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There is an alarming rate of human African trypanosomiasis recrudescence in many parts of sub-Saharan Africa. Yet, the disease has no successful chemotherapy. Trypanosoma lacks the enzymatic machinery for the de novo synthesis of purine nucleotides, and is critically dependent on salvage mechanisms. Inosine 5′-monophosphate dehydrogenase (IMPDH) is responsible for the rate-limiting step in guanine nucleotide metabolism. Here, we characterize recombinant Trypanosoma brucei IMPDH (TbIMPDH) to investigate the enzymatic differences between TbIMPDH and host IMPDH. Size-exclusion chromatography and analytical ultracentrifugation sedimentation velocity experiments reveal that TbIMPDH forms a heptamer, different from type 1 and 2 mammalian tetrameric IMPDHs. Kinetic analysis reveals calculated Km values of 30 and 1300 μm for IMP and NAD, respectively. The obtained Km value of TbIMPDH for NAD is approximately 20–200-fold higher than that of mammalian enzymes and indicative of a different NAD binding mode between trypanosomal and mammalian IMPDHs. Inhibition studies show Ki values of 3·2 μm, 21 nM and 3·3 nM for ribavirin 5′-monophosphate, mycophenolic acid and mizoribine 5′-monophosphate, respectively. Our results show that TbIMPDH is different from its mammalian counterpart and thus may be a good target for further studies on anti-trypanosomal drugs.
The polarization change invoked by bipolar pulse cycling stress (voltage cycling) was investigated in detail for a Pt/PZT/Pt ferroelectric capacitor. The remnant polarization increased after voltage cycling, then, it decreased during storage and approached to the initial value. The estimated activation energy of the decay of the gained-polarization during the storage was 0.52eV. This value suggests that the valence change between Ti3+ and Ti4+ is the key of this phenomenon. The model where Ti-related defects pin the polarization was introduced to explain the result. Based on the findings and the model, a combination of voltage cycling and storage is useful to characterize internal defects. We propose this characterization method, named voltage cycling method, as an effective way to analyze internal defects in a ferroelectric capacitor.
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