α-Crystallin chaperone mimetic drugs inhibit lens γ-crystallin aggregation: Potential role for cataract prevention.

Γ-Crystallins play a major role in age-related lens transparency. Their destabilization by mutations and physical chemical insults are associated with cataract formation. Therefore, drugs that increase their stability should have anticataract properties. To this end, we screened 2560 Federal Drug Agency-approved drugs and natural compounds for their ability to suppress or worsen H2O2 and/or heat-mediated aggregation of bovine γ-crystallins. The top two drugs, closantel (C), an antihelminthic drug, and gambogic acid (G), a xanthonoid, attenuated thermal-induced protein unfolding and aggregation as shown by turbidimetry fluorescence spectroscopy dynamic light scattering and electron microscopy of human or mouse recombinant crystallins. Furthermore, binding studies using fluorescence inhibition and hydrophobic pocket-binding molecule bis-8-anilino-1-naphthalene sulfonic acid revealed static binding of C and G to hydrophobic sites with medium-to-low affinity. Molecular docking to HγD and other γ-crystallins revealed two binding sites, one in the "NC pocket" (residues 50-150) of HγD and one spanning the "NC tail" (residues 56-61 to 168-174 in the C-terminal domain). Multiple binding sites overlap with those of the protective mini αA-crystallin chaperone MAC peptide. Mechanistic studies using bis-8-anilino-1-naphthalene sulfonic acid as a proxy drug showed that it bound to MAC sites, improved Tm of both H2O2 oxidized and native human gamma D, and suppressed turbidity of oxidized HγD, most likely by trapping exposed hydrophobic sites. The extent to which these drugs act as α-crystallin mimetics and reduce cataract progression remains to be demonstrated. This study provides initial insights into binding properties of C and G to γ-crystallins.

Understanding the conversion mechanism and performance of monodisperse FeF2 nanocrystal cathodes.

The application of transition metal fluorides as energy-dense cathode materials for lithium ion batteries has been hindered by inadequate understanding of their electrochemical capabilities and limitations. Here, we present an ideal system for mechanistic study through the colloidal synthesis of single-crystalline, monodisperse iron(II) fluoride nanorods. Near theoretical capacity (570 mA h g-1) and extraordinary cycling stability (>90% capacity retention after 50 cycles at C/20) is achieved solely through the use of an ionic liquid electrolyte (1 m LiFSI/Pyr1,3FSI), which forms a stable solid electrolyte interphase and prevents the fusing of particles. This stability extends over 200 cycles at much higher rates (C/2) and temperatures (50 °C). High-resolution analytical transmission electron microscopy reveals intricate morphological features, lattice orientation relationships and oxidation state changes that comprehensively describe the conversion mechanism. Phase evolution, diffusion kinetics and cell failure are critically influenced by surface-specific reactions. The reversibility of the conversion reaction is governed by topotactic cation diffusion through an invariant lattice of fluoride anions and the nucleation of metallic particles on semicoherent interfaces. This new understanding is used to showcase the inherently high discharge rate capability of FeF2.

Size-Dependent Sensitivity of Aquatic Insects to Metals.

Laboratory assessments of aqueous metal toxicity generally demonstrate aquatic insects tolerate relatively high concentrations of metals in aqueous exposures; however, mesocosm experiments and field biomonitoring often indicate effects at relatively low metal concentrations. One hypothesis proposed to reconcile this discrepancy is an increased sensitivity of smaller size classes of organisms. We exposed field colonized benthic communities to aqueous metals in a series of mesocosm experiments. In addition, a novel single-species test system was used to expose first instar, mid-instar, and late instar mayflies (Ephemeroptera, Baetis tricaudatus) to Zn. These experimental approaches tested the hypothesis that small invertebrate size classes are more sensitive than large, mature size classes. Mesocosm results demonstrated strong size-dependent responses of aquatic insects to metals. Smaller organisms generally displayed greater mortality than large, mature individuals, and models were improved when size was included as a predictor of mortality. Size-dependent responses of Baetis spp. occurred in mesocosm experiments and in our single-species test system. The median lethal concentration (LC50) for early instar B. tricaudatus was less than 6% of the previously reported LC50 for late instars. Together, these results suggest that aquatic insect body size is an important predictor of susceptibility to aqueous metals. Toxicity models that account for insect phenology by integrating the natural size progression of organisms have the potential to improve accuracy in predicting effects of metals in the field.

Enzymatically triggered rupture of polymersomes.

Polymersomes are robust vesicles made from amphiphilic block co-polymers. Large populations of uniform giant polymersomes with defined, entrapped species can be made by templating of double-emulsions using microfluidics. In the present study, a series of two enzymatic reactions, one inside and the other outside of the polymersome, were designed to induce rupture of polymersomes. We measured how the kinetics of rupture were affected by altering enzyme concentration. These results suggest that protocells with entrapped enzymes can be engineered to secrete contents on cue.

Filling vacancies in a Prussian blue analogue using mechanochemical post-synthetic modification.

Mechanochemical grinding of polycrystalline powders of the Prussian blue analogue (PBA) Mn[Co(CN)6]2/3□1/3·xH2O and K3Co(CN)6 consumes the latter and chemically modifies the former. A combination of inductively-coupled plasma and X-ray powder diffraction measurements suggests the hexacyanometallate vacancy fraction in this modified PBA is reduced by approximately one third under the specific conditions we explore. We infer the mechanochemically-driven incorporation of [Co(CN)6]3- ions onto the initially-vacant sites, coupled with intercalation of charge-balancing K+ ions within the PBA framework cavities. Our results offer a new methodology for the synthesis of low-vacancy PBAs.

Cumulative deamidations of the major lens protein γS-crystallin increase its aggregation during unfolding and oxidation.

Age-related lens cataract is the major cause of blindness worldwide. The mechanisms whereby crystallins, the predominant lens proteins, assemble into large aggregates that scatter light within the lens, and cause cataract, are poorly understood. Due to the lack of protein turnover in the lens, crystallins are long-lived. A major crystallin, γS, is heavily modified by deamidation, in particular at surface-exposed N14, N76, and N143 to introduce negative charges. In this present study, deamidated γS was mimicked by mutation with aspartate at these sites and the effect on biophysical properties of γS was assessed via dynamic light scattering, chemical and thermal denaturation, hydrogen-deuterium exchange, and susceptibility to disulfide cross-linking. Compared with wild type γS, a small population of each deamidated mutant aggregated rapidly into large, light-scattering species that contributed significantly to the total scattering. Under partially denaturing conditions in guanidine hydrochloride or elevated temperature, deamidation led to more rapid unfolding and aggregation and increased susceptibility to oxidation. The triple mutant was further destabilized, suggesting that the effects of deamidation were cumulative. Molecular dynamics simulations predicted that deamidation augments the conformational dynamics of γS. We suggest that these perturbations disrupt the native disulfide arrangement of γS and promote the formation of disulfide-linked aggregates. The lens-specific chaperone αA-crystallin was poor at preventing the aggregation of the triple mutant. It is concluded that surface deamidations cause minimal structural disruption individually, but cumulatively they progressively destabilize γS-crystallin leading to unfolding and aggregation, as occurs in aged and cataractous lenses.

Contextual Choices in Online Physics Problems: Promising Insights Into Closing the Gender Gap.

Throughout the world, female students are less likely than males to take advanced physics courses. This mixed-methods study uses a concurrent, nested design to study an online homework intervention designed to address choice and achievement. A choice of three different contexts (biological, sports, and traditional) were offered to students for each physics problem, intending to stimulate females' interest and enhance achievement. Informed by aspects of Artino's social-cognitive model of academic motivation and emotion, we investigated: Which context of physics problems do males and females select?; What explanations do students give for their choices?; Are there differences in the achievement of males and females?; and Is there a relationship between student achievement and the context selected? Fifty-two high school physics students from five US states participated. Data included pre- and post-Force Concept Inventory scores, homework context choices and achievement, and rationales for choices. Findings indicate that females were most likely to select biology contexts; males, traditional. All students made more attempts on video questions over word questions, although females did not score as well. For all questions, students generally persisted until they answered them correctly, with females taking fewer attempts on problems. Context choice was mostly driven by interest, for males, and perceptions of difficulty level for females; however, rationales were indistinguishable by gender. On their first homework question attempt, females scored significantly better than the males. Initially, males had significantly higher FCI scores; post homework intervention, females increased their mean scores significantly on the FCI, erasing the initial gender gap, with no growth nor decline in males' scores. Females with FCI growth were equally as likely to choose biology contexts as traditional contexts; males were more likely to choose biology contexts. Findings from this study suggest that modest changes to homework problems that provide choice and make the physics problems more contextually interesting-even without changes in classroom instruction-could increase interest and motivation in students and increase achievement for both male and female students. Recommendations will be discussed.