RESUMEN
The aim of this study was to analyse the circadian behavioural responses of mice carrying a functional knockout of the Per3 gene (Per3(-/-)) to different light : dark (L : D) cycles. Male adult wild-type (WT) and Per3(-/-) mice were kept under 12-hour light : 12-hour dark conditions (12L : 12D) and then transferred to either a short or long photoperiod and subsequently released into total darkness. All mice were exposed to both conditions, and behavioural activity data were acquired through running wheel activity and analysed for circadian characteristics during these conditions. We observed that, during the transition from 12L : 12D to 16L : 8D, Per3(-/-) mice take approximately one additional day to synchronise to the new L : D cycle compared to WT mice. Under these long photoperiod conditions, Per3(-/-) mice were more active in the light phase. Our results suggest that Per3(-/-) mice are less sensitive to light. The data presented here provides further evidence that Per3 is involved in the suppression of behavioural activity in direct response to light.
Asunto(s)
Ritmo Circadiano , Proteínas Circadianas Period/deficiencia , Fotoperiodo , Animales , Femenino , Luz , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Circadianas Period/metabolismoRESUMEN
Genetic crosses between phenotypically resistant and sensitive schistosomes demonstrated that resistance to hycanthone and oxamniquine behaves like a recessive trait, thus suggesting that resistance is due to the lack of some factor. We hypothesized that, in order to kill schistosomes, hycanthone and oxamniquine need to be converted into an active metabolite by some parasite enzyme which, if inactive, results in drug resistance. Esterification of the drugs seemed to be the most likely event as it would lead to the production of an alkylating agent upon dissociation of the ester. An artificial ester of hycanthone was indeed active even in resistant worms, thus indirectly supporting our hypothesis. In addition, several lines of evidence demonstrated that exposure to hycanthone and oxamniquine results in alkylation of worm macromolecules. Thus, radioactive drugs formed covalent bonds with the DNA of sensitive (but not of resistant) schistosomes; an antiserum raised against hycanthone detected the presence of the drug in the purified DNA fraction of sensitive (but not of resistant) schistosomes; a drug-DNA adduct was isolated from hycanthone-treated worms and fully characterized as hycanthone-deoxyguanosine.