Advances in the Mathematical Modelling of Hepatitis C Virus Dynamics

Mathematical models have provided key insights into the pathogenesis of hepatitis C virus (HCV) in vivo, suggested predominant mechanism(s) of drug action, explained confounding patterns of viral load changes in HCV infected patients undergoing therapy, and presented a framework for therapy optimization. In this article, I present an overview of the major advances in the mathematical modeling of HCV dynamics.

Dramatic Structural Changes Resulting from the Loss of a Crucial Hydrogen Bond in the Hinge Region Involved in C-Terminal Helix Swapping in SurE: A Survival Protein from Salmonella typhimurium

Domain swapping is an interesting feature of some oligomeric proteins in which each protomer of the oligomer provides an identical surface for exclusive interaction with a segment or domain belonging to another protomer. Here we report results of mutagenesis experiments on the structure of C-terminal helix swapped dimer of a stationary phase survival protein from Salmonella typhimurium (StSurE). Wild type StSurE is a dimer in which a large helical segment at the C-terminus and a tetramerization loop comprising two beta strands are swapped between the protomers. Key residues in StSurE that might promote C-terminal helix swapping were identified by sequence and structural comparisons. Three mutants in which the helix swapping is likely to be avoided were constructed and expressed in E. coli. Three-dimensional X-ray crystal structures of the mutants H234A and D230A/H234A could be determined at 2.1 angstrom and 2.35 angstrom resolutions, respectively. Contrary to expectations, helix swapping was mostly retained in both the mutants. The loss of the crucial D230 OD2- H234 NE2 hydrogen bond (2.89 angstrom in the wild type structure) in the hinge region was compensated by new inter and intra-chain interactions. However, the two fold molecular symmetry was lost and there were large conformational changes throughout the polypeptide. In spite of these changes, the dimeric structure and an approximate tetrameric organization were retained, probably due to the interactions involving the tetramerization loop. Mutants were mostly functionally inactive, highlighting the importance of precise inter-subunit interactions for the symmetry and function of StSurE.

Human la protein interaction with GCAC near the initiator AUG enhances hepatitis C virus RNA replication by promoting linkage between 5 ` and 3 ` untranslated regions

Human La protein has been implicated in facilitating the internal initiation of translation as well as replication of hepatitis C virus (HCV) RNA. Previously, we demonstrated that La interacts with the HCV internal ribosome entry site (IRES) around the GCAC motif near the initiator AUG within stem-loop IV by its RNA recognition motif (RRM) (residues 112 to 184) and influences HCV translation. In this study, we have deciphered the role of this interaction in HCV replication in a hepatocellular carcinoma cell culture system. We incorporated mutation of the GCAC motif in an HCV monocistronic subgenomic replicon and a pJFH1 construct which altered the binding of La and checked HCV RNA replication by reverse transcriptase PCR (RT-PCR). The mutation drastically affected HCV replication. Furthermore, to address whether the decrease in replication is a consequence of translation inhibition or not, we incorporated the same mutation into a bicistronic replicon and observed a substantial decrease in HCV RNA levels. Interestingly, La overexpression rescued this inhibition of replication. More importantly, we observed that the mutation reduced the association between La and NS5B. The effect of the GCAC mutation on the translation-to-replication switch, which is regulated by the interplay between NS3 and La, was further investigated. Additionally, our analyses of point mutations in the GCAC motif revealed distinct roles of each nucleotide in HCV replication and translation. Finally, we showed that a specific interaction of the GCAC motif with human La protein is crucial for linking 5' and 3' ends of the HCV genome. Taken together, our results demonstrate the mechanism of regulation of HCV replication by interaction of the cis-acting element GCAC within the HCV IRES with human La protein.

On the Utility of Microscopy and C-Scan Techniques in the Study of Defects Arising From Resin Infusion Process and a Study on the Influence of Voids on the Impact Behavior of CFRP Composites

Carbon Fiber Reinforced Plastic composites were fabricated through vacuum resin infusion technology by adopting two different processing conditions, viz., vacuum only in the first and vacuum plus external pressure in the next, in order to generate two levels of void-bearing samples. They were relatively graded as higher and lower void-bearing ones, respectively. Microscopy and C-scan techniques were utilized to describe the presence of voids arising from the two different processing parameters. Further, to determine the influence of voids on impact behavior, the fabricated +45 degrees/90 degrees/-45 degrees composite samples were subjected to low velocity impacts. The tests show impact properties like peak load and energy to peak load registering higher values for the lower void-bearing case where as the total energy, energy for propagation and ductility indexes were higher for the higher void-bearing ones. Fractographic analysis showed that higher void-bearing samples display lower number of separation of layers in the laminate. These and other results are described and discussed in this report.

The pottery from A and C-Group tombs at Serra West in the Museum of Natural History, La Plata

Abstract: The Museum of Natural History, La Plata, Argentina, houses a ceramic collection of the A-Group and C-Group cultures from Nubian tombs at Serra West (AA and ACS cemeteries), on the west bank of the Nile in Lower Nubia. It has been originated from the division after the excavations made by the Franco-Argentine Archaeological Expedition in Sudan between 1961 and 1963, as part of the UNESCO campaigns to save the Nubian monuments.

Annual report 1992 - North Pacific Marine Science Organization (PICES). First meeting, Victoria, B.C., Canada, October 12-17, 1992

Document has 52 pages.

Role of Monoubiquitylation on the Control of IκBα Degradation and NF-κB Activity

9 p.

Can the change in the composition of the US GDP explain the Great Moderation? A test via oil price shocks

The paper investigates whether the growing GDP share of the services sector can contribute to explain the great moderation in the US. We identify and analyze three oil price shocks and use a SVAR analysis to measure their economic impact on the US economy at both the aggregate and the sectoral level. We find mixed support for the explanation of the great moderation in terms of shrinking oil shock volatilities and observe that increases (decreases) in oil shock volatilities are contrasted by a weakening (strengthening) in their transmission mechanism. Across sectors, services are the least affected by any oil shock. As the contribution of services to the GDP volatility increases over time, we conclude that a composition effect contributed to moderate the conditional volatility to oil shocks of the US GDP.

Cruise no. 2 of the M/V N.B. Scofield for 1957, 57S2-Albacore. Cruise report 57-S-2

(PDF contains 6 pages.)

Spatial distribution of Chlorpyrifos and Endosulfan in USA coastal waters and the Great Lakes

Between 1994 and 1997, 258 tissue and 178 sediment samples were analyzed for chlorpyrifos throughout the coastal United States and the Great Lakes. Subsequently, 95 of the 1997 tissue samples were reanalyzed for endosulfan. Tissue chlorpyrifos concentrations, which exceeded the 90th percentile, were found in coastal regions known to have high agricultural use rates but also strongly correlated with sites near high population. The highest concentrations of endosulfans in contrast, were generally limited to agricultural regions of the country. Detections of chlorpyrifos at several Alaskan sites suggest an atmospheric transport mechanism. Many Great Lakes sites had chlorpyrifos tissue concentrations above the 90th percentile which decreased with increasing distance from the Corn Belt region (Iowa, Indiana, Illinois, and Wisconsin) where most agriculturally applied chlorpyrifos is used. Correlation analysis suggests that fluvial discharge is the primary transport pathway on the Atlantic and Gulf of Mexico coasts for chlorpyrifos but not necessarily for endosulfans. (PDF contains 28 pages)

Cruise 1 of the M.V. N.B. Scofield for 1955. Cruise Report 55-S-1

(PDF contains 3 pages.)

Cruise of the M/V N.B. Scofield for 1956. Cruise Report 56-S-1

(PDF contains 6 pages.)

Cruise 4 of the M/V N.B. Scofield for 1957.

(PDF contains 3 pages.)