Simple oxidation of pyrimidinylhydrazones to triazolopyrimidines and their inhibition of Shiga toxin trafficking

The oxidative cyclisation of a range of benzothieno[2,3-d]pyrimidine hydrazones (7a–j) to the 1,2,4-triazolo[4,3-c]pyrimidines (8a–j) catalysed by lithium iodide or to the 1,2,4-triazolo[1,5-c]pyrimidines (10a–j) with sodium carbonate is presented. A complementary synthesis of the 1,2,4-triazolo[1,5-c]pyrimidines starting from the amino imine 11 is also reported. The effect of these compounds on Shiga toxin (STx) trafficking in HeLa cells and comparison to the previously reported Exo2 is also detailed

Proteome-wide analysis identifies plasma immune regulators of amyloid-beta progression

While immune function is known to play a mechanistic role in Alzheimer's disease (AD), whether immune proteins in peripheral circulation influence the rate of amyloid-β (Aβ) progression - a central feature of AD - remains unknown. In the Baltimore Longitudinal Study of Aging, we quantified 942 immunological proteins in plasma and identified 32 (including CAT [catalase], CD36 [CD36 antigen], and KRT19 [keratin 19]) associated with rates of cortical Aβ accumulation measured with positron emission tomography (PET). Longitudinal changes in a subset of candidate proteins also predicted Aβ progression, and the mid- to late-life (20-year) trajectory of one protein, CAT, was associated with late-life Aβ-positive status in the Atherosclerosis Risk in Communities (ARIC) study. Genetic variation that influenced plasma levels of CAT, CD36 and KRT19 predicted rates of Aβ accumulation, including causal relationships with Aβ PET levels identified with two-sample Mendelian randomization. In addition to associations with tau PET and plasma AD biomarker changes, as well as expression patterns in human microglia subtypes and neurovascular cells in AD brain tissue, we showed that 31 % of candidate proteins were related to mid-life (20-year) or late-life (8-year) dementia risk in ARIC. Our findings reveal plasma proteins associated with longitudinal Aβ accumulation, and identify specific peripheral immune mediators that may contribute to the progression of AD pathophysiology

All-acrylic film-forming colloidal polymer/silica nanocomposite particles prepared by aqueous emulsion polymerization

The efficient synthesis of all-acrylic, film-forming, core–shell colloidal nanocomposite particles via in situ aqueous emulsion copolymerization of methyl methacrylate with n-butyl acrylate in the presence of a glycerol-functionalized ultrafine silica sol using a cationic azo initiator at 60 °C is reported. It is shown that relatively monodisperse nanocomposite particles can be produced with typical mean weight-average diameters of 140–330 nm and silica contents of up to 39 wt %. The importance of surface functionalization of the silica sol is highlighted, and it is demonstrated that systematic variation of parameters such as the initial silica sol concentration and initiator concentration affect both the mean particle diameter and the silica aggregation efficiency. The nanocomposite morphology comprises a copolymer core and a particulate silica shell, as determined by aqueous electrophoresis, X-ray photoelectron spectroscopy, and electron microscopy. Moreover, it is shown that films cast from n-butyl acrylate-rich copolymer/silica nanocomposite dispersions are significantly more transparent than those prepared from the poly(styrene-co-n-butyl acrylate)/silica nanocomposite particles reported previously. In the case of the aqueous emulsion homopolymerization of methyl methacrylate in the presence of ultrafine silica, a particle formation mechanism is proposed to account for the various experimental observations made when periodically sampling such nanocomposite syntheses at intermediate comonomer conversions