Zika virus (ZIKV) is currently undergoing pandemic emergence. While disease is typically subclinical, severe neurologic manifestations in fetuses and newborns after congenital infection underscore an urgent need for antiviral interventions. The adenosine analog BCX4430 has broad-spectrum activity against a wide range of RNA viruses, including potent in vivo activity against yellow fever, Marburg and Ebola viruses. We tested this compound against African and Asian lineage ZIKV in cytopathic effect inhibition and virus yield reduction assays in various cell lines. To further evaluate the efficacy in a relevant animal model, we developed a mouse model of severe ZIKV infection, which recapitulates various human disease manifestations including peripheral virus replication, conjunctivitis, encephalitis and myelitis. Time-course quantification of viral RNA accumulation demonstrated robust viral replication in several relevant tissues, including high and persistent viral loads observed in the brain and testis. The presence of viral RNA in various tissues was confirmed by an infectious culture assay as well as immunohistochemical staining of tissue sections. Treatment of ZIKV-infected mice with BCX4430 significantly improved outcome even when treatment was initiated during the peak of viremia. The demonstration of potent activity of BCX4430 against ZIKV in a lethal mouse model warrant its continued clinical development.
Cooling (Pb,La)(Zr,Ti)O3 films from their pulsed laser deposition temperature in a reducing ambient yields a voltage offset in the polarization–voltage characteristics. Reversing the as-processed polarization at 120 °C nearly removes the offset. By reversing the polarization at room temperature and either heating the film at zero voltage or illuminating the film with UV light, the offset can be partially changed. All changes are recoverable using the same processes with opposite polarity polarization. This behavior is explained by a process-induced accumulation of oxygen vacancies at one interface, oxygen vacancy defect-dipole complexes throughout the film, and trapping of free electrons at the interface of positive polarization. Voltage offset and shift effects are not observed in films cooled in 1 atm of oxygen
Voltage offsets in the polarization-voltage characteristics of Pb(Zr,Ti)O3 capacitors can be induced by either thermal or optical processes. The thermally (optically) induced voltage shift occurs by heating (illuminating) the sample under remanence or a saturating bias. Generally speaking, the thermally induced voltage shifts are greater than those obtained optically; this is attributed to the role of oxygen vacancy-related defect dipoles throughout the film. We find that the inclusion of a dopant element that occupies a portion of the Ti(Zr) sites and has an oxidation state greater than +4 reduces the thermally induced voltage shifts observed in the capacitors. This may result because these particular dopants reduce the oxygen vacancy density and, hence, the defect-dipole contribution to the voltage shift.
We show that voltage offsets in the polarization-voltage characteristics of Pb(Zr, Ti)O3 capacitors can lead to imprint in ferroelectric memory devices. The thermal-induced voltage shifts (internal bias field) are in part attributed to the role of oxygen vacancy-related defect dipoles throughout the film. In support of this, it is found that donor doping at the Ti(Zr) sites reduces the thermally-induced voltage shifts. The stress-induced voltage shifts are found to be dependent on the Zr/Ti cation ratio. This compositional dependence is explained by considering the role of deep bulk Ti3+ centers and/or a compositional dependent oxygen vacancy density.
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