A model of cell death

Best stiffness for striation small change in substrate stiffness can deter striated muscle differentiation, as shown on page 877 by Engler et al. As stiffness changes of this magnitude are not uncommon in diseased tissues, injections of stem cells may be useless unless the target environment is also treated. Muscular dystrophy patients suffer from stiffened muscle tissue. Although muscle precursors are abundant in mdx mice, a muscular dystrophy model, they fail to regenerate injured muscle. The new article shows that this failure may be due to their overly stiff environment, which prevents skeletal muscle striation. Skeletal muscle precursors spread, assumed a spindle shape, and fused into multinucleated cells when grown on surfaces within a wide range of stiffness. However, striation—the alignment of actin and myosin into repeated units— was blocked if the substrates were either too soft (e.g., fibroblasts or weak gels) or A A model of cell death n page 839, Bentele et al. use a mathematical model to simplify a complex biological problem—programmed cell death. Models are mostly used to study relatively simple and well-understood biological systems. Complex systems, in contrast, have so many unknowns that an overwhelming amount of data is needed to complete a model. But Bentele et al. show that CD95-induced cell death can be simplified. The authors found that the activity or concentration of many molecules involved in this death pathway (such as caspases and Bcl family proteins) are unaffected by large changes in most parameters (including binding kinetics and reaction speeds). So they broke down their original model into modules—groups of molecules that change in response to changes in the same set of parameters. As a result, only a subset of molecules needs to be examined when certain parameters are changed in simulations. Using these simulations, the group identified the pathway's most critical molecules as those that reacted strongly to parameter changes. The concentrations of these critical molecules were measured in lab experiments over time following CD95 activation to estimate some of the remaining unknown parameters and thus refine the model. Both the refined model and lab experiments predicted that a threshold concentration of CD95 ligand is required for cell O death to occur. One candidate that might control the threshold is c-FLIP, whose binding to the CD95-containing complex competes with activation of caspase-8. Death simulations run in the absence of c-FLIP abolished the threshold. Cell death now occurred under low concentrations of …