Background: Blood coagulation occurs by a cascade of zymogen activation resulting from minor proteolysis. The final stage of coagulation involves thrombin generation and limited proteolysis of fibrinogen to give spontaneously polymerizing fibrin. The resulting fibrin network is covalently crosslinked by factor XIIIa to yield a stable blood clot. Fibrinogen is a 340 kDa glycoprotein composed of six polypeptide chains, (␣␤␥) 2 , held together by 29 disulfide bonds. The globular C terminus of the ␥ chain contains a fibrin-polymerization surface, the principal factor XIIIa crosslinking site, the platelet receptor recognition site, and a calcium-binding site. Structural information on this domain should thus prove helpful in understanding clot formation. Results:The X-ray crystallographic structure of the 30 kDa globular C terminus of the ␥ chain of human fibrinogen has been determined in one crystal form using multiple isomorphous replacement methods. The refined coordinates were used to solve the structure in two more crystal forms by molecular replacement; the crystal structures have been refined against diffraction data to either 2.5 Å or 2.1 Å resolution. Three domains were identified in the structure, including a C-terminal fibrin-polymerization domain (P), which contains a single calcium-binding site and a deep binding pocket that provides the polymerization surface. The overall structure has a pronounced dipole moment, and the C-terminal residues appear highly flexible. Conclusions:The polymerization domain in the ␥ chain is the most variable among a family of fibrinogen-related proteins and contains many acidic residues. These residues contribute to the molecular dipole moment in the structure, which may allow electrostatic steering to guide the alignment of fibrin monomers during the polymerization process. The flexibility of the C-terminal residues, which contain one of the factor XIIIa crosslinking sites and the platelet receptor recognition site, may be important in the function of this domain.

Mitochondrial DNA levels are significantly decreased in patients with symptomatic, nucleoside-related hyperlactatemia, an effect that resolves on the discontinuation of therapy.

An analysis of several multidecadal simulations of the present (1971–90) and future (2041–60) climate from the Canadian Regional Climate Model (CRCM) is presented. The effects on the CRCM climate of model domain size, internal variability of the general circulation model (GCM) used to provide boundary conditions, and modifications to the physical parameterizations used in the CRCM are investigated. The influence of boundary conditions is further investigated by comparing the GCM-driven simulations of the current climate with simulations performed using boundary conditions from meteorological reanalyses. The present climate of the model in these different configurations is assessed by comparing the seasonal averages and interannual variability of precipitation and surface air temperature with an observed climatology. Generally, small differences are found between the two simulations on different domains, though both domains are quite large as compared with previously reported results. Simulations driven by GCM output show a significant warm bias for wintertime surface air temperatures over northern regions. This warm bias is much reduced in the GCM-driven simulation when an updated set of physical parameterizations is used in the CRCM. The warm bias is also reduced for simulations with the standard set of physical parameterizations when the CRCM is driven with reanalysis data. However, use of the modified physics package for reanalysis-driven simulations results in surface air temperatures that are colder than the observations. Summertime precipitation in the model is much larger than observed, a bias that is present in both the GCM-driven and reanalysis-driven simulations. The bias in summertime precipitation is reduced for both types of driving data when the updated set of physical parameterizations is used. Model projections of climate change between the present and future periods are also presented and the sensitivity of these projections to many of the above-mentioned modifications is assessed. Changes in surface air temperature are predicted to be largest over northern regions in winter, with smaller changes over more southerly regions and in the summer season. Changes in seasonal average precipitation are projected to be in the range of ±10% of present-day amounts for most regions and seasons. The CRCM projections of surface air temperature changes are strongly affected by the internal variability of the driving GCM over high northern latitudes and to changes in the physical parameterizations over many regions for the summer season.