The cap of the bacterial flagellum plays an essential role in the growth of the long helical filament by promoting the efficient self-assembly of flagellin transported to the distal end through the narrow central channel of the flagellum. The structure of the cap-filament complex was analyzed by electron cryomicroscopy and single-particle image analysis to understand how the cap stays attached while allowing the flagellin insertion between the cap and the filament end and also allowing the HAP proteins to pass through. In the images of the complex, the projection pattern of the helical subunit array in the filament portion occupied the major fraction but was variable depending on the azimuthal orientation of the filament; therefore the images showed a strong tendency to be misaligned. Various methods had to be newly developed to correctly align the images by overcoming this misalignment problem. The structure thus obtained clearly demonstrated the pentameric structure of the cap and how the cap operates. The new methods of analysis presented here would be generally applicable to cap structures of various filaments that play biologically important roles in cellular activities.

Bacteria↗

PubMedDate not supplied

Variability of oral bioavailability for low dose methotrexate in rats.

The effects of food, antibiotics, diclofenac sodium (DS) and methotrexate (MTX) on oral bioavailability (BA) of MTX were examined in rats. Feeding didn't vary the plasma concentrations after intravenous dosing of 0.5 mg/kg MTX, but enhanced those after oral dosing, and the oral BA. The twice daily oral doses of 40 mg/kg neomycin sulfate (NS) or mixed antibiotics (200 mg/kg NS + 200 mg/kg streptomycin sulfate + 200 mg/kg bacitracin) for 5 days didn't influence the plasma concentrations after intravenous dosing of 0.5 mg/kg MTX, but induced the decreased Cmax and the delayed MRT after oral dosing. The plasma concentrations after intravenous or oral dosing of 2.5 mg/kg MTX in rats orally dosed with 1 or 5 mg/kg/day DS for 4 days were similar to those in the control rats, while the pre-treatment of 25 mg/kg/day DS delayed the elimination of MTX but didn't change the oral BA. The plasma concentrations after intravenous or oral dosing of 2.5 mg/kg MTX in rats, which received the intermittent oral doses of 7.5 mg/kg/3 doses/week MTX for 4 weeks, were comparable to those in the control rats, but the daily pre-treatment of 0.2 mg/kg/day MTX for 4 weeks increased the plasma concentrations after oral dosing, and the BA.

Administration, Oral↗

PubMedDate not supplied

Antihypertensive effects of a new transdermal delivery system for clonidine (M-5041T) in spontaneously hypertensive rats.

The antihypertensive effects of a new transdermal delivery system for clonidine (clonidine tape; M-5041T) were investigated in spontaneously hypertensive rats and normotensive Wistar-Kyoto rats. In spontaneously hypertensive rats, M-5041T, at doses of 0.5-4.5 mg/kg (1.25-11.25 cm2/kg), produced a dose-dependent decrease of both systolic blood pressure and heart rate for 24 hr during transdermal application. These significant hypotensive effects lasted for 24 hr following the patching of M-5041T on the back of the animals at a dose of 4.5 mg/kg. In normotensive Wistar-Kyoto rats, the hypotensive and bradycardic effects of M-5041T were weak compared with those in spontaneously hypertensive rats. In both rat strains, M-5041T (4.5 mg/kg) caused behavioral changes such as sedation, piloerection and exophthalmos, accompanied by hypotensive effects. Both M-5041T (1.5 mg/kg) and clonidine (50 micrograms/kg, subcutaneously and 100 micrograms/kg, orally) induced similar hypotensive effects, accompanied by sedation. The hypotensive effects following transdermal M-5041T or systemic clonidine administrations were correlated with the time courses of the plasma clonidine concentration. In contrast to clonidine administered subcutaneously or orally, M-5041T produced a gradual increase in the plasma clonidine concentration, which persisted at a consistent level for at least 12 hr thereafter. Significant hypotensive effects lasted for 12 and 24 hr following M-5041T patching at 1.5 and 4.5 mg/kg, respectively. The present findings suggest that M-5041T can serve as an efficient and useful antihypertensive transdermal delivery system to achieve persistent blood pressure control.

Administration, Cutaneous↗