A straightforward preparation of chiral 5-(aminomethyl)oxazole derivatives from α-amino esters and α-lithiated isocyanides

An efficient and general preparation of several chiral N-protected 5- (aminomethyl)oxazoles has been accomplished by treatment of N-protected α- amino esters with α-lithiated isocyanides, obtained by metalation of methyl and benzyl isocyanides with BuLi or of ethyl isocyanide with lithium diisopropylamide

PKCα mediates TGFβ-induced growth inhibition of human keratinocytes via phosphorylation of S100C/A11

Growth regulation of epithelial cells is of major concern because most human cancers arise from them. We demonstrated previously a novel signal pathway involving S100C/A11 for high Ca2+-induced growth inhibition of normal human keratinocytes (Sakaguchi, M., M. Miyazaki, M. Takaishi, Y. Sakaguchi, E. Makino, N. Kataoka, H. Yamada, M. Namba, and N.H. Huh. 2003. J. Cell Biol. 163:825–835). This paper addresses a question whether transforming growth factor β (TGFβ) shares the pathway with high Ca2+. On exposure of the cells to TGFβ1, S100C/A11 was phosphorylated, bound to nucleolin, and transferred to the nucleus, resulting in induction of p21WAF1/CIP1 and p15INK4B through activation of Sp1. Protein kinase C α (PKCα) was shown to phosphorylate 10Thr of S100C/A11, which is a critical event for the signal transduction. The TGFβ1-induced growth inhibition was almost completely mitigated when PKCα activity was blocked or when S100C/A11 was functionally sequestered. These results indicate that, in addition to the well-characterized Smad-mediated pathway, the PKCα–S100C/A11-mediated pathway is involved in and essential for the growth inhibition of normal human keratinocytes cells by TGFβ1

Liganded Thyroid Hormone Receptor Inhibits Phorbol 12-O-Tetradecanoate-13-Acetate-Induced Enhancer Activity via Firefly Luciferase cDNA

Thyroid hormone receptor (TR) belongs to the nuclear hormone receptor (NHR) superfamily and regulates the transcription of its target genes in a thyroid hormone (T3)-dependent manner. While the detail of transcriptional activation by T3 (positive regulation) has been clarified, the mechanism of T3-dependent repression (negative regulation) remains to be determined. In addition to naturally occurring negative regulations typically found for the thyrotropin β gene, T3-bound TR (T3/TR) is known to cause artificial negative regulation in reporter assays with cultured cells. For example, T3/TR inhibits the transcriptional activity of the reporter plasmids harboring AP-1 site derived from pUC/pBR322-related plasmid (pUC/AP-1). Artificial negative regulation has also been suggested in the reporter assay with firefly luciferase (FFL) gene. However, identification of the DNA sequence of the FFL gene using deletion analysis was not performed because negative regulation was evaluated by measuring the enzymatic activity of FFL protein. Thus, there remains the possibility that the inhibition by T3 is mediated via a DNA sequence other than FFL cDNA, for instance, pUC/AP-1 site in plasmid backbone. To investigate the function of FFL cDNA as a transcriptional regulatory sequence, we generated pBL-FFL-CAT5 by ligating FFL cDNA in the 5' upstream region to heterologous thymidine kinase promoter in pBL-CAT5, a chloramphenicol acetyl transferase (CAT)-based reporter gene, which lacks pUC/AP-1 site. In kidney-derived CV1 and choriocarcinoma-derived JEG3 cells, pBL-FFL-CAT5, but not pBL-CAT5, was strongly activated by a protein kinase C activator, phorbol 12-O-tetradecanoate-13-acetate (TPA). TPA-induced activity of pBL-FFL-CAT5 was negatively regulated by T3/TR. Mutation of nt. 626/640 in FFL cDNA attenuated the TPA-induced activation and concomitantly abolished the T3-dependent repression. Our data demonstrate that FFL cDNA sequence mediates the TPA-induced transcriptional activity, which is inhibited by T3/TR

Power generation characteristics of pulse jet rechargeable direct carbon fuel cells at different isooctane fuel supply frequency

INTRODUCTION Our research group previously proposed a new type of a direct carbon fuel cell (DCFC) called a rechargeable direct carbon fuel cell (RDCFC), which uses as fuel the solid-state carbon deposited on the electrode [1~6]. In a typical RDCFC, lower hydrocarbons such as propane are the supplied fuel, and deposition of the solid-state carbon (charging) into the anode is done by pyrolysis. In an RDCFC, this charging method causes several problems, such as low carbon extraction efficiency and batch-type rather than continuous operation. Our research group thus developed a pulse jet RDCFC because a constant power density can be maintained by supplying small amounts of high energy density liquid fuel by a pulse jet while generating electricity and continuous power generation by repeating the charging and power generation at short intervals. In addition, in a pulse jet RDCFC, deterioration of anodes due to carbon is minimized by frequent carbon removal and high energy conversion efficiency by utilizing hydrogen, methane, and other hydrocarbons as well as the solid-state carbon generated by the pyrolysis of liquid fuel. In a pulse jet RDCFC, the frequency at which isooctane fuel is supplied influences the power generation characteristics. When this supply frequency is increased, the power generation characteristics of a pulse jet RDCFC are thought to change to those of a flow-type SOFC. In this study, the effect of a supply frequency of isooctane on power generation characteristics of a pulse jet RDCFC was investigated

Association of depressive symptomatology and dry-mouth feeling in relation to state of taking medicine in citizens from their 40s to 70s selected randomly from two cities in Hokkaido, Japan

Background: Troponin I (TnI) are highly specific to the myocardium, and measurement of the plasma TnI levels has been widely used to evaluate myocardial damage. This study was performed to ascertain the pathologic or perioperative variables that are significantly associated with the plasma cardiac TnI level. We also intended to provide reference range of TnI elevation after uncomplicated pediatric open heart surgery.Methods: One hundred fifty-one patients undergoing repair of atrial septal defects (ASDs) (n = 61), ventricular septal defects (VSDs) (n = 71), tetralogy of Fallot (TOF) (n = 14), or complete atrioventricular septal defects (CAVSDs) (n = 5) were included. The plasma TnI level was measured prior to surgery, on days 1 and 7 postoperatively. We analyzed the relationship between the TnI level and pathology, cardiopulmonary bypass, and other perioperative actors.Results: All patients underwent uncomplicated surgery and postoperative course. With all pathologies, the plasma TnI level peaked on postoperative day 1 and rapidly declined. The TnI level on postoperative day 1 was higher in VSD than ASD, and there was a further rise in TOF and CAVSD but no significant difference between them. The TnI level on postoperative day 1 was strongly correlated with the operative time, cardiopulmonary bypass time, and aortic cross-clamp (ACC) time. Multiple linear regression analysis showed that the operative time, ACC time, lowest rectal temperature, TOF lesion, and inotropic support period could influence the TnI level.Conclusions: Elevation of plasma TnI after pediatric open heart surgery for various congenital heart diseases is mainly associated with the condition of cardiopulmonary bypass (operative and ACC times) and is not affected with surgical procedures expect for ventricular muscle resection during repair of TOF. Level of TnI elevation confirmed in the study could provide reference range in uncomplicated open heart surgery for each four pathologies. (298 words

Stromal interaction molecule 1 haploinsufficiency causes maladaptive response to pressure overload

Stromal interaction molecule 1 (STIM1), an endo/sarcoplasmic reticulum Ca2+ sensor, has been shown to control a Ca2+- dependent signal that promotes cardiac hypertrophy. However, whether STIM1 has adaptive role that helps to protect against cardiac overload stress remains unknown. We hypothesized that STIM1 deficiency causes a maladaptive response to pressure overload stress. We investigated STIM1 heterozygous KO (STIM1(+/)-) mice hearts, in which STIM1 protein levels decreased to 27% of wild-type (WT) with no compensatory increase in STIM2. Under stress-free conditions, no significant differences were observed in electrocardiographic and echocardiographic parameters or blood pressure between STIM1(+/)-and WT mice. However, when STIM1(+/)-mice were subjected to transverse aortic constriction (TAC), STIM1(+/-) mice had a higher mortality rate than WT mice. The TAC-induced increase in the heart weight to body weight ratio (mean mg/g +/- standard error of the mean) was significantly inhibited in STIM1(+/-) mice (WT sham, 4.12 +/- 0.14; WT TAC, 6.23 +/- 0.40; STIM1(+/-) sham, 4.53 +/- 0.16; STIM1(+/-) TAC, 4.63 +/- 0.08). Reverse transcription- polymerase chain reaction analysis of the left ventricles of TAC-treated STIM1(+/-) mice showed inhibited induction of cardiac fetal genes, including those encoding brain and atrial natriuretic proteins. Western blot analysis showed upregulated expression of transient receptor potential channel 1 (TRPC1) in TAC-treated WT mice, but suppressed expression in TAC-treated STIM1(+/-) mice. Taken together, the hearts of STIM1 haploinsufficient mice had a superficial resemblance to the WT phenotype under stress-free conditions; however, STIM1 haploinsufficient mice showed a maladaptive response to cardiac pressure overload

Association of depressive symptomatology and dry-mouth feeling in relation to state of taking medicine in citizens from their 40s to 70s selected randomly from two cities in Hokkaido, Japan

Background: Troponin I (TnI) are highly specific to the myocardium, and measurement of the plasma TnI levels has been widely used to evaluate myocardial damage. This study was performed to ascertain the pathologic or perioperative variables that are significantly associated with the plasma cardiac TnI level. We also intended to provide reference range of TnI elevation after uncomplicated pediatric open heart surgery.Methods: One hundred fifty-one patients undergoing repair of atrial septal defects (ASDs) (n = 61), ventricular septal defects (VSDs) (n = 71), tetralogy of Fallot (TOF) (n = 14), or complete atrioventricular septal defects (CAVSDs) (n = 5) were included. The plasma TnI level was measured prior to surgery, on days 1 and 7 postoperatively. We analyzed the relationship between the TnI level and pathology, cardiopulmonary bypass, and other perioperative actors.Results: All patients underwent uncomplicated surgery and postoperative course. With all pathologies, the plasma TnI level peaked on postoperative day 1 and rapidly declined. The TnI level on postoperative day 1 was higher in VSD than ASD, and there was a further rise in TOF and CAVSD but no significant difference between them. The TnI level on postoperative day 1 was strongly correlated with the operative time, cardiopulmonary bypass time, and aortic cross-clamp (ACC) time. Multiple linear regression analysis showed that the operative time, ACC time, lowest rectal temperature, TOF lesion, and inotropic support period could influence the TnI level.Conclusions: Elevation of plasma TnI after pediatric open heart surgery for various congenital heart diseases is mainly associated with the condition of cardiopulmonary bypass (operative and ACC times) and is not affected with surgical procedures expect for ventricular muscle resection during repair of TOF. Level of TnI elevation confirmed in the study could provide reference range in uncomplicated open heart surgery for each four pathologies. (298 words

Pharmacokinetic Modeling of (R)-[11C]verapamil to Measure the P-Glycoprotein Function in Nonhuman Primates

(R)-[(11)C]verapamil is a radiotracer widely used for the evaluation of the P-glycoprotein (P-gp) function at the blood-brain barrier (BBB). Several studies have evaluated the pharmacokinetics of (R)-[(11)C]verapamil in rats and humans under different conditions. However, to the best of our knowledge, the pharmacokinetics of (R)-[(11)C]verapamil have not yet been evaluated in nonhuman primates. Our study aims to establish (R)-[(11)C]verapamil as a reference P-gp tracer for comparison of a newly developed P-gp positron emission tomography (PET) tracer in a species close to humans. Therefore, the study assesses the kinetics of (R)-[(11)C]verapamil and evaluates the effect of scan duration and P-gp inhibition on estimated pharmacokinetic parameters. Three nonhuman primates underwent two dynamic 91 min PET scans with arterial blood sampling, one at baseline and another after inhibition of the P-gp function. The (R)-[(11)C]verapamil data were analyzed using 1-tissue compartment model (1-TCM) and 2-tissue compartment model fits using plasma-corrected for polar radio-metabolites or non-corrected for radio-metabolites as an input function and with various scan durations (10, 20, 30, 60, and 91 min). The preferred model was chosen according to the Akaike information criterion and the standard errors (SE %) of the estimated parameters. 1-TCM was selected as the model of choice to analyze the (R)-[(11)C]verapamil data at baseline and after inhibition and for all scan durations tested. The volume of distribution (V(T)) and the efflux constant k(2) estimations were affected by the evaluated scan durations, whereas the influx constant K(1) estimations remained relatively constant. After P-gp inhibition (tariquidar, 8 mg/kg), in a 91 min scan duration, the whole-brain V(T) increased significantly up to 208% (p < 0.001) and K(1) up to 159% (p < 0.001) compared with baseline scans. The k(2) values decreased significantly after P-gp inhibition in all the scan durations except for the 91 min scans. This study suggests the use of K(1), calculated with 1-TCM and using short PET scans (10 to 30 min), as a suitable parameter to measure the P-gp function at the BBB of nonhuman primate