THE SELECTIVE INHIBITION OF VIRAL DNA SYNTHESIS BY CHEMOTHERAPEUTIC AGENTS: AN INDICATOR OF CLINICAL USEFULNESS? *

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72533/1/j.1749-6632.1977.tb21976.x.pd

Recent Decisions

Comments on recent decisions by Larry E. Corr, John J. Malik, Richard E. Shipman, Paul R. Jackiewicz, Mark S. Tolle, Harry L. Buch, Stanley R. Herrlinger, John W, Houck, Donald J. Prebenda, Donald W, Bebenek, Michael C. Dionise, and J. Robert Geiman

The dynamic behavior of bacterial macrofibers growing with one end prevented from rotating: variation in shaft rotation along the fiber's length, and supercoil movement on a solid surface toward the constrained end

BACKGROUND: Bacterial macrofibers twist as they grow, writhe, supercoil and wind up into plectonemic structures (helical forms the individual filaments of which cannot be taken apart without unwinding) that eventually carry loops at both of their ends. Terminal loops rotate about the axis of a fiber's shaft in contrary directions at increasing rate as the shaft elongates. Theory suggests that rotation rates should vary linearly along the length of a fiber ranging from maxima at the loop ends to zero at an intermediate point. Blocking rotation at one end of a fiber should lead to a single gradient: zero at the blocked end to maximum at the free end. We tested this conclusion by measuring directly the rotation at various distances along fiber length from the blocked end. The movement of supercoils over a solid surface was also measured in tethered macrofibers. RESULTS: Macrofibers that hung down from a floating wire inserted through a terminal loop grew vertically and produced small plectonemic structures by supercoiling along their length. Using these as markers for shaft rotation we observed a uniform gradient of initial rotation rates with slopes of 25.6°/min. mm. and 36.2°/min. mm. in two different fibers. Measurements of the distal tip rotation in a third fiber as a function of length showed increases proportional to increases in length with constant of proportionality 79.2 rad/mm. Another fiber tethered to the floor grew horizontally with a length-doubling time of 74 min, made contact periodically with the floor and supercoiled repeatedly. The supercoils moved over the floor toward the tether at approximately 0.06 mm/min, 4 times faster than the fiber growth rate. Over a period of 800 minutes the fiber grew to 23 mm in length and was entirely retracted back to the tether by a process involving 29 supercoils. CONCLUSIONS: The rate at which growing bacterial macrofibers rotated about the axis of the fiber shaft measured at various locations along fibers in structures prevented from rotating at one end reveal that the rate varied linearly from zero at the blocked end to maximum at the distal end. The increasing number of twisting cells in growing fibers caused the distal end to continuously rotate faster. When the free end was intermittently prevented from rotating a torque developed which was relieved by supercoiling. On a solid surface the supercoils moved toward the end permanently blocked from rotating as a result of supercoil rolling over the surface and the formation of new supercoils that reduced fiber length between the initial supercoil and the wire tether. All of the motions are ramifications of cell growth with twist and the highly ordered multicellular state of macrofibers

First Ultraviolet Spectrum of a Brown Dwarf: Evidence for H_2 Fluorescence and Accretion

We analyze an HST/STIS ultraviolet spectrum of the young brown dwarf 2MASSW J1207334-393254, a member of the ten million-year old TW Hya Association that has a planetary-mass companion. We detect and identify numerous emission lines. CIV and other ions are seen that arise in hot gas. We identify a series of lines with Lyman-pumped H_2 molecular lines, indicating that cool gas is also present. Overall, this substellar object shows many of the same characteristics as classical T Tauri stars. We interpret our results as direct evidence of accretion from a circumstellar gas disk, consistent with previous claims. The lack of SiIV emission from the accreting gas indicates that silicon has been depleted into grains.Comment: 8 pages, to appear in Astrophysical Journal Letter

Selective inhibition of herpes simplex virus ribonucleoside diphosphate reductase by derivatives of 2-acetylpyridine thiosemicarbazone

The effects of thiosemicarbazone derivatives of 2-acetylpyridine on mammalian and viral ribonucleoside diphosphate reductases were investigated. The enzymes were partially purified from uninfected and herpes simplex virus type-1 (HSV-1)-infected KB cells by sequential salt fractionation with streptomycin sulfate and ammonium sulfate and by affinity chromatography on ATP-agarose. The five thiosemicarbazone derivatives investigated were all potent inhibitors of the virus-induced reductase. Fifty percent inhibitory concentrations (50 values) range from 2 to 13 [mu]M. Four of the five derivatives also were inhibitors of the host cell reductase . A semicarbazone was inactive against the cellular enzyme and relatively weak as an inhibitor of the viral enzyme . Four of the six compounds were preferential inhibitors of the viral reductase based on a comparison of 50 values (5- to > 85-fold difference). Kinetic experiments revealed that inhibition of the HSV-1 reductase by the thiosemicarbazones was noncompetitive with respect to CDP and dithiothreitol. A comparison of the inhibitory effects of 2-acetylpyridine thiosemicarbazone itself on viral reductase and on virus replication in vitro demonstrated a similarity in the dose-response relationships for the two parameters. This observation supports the hypothesis that the HSV-induced ribonucleoside diphosphate reductase is an important target for the design of antiviral drugs.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26189/1/0000268.pd