To understand the role of these residues in virus replication, we mutated them

to either lysine (K), alanine (A), or aspartic acid (D). We could generate viruses possessing either single or combination substitutions with K or single substitution with A at any of these positions, but not those with double substitutions with A or a single substitution with D. Viruses with the single substitution with A exhibited slower growth and had lower nucleoprotein/M1 quantitative ratio in virions compared to the wild-type virus. In cells infected with a virus possessing the single substitution with A at position 77 or 78 (R77A or R78A, respectively), the mutated M1 localized in patches at the cell periphery where nucleoprotein and hemagglutinin colocalized QNZ in vivo more often than the wild-type did. Transmission electron microscopy showed that virus possessing M1 R77A or R78A, but not the wild-type virus, was present in vesicular structures, indicating a defect in virus assembly and/or budding. The M1 mutations that did not support virus generation exhibited an aberrant M1 intracellular localization and affected protein incorporation into virus-like particles. These results indicate that the basic amino acid stretch of M1 plays a critical role

in influenza virus replication.”
“Dependence can develop during chronic opioid use, and the emergence of withdrawal might promote drug taking.

This study examined how chronic morphine administration or withdrawal modified self administration of heroin or cocaine.

Four monkeys responded under a Epoxomicin ic50 fixed ratio 10 schedule to receive i.v. infusions of heroin (0.56-560 A mu g/kg/infusion) or cocaine (1-100 mu g/kg/infusion). Monkeys received morphine twice daily; the final dose was 10 mg/kg/12 h. Dose-effect curves for heroin or cocaine were determined

in 150-min sessions throughout morphine Silibinin administration and during temporary suspension when withdrawal signs were also monitored. Heroin dose-effect curves and withdrawal signs were determined daily following termination of morphine administration.

Before monkeys received morphine, heroin, and cocaine maintained responding with unit doses of 1.78 A mu g/kg of heroin and 10 A mu g/kg/injection of cocaine resulting in, on average, 13.4 and 20.8 infusions, respectively. When monkeys received morphine daily, self administration of heroin and cocaine decreased to, on average, 3.1 and 11.3 infusions, respectively. Responding for heroin or cocaine recovered following temporary (17-53 h) suspension of morphine administration. The number of heroin infusions and total withdrawal signs increased when morphine administration was terminated. Withdrawal signs peaked 3-4 days after morphine; however, the number of infusions remained elevated for 8 weeks.