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In vivo activities of absorption enhancers coencapsulated with poorly absorptive drugs in the same enteric-coated particles were evaluated. Lopinavir [a substrate of cytochrome P450 3 A ( CYP3 A)] and ritonavir (an inhibitor of CYP3 A-mediatd metabolism) were used as a model drug and a model absorption enhancer, respectively. Lopinavir and ritonavir were encapsulated into enteric-coated particles as amorphous forms using coaxial electrospray deposition. The electrospray treatment resulted in dramatic improvement of dissolution profiles of both compounds, probably because of complete amorphization and superior dispersion efficiency of the particles. Poor absorption of lopinavir in rats was observed after oral administration of enteric-coated particles containing lopinavir alone. When the particles were coadministered with enteric-coated particles containing ritonavir alone, lopinavir absorption was boosted. The boosting effect was further enhanced when ritonavir was coencapsulated with lopinavir into the same enteric-coated particles. A significant increase in area under the plasma concentration-time curve reflected an extension of mean residence time rather than an elevation of Cmax. Lopinavir absorption was improved presumably because lopinavir was always accompanied by a practical amount of ritonavir required for the boosting during the gastrointestinal transit of the particles. Not only did the electrospray coencapsulation technique improve drug absorption, but also increased trough concentration that might result in the reduction of the number of doses. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:2977-2985, 2015 [ABSTRACT FROM AUTHOR]

Gravity affects the stability of Marangoni flow in floating half zone of low-Pr fluids through two different factors, i.e., the buoyancy and the static deformation of the free surface shape. In the present study, influence of these two factors are evaluated by unsteady three-dimensional (3D) simulations for a realistic model of floating half zone of molten tin (Pr = 0.009) with an aspect ratio As = 2.0 under a ramped temperature difference (1.19 K/min) between the top and bottom ends of two iron supporting rods. The corresponding first critical conditions for the onset of 3D asymmetric non-oscillatory flows and the second critical conditions for the onset of 3D oscillatory flows are determined. Simulation results indicate that the fee surface deformation is the most influential factor for the critical conditions of the flow transitions. Buoyancy is less influential to the flow transitions. However, buoyancy causes multiple step transitions between different 3D asymmetric non-oscillatory flow modes. [ABSTRACT FROM AUTHOR]

Abstract: [{(R)-binap}Pt(μ-OH)]22X is a weak Lewis acid, which can catalyze the enantioselective aldol reaction of aldehydes with ketene silyl acetals in DMF at room temperature. The platinum(II) complex-catalyzed the enantioselective aldol reaction of aldehydes with 1-methoxy-2-methyl-(1-trimethylsilyloxy)propene gave the corresponding aldols in high yields with enantioselectivity up to 92%. With 5mol% loading of the complexes, the enantioselective aldol reaction of aldehydes with 1-benzyloxy-1-(trimethylsilyloxy)propene smoothly proceeded in DMF containing 10% HMPA as to predominantly give anti-propionates with enantioselectivity up to 89%, irrespective of the silyl nucleophile geometry. [Copyright &y& Elsevier]

Abstract: Enantioselective construction of nitrogen-substituted quaternary carbon centers adjacent to the carbonyl group in the cyclohexane ring was performed with respect to the asymmetric synthesis of anesthetic (S)-ketamine 1. Diastereoselective nucleophilic 1,2-addition reaction of phenyllithium to α-ketoxime-ether acetal 9 bearing chiral auxiliary on the α-carbonyl function gave benzyloxyamine 11 major in 83% yield with 82% de, which was converted to the corresponding amino ketone 12. However, the reaction of 2-chlorophenyllithium did not work in which this route was unavailable for the synthesis of 1. Then, an alternative strategy directed toward 1, starting with a compound having 2-chlorophenyl groups in advance, was designed in which the chiral quaternary carbon center bearing a nitrogen atom in the ring is created by the enantioselective reduction of the atropisomeric intermediate ketone 18, and the sequential allyl cyanate-to-isocyanate rearrangement with complete 1,3-chirality transfer. The first asymmetric synthesis of 1 with excellent selectivity (>99% ee) was accomplished by a short path according to the strategy. [Copyright &y& Elsevier]

Abstract: A new strategy for increasing the power density of an air-breathing small proton exchange membrane fuel cell (PEMFC) system for the main energy source of portable consumer electronics is presented. The small PEMFC system is composed of a single cell. Utilizing the output voltage of the single cell, we introduce a newly designed ultra-low voltage input boost converter. The boost converter can generate 4.1V output from input sources with low voltage ranges, such as under 1.0V. The cathode plate is made from a thin SUS 316L stainless steel plate and has ribs that prevent the cathode from bending. The hydrogen is supplied by a metal hydride (MH) tank cartridge. The MH tank contains highly packed AB5-type MH. The MH tank cartridge has a volume of 13.2cm3 and can absorb 6.7L of hydrogen. The maximum power of the small PEMFC is 4.42W at room temperature. Using 6.7L of hydrogen, the small PEMFC can generate 11Wh of electricity. The power density of the small PEMFC reaches 0.51Whcm−3. And the power density of the whole small PEMFC system, which contains the boost converter, a small Li-ion battery for a load absorber, and a case for the system, reaches 0.14Whcm−3. This value matches that of external Li-ion battery chargers for cell phones. We installed the small PEMFC system in a cell phone and confirmed the operations of calling, receiving, videophone, connecting to the Internet, and watching digital TV. And also confirmed that the small PEMFC system provides approximately 8.25h of talk time, which is about three times as long as that for the original Li-ion battery. [Copyright &y& Elsevier]

Abstract: [((R)-BINAP)Pt(μ-OH)]2·2OTf catalyzed the enantioselective aldol reaction of aldehydes with 1-methoxy-2-methyl-(1-trimethylsilyloxy)propene at room temperature in dry DMF in high yields with enantioselectivity up to 92%. This is a versatile example of the catalytic enantioselective aldol reaction using a silyl ketene acetal promoted by (μ-hydroxo)-platinum complexes under mild conditions. [Copyright &y& Elsevier]

Abstract: Local cooling of the testis was reported to cause testicular abnormality, but there is no information regarding the effect of whole body cooling, such as hypothermia on spermatogenesis. We investigated whether hypothermia would cause testicular toxicity in mice. Male mice were administered with a single intraperitoneal dose of 100mg/kg of reserpine. The rectal temperature decreased to 29°C 6h post dosing and thereafter sustained at lower values (24−25°C) until 96h post dosing. The histopathological examination of the testis showed nuclear vacuolation of round spermatids at stages I−V in mice examined 24, 48, 72 and 96h post dosing. The lesions were more severe in the groups examined 72 and 96h post dosing than in the groups examined 24 and 48h post dosing. These results suggested that hypothermia condition at lower than 30°C and sustained for more than 18h could induce nuclear vacuolation of round spermatids at stages I−V in the testis. In order to demonstrate that the testicular lesion in the reserpine-treated mice was induced by hypothermia, mice were given a single intraperitoneal dose of 100mg/kg of reserpine, and each dosed group was housed under different environmental conditions for 72h; one consisted of housing the mice individually at room temperature, and the other consisted of housing the mice individually under heated condition. In the mice administered with reserpine and housed at room temperature, hypothermia below 30°C with a minimal of 26°C was observed for 66h. In contrast, the mice administered with reserpine and housed under heated condition maintained the rectal temperature of 33−36°C. Nuclear vacuolation of round spermatids at stages I−V in the testis was observed in reserpine-treated mice maintained at room temperature, but not in reserpine-treated mice kept under heated condition. These data strongly indicated that nuclear vacuolation of round spermatids at stages I−V observed in reserpine-treated mice was related to hypothermia. [Copyright &y& Elsevier]

Background & Aims: It has been unclear which chemokine network is involved in migration of T-cell subsets to chronically inflamed lesions of the intestine. SAMP1/YP mice develop a spontaneous chronic transmural intestinal lesion specifically in the ileum. Using these mice, we investigated the gut chemokine network involved in specific migration of T-cell subsets to the inflamed lesion of the intestine. Methods: We performed expression analyses of chemokines and their receptors, chemokine receptor blocking studies, and migration studies in vitro and in vivo to identify the gut chemokine network induced in intestinal inflammation and to determine its role in migration of conventional and FoxP3+ suppressor T cells to the inflamed intestine. Results: The expression of homeostatic chemokines was largely unchanged in the inflamed lesion of SAMP1/YP mice compared with control mice. However, an additional chemokine axis (CCL5-CCR5) was up-regulated in the inflamed intestine of SAMP1/YP mice compared with control mice. Activated T cells of SAMP1/YP mice compared with control mice were hyperresponsive to CCL5 in chemotaxis. CCR5+ T cells preferentially migrated to the inflamed lesion, which can be blocked by a CCR5 antagonist. Importantly, the FoxP3+ regulatory T cells of the inflamed lesion of SAMP1/YP mice highly expressed CCR5. CCR5 blockade suppressed the migration of FoxP3+ T cells into the inflamed intestine and significantly exacerbated the intestinal inflammation. Conclusions: The CCL5-CCR5 chemokine axis is involved in preferential recruitment of FoxP3+ regulatory T cells, which prevents further exacerbation of chronic inflammation in the intestine. [Copyright &y& Elsevier]

Abstract: Soft X-ray absorption spectra of sulfur K edge were measured for diesel exhaust particles from three different vehicles. The X-ray spectra were measured using a synchrotron radiation beamline. The spectra were measured by surface sensitive total electron yield method and bulk sensitive X-ray fluorescence yield method. One vehicle concentrated the S2− on the surface of the emission particles; the others did not concentrate S2−. This type of chemical state analysis method is useful for the process analysis such as diesel emissions. [Copyright &y& Elsevier]

The effect of human serum albumin (HSA), in its endogenous, free fatty acid free (FAF) and globulin free (GF) form, on the activity of CYP2C9 was studied in human liver microsomes using tolbutamide as the substrate. The widely used BSA was included to assess the differential effect of BSA and HSA. CYP2C9 activity was expressed as CLint (Vmax/Km). HSA(FAF) and BSA showed a concentration-dependent and biphasic (activation and inhibition) interaction with CYP2C9 activity. HSA(GF) and HSA exhibited an inhibitory effect, with an inhibition constant, Ki, of 19.9 μM (0.13% albumin) and 42.2 μM (0.35% albumin), respectively. Enzyme-kinetics revealed that the activation is accompanied by a decrease in Km values, while with inhibition Km values increased. A simplified method to calculate clearance, utilizing a single slope (V/S) determination based on V over the lowest linear range of [S] (designated as CLone) was assessed. Virtually identical values were obtained for CLint and CLone. The free-drug hypothesis was tested by comparing ratios of relative CLint/unbound fraction (FDH Test ratio). The FDH Test ratio for HSA was about 1, indicating that HSA binding of tolbutamide reduced the CYP2C9 activity in accord with the free-drug hypothesis. The FDH Test ratios for BSA and HSA(FAF) were 3.7 and 3.0, revealing a monophasic activation of CYP2C9. For 2%HSA(GF) the ratio of 0.3 confirmed inhibition. As revealed by their removal, free fatty acids and globulins, significantly alter the interaction of HSA with CYP2C9. In addition, HSA and BSA showed different effects on the oxidation of tolbutamide by CYP2C9. [Copyright &y& Elsevier]

Senescence-accelerated mouse (SAM) P1/Yit mouse showed spontaneous ileitis and cecitis when reared under specific-pathogen-free (SPF) conditions. Intestinal lesions in the SAMP1/Yit strain exhibit discontinuous and transmural inflammation accompanied by numerous inflammatory infiltrates. Granulomas were often located in peyer''s patches. These characteristics resembled the features of Crohn''s disease (CD). Intravenous injection of gut-associated-lymphoid-tissue (GALT)-derived CD4+ αβ T cells isolated from SAMP1/Yit mice into SPF scid mice induced ileitis and cecitis in recipient''s scid mice. However, the intestinal inflammation was absent in germfree (GF) SAMP1/Yit mice. Here we demonstrated the specific interaction between GALT-derived CD4+ αβ T cells and enteric bacteria in the immunopathogenesis of the Crohn''s disease-like inflammatory bowel disease (IBD) in SAMP1/Yit mice. [Copyright &y& Elsevier]

The thermal 1,2-hydrogen shift of the hydrazone generates the NH-azomethine imine intermediate in the 4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbaldehyde system under mild conditions. Therein, the resulting NH-azomethine imine should be stabilized by forming an internal hydrogen bond with the carbonyl oxygen at the 4-position. Its smooth stereoselective intermolecular cycloaddition reaction with olefinic dipolarophiles giving pyrazolidine derivatives is discussed. [Copyright &y& Elsevier]

The effects of human and bovine serum proteins on CYP3A activity, using testosterone as the probe substrate, were investigated in human liver microsomes. Serum albumin, α-globulins, and α1-acid glycoprotein (α1-AGP) of both species significantly inhibited testosterone 6β-hydroxylation. When the inhibitory effects of serum proteins were compared with serum protein binding data, human α-globulins, with a ratio (relative metabolic activity/unbound fraction) of 0.3, showed higher, and bovine α1-AGP, with the ratio of 1.4, showed lower inhibitory effects than those expected from protein binding of testosterone. The effects of the other serum proteins were close to those expected from protein binding, according to the free drug hypothesis. The Ki values obtained from the Dixon plots were 0.32% (w/v, 48 μM) for human serum albumin (HSA), 0.48% for human α-globulins, and 0.23% (52 μM) for human α1-AGP. Ki values of bovine serum albumin, bovine α-globulins and bovine α1-AGP were 3–5 times higher than those of the respective human proteins. The results suggest a direct interaction of some of these serum proteins with the active site of the CYP3A isoform. Since the bovine serum proteins showed weaker inhibitory effects than human serum proteins, the wide use of BSA, which is viewed as interchangeable with HSA, needs to be cautioned. [Copyright &y& Elsevier]

Abstract: The Mukaiyama aldol reaction of 2-aryl-1-cyclohexene-1-carboxaldehydes with phenyl trimethylsilyl ketene acetal unexpectedly resulted in the formation of 9-substituted-1,2,3,4-tetrahydrofluorene derivatives via a novel intramolecular titanium-promoted deoxygenative cyclization. By successive treatment of the corresponding allyl alcohols with n-butyllithium and titanium tetrachloride, the cyclization products were obtained in good yields. [Copyright &y& Elsevier]

Background & Aims: Retinoic acid plays a positive role in induction of FoxP3+ regulatory T cells. Because retinoic acid is produced as a metabolite of vitamin A in the intestine and FoxP3+ T cells regulate intestinal inflammation, we investigated the impact of vitamin A status on the regulatory T cells and inflammation in the intestine. Methods: The SAMP1/YP model is a mouse model of Crohn''s disease. We made vitamin A–deficient, vitamin A–excessive, and normal SAMP1/YP mice and assessed the intestinal inflammation. We also investigated the phenotype and function of FoxP3+ T cells induced in different levels of vitamin A availability in regulation of intestinal inflammation in a T-cell–induced inflammation model in SCID mice. Results: The limited and excessive vitamin A conditions induced distinct FoxP3+ T-cell subsets in vivo, and both ameliorated the intestinal inflammation in SAMP1/YP mice. The limited vitamin A condition greatly induced unusual CD103+CCR7+ FoxP3+ cells, while the high vitamin A condition induced CCR9+α4β7+ FoxP3+ T cells in the intestine. Both FoxP3+ T-cell populations, when transferred into mice with ongoing intestinal inflammation, were highly effective in reversing the inflammation. Blockade or lack of occupancy of RARα is a mechanism to induce highly suppressive CD103+CCR7+ FoxP3+ cells in both the thymus and periphery in limited vitamin A availability. Conclusions: Our results identify novel pathways of inducing highly suppressive FoxP3+ regulatory T cells that can effectively control intestinal inflammation. The results have significant ramifications in treating inflammatory bowel diseases. [Copyright &y& Elsevier]

Highlights: [•] The thin-film RESURF SOI p-channel power MOSFET can operate at 573K. [•] Increase in leakage current is suppressed by increasing the channel length. [•] Thinning the top silicon layer thickness can suppress increase in on-resistance. [Copyright &y& Elsevier]

Abstract: This paper proposes the design guidelines of the thin-film reduced surface field (RESURF) SOI power MOSFET for high thermal stability based on experimental and simulation results. The results show that the thinner top silicon layer is preferable, which realize the lower leakage current and smaller degradation of the on-resistance. In higher temperature operation, it is important to suppress the parasitic bipolar effect to prevent the reduction of the breakdown voltage. [Copyright &y& Elsevier]

We investigate the crystal growth process of an InAs–GaAs binary semiconductor by the Travelling Liquidus-Zone (TLZ) method numerically and discuss the possibility of growing a bulk In0.3Ga0.7As crystal. First, we explain this new crystal growth technique and then develop a numerical model and calculation method of the growth of binary crystals, by which the flow field in the solution, the temperature and concentration fields in both the solution and crystals, and the shape and movement of the crystal–solution interfaces are determined. We focus, in particular, on the effect of the solution zone width on the crystal growth process and the generation of supercooling in the solution in order to grow In0.3Ga0.7As. We find that a uniform In0.3Ga0.7As can be grown by the TLZ method under 1 μg conditions by adjusting the solution zone width and the temperature gradient in the solution at appropriate values, in which case buoyancy convection and supercooling induced in the solution are remarkably reduced. [Copyright &y& Elsevier]

A facile oxime–nitrone isomerization through the 1,2-hydrogen shift in 4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbaldehyde oximes is discussed. The resultant NH-nitrones are trapped by maleimides to afford intermolecular cycloadducts. The reaction of the oximes with electron-deficient acetylenes undergoes via another path initiated by a nucleophilic attack of the oxime to acetylene moiety. [Copyright &y& Elsevier]

In the major hepatectomies, the right lateral sectoriectomy must be one of higher difficulty operation because of large resection area and difficulty of Glissonean approach and making the resection direction. After that, liver resection of dorsal side of the Rouvier's sulcus and dissection of the ventral side of the posterior Glisson are conducted by clamp and crush method using LCS. At this point, previous small area liver resection of the caudal side of the liver might be effective to make correct direction of the resection. [Extracted from the article]

Thermocapillary-driven convection in a hanging droplet is experimentally investigated under normal- and micro-gravity conditions. A droplet is hung on a heated cylindrical rod facing downward, and another rod cooled is placed just beneath the droplet to create the designated temperature difference between both ends of the droplet. A transition of the flow field from a two-dimensional axisymmetric ‘steady’ flow to three-dimensional time-dependent ‘oscillatory’ ones by increasing temperature difference is realized. The oscillatory flow is accompanied with thermal waves due to so-called hydrothermal wave (HTW) instability, which propagates over the free surface at a constant frequency. The present study aims to understand the transition conditions of the flow from the steady to the oscillatory ones, and to characterize the convective field inside the droplet with the HTW by imposing a range of temperature differences. We discuss the transition condition and the flow fields in the oscillatory regimes after the transition obtained in the terrestrial and on-orbit experiments in ‘Kibo,’ the Japanese Experiment Module aboard the International Space Station. [ABSTRACT FROM AUTHOR]