Pyrazolo[1,5-a]pyrimidine-based inhibitors of HCV polymerase

The present paper describes a novel series of HCV RNA polymerase inhibitors based on a pyrazolo[1,5-a]pyrimidine scaffold bearing hydrophobic groups and an acidic functionality. Several compounds were optimized to low nanomolar potencies in a biochemical RdRp assay. SAR trends clearly reveal a stringent preference for a cyclohexyl group as one of the hydrophobes, and improved activities for carboxylic acid derivatives.     

In-vitro examination and isolation of antidiarrheal compounds using five bacterial strains from invasive species Bidens bipinnata L.

Bidens bipinnata is widely utilized medicinal plant for treatment of diseases like malaria, sore throat, acute nephritis and dysentery. However, despite its traditional uses Bidens bipinnata is not widely explored for its antimicrobial effect. Thus, the current study is aimed to form antimicrobial activity report of Bidens bipinnata extracts, along with isolation and evaluation of antibacterial activity of the isolated compounds through bioassay-guided purification. Hexane extract of its leaves has appeared to be most active thus it is exposed to automated column chromatography. Further purification using High-performance liquid chromatography has led to isolation of active peaks, identified by Gas Chromatography-mass spectrometry, as 16-Pregnenolone and 9-Octadecenoic acid (Z)-, methyl ester. Their antimicrobial activity was confirmed via broth dilution procedure on Staphylococcus aureus, 16-Pregnenolone revealed a strong antimicrobial activity with MIC₅₀ of 72 μg/mL whereas 9-Octadecenoic acid (Z)-, methyl ester display an MIC₅₀ of >250 μg/mL. Present study is the first report on isolation of these compounds from Bidens bipinnata.     

Tubulin and FtsZ structures: functional and therapeutic implications

The microtubule cytoskeleton has lagged nearly a decade behind the actin cytoskeleton with respect to structural information on the basic polymer subunit. This structural inferiority complex has finally been lifted by two recent papers describing the structures of the αβ tubulin dimer⁽¹⁾ and FtsZ,⁽²⁾ a protein similar to tubulin that is essential for cell division in prokaryotes. BioEssays 20 :523–527, 1998. © 1998 John Wiley & Sons Inc.     

Repeatability and reproducibility of a handheld quantitative G6PD diagnostic

BackgroundThe introduction of novel short course treatment regimens for the radical cure of Plasmodium vivax requires reliable point-of-care diagnosis that can identify glucose-6-phosphate dehydrogenase (G6PD) deficient individuals. While deficient males can be identified using a qualitative diagnostic test, the genetic make-up of females requires a quantitative measurement. SD Biosensor (Republic of Korea) has developed a handheld quantitative G6PD diagnostic (STANDARD G6PD test), that has approximately 90% accuracy in field studies for identifying individuals with intermediate or severe deficiency. The device can only be considered for routine care if precision of the assay is high.Methods and findingsCommercial lyophilised controls (ACS Analytics, USA) with high, intermediate, and low G6PD activities were assessed 20 times on 10 Biosensor devices and compared to spectrophotometry (Pointe Scientific, USA). Each device was then dispatched to one of 10 different laboratories with a standard set of the controls. Each control was tested 40 times at each laboratory by a single user and compared to spectrophotometry results.When tested at one site, the mean coefficient of variation (CV) was 0.111, 0.172 and 0.260 for high, intermediate, and low controls across all devices respectively; combined G6PD Biosensor readings correlated well with spectrophotometry (r_s = 0.859, p<0.001). When tested in different laboratories, correlation was lower (r_s = 0.604, p<0.001) and G6PD activity determined by Biosensor for the low and intermediate controls overlapped. The use of lyophilised human blood samples rather than fresh blood may have affected these findings. Biosensor G6PD readings between sites did not differ significantly (p = 0.436), whereas spectrophotometry readings differed markedly between sites (p<0.001).ConclusionsRepeatability and inter-laboratory reproducibility of the Biosensor were good; though the device did not reliably discriminate between intermediate and low G6PD activities of the lyophilized specimens. Clinical studies are now required to assess the devices performance in practice.     

Removal of Micrometer Size Morphological Defects and Enhancement of Ultraviolet Emission by Thermal Treatment of Ga-Doped ZnO Nanostructures

Mixed morphologies of Ga-doped Zinc Oxide (ZnO) nanostructures are synthesized by vapor transport method. Systematic scanning electron microscope (SEM) studies of different morphologies, after periodic heat treatments, gives direct evidence of sublimation. SEM micrographs give direct evidence that morphological defects of nanostructures can be removed by annealing. Ultra Violet (UV) and visible emission depends strongly on the annealing temperatures and luminescent efficiency of UV emission is enhanced significantly with each subsequent heat treatment. X-Ray diffraction (XRD) results suggest that crystal quality improved by annealing and phase separation may occur at high temperatures.     

Nmnat3 Is Dispensable in Mitochondrial NAD Level Maintenance In Vivo

Nicotinamide adenine dinucleotide (NAD) is an essential co-enzyme mediating various enzymatic reactions. Mitochondrial NAD particularly occupies a considerable amount of total NAD in cells, and serves as a co-enzyme in tricarboxylic acid cycle (TCA cycle), β-oxidation, and oxidative phosphorylation. Despite the importance of mitochondrial NAD, its synthesis pathway remains unknown. It has been proposed that NAD synthesis enzyme, Nmnat3, was localized in mitochondria, but its physiological relevance to the metabolism in mitochondria was not fully elucidated. Previously, we have reported that murine Nmnat3 protein was strongly expressed in the cytoplasm of mature erythrocytes, in which mitochondria were absent, and Nmnat3-deficient mice (Nmnat3-KO mice) exhibited splenomegaly and hemolytic anemia due to reduced NAD levels in mature erythrocytes. These results challenged the role of Nmnat3 in mitochondrial NAD synthesis. In this study, we demonstrated that mitochondrial NAD levels in various tissues, except for red blood cells, were unchanged in Nmnat3-KO mice. We also analyzed the metabolites in glycolysis and TCA cycle and found that there were no differences between Nmnat3-KO and WT mice. In addition, the aged Nmnat3-KO mice had comparable NAD levels to that observed in WT mice. Our results indicated that Nmnat3 is dispensable in the maintenance of mitochondrial NAD levels, and that other NAD regulatory pathways may exist in mitochondria.     

Correction to: In-Silico analyses of Nonsynonymous Variants in the BRCA1 Gene

Biochemical Genetics -