Several mouse models of sickle cell disease have been developed for the study of the pathophysiology of sickle cell disease and the investigation of drug and gene therapies. In previous years, we produced a sickle cell anemia mouse model in which the endogenous mouse alpha- and beta-globin genes were knocked out and replaced by the human alpha- and beta(s)-globin transgenes. The beta(s)-globin gene was contained in a 240 kb YAC that preserved the entire native genomic context of the beta-globin locus. These mice have hemolytic anemia, reticulocytosis and irreversible sickle cells in the peripheral blood, as well as other pathological features of sickle cell disease. However, in the embryo, the gamma-globin, like the mouse embryonic globin, declined quickly, and was replaced by beta(s)-globin expression from 12 days of gestation. The low level of fetal hemoglobin expression in utero led to intrauterine sickling and fetal death so that very few live-born sickle cell anemia mice could be obtained. To rescue these mice from intrauterine death, we investigated the effect of placing the pregnant mothers in a high O(2) environment. From the tenth day of gestation onwards, we placed the mothers into a chamber containing 50% O(2) and kept them with the newborn pups in it for another 10 days after birth. The frequency of sickle cell anemia mice we obtained was increased from less than 2% to 35%. The survived sickle cell anemia mice develop congestion, atrophy, and infarcts in multiple organs similar to those found in patients with sickle cell disease. We conclude that a high oxygen environment can be used to obtain more sickle cell anemia mice in those models that have a high perinatal mortality. The higher yield of these mice has facilitated physiological and therapeutic studies of sickle cell anemia.
"Knock-in mice that express exclusively hHb have been previously generated. However, hHb knock-in mice are notoriously difficult to breed and are therefore unsuitable for infection models, which require high numbers of subjects in order to evaluate statistical significance (Ye et al., 2008). "
[Show abstract][Hide abstract] ABSTRACT: Iron is required for bacterial proliferation, and Staphylococcus aureus steals this metal from host hemoglobin during invasive infections. This process involves hemoglobin binding to the cell wall of S. aureus, heme extraction, passage through the cell envelope, and degradation to release free iron. Herein, we demonstrate an enhanced ability of S. aureus to bind hemoglobin derived from humans as compared to other mammals. Increased specificity for human hemoglobin (hHb) translates into an improved ability to acquire iron and is entirely dependent on the staphylococcal hemoglobin receptor IsdB. This feature affects host-pathogen interaction as demonstrated by the increased susceptibility of hHb-expressing mice to systemic staphylococcal infection. Interestingly, enhanced utilization of human hemoglobin is not a uniform property of all bacterial pathogens. These results suggest a step in the evolution of S. aureus to better colonize the human host and establish hHb-expressing mice as a model of S. aureus pathogenesis.
[Show abstract][Hide abstract] ABSTRACT: To realize the concurrent development of engine hardware and control software, a rapid modeling method has been proposed based on "projection method" for mechanical portions and conservation laws for the other portions. Those methods can preserve the assembling model components of the actual engine represented by the visual image. In order to realize the rapid modeling environment, the concept of "base model" and "model library" has been also introduced. The base model defines partitioning of engine model and the interfaces among the model components. It can be used as the template for the required engine model. The model of a targeted subsystem control, an actuator control as an example, can be rapidly developed abstracting the necessary portions which are revised or simplified according to the required fidelity.
Control Applications, 2004. Proceedings of the 2004 IEEE International Conference on; 10/2004
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