Synthesis of a naphthyridone p38 MAP kinase inhibitor

Compound 1 is a p38 MAP kinase inhibitor potentially useful for the treatment of rheumatoid arthritis and psoriasis. A novel six-step synthesis suitable for large-scale preparation was developed in support of a drug development program at Merck Research Laboratories. The key steps include a tandem Heck-lactamization, N-oxidation, and a highly chemoselective Grignard addition of 4-(N-tert-butylpiperidinyl)magnesium chloride to a naphthyridone N-oxide. The N-oxide exerted complete chemoselectivity via chelation in directing the Grignard addition to the alpha position as opposed to 1,4-addition on the ene-lactam. The dihydropyridyl adduct was in situ aromatized with isobutylchloroformate followed by heating in pyridine. Syntheses of Grignard precursor, N-tert-butyl-4-chloro-piperidine, were accomplished via transamination with a quaternary ammonium piperidone or via addition of methylmagnesium chloride to an iminium ion. Utilizing this chemistry, multi-kilogram preparation of compound 1 was successfully demonstrated.     

Extended resolution wide-field optical imaging: objective-launched standing-wave total internal reflection fluorescence microscopy

Standing-wave total-internal-reflection fluorescence (SW-TIRF) microscopy uses a super-diffraction-limited standing evanescent wave to extract the high-spatial-frequency content of an object through a diffraction-limited optical imaging system. The effective point-spread function is better than a quarter of the emission wavelength. With a 1.45 numerical aperture objective and 532 nm excitation wavelength, a Rayleigh resolution of approximately 100 nm can be achieved, which is better than twice the resolution of conventional TIRF microscopy. This first experimental realization of SW-TIRF in an objective-launched geometry demonstrates the potential for extended resolution imaging at high speed by using wide-field microscopy.     

Solid-state laser spectral narrowing using a volumetric photothermal refractive Bragg grating cavity mirror

Dramatic spectral narrowing of two normally broadband lasers, Ti:sapphire and Cr:LiSAF, was achieved by simply replacing the output mirror with a reflective, volumetric Bragg grating recorded in photothermal refractive glass. The output power of each laser was unchanged from that obtained using dielectric coated output mirrors with the same output coupling as the Bragg grating while spectral brightness increased by 3 orders of magnitude.     

Design of a circular Dammann grating

A novel circular Dammann grating is proposed to generate uniform-intensity impulse rings corresponding to different diffraction orders in the far field. The intensities of the rings are determined by the coefficients of the circular sine series decomposition of the grating function. The definition of diffraction efficiency and uniformity for this novel device are described. Numerical solutions of binary phase circular Dammann gratings are presented. A binary phase three-order circular Dammann grating of pi phase depth is fabricated by an e-beam direct writing technique and is experimentally demonstrated.     

Direct determination of nucleosides in the urine of patients with breast cancer using column-switching liquid chromatography-tandem mass spectrometry

We developed an analytical method for a simple, sensitive and simultaneous determination of oxidized nucleosides in urine using column-switching liquid chromatography-electrospray/tandem mass spectrometry (LC-ESI/MS/MS). We connected two columns through a six-way switching valve and effectively separated nucleosides in the urine from the interference by column-switching liquid chromatography. We monitored separated nucleosides using positive ionization tandem mass spectrometry in selective reaction monitoring (SRM) mode. The calibration ranges of nucleosides were 0.2-100 nmol/mL. The linearity of the method was 0.994-0.999, and the limits-of-detection (LOD) at a signal-to-noise (S/N) ratio of 3 were 0.1-0.2 nmol/mL. The coefficients of variation were in the range 2.28-11.74% for within-day variation and 4.36-11.15% for day-to-day variation, respectively. To explore the relationship between breast cancer and the nucleosides level in human urine, we measured the concentrations of nucleosides in female patients with breast cancer (n = 30) and in normal female subjects (n = 30). The concentration of nucleosides was significantly increased in patients with breast cancer when compared with the normal controls (1-methyladenosine; p < 0.005, N(2),N(2)-dimethylguanosine; p < 0.01, 5-hydroxymethyl-2'-deoxyuridine; p < 0.001, 8-hydroxy-2-deoxyguanosine; p < 0.001). Therefore, the elevated levels of nucleosides could be used as an important biomarker for breast-cancer research.     

A LES-CMC formulation for premixed flames including differential diffusion

A finite volume large eddy simulation–conditional moment closure (LES-CMC) numerical framework for premixed combustion developed in a previous studyhas been extended to account for differential diffusion. The non-unity Lewis number CMC transport equation has an additional convective term in sample space proportional to the conditional diffusion of the progress variable, that in turn accounts for diffusion normal to the flame front and curvature-induced effects. Planar laminar simulations are first performed using a spatially homogeneous non-unity Lewis number CMC formulation and validated against physical-space fully resolved reference solutions. The same CMC formulation is subsequently used to numerically investigate the effects of curvature for laminar flames having different effective Lewis numbers: a lean methane–air flame with Le_eff = 0.99 and a lean hydrogen–air flame with Le_eff = 0.33. Results suggest that curvature does not affect the conditional heat release if the effective Lewis number tends to unity, so that curvature-induced transport may be neglected. Finally, the effect of turbulence on the flame structure is qualitatively analysed using LES-CMC simulations with and without differential diffusion for a turbulent premixed bluff body methane–air flame exhibiting local extinction behaviour. Overall, both the unity and the non-unity computations predict the characteristic M-shaped flame observed experimentally, although some minor differences are identified. The findings suggest that for the high Karlovitz number (from 1 to 10) flame considered, turbulent mixing within the flame weakens the differential transport contribution by reducing the conditional scalar dissipation rate and accordingly the conditional diffusion of the progress variable.     

Investigation of DKP equation for spin-zero system in the presence of Gödel-type background space-time

This paper contains a discussion of a relativistic spin-0 system in the presence of a Gödel-type background space-time. The Duffin–Kemmer–Petiau (DKP) equation in the presence of a Gödel-type background space-time is studied in detail. After a derivation of the final form of this equation in the considered framework, free spin-0 particles have been studied.     

Upshot of Chemical Species and Nonlinear Thermal Radiation on Oldroyd-B Nanofluid Flow Past a Bi-directional Stretched Surface with Heat Generation/Absorption ina Porous Media

A three-dimensional mathematical model is developed to examine the flow of nonlinear thermal radiation Oldroyd-B nanofluid past a bidirectional linearly stretched surface in a porous medium. The flow is induced by temperature dependent thermal conductivity, chemical reaction and convective heat and mass conditions. Novel characteristics of Brownian motion and thermophoresis are accompanied by magnetohydrodynamic and heat generation/absorption. Self-similar transformations are employed to convert the system of nonlinear partial differential equations to a system of ordinary differential equations with high nonlinearity and are solved by strong analytic technique named as Homotopy Analysis method (HAM). Effects of varied arising parameters on involved distributions are reflected through graphical illustrations. From this study, it is perceived that strong magnetic field hinders the fluid's motion and leads to rise in temperature that eventually lowers heat transfer rate from the surface. Further, decrease in heat transfer rate is also observed for enhanced values of thermal radiation parameter. To validate our results, a comparison with already published paper in limiting case is also given and results are found in excellent oncurrence; hence reliable results are being presented.     

Multifunctional carbon-coated magnetic sensing graphene oxide-cyclodextrin nanohybrid for potential cancer theranosis

Journal of Nanoparticle Research - Over the last years, an environmentally friendly and economically efficient way of nanoparticle production has been found in the biosynthesis of metal...