Polyurethane elastomers (PUEs) were prepared with poly(oxytetramethylene) glycol (M n ¼2000), 4,4¢-diphenylmethane diisocyanate, 1,4-butanediol (BD) and 1,1,1-trimethylol propane (TMP) by a prepolymer method. To evaluate the effect of curing temperature and the ratio of curing and crosslinking agents ((BD/TMP)¼(10/0 and 8/2)(wt/wt)) on deformation behavior, four different samples were prepared. In the small-angle X-ray scattering (SAXS) profile for the PUEs prepared at 120 1C, a four-point pattern was observed with the preferred tilt being produced by local torques exerted within the strained soft segments from the initial deformation. At near failure strains, strong meridional scattering appeared and the four-point pattern disappeared. In contrast, the PUEs at 80 1C produced meridional scattering through the deformation. As the microdomain structure of the PUEs prepared at 120 and 80 1C initially possessed cylinder-and sphere-like structures, respectively, the cylinder-like structure might have produced the four-point pattern. Obvious changes in interdomain spacing of PUEs at 120 1C during the deformation process were observed in comparison with the spacing at 80 1C. This was due mainly to the formation of a well-developed, networked, cylinder-like microdomain structure. Strain-induced crystallization of the soft-segment chains evaluated by wide-angle X-ray diffraction results was also consistent with the results from SAXS.
The authors obtained an ictal electrocorticogram with chronically implanted subdural electrodes from a 30-year-old man with a low grade glioma in the right postcentral gyrus who had a focal inhibitory seizure of the left arm. During the ictal paresis, the authors observed epileptic discharges in the positive arm motor area of the right precentral gyrus and in its rostral area, but not in the negative motor area. The epileptic activity probably inhibited the spinal motoneuron pool without eliciting excitatory activity in the corticospinal pathway.
FF-ATP synthase (FF) couples H flow in F domain and ATP synthesis/hydrolysis in F domain through rotation of the central rotor shaft, and the H/ATP ratio is crucial to understand the coupling mechanism and energy yield in cells. Although H/ATP ratio of the perfectly coupling enzyme can be predicted from the copy number of catalytic β subunits and that of H binding subunits as/β, the actual H/ATP ratio can vary depending on coupling efficiency. Here, we report actual H/ATP ratio of thermophilic FF, whose /β is 10/3. Proteoliposomes reconstituted with the FF were energized with ΔpH and Δψ by the acid-base transition and by valinomycin-mediated diffusion potential of K under various [ATP]/([ADP]⋅[Pi]) conditions, and the initial rate of ATP synthesis/hydrolysis was measured. Analyses of thermodynamically equilibrated states, where net ATP synthesis/hydrolysis is zero, show linear correlation between the chemical potential of ATP synthesis/hydrolysis and the proton motive force, giving the slope of the linear function, that is, H/ATP ratio, 3.3 ± 0.1. This value agrees well with the /β ratio. Thus, chemomechanical coupling between F and F is perfect.
-Heat shock protein 90 (Hsp90) is a constitutively expressed molecular chaperone and plays an important role in the folding of client proteins with key regulatory roles in growth, survival, differentiation and metastasis. Because inhibition of Hsp90 degrades multiple oncogenic client proteins, it is considered to be an attractive anticancer therapy, and clinical trials of several Hsp90 inhibitors have been carried out. In the present study, two structurally distinct Hsp90 inhibitors, CH5164840 and CH5449302, were orally administered to beagle dogs to evaluate systemic toxicity. CH5164840 induced symptoms that suggest visual disorder, and ophthalmological observation and electroretinography (ERG) revealed loss of pupillary light reflex and abnormal waveforms, respectively. Histopathological examination showed changes in the photoreceptor cell layer and the outer nuclear layer of retina. On the other hand, while there were no clinical symptoms related to visual disorder, animals treated with CH5449302 showed similar abnormalities of ERG responses and histopathological changes in the photoreceptor cell layer and the outer nuclear layer of retina. The visual symptoms and abnormalities of ERG responses were noted at an earlier stage or lower dose than other toxicities in both compounds. Considering that two structurally distinct Hsp90 inhibitors induced a retinal toxicity in dogs after repeated administration, and that visual disorders were also reported in some clinical trials of Hsp90 inhibitors, it would seem highly likely that Hsp90 inhibition induces retinal toxicity. Also, our study indicated that a detailed ocular examination to evaluate the safety of Hsp90 inhibitors would be useful in both preclinical and clinical studies.
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