Modeling myosin Va liposome transport through actin filament networks reveals a percolation threshold that modulates transport properties.

Myosin Va (myoVa) motors transport membrane-bound cargo through three-dimensional, intracellular actin filament networks. We developed a coarse-grained, in silico model to predict how actin filament density (3-800 filaments) within a randomly oriented actin network affects fluid-like liposome (350 nm vs. 1750 nm) transport by myoVa motors. Five thousand simulated liposomes transported within each network adopted one of three states: transport, tug-of-war, or diffusion. Diffusion due to liposome detachment from actin rarely occurred given at least 10 motors on the liposome surface. However, with increased actin density, liposomes transitioned from primarily directed transport on single actin filaments to an apparent random walk, resulting from a mixture of transport and tug-of-wars as the probability of encountering additional actin filaments increased. This phase transition arises from a percolation phase transition at a critical number of accessible actin filaments, Nc. Nc is a geometric property of the actin network that depends only on the position and polarity of the actin filaments, transport distance, and the liposome diameter, as evidenced by a fivefold increase in liposome diameter resulting in a fivefold decrease in Nc. Thus in cells, actin network density and cargo size may be regulated to match cargo delivery to the cell's physiological demands.

Regional nutrient decrease drove redox stabilisation and metazoan diversification in the late Ediacaran Nama Group, Namibia.

The late Ediacaran witnessed an increase in metazoan diversity and ecological complexity, marking the inception of the Cambrian Explosion. To constrain the drivers of this diversification, we combine redox and nutrient data for two shelf transects, with an inventory of biotic diversity and distribution from the Nama Group, Namibia (~550 to ~538 Million years ago; Ma). Unstable marine redox conditions characterised all water depths in inner to outer ramp settings from ~550 to 547 Ma, when the first skeletal metazoans appeared. However, a marked deepening of the redoxcline and a reduced frequency of anoxic incursions onto the inner to mid-ramp is recorded from ~547 Ma onwards, with full ventilation of the outer ramp by ~542 Ma. Phosphorus speciation data show that, whilst anoxic ferruginous conditions were initially conducive to the drawdown of bioavailable phosphorus, they also permitted a limited degree of phosphorus recycling back to the water column. A long-term decrease in nutrient delivery from continental weathering, coupled with a possible decrease in upwelling, led to the gradual ventilation of the Nama Group basins. This, in turn, further decreased anoxic recycling of bioavailable phosphorus to the water column, promoting the development of stable oxic conditions and the radiation of new mobile taxa.

Alterations in skeletal muscle structure are minimized with steroid withdrawal after renal transplantation.

BACKGROUND: Limitations in exercise capacity in kidney transplant recipients are thought to result in part from changes in muscle structure and function associated with immunosuppression therapy. METHODS: We compared the percent distribution of skeletal muscle fiber types, cross-sectional areas, and ultrastructural morphologies in kidney transplant recipients treated with standard prednisone maintenance therapy (n=21) to those undergoing rapid withdrawal of prednisone using Simulect (interleukin 2 receptor inhibitor) (n=13). Skeletal muscle biopsy specimens from the vastus lateralis were analyzed at 3 and 12 months after transplantation and compared with sedentary controls (n=15). RESULTS: Compared with the control group, the group receiving prednisone maintenance therapy had a significantly lower percentage of type I fibers and a higher percentage of type IIB/x fibers, evident at 3 and 12 months. Fiber type distribution in patients withdrawn from prednisone did not differ from controls. In patients withdrawn from prednisone, the cross-sectional areas of type I and IIA fibers were lower and the area of type IIB/x fibers was higher compared with controls. Likewise, ultrastructural studies revealed reduced volume densities of myofibrils and higher densities of interfibrillar and subsarcolemmal mitochondria. At 12 months there were no ultrastructural differences between the patients withdrawn from prednisone and controls. CONCLUSIONS: We conclude that prednisone maintenance therapy contributes to the lower exercise capacity by altering the ratio of type I to type IIB/x fibers and by reducing myofilament density. The increase in mitochondria in patients receiving prednisone may reflect a switch from carbohydrate to lipid metabolism resulting from the glucocorticoid therapy.

Intra-epithelial vaccination with COPV L1 DNA by particle-mediated DNA delivery protects against mucosal challenge with infectious COPV in beagle dogs.

Protection against viral challenge with canine oral papillomavirus (COPV) was achieved by immunisation via particle-mediated DNA delivery (PMDD) of a plasmid encoding the COPV L1 gene to cutaneous and oral mucosal sites in beagle dogs. The initial dose of approximately 9 microg of DNA was followed by two booster doses at 6 week intervals. A similar approach was used to vaccinate a control group of animals with plasmid DNA encoding the Hepatitis B virus S gene. Following challenge at the oral mucosa with COPV all animals vaccinated with the COPV L1 gene were protected against disease. However five of six animals in the control group developed COPV induced papillomas at the oral mucosa. Both cell-mediated lymphoproliferative and humoral antibody responses to the DNA vaccine were observed. Our data indicate that PMDD of plasmid DNA can protect against mucosal challenge with papillomavirus.

4-Guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid is a highly effective inhibitor both of the sialidase (neuraminidase) and of growth of a wide range of influenza A and B viruses in vitro.

The sialidase (neuraminidase) inhibitor 4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid (4-guanidino-Neu5Ac2en) has been examined for the ability to inhibit the growth of a wide range of influenza A and B viruses in vitro in comparison with amantadine, rimantadine, and ribavirin. 4-Guanidino-Neu5Ac2en inhibited plaque formation by laboratory-passaged strains of influenza A and B viruses, with 50% inhibitory concentrations ranging from 0.005 to 0.014 microM. A wider range of values (0.02 to 16 microM) was obtained with more recent clinical isolates, but in all cases 4-guanidino-Neu5Ac2en inhibited influenza A and B virus replication at lower concentrations than amantadine, rimantadine, or ribavirin. Inhibition by 4-guanidino-Neu5Ac2en was not obviously affected by the passage history of the viruses or by resistance to amantadine or rimantadine. 4-Guanidino-Neu5Ac2en was a very potent inhibitor of the sialidases of all the influenza viruses examined, with 50% inhibitory concentrations ranging from 0.00064 to 0.0079 microM. No cytotoxicity was observed with 4-guanidino-Neu5Ac2en at up to 10 mM. 4-Guanidino-Neu5Ac2en therefore represents a new potent and selective inhibitor of influenza A and B virus sialidase activity and replication in vitro.