A Novel Target and Approach for Identifying Antivirals against Molluscum Contagiosum Virus

The dermatological disease molluscum contagiosum (MC) presents as lesions restricted solely to the skin. The poxvirus molluscum contagiosum virus (MCV) is responsible for this skin disease that is easily transmitted through casual contact among all populations, with greater frequency in children and immunosuppressed individuals. In addition, sexual transmission of MCV in adolescents and adults is a health concern. Although the skin lesions ultimately resolve in immunocompetent individuals, they can persist for extended periods, be painful, and result in scarring. Treatment is problematic, and there is no drug that specifically targets MCV. The inability of MCV to propagate in cell culture has impeded drug development. To overcome these barriers, we integrated three new developments. First, we identified a new MCV drug target (mD4) that is essential for processive DNA synthesis in vitro. Second, we discovered a small chemical compound that binds to mD4 and prevents DNA synthesis in vitro. Third, and most significant, we engineered a hybrid vaccinia virus (mD4-VV) in which the natural vaccinia D4 (vD4) gene is replaced by the mD4 target gene. This hybrid virus is dependent on mD4 for viral growth in culture and is inhibited by the small compound. This target system provides, for the first time, a platform and approach for the discovery and evaluation of new therapeutics that can be used to treat MC.     

Down-Regulation of the Ultraviolet-Sensitive Visual Pigment of the Cockroach Decreases the Masking Effect in Short-Wavelength Illumination

Neuroscience and Behavioral Physiology - Light falling onto the eyes of insects carries information not only on the shape and color of surrounding objects, but also the overall illumination level,...     

Activity of O6-alkylguanine-DNA alkyl transferase in the liver, kidney and white blood cells of rats of different ages.

Age-related differences in the sensitivity of rats to alkylating carcinogens may be dependent on various factors, including the cellular levels of O6-alkylguanine-DNA alkyltransferase (AT). In the present study, the levels of AT were measured in protein extracts prepared from liver, kidney and peripheral white blood cells of male outbred rats aged 1, 4, 14, 22 and 36 months. The AT level (expressed as activity per milligram protein) in liver extracts was lower in rats aged 1, 4 or 36 months than in extracts prepared from rats aged 14 or 22 months. This observation of a variation in AT level with age is in agreement with our previous results. The AT levels in kidney and white blood cells did not differ significantly with age, and in all cases the AT levels were lower than those observed in the liver extracts, the kidney extracts having more AT activity than the white blood cell extracts. The total protein content of both liver and kidney tissues, calculated per gram of wet tissue, increased to a maximum at 14 months and subsequently declined, the total protein content being always higher in the liver than in the kidney. In contrast, the DNA content per gram of wet tissue was highest in young animals and subsequently declined to a minimum at 14 months. The implications of this inverse relationship to the levels of AT activity are discussed.     

Effect of age on development of tumours in the intrasplenic ovarian grafts in ovariectomized rats

Summary Female rats at the age of 1, 3, and 14–16 months (young, adult and old groups respectively) were bilaterally ovariectomized and one of the removed ovaries was autoimplanted into the spleen. The total intrasplenic ovarian tumour incidence was equal in the rats subjected to the operation at 3 and 14–16 months (77.4% and 80.6% respectively) and tumours developed more frequently in rats exposed to surgery at the age of 1 month (94.5%),P<0.05. The incidence of Sertoli and Leydig cell tumours was increased and their latency was decreased in the old group in comparison to the adult one. In rats exposed to the operation at the age of 3 months, granulosotheca cell tumours developed more frequently than other tumour types, and in the young group thecomas were discovered more often than in both older groups. Dysgerminomas and luteomas were discovered only in intrasplenic grafts of rats of the young group. It is supposed that the differences in structure and proliferative activity of various ovarian tissues between young, adult and old rats at the moment of intrasplenic transplantation, as well as the differences in their response to gonadotropic stimulation play a significant role in the development of ovarian tumours of varied histogenesis in the intrasplenic ovarian grafts.     

Inactivation of O6-alkylguanine-DNA alkyltransferase in the rat liver due to an intraperitoneal administration of methylated DNA

Intraperitoneal administration of 6.5 mg of in vitro methylatedDNA (meDNA) containing 1.5 x 10^–44 mM of O⁶-methylguanine(6MG) to male outbred rats weighing 150 g led to a considerabledecrease in the activity of liver O⁶-alkylguanine - DNA alkyltransferase(AT). One hour after treatment there occurred a 4- to 5-folddecrease in the AT activity followed by its slow recovery. However,after 48 h, AT activity considerably exceeded control levels.A 5-fold decrease in the amount of administered meDNA resultedin the absence of its effect, whereas administration of higheramounts produced a further AT inactivation. A similar treatmentwith non-methylated DNA did not change AT activity. The possibilityof AT exhaustion under in vivo conditions and thereby inhibitionof repair of O⁶-alkylguanine in DNA, playing a key role in mutagenic,carcinogenic and antineoplastic effects of certain alkylatingagents, might be helpful in increasing susceptibility of animalsto such compounds.     

Age-dependent antileukemic action and suppression of immune response by 1,4-benzoquinone-guanylhydrazone-thiosemicarbazone (ambazone) in mice

The antineoplastic activity of 1,4-benzoquinone-guanylhydrazone-thiosemicarbazone (ambazone) against murine leukemia P388 was found to be markedly reduced in 12- and 18-month-old mice as compared to young animals. The immune response against sheep red blood cells (SRBC), a T cell-dependent antigen, was also strongly diminished in tumor-free old mice and was further suppressed after ambazone treatment. Since the antileukemic effect of ambazone disappeared more or less in congenitally athymic nude mice, in neonatally thymectomized or silica-pretreated animals, it has been concluded that the action of the compound seems to be limited to young adult immunocompetent tumor-bearing hosts. Therefore immunosenescence, primarily of T cell functions of old tumor-bearers, may represent a decisive factor influencing the antileukemic, especially curative effect of ambazone in aged animals. A combined treatment with ambazone and immunomodulators (thymalin or a splenopentin derivative) failed to improve the antileukemic effect in young and old leukemia P388-bearing mice.