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Evan Smith

Publications and source records attributed to Evan Smith.

3 recordsLinked to original sources
PubMed2006

In vitro metabolic activation of thiabendazole via 5-hydroxythiabendazole: identification of a glutathione conjugate of 5-hydroxythiabendazole.

Thiabendazole (TBZ) is a broad-spectrum antihelmintic used for treatment of parasitic infections in animals and humans and as an agricultural fungicide for postharvest treatment of fruits and vegetables. It is teratogenic and nephrotoxic in mice, and cases of hepatotoxicity have been observed in humans. Recent reports have demonstrated a correlation between 5-hydroxythiabendazole (5-OHTBZ) formation, a major metabolite of TBZ, and covalent binding of [(14)C]TBZ to hepatocytes, suggesting another pathway of activation of TBZ. Current in vitro studies were undertaken to probe the bioactivation of TBZ via 5-OHTBZ by cytochrome P450 (P450) and peroxidases and identify the reactive species by trapping with reduced glutathione (GSH). Microsomal incubation of TBZ or 5-OHTBZ supplemented with NADPH and GSH afforded a GSH adduct of 5-OHTBZ and was consistent with a bioactivation pathway that involved a P450-catalyzed two-electron oxidation of 5-OHTBZ to a quinone imine. The same adduct was detected in GSH-fortified incubations of 5-OHTBZ with peroxidases. The identity of the GSH conjugate suggested that the same reactive intermediate was formed by both these enzyme systems. Characterization of the conjugate by mass spectrometry and NMR revealed the addition of GSH at the 4-position of 5-OHTBZ. In addition, the formation of a dimer of 5-OHTBZ was discernible in peroxidase-mediated incubations. These results were consistent with a one-electron oxidation of 5-OHTBZ to a radical species that could undergo disproportionation or an additional one-electron oxidation to form a quinone imine. Overall, these studies suggest that 5-OHTBZ can also play a role in TBZ-induced toxicity via its bioactivation by P450 and peroxidases.

Animals↗
PubMed2005

Efficient coding of time-relative structure using spikes.

Nonstationary acoustic features provide essential cues for many auditory tasks, including sound localization, auditory stream analysis, and speech recognition. These features can best be characterized relative to a precise point in time, such as the onset of a sound or the beginning of a harmonic periodicity. Extracting these types of features is a difficult problem. Part of the difficulty is that with standard block-based signal analysis methods, the representation is sensitive to the arbitrary alignment of the blocks with respect to the signal. Convolutional techniques such as shift-invariant transformations can reduce this sensitivity, but these do not yield a code that is efficient, that is, one that forms a nonredundant representation of the underlying structure. Here, we develop a non-block-based method for signal representation that is both time relative and efficient. Signals are represented using a linear superposition of time-shiftable kernel functions, each with an associated magnitude and temporal position. Signal decomposition in this method is a non-linear process that consists of optimizing the kernel function scaling coefficients and temporal positions to form an efficient, shift-invariant representation. We demonstrate the properties of this representation for the purpose of characterizing structure in various types of nonstationary acoustic signals. The computational problem investigated here has direct relevance to the neural coding at the auditory nerve and the more general issue of how to encode complex, time-varying signals with a population of spiking neurons.

Algorithms↗