The synthesis of three 4-substitutedbenzo[b]thiophene-2-carboxamidines as potent and selective inhibitors of urokinase

Efficient syntheses of structurally novel 4-substituted benzo[b]thiophene-2-carboxamidmes 1–3, which selectively inhibit urokinase-type plasminogen activator (uPA) with IC₅₀ values of 70–320 nM, are described. The key intermediate, methyl 4-iodobenzo[b]thiophene-2-carboxylate (7), is prepared from 3-fluoroiodobenzene in two steps in 70% overall yield via fluorine-directed metalation/formylation and subsequent thiophene annulation. Amidination of ester 7 gives the 320 nM inhibitor 1. Palladium-catalyzed arylacetylene and vinyl stannane couplings with ester 7 or 4-iodobenzo[b]thiophene-2-carbonitrile (16, derived from 7), respectively, followed by amidination leads to the more potent inhibitors 2 (IC₅₀ = 133 nM) and 3 (IC₅₀ = 70 nM). These compounds represent an important new class of synthetic uPA inhibitors, with carboxamidine 3 being the most potent selective inhibitor currently described in the literature.     

The Fine Structure of Nerve Cells and Fibers, Neuroglia, and Sheaths of the Ganglion Chain in the Cockroach (Periplaneta americana)

The abdominal nerve cord of Periplaneta americana was studied utilizing light and electron microscopes. In the nerve cells, delicate granules, similar to those probably responsible for cytoplasmic basophilia, are evenly distributed in "dark" cells and clumped in "light" cells. Neuroglial cells are stained metachromatically by cresyl violet. The neuroglial cells have many processes which ramify extensively and are enmeshed to form overlapping layers. These imbricated processes ensheath the nerve cells; the inner layer of the sheath penetrates into the neuron and is responsible for the appearance of the trophospongium of Holmgren. Nerve fibers are embedded within glial cells and surrounded by extensions of the plasma membrane similar to mesaxons. Depending on their size, two or several nerve fibers may share a single glial cell. Nerve fibers near their terminations on other nerve fibers contain particles and numerous, large mitochondria. The ganglion is ensheathed by a thick feltwork of connective tissue and perilemmal cells. The abdominal connective has a thinner connective tissue sheath which is without perilemmal cells. The nerve fibers and sheaths in the connective become thinner as they pass through ganglia.     

Coding of odor intensity in a steady-state deterministic model of an olfactory receptor neuron

The coding of odor intensity by an olfactory receptor neuron model was studied under steady-state stimulation. Our model neuron is an elongated cylinder consisting of the following three components: a sensory dendritic region bearing odorant receptors, a passive region consisting of proximal dendrite and cell body, and an axon. First, analytical solutions are given for the three main physiological responses: (1) odorant-dependent conductance change at the sensory dendrite based on the Michaelis-Menten model, (2) generation and spreading of the receptor potential based on a new solution of the cable equation, and (3) firing frequency based on a Lapicque model. Second, the magnitudes of these responses are analyzed as a function of odorant concentration. Their dependence on chemical, electrical, and geometrical parameters is examined. The only evident gain in magnitude results from the activation-to-conductance conversion. An optimal encoder neuron is presented that suggests that increasing the length of the sensory dendrite beyond about 0.3 space constant does not increase the magnitude of the receptor potential. Third, the sensivities of the responses are examined as functions of (1) the concentration at half-maximum response, (2) the lower and upper concentrations actually discriminated, and (3) the width of the dynamic range. The overall gain in sensitivity results entirely from the conductance-to-voltage conversion. The maximum conductance at the sensory dendrite appears to be the main tuning constant of the neuron because it determines the shift toward low concentrations and the increase in dynamic range. The dynamic range of the model cannot exceed 5.7 log units, for a sensitivity increase at low odor concentration is compensated by a sensitivity decrease at high odor concentration.     

Effect of Agricultural Operations and Precipitation on Vertical Distribution of a Nuclear Polyhedrosis Virus in Soil

TheAnticarsia gemmatalisnuclear polyhedrosis virus (AgNPV) was released in two soybean plots in September, 1991; the soil in the plots was then sampled periodically through July, 1992, to determine the effects of normal agricultural soil manipulations and precipitation on vertical distribution of the polyhedral occlusion bodies (POBs). The amount of AgNPV increased at all depths down to 37.5–50 cm as long as there was virus-contaminated plant matter, even dead soybean refuse, above the soil surface. Agricultural operations (disking, harrowing, mowing, planting, cultivating) had no effect on the amount or vertical distribution of AgNPV in soil. After the crop refuse was disked into the soil in November, the amount of POBs began decreasing at all depths; these decreases continued over winter and at times appeared to be associated with precipitation. The POBs were no longer detected below 37.5 cm by April, 1992, or below 25 cm by July, 1992. However, in July there were still 274 POBs/g in the top 2.5 cm of soil. Thus, agricultural operations should not hinder contamination of soybean leaves by AgNPV from its soil reservoir.     

Prebiotic polymerization: Oxidative polymerization of 2,3-dimercapto-l-propanol on the surface of iron(III) hydroxide oxide

The oxidation of 2,3-dimercapto-l-propanol by ferric ions on the surface of iron(III) hydroxide oxide (Fe(OH)O) yielded polydisulfide oligomers. This polymerization occurred readily at low dithiol concentration under mild aqueous conditions. Polydisulfide polymers up to the 15-mer were synthesized from 1 mM dithiol in 5 ml water reacted with iron(III) hydroxide oxide (20 mg, 160 µ mole Fe) for 3 days under anaerobic conditions at 40 °C and pH 4. About 91% of the dithiol was converted to short soluble oligomers and 9% to insoluble larger oligomers that were isolated with the Fe (OH)O phase. Reactions carried out at the same ratio of dithiol to Fe(OH)O but at higher dithiol concentrations gave higher yields of the larger insoluble oligomers. The relationship of these results to prebiotic polymer synthesis is discussed.     

Characterization of a novel plant poly(A) polymerase

We have purified and characterized poly(A) polymerases (PAPs) from Pisum sativum, Brassica juncea, and Zea mays. Through chromatography on DEAE-Sepharose and heparin-Sepharose, these PAPs copurified as a single enzyme along with RNPs that could provide RNA substrates for the enzyme. More extensive purification by chromatography on MonoQ resulted in the resolution of the PAPs into as many as three fractions. One of these (PAP-I) contained a 43-kDa polypeptide immunologically related to the yeast PAP, and two others (PAP-II and PAP-III) contained RNAs that could serve as substrates for polyadenylation. These fractions by themselves possessed little PAP activity, but mixtures containing combinations of these displayed substantial activity. Similar PAP factors (PAP-I and PAP-III) were identified after fractionation of extracts prepared from Brassica juncea and Zea mays. The factors from one plant were completely interchangeable with those from different plants. We conclude that the poly(A) polymerases present in vegetative plant tissues consist of more than one component. In this respect, they are substantially different from other reported plant, mammalian, and yeast PAPs.     

Auditory sensitivity and psychophysical tuning curves in the elephant nose fish,Gnathonemus petersii

Summary Hearing sensitivity and psychophysical tuning curves were determined for the mormyridGnathonemus petersii. Pure tone hearing thresholds were determined from 100 Hz to 2,500 Hz, with best sensitivity being about –31 dB (re: 1 dyne/ cm²) from 300 Hz to 1,000 Hz. In order to determine frequency tuning of the auditory system, psychophysical tuning curves (PTC's) were measured with the masker presented simultaneously with, or just ahead of, the 500 Hz test signal. The sound level for different frequencies needed to just mask the test tone were determined from 100 to 800 Hz. Maximum masking occurred in both forward and simultaneous conditions when the masker and the test tone were at the same frequency. As the masker was moved in frequency from 500 Hz, higher sound levels of maskers were needed to afford masking of the test tone. The data were similar in simultaneous and forward masking, with theQ _{10 dB}, a measure of sharpness of tuning, being about 5 in both cases. Data were compared for other species for which behavioral thresholds and PTC's are available.Gnathonemus hears about as wide a range of frequencies as the goldfish,Carassius auratus, although the PTC's for the two species are strikingly different. The PTC's forGnathonemus resemble those determined in a forward-masking paradigm for the clown knife fish,Notopterus chitala, even thoughGnathonemus has a wider hearing bandwidth.Abbreviations AM amplitude modulated - EOD electric organ discharge - PTC psychophysical tuning curve     

Poly (8-bromo-2′-deoxyadenylic acid): The syn/anti relationship

The synthesis of a high-molecular-weight, putatively all-syn DNA analogue, poly(8-bromo-2′-deoxyadenylic acid), is described. The syn → anti transition was shown to be both salt and temperature dependent. Conditions were found which favored ‘normal’ Watson-Crick pairing and duplex formation with poly(dT).     

Cell surface topography of Candida and Leucosporidium yeasts as revealed by scanning electron microscopy.

The cell surface topography of the following yeast strains was examined by scanning electron microscopy: Candida slooffii, C. lipolytica, Leucosporidium frigidum, and L. nivalis. Multipolar and lateral budding were observed in the Candida yeasts in contrast to bipolar budding in the Leucosporidium species. The cell surface topography and the morphology of the bud and birth scars in these yeasts differed markedly. Apart from the bud and birth scars, the cells of C. slooffii showed a relatively smooth topography. The bud scars were seen as a circular ridge of wall material surrounding a markedly convex scar plug. Birth scars were raised, rounded structures, which appeared to distend upon cell growth. In contrast, bud scars of C. lipolytica were platelike, lacked a distinct annulus of wall material, and were much less protuberent than those of C. slooffii. Birth scars were a more permanent feature of these cells. The topography of Leucosporidium yeasts was characterized by the presence of numerous protrusions on the cell surface. In some cases, the entire cell surface was covered by these protrusions. There appeared to be some correlations between the age of the cell and the extent of surface protrusions and degree of surface convolution...