Mixed MD/MC simulation at fixed difference in chemical potential (Δμ) between two lipid types provides a computational indicator of the relative affinities of the two lipids for different environments. Applying this technique to ternary DPPC/DOPC/cholesterol bilayers yields a DPPC/DOPC ratio that increases with increasing cholesterol content at fixed Δμ, consistent with the known enrichment of DPPC and cholesterol-rich in liquid-ordered phase domains in the fluid-fluid coexistence region of the ternary phase diagram. Comparison of the cholesterol-dependence of PC compositions at constant Δμ with experimentally measured coexistence tie line end point compositions affords a direct test of the faithfulness of the atomistic model to experimental phase behavior. DPPC/DOPC ratios show little or no dependence on cholesterol content at or below 16% cholesterol in the DOPC-rich region of the composition diagram, indicating cooperativity in the favorable interaction between DPPC and cholesterol. The relative affinity of DPPC and DOPC for high cholesterol bilayer environments in simulations is explicitly shown to depend on the degree of cholesterol alignment with the bilayer normal, suggesting that a source of the cooperativity is the composition dependence of cholesterol tilt angle distributions.
Induction of growth arrest-specific genes (gas1) prevents cell proliferation and/or leads to apoptosis in different cell types. In neurons, it has been recently reported that mild excitotoxic neuronal death is associated with gas1 induction, and that overexpression of Gas1 induces apoptosis in terminally differentiated neurons or in proliferating neuroblastoma cells. In the present study, we have analysed the effects of the transcriptionally mediated targeting of gas1 to C6 rat glioma cells. Expression of Gas1 decreased glial proliferation and induced C6 cell apoptosis. While the identity of the caspase(s) responsible for Gas1-induced apoptosis in neurons has remained elusive, in C6 glioma cells, overexpression of Gas1 reproducibly activated caspase-3. Our results support the concept of targeted expression of gas1 as a potentially useful gene therapy strategy in the treatment of human gliomas.
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