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A shorter synthesis of the demethyl(oxy)aaptamine skeleton was developed via oxidative intramolecular cyclization of 1-(2-azidoethyl)-6-methoxyisoquinolin-7-ol followed by dehydrogenation with a hypervalent iodine reagent. This is the first example of oxidative cyclization at the ortho-position of phenol that does not involve spiro-cyclization, resulting in the improved total synthesis of 3-(phenethylamino)demethyl(oxy)aaptamine, a potent anti-dormant mycobacterial agent. [ABSTRACT FROM AUTHOR]

Three Ogataea minuta var. minuta strains have been deposited as NBRC 0975, NBRC 10402, and NBRC 10746 in the National Institute of Technology and Evaluation (NITE) Biological Resource Center (NBRC) collection. We investigated the ability to produce secretory proteins and several genotypic and phenotypic characteristics in order to select the best strain for heterologous protein expression. NBRC 10746 showed the best performance as evaluated by Cypridina noctiluca luciferase expression. Subsequently, clone #5–30 named tat06213, which was obtained by single-colony isolation from NBRC 10746, was established as a promising host for heterologous protein expression. To deepen our understanding of the characteristics of O. minuta var. minuta strains, sequence analysis of the D1/D2 domain of large subunit rRNA was conducted and the resulting phylogenetic tree derived from the D1/D2 domain showed that NBRC 10402 and NBRC 10746 were grouped into a different cluster far from NBRC 0975. Furthermore, a chromosome structure topology with electrophoretic karyotype and AOX1 loci analyzed by pulsed-field gel electrophoresis with Southern blotting showed different chromosome patterns and AOX1 -hybridization loci among the strains. Additionally, the sequences of the promoter regions of the cloned AOX1 genes were not identical among the three strains. These findings might explain the differences in heterologous protein expression among the tested O. minuta var. minuta strains. [ABSTRACT FROM AUTHOR]

This study aimed to determine the effect of long-term exercise on the risk of developing cardiovascular diseases (CVD) and all-cause mortality in patients with diabetic kidney disease (DKD). A single-center, prospective intervention study using propensity score matching was performed over 24 months. The intervention group (n = 67) received six months of individual exercise instruction from a physical therapist, who performed aerobic and muscle-strengthening exercises under unsupervised conditions. New events were defined as the composite endpoint of stroke or CVD requiring hospitalization, initiation of hemodialysis or peritoneal dialysis, or all-cause mortality. The cumulative survival rate without new events at 24 months was significantly higher in the intervention group (0.881, p = 0.016) than in the control group (n = 67, 0.715). Two-way analysis of variance revealed a significant effect of the group factor on high density lipoprotein-cholesterol (HDL-C) which was higher in the intervention group than in the control group (p = 0.004); eGFRcr showed a significant effect of the time factor, which was lower at 24 months than before intervention (p = 0.043). No interactions were observed for all items. In conclusion, aerobic exercises combined with upper and lower limb muscle strengthening for six months reduce the risk of developing CVD and all-cause mortality in patients with DKD. [ABSTRACT FROM AUTHOR]

Hemodialysis patients with diabetic kidney disease (DKD) experience blood glucose fluctuations owing to insulin removal. We evaluated the effects of single and long-term application of neuromuscular electrical stimulation (NMES) during hemodialysis on glycemic control. This trial was conducted in two stages: Stage 1, following a crossover design and 4 week washout period, eleven outpatients with DKD either underwent a single bout of NMES for 30 min (NMES period) or rested (control period) after receiving nutritional support during hemodialysis; Stage 2, following a crossover design and 4 week washout period, each participant received the intervention for 12 weeks. NMES was administered for 30 min at the maximum tolerable intensity. The mean subcutaneous glucose concentration and mean amplitude of glycemic excursion (MAGE) were determined by flash glucose monitoring for 24 h. Changes in glycoalbumin and MAGE before and after NMES initiation were evaluated. The mean blood glucose level and MAGE after a single bout of NMES were significantly lower than those after rest. Glycoalbumin levels and echo intensity of the rectus femoris tended to decrease, but not significantly by ANOVA due to a lack in statistical power after the dropout of three patients. NMES in end-stage DKD decreased blood glucose levels during and after hemodialysis. [ABSTRACT FROM AUTHOR]

Hepatocyte growth factor (HGF) has been investigated as a regulator for immune reactions caused by transplantation and autoimmune diseases and other biological functions. Previous studies demonstrated that cDNA-encoding HGF administration could inhibit acute graft-versus-host disease (GVHD) after treatment via hematopoietic stem cell transplantation. This study aimed to show the preparation of HGF protein on yeast cell surfaces to develop a tool for the oral administration of HGF to a GVHD mouse model. In this study, full-length HGF and the heavy chain of HGF were genetically fused with α-agglutinin and were successfully displayed on the yeast cell surface. This study suggested that yeast cell surface display engineering could provide a novel administration route for HGF. [ABSTRACT FROM AUTHOR]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2006.02.017 Byline: Sae Sakaguchi (a), Yuki Nakatani (a), Naofumi Takamatsu (b), Hiroshi Hori (b), Atsushi Kawakami (a), Keiji Inohaya (a), Akira Kudo (a) Keywords: Medaka; Oryzias latipes; hoxb8a; fin; Cell migration; Osteoblast; wnt5a Abstract: Hoxb8 has been suggestively implicated in the formation of the zone of polarizing activity (ZPA) in the limb bud. However, as hoxb8.sup.-/- mice did not show any defects in their limb development, the role of Hoxb8 during limb development has not been fully elucidated. Here, we report the identification of the medaka hoxb8a mutant, unextended-fin (ufi), in which all the fin tissues were malformed. Since the abnormal phenotype was observed in the caudal fin, the ufi phenotype suggests that the medaka Hoxb8a has a fundamental role in the formation of appendages protruding from the trunk. Our analyses revealed that the expression of wnt5a, a regulator of cell migration that signals through the non-canonical Wnt/Ca.sup.2+ pathway, was down-regulated in the ufi fin-folds. In fact, we found that the proximal-distal cell migration was impaired in ufi mutants and that the defect could be reversed by the injection of a Wnt5a protein. Moreover, we show herein that the numbers of proliferating cells and osteoblastic cells were increased in the ufi mutants. According to these results, we propose that the medaka Hoxb8a protein functions in the outgrowth of appendages through the regulation of cell migration and osteoblast differentiation. Author Affiliation: (a) Department of Biological Information, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku, Yokohama 226-8501, Japan (b) Division of Biological Science, Graduate School of Science, Nagoya University, Nagoya 464-8602, Japan Article History: Received 17 January 2006; Revised 8 February 2006; Accepted 13 February 2006

Lambert-Eaton myasthenic syndrome (LEMS) is a representative paraneoplastic neurological syndrome. Recently, nivolumab, an anti-programmed cell death 1 inhibitor, has been approved for advanced non-small-cell lung cancer. Careful attention should be paid to immune-related adverse events (irAEs), including neurotoxicity. We herein report a 73-year-old woman with LEMS that occurred during nivolumab treatment for pulmonary squamous cell carcinoma. After the 20th week of nivolumab, she experienced various neurological symptoms such as ptosis, lower limb weakness, and photophobia. Findings from a nerve conduction study and a positive anti-P/Q-type voltage-gated calcium channel antibody made a diagnosis of LEMS. Pyridostigmine and 3,4-diaminopyridine temporarily improved her symptoms. This was the first case of LEMS as a neurological irAE. LEMS should be considered as a possible neurological irAE. [ABSTRACT FROM AUTHOR]

Objective: Our aim was to investigate the effect of 1-year treatment with raloxifene, a selective estrogen receptor modulator, on plasma lipid profiles in Japanese postmenopausal type 2 diabetic patients. Subjects and Methods: A total of 43 Japanese women with postmenopausal osteoporosis and type 2 diabetes with serum low-density lipoprotein cholesterol (LDL-C) <3.59 mmol/l, serum triglyceride <1.68 mmol/l and serum high-density lipoprotein cholesterol (HDL-C) >1.03 mmol/l, who took 60 mg/day of raloxifene for 12 months, were enrolled. For analysis, they were divided into 2 groups: nonhyperlipidemia (n = 23) and hyperlipidemia treated with statin (n = 20). Results: Raloxifene treatment significantly induced a mean reduction in serum LDL-C from 2.90 to 2.36 and 2.67 mmol/l in the nonhyperlipidemia and statin-treated group, respectively. However, the reduction ratio of serum LDL-C showed a significant difference in the nonhyperlipidemia group (17%) compared to the statin-treated group (7%; p = 0.03). Although serum HDL-C showed an increase in both groups (from 1.45 to 1.58 vs. from 1.40 to 1.47 mmol/l), the increase ratio of serum HDL-C was not significant between the two groups. Raloxifene administration showed 15% reduction in the nonhyperlipidemia group (p = 0.02) and 13% reduction in the statin-treated group (p = 0.02) of urinary N-telopeptide of type I collagen. No significant change in blood HbA1c was observed in either group. Conclusion: The administration of raloxifene to type 2 diabetic women showed favorable efficacy on serum lipid profiles, particularly in patients without statin treatment. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: It is well known that low-molecular weight hyaluronan (HA) is detected in human periodontal tissue under inflammatory conditions. HA oligosaccharide (HAoligo) has been demonstrated to induce matrix metalloproteinase (MMP)-1 expression in dendritic cells and chondrocytes, however, the bioactivities of HAoligo in periodontal ligament (PDL) cells remain unclear. In this study, we investigated the effect of HAoligo on MMP-1 expression in human PDL (HPDL) cells and the mechanisms in terms of the signal transmission. HAoligo was generated and purified from commercial human umbilical cord HA. HPDL cells were isolated from healthy ligaments, and cultured with HAoligo for 0–24h. The expression of MMP-1, tissue inhibitor of MMPs (TIMP)-1 and TIMP-2 was analyzed by real-time PCR and Western blot analyses. Effects of specific inhibitors of p38 mitogen-activated protein kinase (MAPK) activity, MAPK kinase activity and NFkB activity on HAoligo-induced MMP-1 expression in HPDL cells were also investigated by real-time PCR and Western blot analyses. HAoligo remarkably enhanced MMP-1 expression in both mRNA and protein levels, but no effect was shown on the expression of TIMP-1 and TIMP-2 mRNAs. Inhibition of p38MAPK activity decreased the MMP-1 expression. Neither inhibition of NFkB nor MAPKK activity affected the MMP-1 expression. It was suggested that HAoligo induces MMP-1 expression in HPDL cells, and p38MAPK plays a crucial role in signal transduction for MMP-1 inducted by HAoligo. [Copyright &y& Elsevier]

Abstract: Hyaluronan (HA) exists in various living tissues as one of the major matrix macromolecules, and is well known to play an integral role in cell differentiation and proliferation. The present study was conducted to elucidate whether or not the proliferation of periodontal ligament (PDL) cells are affected specifically by the degradation of HA by hyaluronidasze (HAase). Human PDL fibroblasts were isolated and cultured with and without 15–150U/ml bovine testicular HAase from 1 to 11 days after seeding. The cells were also cultured with anti-CD44 antibody of 2μg/ml. For the control against the anti-CD44 antibody treatment, 2μg/ml IgG was used. The HA-dependent pericellular matrix was visualized by particle-exclusion assay. The number of cells was counted by MTT assay during the proliferation. The mRNA levels of HA synthases (HASs), HAases (HYALs) and CD44s were examined by a quantitative real-time PCR analysis. The cell proliferation was inhibited by the treatment with HAase and anti-CD44 antibody in cultured PDL fibroblasts. HASs mRNAs were down-regulated, whereas HYALs mRNAs were up-regulated significantly by the treatment with HAase and anti-CD44 antibody. The CD44s mRNA level exhibited no significant changes. These results suggest that HA may contribute to modulate the proliferation of cultured human PDL cells through a CD44-mediated mechanism. [Copyright &y& Elsevier]