Peptide probes detect misfolded transthyretin oligomers in plasma of hereditary amyloidosis patients.

Increasing evidence supports the hypothesis that soluble misfolded protein assemblies contribute to the degeneration of postmitotic tissue in amyloid diseases. However, there is a dearth of reliable nonantibody-based probes for selectively detecting oligomeric aggregate structures circulating in plasma or deposited in tissues, making it difficult to scrutinize this hypothesis in patients. Hence, understanding the structure-proteotoxicity relationships driving amyloid diseases remains challenging, hampering the development of early diagnostic and novel treatment strategies. We report peptide-based probes that selectively label misfolded transthyretin (TTR) oligomers circulating in the plasma of TTR hereditary amyloidosis patients exhibiting a predominant neuropathic phenotype. These probes revealed that there are much fewer misfolded TTR oligomers in healthy controls, in asymptomatic carriers of mutations linked to amyloid polyneuropathy, and in patients with TTR-associated cardiomyopathies. The absence of misfolded TTR oligomers in the plasma of cardiomyopathy patients suggests that the tissue tropism observed in the TTR amyloidoses is structure-based. Misfolded oligomers decrease in TTR amyloid polyneuropathy patients treated with disease-modifying therapies (tafamidis or liver transplant-mediated gene therapy). In a subset of TTR amyloid polyneuropathy patients, the probes also detected a circulating TTR fragment that disappeared after tafamidis treatment. Proteomic analysis of the isolated TTR oligomers revealed a specific patient-associated signature composed of proteins that likely associate with the circulating TTR oligomers. Quantification of plasma oligomer concentrations using peptide probes could become an early diagnostic strategy, a response-to-therapy biomarker, and a useful tool for understanding structure-proteotoxicity relationships in the TTR amyloidoses.

Reduction of U(VI) by Fe(II) during the Fe(II)-accelerated transformation of ferrihydrite.

X-ray absorption spectroscopy has been used to study the reduction of adsorbed U(VI) during the Fe(II)-accelerated transformation of ferrihydrite to goethite. The fate of U(VI) was examined across a variety of pH values and Fe(II) concentrations, with results suggesting that, in all cases, it was reduced over the course of the Fe(III) phase transformation to a U(V) species incorporated in goethite. A positive correlation between U(VI) reduction and ferrihydrite transformation rate constants implies that U(VI) reduction was driven by the production of goethite under the conditions used in these studies. This interpretation was supported by additional experimental evidence that demonstrated the (fast) reduction of U(VI) to U(V) by Fe(II) in the presence of goethite only. Theoretical redox potential calculations clearly indicate that the reduction of U(VI) by Fe(II) in the presence of goethite is thermodynamically favorable. In contrast, reduction of U(VI) by Fe(II) in the presence of ferrihydrite is largely thermodynamically unfavorable within the range of conditions examined in this study.

Effect of solution and solid-phase conditions on the Fe(II)-accelerated transformation of ferrihydrite to lepidocrocite and goethite.

Aqueous ferrous iron (Fe(II)) accelerates the transformation of ferrihydrite into secondary, more crystalline minerals however the factors controlling the rate and, indeed, the underlying mechanism of this transformation process remain unclear. Here, we present the first detailed study of the kinetics of the Fe(II)-accelerated transformation of ferrihydrite to goethite, via lepidocrocite, for a range of pH and Fe(II) concentrations and, from the results obtained, provide insight into the factors controlling the transformation rate and the processes responsible for transformation. A reaction scheme for the Fe(II)-accelerated secondary mineralization of ferrihydrite is developed in which an Fe(II) atom attaches to the ferrihydrite surface where it is immediately oxidized to Fe(III) with the resultant electron transferred, sequentially, to other iron oxyhydroxide Fe(III) atoms before release to solution as Fe(II). This freshly precipitated Fe(III) forms the nuclei for the formation of secondary minerals and also facilitates the ongoing uptake of Fe(II) from solution by creation of fresh surface sites. The concentration of solid-associated Fe(II) and the rate of transport of Fe(II) to the oxyhydroxide surface appear to determine which particular secondary minerals form and their rates of formation. Lepidocrocite growth is enhanced at lower solid-associated Fe(II) concentrations while conditions leading to more rapid uptake of Fe(II) from solution lead to higher goethite growth rates.

Synthesis and characterization of antibacterial silver nanoparticle-impregnated rice husks and rice husk ash.

Silver nanoparticle (AgNP)-impregnated rice husks/rice hush ash (RHs/RHA) were successfully synthesized, and their potential application as antibacterial materials in water disinfection was investigated with particular attention given to the use of both white rice husk ash (WRHA) and black rice husk ash (BRHA) produced by the combustion of RHs as AgNP supports. AgNPs, with diameter of ∼20 nm, were anchored tightly onto RHA, with the emplacement of the AgNPs on these supports increasing the antibacterial activity of the AgNPs through diminution in the extent of nanoparticle aggregation. Ag K-edge XANES analysis revealed that AgNP-impregnated RHs/RHA are composed of both Ag(0) and Ag(I) species with the Ag(I)/Ag(0) ratio following the order WRHA (65:35) > RHs (59:41) > BRHA (7:93). Sodium thioglycolate, a strong Ag(I) ligand, significantly affected the bactericidal activities of AgNP-impregnated RHs/RHA, suggesting that Ag(I) released from AgNP-impregnated RHs/RHA plays an important role in disinfection. The rate constants of oxidative and dissociative dissolution of Ag(0) and Ag(I) species associated with BRHA are 5.0 × 10(-4) M(-1)s(-1) and 1.0 × 10(-5) s(-1), respectively, while those associated with WRHA are 7.0 × 10(-2) M(-1)s(-1) and 2.0 × 10(-4) s(-1) respectively, demonstrating that the rate of dissolution of silver associated with BRHA is particularly slow. As such, the bactericidal "lifetime" of this material is long and exhibits a lower health risk as a result of release of Ag(I) to consumers than does AgNP-impregnated WRHA.

Effect of amorphous Fe(III) oxide transformation on the Fe(II)-mediated reduction of U(VI).

It has recently been reported that the Fe(II)-catalyzed crystallization of 2-line ferrihydrite to goethite and magnetite can result in the immobilization of uranium. Although it might be expected that interference of the crystallization process (for example, by the presence of silicate) would prevent uranium immobilization, this has not yet been demonstrated. Here we present results of an X-ray absorption spectroscopy study on the fate of hexavalent uranium (U(VI)) during the Fe(II)-catalyzed transformations of 2-line ferrihydrite and ferrihydrite coprecipitated with silicate (silicate-ferrihydrite). Two-line ferrihydrite transformed monotonically to goethite, whereas silicate-ferrihydrite transformed into a form similar to ferrihydrite synthesized in the absence of silicate. Modeling of U L(III)-edge EXAFS data indicated that both coprecipitated and adsorbed U(VI) were initially associated with ferrihydrite and silicate-ferrihydrite as a mononuclear bidentate surface complex. During the Fe(II)-catalyzed transformation process, U(VI) associated with 2-line ferrihydrite was reduced and partially incorporated into the newly formed goethite mineral structure, most likely as U(V), whereas U(VI) associated with silicate-ferrihydrite was not reduced and remained in a form similar to its initially adsorbed state. Uranium(VI) that was initially adsorbed to silicate-ferrihydrite did, however, become more resistant to reductive dissolution indicating at least a partial reduction in mobility. These results suggest that when the Fe(II)-catalyzed transformation of ferrihydrite-like iron oxyhydroxides is inhibited, at least under conditions similar to those used in these experiments, uranium reduction will not occur.