The mechanism of pI258 arsenate reductase (ArsC) catalyzed arsenate reduction, involving its P-loop structural motif and three redox active cysteines, has been unraveled. All essential intermediates are visualized with x-ray crystallography, and NMR is used to map dynamic regions in a key disulfide intermediate. Steadystate kinetics of ArsC mutants gives a view of the crucial residues for catalysis. ArsC combines a phosphatase-like nucleophilic displacement reaction with a unique intramolecular disulfide bond cascade. Within this cascade, the formation of a disulfide bond triggers a reversible ''conformational switch'' that transfers the oxidative equivalents to the surface of the protein, while releasing the reduced substrate.
Total Hg and MMHg concentrations were assessed in more than 350 fish and shellfish samples. Hg concentrations in Greater North Sea fish of prey range from 0.039 mg kg(-1) wet weight (ww; for ray) to 0.61 mg kg(-1) ww (for dogfish) and for all other fish species, from 0.045 mg kg(-1) ww (for plaice) to 0.33 mg kg(-1) ww (for sand sole), with 95 +/- 2% of the Hg content in the MMHg form. In Belgian coastal zone, fish concentrations range from 0.063 mg kg(-1) ww for plaice to 0.13 mg kg(-1) ww for flounder, with 82-87% of the Hg content in the MMHg form. In fish of the Scheldt, which is a very polluted estuary, Hg levels, as well as the percent MMHg of the total Hg, were lower than in the two zones previously mentioned. The intraspecies variability is of the order of 50% in each of the three zones. In liver tissue, a much larger variability was observed than in muscle tissue, except for fish species of the Scheldt. In most cases, the MMHg fraction in a particular fish species is inversely related to the intraspecies variability. Bioconcentration and biomagnification factors (BCF and BMF, respectively) were assessed. MMHg-BMFs were a few orders of magnitude higher than Hg(inorganic)-BMFs, and for the same species were always highest in the Greater North Sea and lowest in the Scheldt. For each of the Belgian coastal zone four species, a weak positive correlation between Hg content and fish length was found; however, the larger the size-range, the better the correlation. Taking fish length into account, a statistically significant difference in contamination level was observed for species sampled from the different geographical zones.
Formulating poorly water soluble drugs using ordered mesoporous silica materials is an emerging approach to tackle solubility-related bioavailability problems. The current study was conducted to assess the bioavailability-enhancing potential of ordered mesoporous silica in man. In this open-label, randomized, two-way cross-over study, 12 overnight fasted healthy volunteers received a single dose of fenofibrate formulated with ordered mesoporous silica or a marketed product based on micronized fenofibrate. Plasma concentrations of fenofibric acid, the pharmacologically active metabolite of fenofibrate, were monitored up to 96h post-dose. The rate (C/dose increased by 77%; t reduced by 0.75h) and extent of absorption (AUC/dose increased by 54%) of fenofibrate were significantly enhanced following administration of the ordered mesoporous silica based formulation. The results of this study serve as a proof of concept in man for this novel formulation approach.
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