The metal ions of iron, copper, and zinc have long been associated with the aggregation of β-amyloid (Aβ) plaques in Alzheimer's disease; an interaction that has been suggested to promote increased oxidative stress and neuronal dysfunction. We examined plaque metal load in the hippocampus of APP/PS1 mice using X-ray fluorescence microscopy to assess how the anatomical location of Aβ plaques was influenced by the metal content of surrounding tissue. Immunohistochemical staining of Aβ plaques colocalized with areas of increased X-ray scattering power in unstained tissue sections, allowing direct X-ray based-assessment of plaque metal levels in sections subjected to minimal chemical fixation. We identified and mapped 48 individual plaques in four subregions of the hippocampus from four biological replicates. Iron, Cu, and Zn areal concentrations (ng cm) were increased in plaques compared to the surrounding neuropil. However, this elevation in metal load reflected the local metal makeup of the surrounding neuropil, where different brain regions are enriched for different metal ions. After correcting for tissue density, only Zn levels remained elevated in plaques. This study suggests that the in vivo binding of Zn to plaques is not simply due to increased protein deposition.
The inherent disadvantages of using granulocyte colony-stimulating factor (G-CSF) for hematopoietic stem cell (HSC) mobilization have driven efforts to identify alternate strategies based on single doses of small molecules. Here, we show targeting α9β1/α4β1 integrins with a single dose of a small molecule antagonist (BOP (N-(benzenesulfonyl)-L-prolyl-L-O-(1-pyrrolidinylcarbonyl)tyrosine)) rapidly mobilizes long-term multi-lineage reconstituting HSC. Synergistic engraftment augmentation is observed when BOP is co-administered with AMD3100. Impressively, HSC in equal volumes of peripheral blood (PB) mobilized with this combination effectively out-competes PB mobilized with G-CSF. The enhanced mobilization observed using BOP and AMD3100 is recapitulated in a humanized NODSCIDIL2Rγ−/− model, demonstrated by a significant increase in PB CD34+ cells. Using a related fluorescent analogue of BOP (R-BC154), we show that this class of antagonists preferentially bind human and mouse HSC and progenitors via endogenously primed/activated α9β1/α4β1 within the endosteal niche. These results support using dual α9β1/α4β1 inhibitors as effective, rapid and transient mobilization agents with promising clinical applications.
Extended X-ray absorption fine structure spectroscopy, mass spectrometry, dynamic light scattering and density functional theory are combined to derive structural models for the interaction of neurotoxicity-ablating platinum-based compounds with the amyloid-β peptide.
We have developed a general protocol for the interconversion of diverse protected boronic acids, via intermediate organotrifluoroborates. N-Methyliminodiacetyl boronates, which have been hitherto resistant to direct conversion to trifluoroborates, have been shown to undergo fluorolysis at elevated temperatures. Subsequent solvolysis of organotrifluoroborates in the presence of trimethylsilyl chloride and a wide range of bis-nucleophiles enables the generation of a variety of protected boronic acids.
Light-initiated, radical and hydrogen-bond induced self-assembly of bis-acetamido-functionalized triarylamines is demonstrated to occur in strongly dipolar "push-pull" molecules. This self-assembly process results in the formation of self-assembled nanostructures which in turn increase the efficiency of organic photovoltaic devices.
Carbon-carbon bond formation is one of the most challenging reactions in synthetic organic chemistry, and aldol reactions catalysed by dihydroxyacetone phosphate-dependent aldolases provide a powerful biocatalytic tool for combining C-C bond formation with the generation of two new stereo-centres, with access to all four possible stereoisomers of a compound. Dihydroxyacetone phosphate (DHAP) is unstable so the provision of DHAP for DHAP-dependent aldolases in biocatalytic processes remains complicated. Our research has investigated the efficiency of several different enzymatic cascades for the conversion of glycerol to DHAP, including characterising new candidate enzymes for some of the reaction steps. The most efficient cascade for DHAP production, comprising a one-pot four-enzyme reaction with glycerol kinase, acetate kinase, glycerophosphate oxidase and catalase, was coupled with a DHAP-dependent fructose-1,6-biphosphate aldolase enzyme to demonstrate the production of several rare chiral sugars. The limitation of batch biocatalysis for these reactions and the potential for improvement using kinetic modelling and flow biocatalysis systems is discussed.
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