Biflavonoid-Induced Disruption of Hydrogen Bonds Leads to Amyloid-β Disaggregation

Deposition of amyloid β (Aβ) fibrils in the brain is a key pathologic hallmark of Alzheimer’s disease. A class of polyphenolic biflavonoids is known to have anti-amyloidogenic effects by inhibiting aggregation of Aβ and promoting disaggregation of Aβ fibrils. In the present study, we further sought to investigate the structural basis of the Aβ disaggregating activity of biflavonoids and their interactions at the atomic level. A thioflavin T (ThT) fluorescence assay revealed that amentoflavone-type biflavonoids promote disaggregation of Aβ fibrils with varying potency due to specific structural differences. The computational analysis herein provides the first atomistic details for the mechanism of Aβ disaggregation by biflavonoids. Molecular docking analysis showed that biflavonoids preferentially bind to the aromatic-rich, partially ordered N-termini of Aβ fibril via the π–π interactions. Moreover, docking scores correlate well with the ThT EC₅₀ values. Molecular dynamic simulations revealed that biflavonoids decrease the content of β-sheet in Aβ fibril in a structure-dependent manner. Hydrogen bond analysis further supported that the substitution of hydroxyl groups capable of hydrogen bond formation at two positions on the biflavonoid scaffold leads to significantly disaggregation of Aβ fibrils. Taken together, our data indicate that biflavonoids promote disaggregation of Aβ fibrils due to their ability to disrupt the fibril structure, suggesting biflavonoids as a lead class of compounds to develop a therapeutic agent for Alzheimer’s disease.     

Analysis of Sequence Divergence in Mammalian ABCGs Predicts a Structural Network of Residues That Underlies Functional Divergence

The five members of the mammalian G subfamily of ATP-binding cassette transporters differ greatly in their substrate specificity. Four members of the subfamily are important in lipid transport and the wide substrate specificity of one of the members, ABCG2, is of significance due to its role in multidrug resistance. To explore the origin of substrate selectivity in members 1, 2, 4, 5 and 8 of this subfamily, we have analysed the differences in conservation between members in a multiple sequence alignment of ABCG sequences from mammals. Mapping sets of residues with similar patterns of conservation onto the resolved 3D structure of ABCG2 reveals possible explanations for differences in function, via a connected network of residues from the cytoplasmic to transmembrane domains. In ABCG2, this network of residues may confer extra conformational flexibility, enabling it to transport a wider array of substrates.     

Hesperidin Promotes Osteogenesis and Modulates Collagen Matrix Organization and Mineralization In Vitro and In Vivo

This study evaluated the direct effect of a phytochemical, hesperidin, on pre-osteoblast cell function as well as osteogenesis and collagen matrix quality, as there is little known about hesperidin’s influence in mineralized tissue formation and regeneration. Hesperidin was added to a culture of MC3T3-E1 cells at various concentrations. Cell proliferation, viability, osteogenic gene expression and deposited collagen matrix analyses were performed. Treatment with hesperidin showed significant upregulation of osteogenic markers, particularly with lower doses. Mature and compact collagen fibrils in hesperidin-treated cultures were observed by picrosirius red staining (PSR), although a thinner matrix layer was present for the higher dose of hesperidin compared to osteogenic media alone. Fourier-transform infrared spectroscopy indicated a better mineral-to-matrix ratio and matrix distribution in cultures exposed to hesperidin and confirmed less collagen deposited with the 100-µM dose of hesperidin. In vivo, hesperidin combined with a suboptimal dose of bone morphogenetic protein 2 (BMP2) (dose unable to promote healing of a rat mandible critical-sized bone defect) in a collagenous scaffold promoted a well-controlled (not ectopic) pattern of bone formation as compared to a large dose of BMP2 (previously defined as optimal in healing the critical-sized defect, although of ectopic nature). PSR staining of newly formed bone demonstrated that hesperidin can promote maturation of bone organic matrix. Our findings show, for the first time, that hesperidin has a modulatory role in mineralized tissue formation via not only osteoblast cell differentiation but also matrix organization and matrix-to-mineral ratio and could be a potential adjunct in regenerative bone therapies.     

Clinical Significance of Tumor Infiltrating Lymphocytes in Association with Hormone Receptor Expression Patterns in Epithelial Ovarian Cancer

Hormone receptor expression patterns often correlate with infiltration of specific lymphocytes in tumors. Specifically, the presence of specific tumor-infiltrating lymphocytes (TILs) with particular hormone receptor expression is reportedly associated with breast cancer, however, this has not been revealed in epithelial ovarian cancer (EOC). Therefore, we investigated the association between hormone receptor expression and TILs in EOC. Here we found that ERα, AR, and GR expression increased in EOC, while PR was significantly reduced and ERβ expression showed a reduced trend compared to normal epithelium. Cluster analysis indicated poor disease-free survival (DFS) in AR+/GR+/PR+ subgroup (triple dominant group); while the Cox proportional-hazards model highlighted the triple dominant group as an independent prognostic factor for DFS. In addition, significant upregulation of FoxP3+ TILs, PD-1, and PD-L1 was observed in the triple dominant group compared to other groups. NanoString analyses further suggested that tumor necrosis factor (TNF) and/or NF-κB signaling pathways were activated with significant upregulation of RELA, MAP3K5, TNFAIP3, BCL2L1, RIPK1, TRAF2, PARP1, and AKT1 in the triple dominant EOC group. The triple dominant subgroup correlates with poor prognosis in EOC. Moreover, the TNF and/or NF-κB signaling pathways may be responsible for hormone-mediated inhibition of the immune microenvironment.     

Viscosity of compressed cold lake bitumen

Viscosity data over a temperature range of 37-115°C and a pressure range of 0-10 MPa gauge are presented for a Cold Lake bitumen sample. These data show that the compression of Cold Lake bitumen results in a significant increase in its viscosity. Results are compared with those from a similar study on an Athabasca bitumen sample. Also presented are two correlations for the effects of pressure and temperature on the viscosity of Cold Lake bitumen.     

Determination of Binder Decomposition Kinetics for Specifying Heating Parameters in Binder Burnout Cycles

The decomposition kinetics of poly(vinyl butyral) binder from barium titanate multilayer ceramic capacitors with platinum metal electrodes were analyzed by thermogravimetric analysis as a function of the heating rate. The activation energy and pre-exponential factor for the decomposition kinetics were determined from two types of integral equations, from the Redhead method, and from the variation in heating rate method. The accuracy of the kinetic parameters determined from these methods was then evaluated for describing the observed rate of binder decomposition. Although the individual models yielded very different kinetic parameters, all were capable of describing the experimental data within ±15% accuracy. The kinetic parameters were then used in a coupled transport and kinetic model for describing the buildup of pressure within the ceramic green body as a function of the heating cycle. A methodology based on calculus of variations was also developed to predict the minimum duration for the binder burnout cycle.     

Effects of Composition and Environment on the Fracture of Fluoride Glasses

Indentation-crack-length procedures were used to determine the critical fracture toughness (K_IC) and the sensitivity to environmentally enhanced crack growth in heavy-metal fluoride glasses of varying chemical composition. The data show that while K_IC was more or less invariant with composition, some glasses were more susceptible to subcritical crack growth than others. The results are interpreted in terms of existing crack-growth models. A technique for predicting K_IC from fundamental atomic bonding and crystal-structure data for these glasses is discussed.     

Modelling a circulating fluidized bed riser reactor with gas—solids downflow at the wall

A predictive model was developed for the fully developed zone of a circulating fluidized bed (CFB) riser reactor operating in the fast fluidization regime that overcomes limitations of existing models. The model accounts for the upward flow of gas and solids in the core and downward flow of the two phases in the annulus. Additionally, a numerical solution methodology for the simulation of a riser reactor employing the hydrodynamic model was devised. A simulation was performed using the fast, main Claus reaction to demonstrate the effects of backmixing in the fast fluidization regime. It was found that the molar flow rates of the reactants leaving a fast fluidized CFB riser reactor were significantly higher than those leaving an identical reactor operating in the pneumatic transport regime.