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911.
Reddy KR Colby TJ Fujitaki JM van Poelje PD Erion MD 《Nucleosides, nucleotides & nucleic acids》2005,24(5-7):375-381
A new class of phosphate and phosphonate prodrugs, called HepDirect prodrugs, has been developed to deliver drugs to the liver while simultaneously diminishing drug exposure to extra-hepatic tissues. The technology combines liver-selective cleavage and kinase by pass with high plasma and tissue stability to achieve increased drug levels in the liver. Lamivudine (LMV), a nucleoside analogue, is a currently approved treatment for hepatitis B infection, but shows modest efficacy and significant drug resistance due to inefficient phosphorylation. LMV is inadequately phosphorylated to the corresponding nucleoside triphosphate in rat and human hepatocytes. A HepDirect prodrug of LMV monophosphate generated 34-fold higher levels of the triphosphate in rat hepatocytes and 320-fold higher triphosphate levels in the liver of treated rats relative to LMV. 相似文献
912.
We synthesized analogues of spermine and studied the effects of chemical structure, ionic strength, and temperature on lambda-DNA nanoparticle formation. Effective concentration of polyamines for DNA condensation (EC50) was lowest for hexamines (0.2 microM) and highest for spermine (tetramine, 4.2 microM). The EC50 value increased with [Na+]. Dynamic light scattering showed nanoparticles with hydrodynamic radii (R(h)) of 40-50 nm. Effect of temperature on R(h) was measured between 20 and 70 degrees C. For spermine, R(h) remained relatively stable until 50 degrees C and increased significantly at >60 degrees C. In contrast, the hexa- and penta-valent analogues exhibited a gradual increase in R(h) between 20 and 70 degrees C. The nanoparticles were mainly toroidal, as revealed by electron microscopy (EM). EM studies showed changes in morphology and size of condensed structures with an increase in temperature. A possible mechanism for the differential effects of temperature on DNA nanoparticles might involve different modes of DNA-polyamine interactions. 相似文献
913.
Gailus-Durner V Fuchs H Becker L Bolle I Brielmeier M Calzada-Wack J Elvert R Ehrhardt N Dalke C Franz TJ Grundner-Culemann E Hammelbacher S Hölter SM Hölzlwimmer G Horsch M Javaheri A Kalaydjiev SV Klempt M Kling E Kunder S Lengger C Lisse T Mijalski T Naton B Pedersen V Prehn C Przemeck G Racz I Reinhard C Reitmeir P Schneider I Schrewe A Steinkamp R Zybill C Adamski J Beckers J Behrendt H Favor J Graw J Heldmaier G Höfler H Ivandic B Katus H Kirchhof P Klingenspor M Klopstock T Lengeling A 《Nature methods》2005,2(6):403-404
914.
We made substantial advances in the implementation of a rapamycin-triggered heterodimerization strategy. Using molecular engineering of different targeting and enzymatic fusion constructs and a new rapamycin analog, Rho GTPases were directly activated or inactivated on a timescale of seconds, which was followed by pronounced cell morphological changes. As signaling processes often occur within minutes, such rapid perturbations provide a powerful tool to investigate the role, selectivity and timing of Rho GTPase-mediated signaling processes. 相似文献
915.
Heiden TC Haines AN Manire C Lombardi J Koob TJ 《Journal of experimental zoology. Part A, Comparative experimental biology》2005,303(7):577-589
In the viviparous bonnethead shark, Sphyrna tiburo, a fluid-filled, acellular egg capsule surrounds fertilized eggs and developing embryos throughout gestation. Like other placental shark species, the capsule remains intact even at the placental implantation site. Although its intervention between the uterine and embryonic tissues of the placenta has long been thought to mediate physiological exchange, little information is available concerning even its basic structure or permeability to solutes. The 1 mum thick capsule wall consists of an inner layer of gelatinous material and an outer layer consisting of at least three laminae of orthogonally arranged fibrous material. These fibers are irregular and often branched. Permeability experiments showed that solutes less than 1,355 Da diffuse across the egg capsule whereas those greater than 6,000 Da do not pass through the membrane. Solute movement across the capsule is a concentration-dependent phenomenon indicating diffusion rather than active transport. Experimental data also suggest that there is an increase in the permeability of the egg capsule to low molecular weight materials during mid- and late gestation. These observations are discussed in relation to the function of the egg capsule as a mediator of maternal-embryonic interactions in matrotrophic sharks. 相似文献
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Impairment of motor coordination, or ataxia, is a prominent effect of alcohol ingestion in humans. To date, many models have been created to examine this phenomenon in animals. Evidence suggests that the tasks thought to measure this behavior in mice actually measure different components of this complex trait. We have characterized the parallel rod floor apparatus to quantify ethanol-induced motor incoordination. Using genetically heterogeneous mice, we evaluated the influence of rod diameter and inter-rod distance on dose-related ethanol-induced motor incoordination to select parameters that optimized testing procedures. We then used the DBA/2J and C57BL/6J inbred strains of mice to examine the effect of 2 g/kg of ethanol, by serially testing mice on two floor types, separated by 1 week. Finally, we tested eight inbred strains of mice on four floor types to examine patterns of strain sensitivity to 2 g/kg of intraperitoneal ethanol and determined the test parameters that maximized strain effect size. Motor incoordination varied depending on the floor type and strain. When data from strain 129S1/SvlmJ were removed from the analyses because of their extreme behavior, the greatest strain effect size was observed on one floor type during the first 10 min of testing after 2 g/kg of intraperitoneal ethanol. These findings suggest that the parallel rod floor apparatus provides a useful means for examining ethanol-induced motor incoordination in mice but that specific testing procedures are important for optimizing detection of motor incoordination and genetic influences. 相似文献