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.     

Calibration of quartz load cells; An in-situ procedure for instrumented falling weight impact machines

Quartz load cells have particular problems concerning signal drift and time of load application during calibration. There is currently no available standard method for dealing with these problems. A procedure is suggested that may be used as a routine check in situ on the complete system of quartz cell, amplifier, recording device and data processing unit. It involves loading and unloading a quartz cell with a known mass, recording the output on a suitable storage device and manipulating the data with a computer program to provide a permanent record. The accuracy of the method is considered and the results of a comprehensive series of calibrations in tension and compression are reported.

It was found that, providing good axiality was obtained, then either tensile or compressive loading gave the same calibration. The preferred method was to apply a tensile load, via a hanger system on the end of the striker, which obviates any necessity to remove the load cell from the impact mass and avoids possible errors associated with non-axial loading. Using the procedure, the quartz load cell was calibrated to an accuracy of better than 0·1%.     

UCT-Kirchberg algebras have nuclear dimension one

We prove that every Kirchberg algebra in the UCT class has nuclear dimension 1. We first show that Kirchberg 2-graph algebras with trivial _K0$K_0$ and finite _K1$K_1$ have nuclear dimension 1 by adapting a technique developed by Winter and Zacharias for Cuntz algebras. We then prove that every Kirchberg algebra in the UCT class is a direct limit of 2-graph algebras to obtain our main theorem.     

Spectral beam combining of 2 μm Tm fiber laser systems

Output beams from three independently frequency-stabilized thulium master-oscillator power-amplifier fiber laser systems were spectrally combined using a plane-ruled metal diffraction grating. Two laser channels were frequency-stabilized with guided mode resonance filters and the third was stabilized using a plane-ruled metal diffraction grating. The systems had output wavelengths between 1984 and 2015 nm, each with a spectral width of 100-450 pm and output powers between 40-120 W. The combined beam had powers up to 49 W and was 32% efficient with respect to the launched pump power.     

Oscillatory melting temperature of the vortex smectic phase in layered superconductors

We report on transport measurements of YBa 2Cu 3O (7-delta) single crystals with different oxygen contents in the geometry B, J ||ab (J perpendicularB). Our data show that the vortices become confined between the Cu-O planes below a well-defined temperature at which the effective size 2xi of the vortex core is approximately equal to the period of the Cu-O layers. This confinement strongly increases the vortex liquid freezing temperature. A new melting line is found separating a vortex liquid and a smectic phase, which shows an oscillatory field dependence reflecting differences between commensurate and incommensurate smectic states.     

Chirped pulse amplification in single mode Tm:fiber using a chirped Bragg grating

We report femtosecond pulse generation and chirped pulse amplification in Tm:fiber. A mode-locked oscillator operating in the soliton regime produced 800 fs pulses with 5 nm spectral bandwidth, at 40 pJ pulse energy. This oscillator seeded a pre-amplifier that utilizes a Raman soliton self-frequency shift to produce wavelength tunable pulses with 3 nJ energy, reduced pulse duration of 150 fs, and increased bandwidth of 30 nm. For further amplification, the pulses were stretched up to 160 ps using a chirped Bragg grating (CBG). Stretched pulses were amplified to 85 nJ after compression in single-mode Tm:fiber and recompressed with the CBG as short as 400 fs. Compressed pulses were coupled into a highly nonlinear tellurite fiber to investigate the potential of this ultrashort pulse 2-μm fiber source as a pump for mid-IR supercontinuum generation.     

Dynamics of the Douglas-Rachford Method for Ellipses and <Emphasis Type="Italic">p</Emphasis>-Spheres

We expand upon previous work that examined the behavior of the iterated Douglas-Rachford method for a line and a circle by considering two generalizations:that of a line and an ellipse and that of a line together with a p-sphere. With computer assistance we discover a beautiful geometry that illustrates phenomena which may affect the behavior of the iterates by slowing or inhibiting convergence for feasible cases. We prove local convergence near feasible points, and—seeking a better understanding of the behavior—we employ parallelization in order to study behavior graphically. Motivated by the computer-assisted discoveries, we prove a result about behavior of the method in infeasible cases.     

Energy harvesting from the nonlinear oscillations of magnetic levitation

This paper investigates the design and analysis of a novel energy harvesting device that uses magnetic levitation to produce an oscillator with a tunable resonance. The governing equations for the mechanical and electrical domains are derived to show the designed system reduces to the form of a Duffing oscillator under both static and dynamic loads. Thus, nonlinear analyses are required to investigate the energy harvesting potential of this prototypical nonlinear system. Theoretical investigations are followed by a series of experimental tests that validate the response predictions. The motivating hypothesis for the current work was that nonlinear phenomenon could be exploited to improve the effectiveness of energy harvesting devices.