Determination of midazolam and its metabolite as a probe for cytochrome P450 3A4 phenotype by liquid chromatography-mass spectrometry

This study demonstrated the analysis of midazolam and its metabolites by liquid chromatography-mass spectrometry (LC-MS) with a sonic spray ionization (SSI) interface. The analytical column was a YMC-Pak Pro C18 (50 mm x 2.0 mm i.d.) using 10 mM ammonium acetate (pH 4.8)-methanol (1:1) at a flow rate of 0.2 ml min(-1). The drift voltage was 100 V. The sampling aperture was heated at 110 degrees C and the shield temperature was 230 degrees C. The lower limits for the detection of midazolam and 1'-hydroxymidazolam were 26.3 and 112.76 pg injected, respectively. The calibration curves for midazolam and 1'-hydroxymidazolam were linear in the range of 0.1-5 microg ml(-1). Within-day relative standard deviations was less than 7%. The method was applied to the determination of midazolam in monkey plasma, and the analysis of midazolam and its metabolites in an in vitro study with recombinant cytochrome P450 (CYP) 3A4. This method is sufficiently sensitive and useful to elucidate the kinetics of midazolam metabolite formation. We also investigated the effect of propofol on the metabolism of midazolam using recombinant CYP3A4. Propofol competitively inhibited the metabolism of midazolam to 1'-hydroxymidazolam by CYP3A4.     

An experimental study of the unsteady vortex structures in the wake of a root-fixed flapping wing

An experimental study was conducted to characterize the evolution of the unsteady vortex structures in the wake of a root-fixed flapping wing with the wing size, stroke amplitude, and flapping frequency within the range of insect characteristics for the development of novel insect-sized nano-air-vehicles (NAVs). The experiments were conducted in a low-speed wing tunnel with a miniaturized piezoelectric wing (i.e., chord length, C = 12.7 mm) flapping at a frequency of 60 Hz (i.e., f = 60 Hz). The non-dimensional parameters of the flapping wing are chord Reynolds number of Re = 1,200, reduced frequency of k = 3.5, and non-dimensional flapping amplitude at wingtip h = A/C = 1.35. The corresponding Strouhal number (Str) is 0.33, which is well within the optimal range of 0.2 < Str < 0.4 used by flying insects and birds and swimming fishes for locomotion. A digital particle image velocimetry (PIV) system was used to achieve phased-locked and time-averaged flow field measurements to quantify the transient behavior of the wake vortices in relation to the positions of the flapping wing during the upstroke and down stroke flapping cycles. The characteristics of the wake vortex structures in the chordwise cross planes at different wingspan locations were compared quantitatively to elucidate underlying physics for a better understanding of the unsteady aerodynamics of flapping flight and to explore/optimize design paradigms for the development of novel insect-sized, flapping-wing-based NAVs.     

Sub-100 fs SDPF optical soliton compressor for diode laser pulses

We report our studies on a fiber-optic soliton compressor for generation of sub-100 femtosecond (fs) optical pulses out of picosecond (ps) diode laser pulses. The soliton compressor is rather simple and composed of a 15 ～ 20 m-long step-like dispersion profiled fiber (SDPF) in conjunction with a single Er-doped fiber amplifier (EDFA). Careful design of such a SDPF compressor was performed, leading to demonstration of 20-fs class compression performance, and experimental investigation was carried out in detail on the optical pulse propagation in the compression processes. In addition, nonlinear fiber loops were applied to suppression of pulse pedestals, resulting successfully in high quality optical pulses of the 100-fs range.     

The interstitial atom of the nitrogenase FeMo-cofactor: ENDOR and ESEEM show it is not an exchangeable nitrogen

A recent high-resolution X-ray crystallographic study (1.16 A) of the Azotobacter vinelandii nitrogenase MoFe protein revealed a previously undetected electron density associated with the active site FeMo-cofactor. The density is located inside the cluster at the center of the "trigonal prism" of six irons and is assigned to a species "X". The identity of species X was not resolved, although the electron density is consistent with a single N, O, or C atom. One proposal is that X is an N atom that derives from and exchanges with N from N2 during catalysis. In the present study, we have examined this possibility by employing 14N and 15N isotopes of N2 along with ENDOR and ESEEM spectroscopies. The WT MoFe protein and alpha-359Arg-->Lys and alpha-381Phe-->Leu variants were allowed to turn over in the presence of 14N2 or 15N2, and then were examined as resting enzymes by ENDOR and ESEEM at X- and Q-bands to look for all 14N and 15N signals coupled to the electron spin of the FeMo-cofactor and to determine if any exchanged during turnover. We have found five peaks in Q-band pulsed ENDOR spectra that appear to arise not only from previously reported N1/N2, which give rise to the ESEEM, but also from one or two additional coupled nitrogens. None of the ENDOR and ESEEM signals vanish or are altered by catalytic turnover with 15N2, and no new 15N signal is detected, leading to the conclusion that if species X is a nitrogen atom, it does not exchange during dinitrogen reduction.     

Synthesis of a capillarisin sulfur-analogue possessing aldose reductase inhibitory activity by selective isopropylation

We describe the synthesis of 2-[(4-hydroxyphenyl)thio]-7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one 2 from 3,4,5-trimethoxyphenol 6 via the key intermediate, 3-iodo-7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one 3. An important feature of this synthetic scheme involves selective alkylation, which can be achieved by two different routes. One route involves the selective isopropylation of a triacetate derivative 4 under basic conditions. The second route employs the selective demethylation of a trimethoxy derivative 5 under acidic conditions followed by isopropylation. The product of these alternative routes, compound 3, is then converted to a capillarisin sulfur analogue 2 in a one-pot reaction via the imidazolyl intermediate 22.     

Formation of molecular glasses and the aggregation in solutions for lanthanum(III), calcium(II), and yttrium(III) complexes of octanoyl-DL-alaninate

Octanoylalaninato-metal (metal = calcium(II), yttrium(III), lanthanum(III), and zinc(II)) complexes were prepared and the first three metal complexes were found to readily form transparent and stable molecular glasses from methanol and chloroform solutions. The process of glass formation from solution was studied in detail. The effect of the central metal ions on the formation of glassy states was remarkable: the lanthanum and calcium complexes assumed glassy or crystalline states depending on the isolation method and the yttrium complex had a large tendency to assume an amorphous state, whereas the zinc complex did not assume a pure and stable glassy-state. The glass transition temperatures were 50 degrees C for the yttrium complex and 70-75 degrees C for the lanthanum and calcium complexes when these complexes are monohydrates prepared by a solvent-cast method, whereas they increase by 10-30 degrees for the hemihydrates which were obtained by an annealing treatment at 110 degrees C. The coordinated water was eliminated from the solid above the glass transition temperature. The glassy state was regarded as a result of the self-aggregation of the metal complex in solution by an entanglement of the methylene chains with one another. SAXS showed the presence of two disordered bilayer structures with 2.2 nm and 4.5 nm periods in the glassy states. The structures of the molecular assemblies in the solid states and solutions were compared by SAXS and NMR studies. EXAFS studies confirmed the coordination numbers of oxygen atoms around the yttrium and lanthanum atoms in the glassy states for the yttrium and lanthanum complexes to be about 7.     

On the deflection of a thick plate under a sinusoidal load

Summary The equations of deflection of a thick plate presented in a previous paper are solved for an infinite plate under sinusoidally distributed pressure acting at its upper surface.The deflection and stress of the plate are calculated from the solutions of the approximate equations. The results are compared with those calculated from the exact solution and also with those obtained from other approximate methods.

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Über die Durchbiegung einer dicken Platte unter einer sinusförmigen Last

Übersicht Die in einer früheren Arbeit gegebenen Gleichungen für die Durchbiegung einer dicken Platte werden für den Fall einer unendlichen Platte gelöst, deren Deckfläche durch einen sinusförmigen verteilten Druck belastet wird.Aus den Lösungen der Näherungsgleichungen werden die Durchbiegung und die Spannung einer dicken Platte berechnet. Die Ergebnisse werden mit dem aus der exakten Lösung erlangten Resultat sowie mit den aus anderen Näherungsverfahren erhaltenen Ergebnissen verglichen.