Synthesis and biological evaluation of trans 6-methoxy-1,1-dimethyl-2-phenyl-3-aryl-2,3-dihydro-1H-inden-4-yloxyalkylamine derivatives against drug susceptible,non-replicating M. tuberculosis H37Rv and clinical multidrug resistant strains

Synthesis of a library of novel trans 6-methoxy-1,1-dimethyl-2-phenyl-3-aryl-2,3-dihydro-1H-inden-4-yloxy alkyl amines and their antimycobacterial activity against drug sensitive and multidrug resistant strains of Mycobacterium tuberculosis have been reported. All the new compounds in the series exhibited MIC between 1.56 and 6.25 μg/ml. Two compounds 1i and 1j with low MIC and low cytotoxicity showed significant reduction in CFU in infected mouse macrophages at 1× MIC concentration. The compound 1i inhibited the growth of M. tuberculosis in mice at 100 mg/kg dose with 1.35 log₁₀ reduction of CFU in lungs tissue and was active against non-replicating Mycobacterium tuberculosis under anaerobic condition.     

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Simple and efficient cell disruption of extremely small quantities of mycelium of phytopathogenic mycotoxin-producing moulds for quantitative extraction of genomic DNA

DNA was efficiently and quantitatively isolated from extremely small quantities of mycelia (0.1–10 mg) of different phytopathogenic moulds by grinding freeze-dried mycelia with glass beads and then using a commercial DNA extraction kit. The efficiency of disruption of the mycelia and the quantitative DNA extraction was proved by microscopy and the quantification of isolated DNA by real time PCR. Presented at the 27^th Mykotoxin-Workshop, Dortmund, Germany, June 13–15, 2005 Financial support: German Research Foundation (DFG grant Pr 708/2). J.M. thanks the Cusanuswerk for a doctoral scholarship     

Fine structure of the Gene's organ in the camel tick Hyalomma (Hyalomma) dromedarii (Ixodoidea: Ixodidae)

Gene's organ of the camel tick Hyalomma (Hyalomma) dromedarii is located in the anterodorsal region of the body cavity ventrad to the scutum. It consists of a short stalk, dividing posteriorly into 2 pairs of horns and then into tubular glands. In unfed ticks, the epithelial layer of both the stalk and horns is lined internally by 2 cuticular layers; an inner, thin, greatly folded, dense layer surrounds the organ main lumen, and an outer, thick, slightly folded, less dense layer abuts the cell apices. Only the inner cuticular layer extends into the horn posterior region and appears perforated with numerous pore canals and covered with fine, cuticular projections. The horn and tubular glands epithelium is structurally consistent with a secretory function that apparently increases as feeding progresses. During oviposition, the inner cuticular layer unfolds and inflates into a pair of balloonlike structures that evert through the organ external aperture to receive and manipulate each egg as it is laid, coating it with a waxy layer that prevents desiccation. The fine cuticular projections may have a function in gripping the eggs as they leave the vagina. This organ appears to be everted by hydrostatic pressure from the hemolymph and is retracted by muscles.     

Circadian clock adjustment to plant iron status depends on chloroplast and phytochrome function

Plant chloroplasts are not only the main cellular location for storage of elemental iron (Fe), but also the main site for Fe, which is incorporated into chlorophyll, haem and the photosynthetic machinery. How plants measure internal Fe levels is unknown. We describe here a new Fe‐dependent response, a change in the period of the circadian clock. In Arabidopsis, the period lengthens when Fe becomes limiting, and gradually shortens as external Fe levels increase. Etiolated seedlings or light‐grown plants treated with plastid translation inhibitors do not respond to changes in Fe supply, pointing to developed chloroplasts as central hubs for circadian Fe sensing. Phytochrome‐deficient mutants maintain a short period even under Fe deficiency, stressing the role of early light signalling in coupling the clock to Fe responses. Further mutant and pharmacological analyses suggest that known players in plastid‐to‐nucleus signalling do not directly participate in Fe sensing. We propose that the sensor governing circadian Fe responses defines a new retrograde pathway that involves a plastid‐encoded protein that depends on phytochromes and the functional state of chloroplasts.     

The Hemagglutinin of Bat-Associated Influenza Viruses Is Activated by TMPRSS2 for pH-Dependent Entry into Bat but Not Human Cells

New World bats have recently been discovered to harbor influenza A virus (FLUAV)-related viruses, termed bat-associated influenza A-like viruses (batFLUAV). The internal proteins of batFLUAV are functional in mammalian cells. In contrast, no biological functionality could be demonstrated for the surface proteins, hemagglutinin (HA)-like (HAL) and neuraminidase (NA)-like (NAL), and these proteins need to be replaced by their human counterparts to allow spread of batFLUAV in human cells. Here, we employed rhabdoviral vectors to study the role of HAL and NAL in viral entry. Vectors pseudotyped with batFLUAV-HAL and -NAL were able to enter bat cells but not cells from other mammalian species. Host cell entry was mediated by HAL and was dependent on prior proteolytic activation of HAL and endosomal low pH. In contrast, sialic acids were dispensable for HAL-driven entry. Finally, the type II transmembrane serine protease TMPRSS2 was able to activate HAL for cell entry indicating that batFLUAV can utilize human proteases for HAL activation. Collectively, these results identify viral and cellular factors governing host cell entry driven by batFLUAV surface proteins. They suggest that the absence of a functional receptor precludes entry of batFLUAV into human cells while other prerequisites for entry, HAL activation and protonation, are met in target cells of human origin.     

Purification of prostaglandin E2-9-oxoreductase from human decidua vera

Prostaglandin E2-9- oxoreductase (PGE2-9-OR), the enzyme which converts prostaglandin E2 (PGE2) to prostaglandin F2 alpha (PGF2 alpha), has been detected in human decidua vera. A 105-fold purification was achieved when the centrifuged homogenate was fractionated sequentially by DEAE-Trisacryl, hydroxyapatite-agarose gel, ultrogel AcA 44 and Matrex gel blue A gel chromatographies. The following kinetic constants for PGE2-9-OR have been obtained. The equilibrium constant with respect to PGE2 is 83 microM, the Michaelis constant, Km, for PGE2 is 80 microM, for NADPH 1.6 microM. The maximal velocity for the forward reaction is V1 = .203 pmol/min. The enzyme was inhibited by progesterone, oestradiol-17 beta, cortisol and pharmaceutical drugs. An activating effect could be demonstrated with Ca2+ and oxytocin. The occurrence of PGE2-9-OR in the decidua vera suggests that this enzyme may be responsible for the transformation of PGE2 to PGF2 alpha in these tissues. This may be an important mechanism for the initiation and maintenance of uterine contractions.