Altitudinal changes in Rubisco and APX activities in Aconogonum weyrichii in the alpine region of Mt. Fuji

o identify the determinants of the altitudinal distribution of an alpine herbaceous plant (Aconogonum weyrichii) from an eco-physiological viewpoint, we investigated the leaf characteristics concerned with photosynthetic capacity and tolerance of oxidative stress throughout this species altitude distribution on Mt. Fuji. Larger amounts of leaf nitrogen and Rubisco were found in populations growing at higher altitudes; however, initial activity of Rubisco did not increase with altitude in the summer, indicating that inactivation of Rubisco occurred in the higher populations. This inactivation would lead to a decrease in photosynthetic nitrogen use efficiency. When the leaves of A. weyrichii began to turn yellow in autumn, amounts of leaf nitrogen and Rubisco remarkably decreased in all populations throughout the altitude distribution. However, Rubisco activity in the higher populations did not decline until immediately before defoliation, suggesting that recovery from Rubisco inactivation occurred in these populations. The higher populations had a higher activity of APX than lower populations, contributing to maintaining Rubisco activity and photosynthetic production until the end of the growing period, which, in turn, are necessary for survival at higher altitudes

Stator Design of Alternate Slot Winding for Reducing Torque Pulsation With Magnet Designs in Surface-Mounted Permanent Magnet Motors

This paper proposes a stator design that consists of a combination of an alternate slot winding and dummy slots to minimize pulsating torque in surface-mounted permanent magnet synchronous motors. The alternate arrangement of winding coils is designed to eliminate a harmonic component of back electromotive force that gives rise to a harmonic component of pulsating torque. However, the non-uniform arrangement of slots decreases the frequency of the cogging torque by half and may aggravate torque pulsation. To compensate for the drawback or the decrease in the frequency of the cogging torque, dummy slots are introduced in the alternately slotted stator. A theoretical method is developed for the proposed stator combination. The proposed stator design is applied to a prototype in combination with other rotor magnet design techniques, such as magnet shifting and the adjustment of magnet width, to minimize pulsating torque. The results show that the designed motor reduces the ripple factor of the torque by approximately 30% relative to the original value. In addition, the proposed alternate slot winding is validated by comparing the design with equal slot-winding designs optimized through finite-element method analysis

MicroRNAs from biology to future pharmacotherapy: Regulation of cytochrome P450s and nuclear receptors

金沢大学医薬保健研究域薬学系MicroRNAs (miRNAs) are a family of short, non-coding RNAs whose final product is a 22-nucleotide functional RNA molecule. They regulate the expression of target genes by binding to complementary regions of transcripts to repress their translation or promote mRNA degradation. Since miRNAs regulate every aspect of cellular function, their dysregulation is associated with a variety of diseases including cancer, diabetes, and cardiovascular diseases. Therefore, miRNAs are now considered new therapeutic targets. However, the roles of miRNAs in the metabolism of xenobiotics and endobiotics have only recently been revealed. This review describes the current knowledge on the regulation of cytochrome P450s and nuclear receptors by miRNAs, the physiological and clinical significance. The miRNA expression is readily altered by chemicals, carcinogens, drugs, hormones, stress, or diseases, and the dysregulation of specific miRNAs might lead to changes in the drug metabolism potency or pharmacokinetics as well as pathophysiological changes. In the field of pharmacogenomics, the evaluation of miRNA-related polymorphisms would provide useful information for personalized medicine. Utilizing miRNAs opens a new era in the fields of drug metabolism and pharmacokinetics as well as toxicology. © 2011 Elsevier Inc. All rights reserved

Post-transcriptional regulation of human pregnane X receptor by micro-RNA affects the expression of cytochrome P450 3A4.

金沢大学医薬保健研究域薬学系金沢大学医薬保健研究域薬学系Pregnane X receptor (PXR) is a major transcription factor regulating the inducible expression of a variety of transporters and drug-metabolizing enzymes, including CYP3A4 (cytochrome P450 3A4). We first found that the PXR mRNA level was not correlated with the PXR protein level in a panel of 25 human livers, indicating the involvement of post-transcriptional regulation. Notably, a potential miR-148a recognition element was identified in the 3\u27-untranslated region of human PXR mRNA. We investigated whether PXR might be regulated by miR-148a. A reporter assay revealed that miR-148a could recognize the miR-148a recognition element of PXR mRNA. The PXR protein level was decreased by the overexpression of miR-148a, whereas it was increased by inhibition of miR-148a. The miR-148a-dependent decrease of PXR protein attenuated the induction CYP3A4 mRNA. Furthermore, the translational efficiency of PXR (PXR protein/PXR mRNA ratio) was inversely correlated with the expression levels of miR-148a in a panel of 25 human livers, supporting the miR-148a-dependent regulation of PXR in human livers. Eventually, the PXR protein level was significantly correlated with the CYP3A4 mRNA and protein levels. In conclusion, we found that miR-148a post-transcriptionally regulated human PXR, resulting in the modulation of the inducible and/or constitutive levels of CYP3A4 in human liver. This study will provide new insight into the unsolved mechanism of the large interindividual variability of CYP3A4 expression

Fundamental characteristics of a novel self-starting type permanent magnet synchronous motor

Wide use of permanent magnet synchronous motors produces a request for adding self-starting function to them. We propose a squirrel-cage rotor with permanent magnets for the self-starting synchronous motors. This paper shows the rotor configuration of a proposed motor and investigates the fundamental characteristics associated with the self-starting function.15th International Conference on Electrical Machines and Systems, ICEMS 2012; Sapporo; Japan; 21 October 2012 ～ 24 October 201

Special Section on Epigenetic Regulation of Drug Metabolizing Enzymes and Transporters Epigenetic Regulation Is a Crucial Factor in the Repression of UGT1A1 Expression in the Human Kidney

ABSTRACT Human uridine 59-diphospho-glucuronosyltransferase (UGT) 1A1 catalyzes the metabolism of numerous clinically and pharmacologically important compounds, such as bilirubin and SN-38. UGT1A1 is predominantly expressed in the liver and intestine but not in the kidney. The purpose of this study was to uncover the mechanism of the tissue-specific expression of UGT1A1, focusing on its epigenetic regulation. Bisulfite sequence analysis revealed that the CpG-rich region near the UGT1A1 promoter (285 to +40) was hypermethylated (83%) in the kidney, whereas it was hypomethylated (37%) in the liver. A chromatin immunoprecipitation assay demonstrated that histone H3 near the promoter was hypoacetylated in the kidney but hyperacetylated in the liver; this hyperacetylation was accompanied by the recruitment of hepatocyte nuclear factor (HNF) 1a to the promoter. The UGT1A1 promoter in human kidney-derived HK-2 cells that do not express UGT1A1 was fully methylated, but this promoter was relatively unmethylated in human liver-derived HuH-7 cells that express UGT1A1. Treatment with 5-aza-29-deoxycytidine (5-aza-dC), an inhibitor of DNA methylation, resulted in an increase of UGT1A1 mRNA expression in both cell types, but the increase was much larger in HK-2 cells than in HuH-7 cells. The transfection of an HNF1a expression plasmid into the HK-2 cells resulted in an increase of UGT1A1 mRNA only in the presence of 5-aza-dC. In summary, we found that DNA hypermethylation, along with histone hypoacetylation, interferes with the binding of HNF1a, resulting in the defective expression of UGT1A1 in the human kidney. Thus, epigenetic regulation is a crucial determinant of tissue-specific expression of UGT1A1

Epigenetic regulation of the tissue-specific expression of human UDP-glucuronosyltransferase (UGT) 1A10

Human UDP-glucuronosyltransferase (UGT) 1A10 is not expressed in the liver; however, UGT1A10 is highly expressed in the intestine, contributing to presystemic first-pass metabolism. Earlier studies revealed that hepatocyte nuclear factor (HNF) 1α and Sp1, as well as an intestine-specific transcription factor, caudal type homeobox (Cdx) 2, are involved in the constitutive expression of UGT1A10. However, why UGT1A10 is not expressed in the liver, where HNF1α and Sp1 are abundantly expressed, is unknown. In this study, we sought to elucidate the mechanism, focusing on epigenetic regulation. Bisulfite sequence analysis revealed that the CpG-rich region (-264 to +117) around the UGT1A10 promoter was hypermethylated (89%) in hepatocytes, whereas the UGT1A10 promoter was hypomethylated (11%) in the epithelium of the small intestine. A luciferase assay revealed that the methylation of the UGT1A10 promoter by SssI methylase abrogated transactivity even with overexpressed Cdx2 and HNF1α. The UGT1A10 promoter was highly methylated (86%) in liver-derived HuH-7 cells, where UGT1A10 is not expressed. In contrast, the UGT1A10 promoter was hardly methylated (19%) in colon-derived LS180 cells, where UGT1A10 is expressed. Treatment with 5-aza-2′-deoxycitidine (5-Aza-dC), an inhibitor of DNA methylation, resulted in an increase in UGT1A10 expression only in HuH-7 cells. Moreover, overexpression of HNF1α and Cdx2 further increased UGT1A10 expression only in the presence of 5-Aza-dC. Collectively, we found that DNA hypermethylation would interfere with the binding of HNF1α and Cdx2, resulting in the defective expression of UGT1A10 in human liver. Thus, epigenetic regulation is one of the mechanisms that determine the tissue-specific expression of UGT1A10. © 2013

Performance of segment type switched reluctance motor using grain-oriented

Authors developed a segment type switched reluctance motor (SRM) as a rare earth less motor. The object is to reduce the acoustic noise and vibration as well as improve the torque characteristics. In this paper, we propose the performance improve method using grain-oriented electric steel as the segment core. The validity is confirmed experimentally.15th International Conference on Electrical Machines and Systems, ICEMS 2012; Sapporo; Japan; 21 October 2012 ～ 24 October 201

A characteristic experiment of 4-phase segment type switched reluctance motor

Authors developed a novel segment type switched reluctance motor (SRM) as a rare earth less motor. The torque was increased by 40% and the radial force was decreased by 76% compared with the same size VR type SRM. Increasing the average torque, however, caused increasing torque ripple. In this paper we propose a 4-phase segment type switched reluctance motor and show that the torque ripple can be decreased by controlling the excitation current.15th International Conference on Electrical Machines and Systems, ICEMS 2012; Sapporo; Japan; 21 October 2012 ～ 24 October 201

Prilocaine-and Lidocaine-Induced Methemoglobinemia Is Caused by Human Carboxylesterase-, CYP2E1-, and CYP3A4-Mediated Metabolic Activation

ABSTRACT Prilocaine and lidocaine are classified as amide-type local anesthetics for which serious adverse effects include methemoglobinemia. Although the hydrolyzed metabolites of prilocaine (o-toluidine) and lidocaine (2,6-xylidine) have been suspected to induce methemoglobinemia, the metabolic enzymes that are involved remain uncharacterized. In the present study, we aimed to identify the human enzymes that are responsible for prilocaine-and lidocaine-induced methemoglobinemia. Our experiments revealed that prilocaine was hydrolyzed by recombinant human carboxylesterase (CES) 1A and CES2, whereas lidocaine was hydrolyzed by only human CES1A. When the parent compounds (prilocaine and lidocaine) were incubated with human liver microsomes (HLM), methemoglobin (MetHb) formation was lower than when the hydrolyzed metabolites were incubated with HLM. In addition, Met-Hb formation when prilocaine and o-toluidine were incubated with HLM was higher than that when lidocaine and 2,6-xylidine were incubated with HLM. Incubation with diisopropyl fluorophosphate and bis-(4-nitrophenyl) phosphate, which are general inhibitors of CES, significantly decreased Met-Hb formation when prilocaine and lidocaine were incubated with HLM. An anti-CYP3A4 antibody further decreased the residual formation of Met-Hb. Met-Hb formation after the incubation of o-toluidine and 2,6-xylidine with HLM was only markedly decreased by incubation with an anti-CYP2E1 antibody. o-Toluidine and 2,6-xylidine were further metabolized by CYP2E1 to 4-and 6-hydroxy-o-toluidine and 4-hydroxy-2,6-xylidine, respectively, and these metabolites were shown to more efficiently induce Met-Hb formation than the parent compounds. Collectively, we found that the metabolites produced by human CES-, CYP2E1-, and CYP3A4-mediated metabolism were involved in prilocaine-and lidocaineinduced methemoglobinemia