Structure-activity relationships of 19-norvitamin D analogs having a fluoroethylidene group at the C-2 position

We have synthesized four new geometric isomers of 1alpha,25-dihydroxy-2-(2'-fluoroethylidene)-19-norvitamin D analogs 1 and 2 having a 20R- and 20S-configuration, whose structures are correlated with 2MD possessing high potencies in stimulating bone formation in vitro and in vivo. The E-isomers of (20R)- and (20S)-2-fluoroethylidene analogs 1a and 1b were comparable with the natural hormone 1alpha,25-(OH)(2)D(3) in binding to the vitamin D receptor (VDR), while two Z-isomers 2a and 2b were about 15-20 times less active than the hormone. In inducing expression of the vitamin D responsive element-based luciferase reporter gene, the E-isomers 1a and 1b were 1.2- and 8.6-fold more potent than the hormone, respectively, while the Z-isomers 2a and 2b had 27-55% of the potency. On the basis of the biological activities and a docking simulation based on X-ray crystallographic analysis of the VDR ligand-binding pocket, the structure-activity relationships of the fluorinated 19-norvitamin D analogs are discussed.     

Novel reporter gene expression systems for monitoring activation of the Aspergillus nidulans HOG pathway

The Aspergillus nidulans high-osmolarity glycerol response (AnHOG) pathway is involved in osmoadaptation. We found that fludioxonil, a fungicide, causes improper activation of HogA mitogen-activated protein kinase (MAPK) in A. nidulans. Here we present novel reporter systems for monitoring activation of the AnHOG pathway. The promoter region of gfdB (glycerol-3-phosphate dehydrogenase), whose expression depends on the presence of HogA, was fused to a beta-glucuronidase uidA gene (GUS) to construct the reporter, which was introduced into A. nidulans wild type and hogADelta. Increased GUS activity was detected in the wild type only when it was treated with high osmolarity or fludioxonil, while reporter activity was scarcely stimulated in the hogADelta mutant. These results indicate that the reporter activity is controlled via HogA activation. Furthermore, we present possible applications of the reporter systems in screening new antifungal compounds.     

F-box proteins that contain sugar-binding domains

F-box proteins are the substrate-recognition subunits of the SCF (Skp1-Cul1-F-box protein) complex, which is the largest known class of E3 ubiquitin ligases. They play important roles in ubiquitin-dependent proteolysis in eukaryotes. The human genome contains about 70 genes for F-box proteins, and at least five homologous F-box proteins containing a conserved motif in their C-termini are thought to recognize sugar chain of N-linked glycoproteins. Among theses, Fbs1 and Fbs2 are perhaps involved in the endoplasmic reticulum-associated degradation pathway. In this review, I focus on the in vivo function of Fbs1 and homologous proteins, novel intracellular oligosaccharide recognition molecules involved in the quality control system.     

Length-weight relationships of two varunid crab species, <Emphasis Type="Italic">Helice tridens</Emphasis> and <Emphasis Type="Italic">Chasmagnathus convexus</Emphasis>, in Japan

Estimates of biomass are essential for studies modeling the structure, animal growth, production, and energy flow in ecosystems. The relationships between dry weight and carapace width of two varunid crab species in two different populations were examined. Distribution of the length-weight plots did not show remarkable differences between species, sexes, and populations. Our results suggest that length-weight relationships, regardless of sex or population or including multiple species, are valid for estimation of dry weight.     

Kibizu concentrated liquid suppresses the accumulation of lipid droplets in 3T3-L1 cells

Adipocyte size is closely related to the occurrence of diabetes, metabolic syndrome, and insulin resistance. Thus, researchers are searching for active substances that function to reduce adipocyte size. In the present study, we focused on sugar cane vinegar, Kibizu, and evaluated the function of Kibizu to reduce adipocyte size by using an in vitro model system, because people in Amami Oshima famous for longevity regularly consume Kibizu. Results showed that Kibizu treatment significantly reduced the size and number of lipid droplets in 3T3-L1 cells, relative to treatment with Kurozu, another traditional vinegar. Results of an extraction experiment suggest that the active components in Kibizu are lipophilic and hydrophobic. In addition, an in vivo experiment on rats treated with Kibizu showed that the active components were contained in large vein blood. Results of an additional in vivo experiment suggest that metabolites generated by Kibizu-treated rats are primarily contained or modified specifically in the large vein blood.     

Searching for the origins of musicality across species

In the introduction to this theme issue, Honing et al. suggest that the origins of musicality—the capacity that makes it possible for us to perceive, appreciate and produce music—can be pursued productively by searching for components of musicality in other species. Recent studies have highlighted that the behavioural relevance of stimuli to animals and the relation of experimental procedures to their natural behaviour can have a large impact on the type of results that can be obtained for a given species. Through reviewing laboratory findings on animal auditory perception and behaviour, as well as relevant findings on natural behaviour, we provide evidence that both traditional laboratory studies and studies relating to natural behaviour are needed to answer the problem of musicality. Traditional laboratory studies use synthetic stimuli that provide more control than more naturalistic studies, and are in many ways suitable to test the perceptual abilities of animals. However, naturalistic studies are essential to inform us as to what might constitute relevant stimuli and parameters to test with laboratory studies, or why we may or may not expect certain stimulus manipulations to be relevant. These two approaches are both vital in the comparative study of musicality.     

A Food and Drug Administration-approved Asthma Therapeutic Agent Impacts Amyloid β in the Brain in a Transgenic Model of Alzheimer Disease

Interfering with the assembly of Amyloid β (Aβ) peptides from monomer to oligomeric species and fibrils or promoting their clearance from the brain are targets of anti-Aβ-directed therapies in Alzheimer disease. Here we demonstrate that cromolyn sodium (disodium cromoglycate), a Food and Drug Administration-approved drug already in use for the treatment of asthma, efficiently inhibits the aggregation of Aβ monomers into higher-order oligomers and fibrils in vitro without affecting Aβ production. In vivo, the levels of soluble Aβ are decreased by over 50% after only 1 week of daily intraperitoneally administered cromolyn sodium. Additional in vivo microdialysis studies also show that this compound decreases the half-life of soluble Aβ in the brain. These data suggest a clear effect of a peripherally administered, Food and Drug Administration-approved medication on Aβ economy, supporting further investigation of the potential long-term efficacy of cromolyn sodium in Alzheimer disease.     

KONJAC1 and 2 Are Key Factors for GDP-Mannose Generation and Affect l-Ascorbic Acid and Glucomannan Biosynthesis in Arabidopsis

Humans are unable to synthesize l-ascorbic acid (AsA), yet it is required as a cofactor in many critical biochemical reactions. The majority of human dietary AsA is obtained from plants. In Arabidopsis thaliana, a GDP-mannose pyrophosphorylase (GMPP), VITAMIN C DEFECTIVE1 (VTC1), catalyzes a rate-limiting step in AsA synthesis: the formation of GDP-Man. In this study, we identified two nucleotide sugar pyrophosphorylase-like proteins, KONJAC1 (KJC1) and KJC2, which stimulate the activity of VTC1. The kjc1kjc2 double mutant exhibited severe dwarfism, indicating that KJC proteins are important for growth and development. The kjc1 mutation reduced GMPP activity to 10% of wild-type levels, leading to a 60% reduction in AsA levels. On the contrary, overexpression of KJC1 significantly increased GMPP activity. The kjc1 and kjc1kjc2 mutants also exhibited significantly reduced levels of glucomannan, which is also synthesized from GDP-Man. Recombinant KJC1 and KJC2 enhanced the GMPP activity of recombinant VTC1 in vitro, while KJCs did not show GMPP activity. Yeast two-hybrid assays suggested that the stimulation of GMPP activity occurs via interaction of KJCs with VTC1. These results suggest that KJCs are key factors for the generation of GDP-Man and affect AsA level and glucomannan accumulation through the stimulation of VTC1 GMPP activity.