Visual sensing of saccharides promoted by resorcinol condensation products

[structure: see text] Heating aqueous DMSO solutions of five saccharides in the presence of 1-3 reveals that each receptor promotes solution colors characteristic for each sugar. New compound 3 allows the direct correlation of sugar concentration with visible region absorbance and/or fluorescence intensities.     

Experimental investigation of a 140-GHz coaxial gyrotron oscillator

We report experimental results on a megawatt power level, 140-GHz coaxial gyrotron oscillator. The gyrotron has an inverted magnetron injection gun (IMIG) designed for operation at up to 95 kV and 88 A. The IMIG has an inner grounded anode which extends from the center of the gun down through the entire length of the tube including the cavity and collector. The IMIG was tested at up to 105 kV and 93 A in 3 μs pulses, achieving an electron beam power of 10 MW. The output power from the coaxial gyrotron cavity was transported to an internal mode converter and a single mirror that coupled the power out transversely from the tube axis. A maximum output power of up to 1 MW was obtained in the TE_27,11 mode at 142 GHz at an efficiency of 16%, about one half of the design efficiency. The reduced efficiency was attributed to nonuniformity of the cathode emission and the sensitivity to the relative alignment of the electron gun, coaxial insert, and cavity. The cathode emission over the azimuthal angle was measured for two cathodes and was shown to be nonuniform due to both temperature and emitter work function nonuniformity. The gyrotron was also tested in two alternate configurations: 1) with the internal mode converter removed (axial output), and 2) with both the internal converter and the coaxial insert removed (empty cavity). In operation in the empty cavity configuration, which is equivalent to a conventional gyrotron oscillator, output power of up to 0.9 MW was observed     

Pyrimethamine analogs as strong inhibitors of double and quadruple mutants of dihydrofolate reductase in human malaria parasites

Pyrimethamine acts against malarial parasites by selectively inhibiting their dihydrofolate reductase-thymidylate synthase. Resistance to pyrimethamine in Plasmodium falciparum is due to point mutations in the DHFR domain, initially at residue 108 (S108N), with additional mutations imparting much greater resistance. Our previous work, the development of a simple rational drug design strategy to overcome such resistance, used suitable meta-substituents in the pyrimethamine framework to avoid the unfavorable steric clash with mutant side chains at position 108. Interestingly, the meta-chloro analog of pyrimethamine not only overcame the resistance due to S108N, but also that contributed by the more remote mutation, C59R. The present work improves on this by means of other meta-substituents. Against wild type DHFR, double mutant types A16V + S108T and C59R + S108T, and the highly pyrimethamine/cycloguanil-resistant quadruple-mutant form N51I + C59R + S108N + I164L, pyrimethamine itself gave Ki values of 1.5, 2.4, 72.3 and 859 nM, respectively. The meta-substituted analogs, especially the meta-bromo analog, were much more powerful inhibitors of these DHFRs, including the quadruple-mutant form (meta-bromo analog, Ki 5.1 nM). For comparison, the dihydropyrazine antifolate, WR99210, gave Ki values of 0.9, 3.2, 0.8 and 0.9 nM, respectively. Ki values were also measured against recombinant human DHFR, as were their activities against the growth of Plasmodium falciparum cultures bearing the double mutations (FCB and K1 strains) and quadruple mutation (V1/S) and the wild type (3D7). The meta-analogs were highly active against all of these, with the meta-bromo again being the strongest, having an IC50 of 37 nM against V1/S, compared to > 5000 nM for pyrimethamine itself and 1.1 nM for WR99210.     

Azasugar inhibitors as pharmacological chaperones for Krabbe disease

Krabbe disease is a devastating neurodegenerative disorder characterized by rapid demyelination of nerve fibers. This disease is caused by defects in the lysosomal enzyme β-galactocerebrosidase (GALC), which hydrolyzes the terminal galactose from glycosphingolipids. These lipids are essential components of eukaryotic cell membranes: substrates of GALC include galactocerebroside, the primary lipid component of myelin, and psychosine, a cytotoxic metabolite. Mutations of GALC that cause misfolding of the protein may be responsive to pharmacological chaperone therapy (PCT), whereby small molecules are used to stabilize these mutant proteins, thus correcting trafficking defects and increasing residual catabolic activity in cells. Here we describe a new approach for the synthesis of galacto-configured azasugars and the characterization of their interaction with GALC using biophysical, biochemical and crystallographic methods. We identify that the global stabilization of GALC conferred by azasugar derivatives, measured by fluorescence-based thermal shift assays, is directly related to their binding affinity, measured by enzyme inhibition. X-ray crystal structures of these molecules bound in the GALC active site reveal which residues participate in stabilizing interactions, show how potency is achieved and illustrate the penalties of aza/iminosugar ring distortion. The structure–activity relationships described here identify the key physical properties required of pharmacological chaperones for Krabbe disease and highlight the potential of azasugars as stabilizing agents for future enzyme replacement therapies. This work lays the foundation for new drug-based treatments of Krabbe disease.     

Highly Active Electrocatalysis of the Hydrogen Evolution Reaction by Cobalt Phosphide Nanoparticles

Nanoparticles of cobalt phosphide, CoP, have been prepared and evaluated as electrocatalysts for the hydrogen evolution reaction (HER) under strongly acidic conditions (0.50 M H₂SO₄, pH 0.3). Uniform, multi‐faceted CoP nanoparticles were synthesized by reacting Co nanoparticles with trioctylphosphine. Electrodes comprised of CoP nanoparticles on a Ti support (2 mg cm^?2 mass loading) produced a cathodic current density of 20 mA cm^?2 at an overpotential of ?85 mV. The CoP/Ti electrodes were stable over 24 h of sustained hydrogen production in 0.50 M H₂SO₄. The activity was essentially unchanged after 400 cyclic voltammetric sweeps, suggesting long‐term viability under operating conditions. CoP is therefore amongst the most active, acid‐stable, earth‐abundant HER electrocatalysts reported to date.     

On the enumeration of a class of plane multigraphs

A class of plane multigraphs having a series-parallel structure is defined and enumerated. The enumeration is carried out both for the rooted graphs as originally defined, and also for those where no distinctions are made between the vertices. Some other related problems are also discussed.