502 research outputs found
Inhibition of Human Immunodeficiency Virus Type 1-mediated Cytopathic Effects by Poly(l-lysine)-conjugated Synthetic Antisense Oligodeoxyribonucleotides
No full textThe ability of poly(l-lysine)-conjugated and methylphosphonate-modified synthetic human immunodeficiency virus type 1 (HIV-1) antisense oligodeoxyribonucleotides to protect susceptible host cells from the cytopathic effects of HIV-1 infection was studied. The abundance of viral antigens in oligomer-treated cultures indicated that the oligomers did not significantly affect viral infectivity. Similarly, no significant effects on relative viral RNA accumulation were apparent. The presence of poly(l-lysine)-modified oligomer complementary to the HIV-1 splice donor site resulted in a significant reduction in the production of viral structural proteins and virus titre in infected cultures. In addition, these cells were protected from HIV-1-mediated cytopathic effects while the other cultures rapidly succumbed to the cytotoxic effects of HIV-1 infection. The presence of poly(l-lysine)-conjugated oligomer resulted in the establishment of a persistent HIV-1 infection characterized by a highly productive virus infection in the absence of cell death while treatment of persistently infected cells with phorbol ester resulted in renewed cytopathicity. These results demonstrate the ability of synthetic antisense oligonucleotides to protect susceptible host cells from the cytopathic effects of HIV-1 infection
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Gene-silencing antisense oligomers inhibit Acinetobacter growth in vitro and in vivo
No full textBackground: Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) are synthetic DNA/RNA analogs that silence expression of specific genes. We studied whether PPMOs targeted to essential genes in Acinetobacter lwoffii and A. baumannii are active in vitro and in vivo. Methods: PPMOs were evaluated in vitro using MIC and viability assays, and in vivo using murine pulmonary infection models with intranasal PPMO treatment. Results: MICs of PPMOs ranged from 0.1 and 64 μM (~0.6 to 38 μg/ml). The most effective PPMO tested was (RXR)₄-AcpP, which is targeted to acpP. (RXR)₄-AcpP reduced viability of A. lwoffii and A. baumannii by > 10³ cfu/ml at 5 to 8 x MIC. Mice treated with 0.25 mg/kg or more of (RXR)₄-AcpP survived longer and had less inflammation and bacterial lung burden than mice treated with a scrambled-sequence PPMO or PBS. Treatment could be delayed after infection and still increase survival. Conclusions: PPMOs targeted to essential genes of A. lwoffii and A. baumannii were bactericidal and had MICs in a clinically relevant range. (RXR)₄-AcpP increased survival of mice infected with A. lwoffii or A. baumannii, even when initial treatment was delayed after infection. PPMOs could be a viable therapeutic approach in dealing with multidrug resistant Acinetobacter species.This article is published by Oxford University Press on behalf of the Infectious Diseases Society of America. This is a pre-copy-editing, author-produced PDF of an article accepted for publication in the Journal of Infectious Diseases following peer review. The definitive publisher-authenticated version, Geller, B. L., Marshall-Batty, K., Schnell, F. J., McKnight, M. M., Iversen, P. L., & Greenberg, D. E. (2013). Gene-Silencing Antisense Oligomers Inhibit Acinetobacter Growth In Vitro and In Vivo. Journal of Infectious Diseases, 208(10), 1553-1560. doi:10.1093/infdis/jit460, is available online at: http://jid.oxfordjournals.org/content/208/10/1553.full.pdf?keytype=ref&ijkey=qepbqtxt5pt.Keywords: antisense, infection, respiratory infection, phosphorodiamidate morpholino oligomer, lwoffii, baumannii, oligomer, MIC, Acinetobacter, PMO, morpholino, mous
The case for a symmetric reaction function of the European Central Bank
No full textIn a macro-economic framework where the European Central Bank targets individual country data, the nature of strategic interactions between fiscal authorities in the euro-zone can be described as a stag hunt game with (at least) two equilibria that can be pareto-ranked. In fact we show that, because of the indiscriminate nature of its monetary response, an ECB strategy of monetary retaliation to any individual countrys over-expenditure affects all eleven countries to the same extent. This collective effect is similar to the teachers old favorite all children stay behind in the class if one misbehaves. This mechanism, we show, makes the game between fiscal authorities a multiple equilibria co-ordination game. We subsequently address the problem of equilibrium selection that is of particular importance to co-ordination games. Following Kandori et al. (1993), we apply Harsanyi and Seltens (1988) riskdominance criterion to single out the conditions for fiscal restraint to emerge as the equilibrium selected by interacting actors. Our main conclusions are that the ECB can ensure convergence of fiscal authorities upon the pareto-optimal equilibrium (that is, fiscal restraint) by adopting a reward-oriented, counter-cyclical strategy that compensates fiscal authorities at the output level both for giving up fiscal discretion and for incurring the risk of being hit by a monetary tightening in response to developments elsewhere in the euro-economy. This means that interest rates' movements should smoothen economic fluctuations in order to give economic actors sufficient incentives to maintain restraint. -- In einem makroökonomischen Kontext, in dem die Europäische Zentralbank die wirtschaftlichen Daten einzelner Länder anvisiert, können die strategischen Interaktionen zwischen den Finanzbehörden der Euro-Zone als ein stag hunt- Spiel mit (mindestens) zwei pareto-Equilibrien beschrieben werden. Wir zeigen daß, aufgrund der ungezielten Art der monetären Reaktion, eine EZB-Strategie der monetären Vergeltung für zu hohe Ausgaben eines einzelnen Landes alle elf Länder gleichermaßen betrifft. Dieser Kollektiveffekt erinnert an die alte Lehrermethode: Alle Kinder müssen nachsitzen, wenn eins aus der Reihe tanzt. Dieser Mechanismus macht das Spiel zwischen den Finanzbehörden zu einem Koordinationsspiel mit mehreren Equilibrien. Anschließend befassen wir uns mit dem in Koordinationsspielen besonders bedeutsamen Problem der Wahl zwischen Equilibrien. In Anlehnung an Kandori et al. (1993) wenden wir Harsanyi und Selten's (1988) Risikodominanzkriterium an, um die Bedingungen herauszufiltern, unter denen fiskale Zurückhaltung das Equilibrium bildet, das von den beteiligten Akteuren gewählt wird. Unsere wesentlichen Schlußfolgerungen sind, daß die EZB eine Konvergenz der Finanzbehörden auf das pareto-optimale Equilibrium (d.h. fiskale Zurückhaltung) sicherstellen kann, indem sie eine auf Belohnung ausgerichte, antizyklische Strategie verfolgt, bei der die Finanzbehörden auf der Output-Ebene entschädigt werden -sowohl für die Abgabe fiskaler Entscheidungsfreiheit als auch für das Risiko, einer monetären Kontraktion ausgesetzt zu werden, die auf Entwicklungen anderswo in der Euro-Wirtschaft abzielt. Das bedeutet, daß Zinsentwicklungen wirtschaftliche Fluktuationen ausgleichen sollten, um den relevanten Akteuren ausreichende Anreize für fiskale Zurückhaltung zu bieten.
Bajji on the Beach: Middle-Class Food Practices in Chennai’s New Beach
No full textThis book produced by a group of interdisciplinary and international researchers working on a wide variety of cities throughout Asia, Latin America and Europe, addresses, rethinks and, in some cases, abandons the notions of formal and ..
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