Carbohydroxamido-oxazolidines: antibacterial agents that target lipid A biosynthesis

A series of carbohydroxamido-oxazolidine inhibitors of UDP-3-O-[R-3-hydroxymyristoyl]-GlcNAc deacetylase, the enzyme responsible for the second step in lipid A biosynthesis, was identified. The most potent analog L-161,240 showed an IC50 = 30 nM in the DEACET assay and displayed an MIC of 1-3 microg/mL against wild-type E. coli.     

Differentiation in wild-type allele of the sd1 locus concerning culm length between indica and japonica subspecies of Oryza sativa (rice)

A dwarfing gene (allele) sd1-d has been intensively utilized to develop short-culm indica varieties in southeast Asia up to now. Before the first sd1-d-carrying variety IR8 was released, rice researchers had recognized the general tendency that culm length is higher in indica varieties than in temperate-japonica ones. Inter-subspecific difference of the tall (wild-type) allele SD1 at the sd1 locus was examined on the common genetic background, using five isogenic lines developed by substituting sd1-d of the recurrent parent IR36 by SD1s of two indica varieties, two temperate-japonica varieties and one tropical-japonica variety. The two indica -donor isogenic lines had longer culms than the three japonica-donor isogenic lines consistently in two different environmental conditions. Moreover, nonsynonymous single-nucleotide polymorphism between the two subspecies was detected at two sites in Exon 1 and Exon 3 of the sd1 locus. It is demonstrated that the inter-subspecific differentiation of SD1 contributes height difference between indica and japonica. The indica-originating and japonica-originating alleles at the sd1 locus were designated as SD1-in(t) and SD1-ja(t), respectively.     

Suppression of stop codon UGA in acrB can contribute to antibiotic resistance in Klebsiella pneumoniae ATCC10031

We previously reported that Klebsiella pneumoniae MGH78578 exhibited higher resistance against various antimicrobials than K. pneumoniae ATCC10031. In this study, we showed that the plasmid, pKPN5, in K. pneumoniae MGH78578 played an important role in resistance against aminoglycosides, ampicillin, tetracycline, and chloramphenicol, while genome-derived β-lactamases and drug efflux pumps appeared to be more important in resistance to cloxacillin. acrAB, encoding a potent multidrug efflux pump, was cloned from K. pneumoniae MGH78578 and ATCC10031, to investigate reasons for the high drug resistance of K. pneumoniae MGH78578, and the results revealed that AcrAB from K. pneumoniae ATCC10031 conferred weaker drug resistance than AcrAB from K. pneumoniae MGH78578. DNA sequencing revealed that acrB from K. pneumoniae ATCC10031 carried the nonsense mutation, UGA, which was not found in acrB from K. pneumoniae MGH78578. However, acrB from K. pneumoniae ATCC10031 conferred slightly elevated resistant levels to several antimicrobials. The intact length of AcrB was detected in K. pneumoniae ATCC10031 by Western blot analysis, even though its quantity was small. Therefore, the stop codon UGA in acrB was thought to be overcome to some extent in this strain. We artificially introduced the nonsense mutation, UGA to the cat gene on pACYC184, and the plasmid also elevated the MIC of chloramphenicol in K. pneumoniae ATCC10031. These results suggest that a mechanism to overcome the nonsense mutation in acrB sustained resistance against a few β-lactams, dyes, and cholic acid in K. pneumoniae ATCC10031.     

Integrin Inhibitor Suppresses Bevacizumab-Induced Glioma Invasion

Glioblastoma is known to secrete high levels of vascular endothelial growth factor (VEGF), and clinical studies with bevacizumab, a monoclonal antibody to VEGF, have demonstrated convincing therapeutic benefits in glioblastoma patients. However, its induction of invasive proliferation has also been reported. We examined the effects of treatment with cilengitide, an integrin inhibitor, on bevacizumab-induced invasive changes in glioma. U87ΔEGFR cells were stereotactically injected into the brain of nude mice or rats. Five days after tumor implantation, cilengitide and bevacizumab were administered intraperitoneally three times a week. At 18 days after tumor implantation, the brains were removed and observed histopathologically. Next, the bevacizumab and cilengitide combination group was compared to the bevacizumab monotherapy group using microarray analysis. Bevacizumab treatment led to increased cell invasion in spite of decreased angiogenesis. When the rats were treated with a combination of bevacizumab and cilengitide, the depth of tumor invasion was significantly less than with only bevacizumab. Pathway analysis demonstrated the inhibition of invasion-associated genes such as the integrin-mediated cell adhesion pathway in the combination group. This study showed that the combination of bevacizumab with cilengitide exerted its anti-invasive effect. The elucidation of this mechanism might contribute to the treatment of bevacizumab-refractory glioma.     

Developing a hydro-chemical model of Ise Bay watersheds and the evaluation of climate change impacts on discharge and nitrate-nitrogen loads

Limnology - The objective of this study was to develop a hydro-chemical model using the Soil and Water Assessment Tool (SWAT) and to evaluate the climate change impacts on discharge and...     

N-Iodoacetyl-N'-(5-sulfo-1-naphthyl)ethylenediamine modification of myosin from chicken gizzard

Previously, we (Suzuki et al. (1978) J. Biochem. 84, 1529) reported that the sedimentation constant of chicken gizzard myosin in the presence of ATP was approximately 10S in 0.15 M or 0.2 M KCl and approximately 6S in 0.3 M or higher concentrations of KCl. The 10S-myosin and 6S-myosin were considerably different in conformation from each other. I now report the finding that the transformation of 6S-myosin to the 10S conformation results in a drastic change in the reactivity of thiol groups of gizzard myosin with N-iodoacetyl-N'-(5-sulfo-1-naphthyl)ethylenediamine (abbreviated as IAEDANS). The so-called SH1-type thiol groups (Sekine et al. (1962) J. Biol. Chem. 237, 2769) were present on 68 kilodalton fragments (produced by tryptic digestion) of gizzard myosin. The reactivity of the thiol groups with IAEDANS was greatly decreased by the 6S to 10S transformation of gizzard myosin molecules. Two other findings were obtained. Blocking the SH1-type thiol groups made the Mg-ATPase activities (in the presence of gizzard native tropomyosin) of gizzard myosin and of acto-gizzard myosin insensitive to calcium and to phosphorylation of regulatory light chains, although calcium-dependent phosphorylation of the IAEDANS-modified myosin could still occur. It also made gizzard myosin filaments resistant to the disassembly action of ATP.