As we have previously reported, the preferential accu mulation of the truncated PrP C1 fragment, which is gen erated through endoproteolysis of PrPC during normal protein processing in the brain and the muscle, was closely correlated with myopathic changes in Dox treated Tg sellectchem mice. We hypothesize that it is this C1 fragment that is the toxic species in the Tg model, which is supported by recent reports showing that over expression of the C1 fragment increases cell death and cas secting prion disease pathogenesis. Conclusion In summary, we used microarrays to determine the molec ular mechanism that underlies the myopathy observed in PrP over expressing mice. The transcriptional changes induced in the Dox treated Tg mice are quite differ ent from the changes previously described in systemic dis eases and disuse and denervation atrophy.

Significantly we found that the p53 protein and p53 regulated pro apoptotic pathways are highly activated in the muscles of doxycycline treated Tg mice, correlating well with the Inhibitors,Modulators,Libraries observed myopathic changes. To our best knowledge, this is the first in vivo evidence that directly links p53 to a wild type PrP mediated disease. We hypothesize that it is the preferentially accumulated truncated C1 fragment in the muscles of doxycycline treated Tg mice Inhibitors,Modulators,Libraries that activates the p53 pathway, resulting in the primary myop athy. This is consistent with recent reports showing that over expression of the C1 fragment increase cell death and caspase 3 activity through a p53 dependent mechanism in cell culture models.

Dissecting how PrP regulates the p53 pathways may help understand PrP mediated pathogenesis in both muscle diseases and prion diseases. Neuronal loss, a salient fea ture Inhibitors,Modulators,Libraries of prion diseases, has been reported to be due to neu ronal apoptosis in prion affected humans and animals. p53 has been shown to be a critical player in PrP or PrP fragments mediated cytotoxicity in neurons. Therefore, our finding that p53 plays a major role in PrP mediated myopathy and our future follow up studies on the detailed molecular mechanisms of how PrP over expression leads to p53 activation in the muscles, may also provide some clues on the molecular Inhibitors,Modulators,Libraries mechanism of prion pathogenesis in the brain. Background Drought is a major abiotic stress Inhibitors,Modulators,Libraries that limits crop pro ductivity. Climate change models predict an increase in summer drying in the midlatitudes, which could contribute to an increase in the number of epi sodes of drought. Engineering plants with enhanced tolerance of abiotic stresses such as drought is a major objective of plant biotechnology that is expected to be commercialized full read in the near future.