Design, total synthesis, and biological evaluation of neodysiherbaine A derivative as potential probes

To enable studies to elucidate the detailed biological function of dysiherbaine and neodysiherbaine A, potent and subunit-selective agonists for ionotropic glutamate receptors, the derivative with a hydroxymethyl substituent at the C10 position has been developed. Preliminary biological evaluation of the analogue showed that a C10 hydroxymethyl substituent produced significant alterations in binding affinities for the ionotropic glutamate receptor subtypes.     

The biotron breeding system: a rapid and reliable procedure for genetic studies and breeding in rice

Oryza sativa is widely used as a model organism for many aspects of research in monocots and cereals. However, it has certain disadvantages as a model species compared with Arabidopsis thaliana, the eudicot species most widely used in plant sciences: first, it has a long cultivation time; and second, it requires considerably more space for growth. Here, we introduce a biotron breeding system, which allows rapid and reliable rice cultivation using a well-equipped artificial environmental chamber. This system involves use of regulation of CO? levels, removal of tillers and embryo rescue to overcome the disadvantages of rice cultivation. The rice cultivars Nipponbare, Koshihikari, Taichung 65 and Kasalath all showed vigorous growth and sufficient seed production in the biotron breeding system with accelerated flowering time. Nipponbare, which was the earliest among these cultivars, flowered at about 50 d after sowing. The life cycle of these plants could be further shortened using an embryo rescue technique on immature seeds at 7 d after pollination, thereby avoiding the lengthy process of seed maturation. Overall, it was possible to shorten the life cycle of Nipponbare to about 2 months under the controlled conditions. Furthermore, controlled crosses, which can be difficult with conventional cultivation methods, were easy to perform as we could control the exact timing of anther dehiscence. Thus, our biotron breeding system offers a valuable new approach to genetic and breeding studies in rice.     

High Rate of Awarding Compensation for Claims of Injuries Related to Clinical Trials by Pharmaceutical Companies in Japan: A Questionnaire Survey

Introduction

International norms and ethical standards have suggested that compensation for research-related injury should be provided to injured research volunteers. However, statistical data of incidence of compensation claims and the rate of awarding them have been rarely reported.

Method

Questionnaire surveys were sent to pharmaceutical companies and medical institutions, focusing on industry-initiated clinical trials aiming at new drug applications (NDAs) on patient volunteers in Japan.

Results

With the answers from pharmaceutical companies, the incidence of compensation was 0.8%, including 0.06% of monetary compensation. Of the cases of compensation claims, 99% were awarded. In turn, with the answers from medical institutions, the incidence of compensation was 0.6%, including 0.4% of serious but not death cases, and 0.04% of death cases. Furthermore, most claims for compensation were initiated by medical institutions, rather than by the patients. On the other hand, with the answers from clinical trial volunteers, 3% of respondents received compensations. These compensated cases were 25% of the injuries which cannot be ruled out from the scope of compensation.

Conclusion

Our study results demonstrated that Japanese pharmaceutical companies have provided a high rate of compensation for clinical trial-related injuries despite the possibility of overestimation. In the era of global clinical development, our study indicates the importance of further surveys to find each country''s compensation policy by determining how it is being implemented based on a survey of the actual status of compensation coming from statistical data.     

The Influence of 5-HTTLPR Genotype on the Association between the Plasma Concentration and Therapeutic Effect of Paroxetine in Patients with Major Depressive Disorder

Introduction

The efficacy of treatment with selective serotonin reuptake inhibitors in patients with major depressive disorder (MDD) can differ depending on the patient''s serotonin transporter-linked polymorphic region (5-HTTLPR) genotype, and the effects of varying plasma concentrations of drugs can also vary. We investigated the association between the paroxetine plasma concentration and clinical response in patients with different 5-HTTLPR genotypes.

Methods

Fifty-one patients were enrolled in this study. The Montgomery-Asberg Depression Rating Scale (MADRS) was used to evaluate patients at 0, 1, 2, 4, and 6 weeks. The patients'' paroxetine plasma concentrations at week 6 were measured using high-performance liquid chromatography. Additionally, their 5-HTTLPR polymorphisms (alleles S and L) were analyzed using a polymerase chain reaction with specific primers. We divided the participants into two groups based on their L haplotype: the SS group and the SL and LL group. We performed single and multiple regression analyses to investigate the associations between MADRS improvement and paroxetine plasma concentrations or other covariates for each group.

Results

There were no significant differences between the two groups with regard to demographic or clinical data. In the SS group, the paroxetine plasma concentration was significantly negatively correlated with improvement in MADRS at week 6. In the SL and LL group, the paroxetine plasma concentration was significantly positively correlated with improvement in MADRS at week 6 according to the results of the single regression analysis; however, it was not significantly correlated with improvement in MADRS at week 6 according to the results of the multiple regression analysis.

Conclusion

Among patients with MDD who do not respond to paroxetine, a lower plasma concentration or a lower oral dose of paroxetine might be more effective in those with the SS genotype, and a higher plasma concentration might be more effective in those with the SL or LL genotype.     

Telmisartan Activates Endothelial Nitric Oxide Synthase via Ser1177 Phosphorylation in Vascular Endothelial Cells

Because endothelial nitric oxide synthase (eNOS) has anti-inflammatory and anti-arteriosclerotic functions, it has been recognized as one of the key molecules essential for the homeostatic control of blood vessels other than relaxation of vascular tone. Here, we examined whether telmisartan modulates eNOS function through its pleiotropic effect. Administration of telmisartan to mice significantly increased the phosphorylation level of eNOS (Ser1177) in the aortic endothelium, but administration of valsartan had no effect. Similarly, telmisartan treatment of human umbilical vein endothelial cells significantly increased the phosphorylation levels of AMP-activated protein kinase (Thr172) and eNOS and the concentration of intracellular guanosine 3′,5′-cyclic monophosphate (cGMP). Furthermore, pretreatment with a p38 mitogen-activated protein kinase (p38 MAPK) inhibitor suppressed the increased phosphorylation level of eNOS and intracellular cGMP concentration. These data show that telmisartan increases eNOS activity through Ser1177 phosphorylation in vascular endothelial cells mainly via p38 MAPK signaling.     

Expression of a fusion protein of Pyrus pyrifolia S-RNase with glutathione-S-transferase in E. coli

S-RNase is a style-specific ribonuclease which is associated with gametophytic self-incompatibility. An expression vector of a fusion protein of Pyrus pyrifolia(Japanese pear) S3-RNase with glutathione-S-transferase (GST) was constructed and transformed into E. coli. Using this system, the fusion protein, GST-S3-RNase, was expressed as an active form and can be used for screening pollen S-gene product(s).     

Cauliflower mosaic virus 35 S promoter directs S phase specific expression in plant cells

Summary An experimental system to study cell cycle specific gene expression in plant cells was developed using protoplasts from tobacco cells synchronized by aphidicolin treatment. Chimeric plasmids consisting either of the chloramphenicol acetyltransferase (CAT) gene downstream of the cauliflower mosaic virus (CaMV) 35 S promoter or the nopaline synthase (nos) promoter were introduced into synchronized protoplasts of four cell cycle stages by electroporation. In the case of the CaMV 35 S promoter cyclic oscillation of CAT activity was observed which paralleled the cell cycle of the recipient cells. The peak of CAT activity was found in the S phase, while no such cyclic change was observed in the case of the nos promoter. This system clearly shows that it is feasible to search for a cell cycle specific promoter. The significance of these observations is discussed in relation to the study of plant cells.