B virus (HBV) DNA clones propagated from their sera possessed defects in the precore region. A point mutation from guanine to adenine at nucleotide 83, converting codon 28 for tryptophan (TGG) to a stop codon (TAG), was the commonest, and it was found in all 113 clones from 7 cases. The remaining case displayed 1 clone with this point mutation and 10 clones with an insertion of 2 base pairs after nucleotide 26. Antibody to hepatitis B core antigen (anti-HBc) was detected in a high titer in 1 of 10 pilot plasma samples of blood units transfused to this case. HBV DNA clones propagated from it exhibited the same precore-region defects as those from the recipient. On the basis of these results HBV mutants, defective in the precore region, would appear to be responsible for posttransfusion fulminant hepatitis B, and the exclusion of blood units with high-titered anti-HBc would be efficacious in preventing it.