Abstract-The presence of increased ubiquitinated proteins and amyloid oligomers in failing human hearts strikingly resembles the characteristic pathology in the brain of many neurodegenerative diseases. The ubiquitin-proteasome system (UPS) is responsible for degradation of most cellular proteins and plays essential roles in virtually all cellular processes. UPS impairment by aberrant protein aggregation was previously shown in cell culture but remains to be demonstrated in intact animals. Mechanisms underlying the impairment are poorly understood. We report here that UPS proteolytic function is severely impaired in the heart of a mouse model of intrasarcoplasmic amyloidosis caused by cardiac-restricted expression of a human desmin-related myopathy-linked missense mutation of ␣B-crystallin (CryAB R120G ). The UPS impairment was detected before cardiac hypertrophy, and failure became discernible, suggesting that defective protein turnover likely contributes to cardiac remodeling and failure in this model. Further analyses reveal that the impairment is likely attributable to insufficient delivery of substrate proteins into the 20S proteasomes, and depletion of key components of the 19S subcomplex may be responsible. The derangement is likely caused by aberrant protein aggregation rather than loss of function of the CryAB gene because UPS malfunction was not evident in CryAB-null hearts and inhibition of aberrant protein aggregation by Congo red or a heat shock protein significantly attenuated CryAB R120G -induced UPS malfunction in cultured cardiomyocytes. Because of the central role of the UPS in cell regulation and the high intrasarcoplasmic amyloidosis prevalence in failing human hearts, our data suggest a novel pathogenic process in cardiac disorders with abnormal protein aggregation. Key Words: proteasome Ⅲ ubiquitin Ⅲ protein aggregation Ⅲ ␣B-crystallin Ⅲ desmin-related cardiomyopathy Ⅲ amyloidosis Ⅲ transgenic mice M ost cellular proteins are degraded through the ubiquitin-proteasome system (UPS). UPS-mediated proteolysis includes 2 major steps: attachment of a chain of ubiquitin to the target protein molecule through a process known as ubiquitination and degradation of the ubiquitinated proteins by the 26S proteasome. The latter consists of a barrel-shaped 20S core and the 19S cap on 1 or both ends of the 20S. The actual proteolytic activity resides in the interior of the 20S, whereas the 19S plays a critical role in channeling ubiquitinated protein molecules into the 20S. 1 Ubiquitinated proteins accumulate in the cell when the proteasome is inhibited. 1 Aberrant protein aggregation is a common process in many neural degenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases. 2,3 Remaining to be demonstrated in intact animals, this process was shown in cell culture to impair UPS-mediated proteolysis. 4 Therefore, UPS malfunction is considered an important pathogenic mechanism in neurodegeneration. 5 Recent studies revealed that abnormal protein aggregation, intrasarcoplasmic amyl...

The inverse problem of parameter identification is deal with by minimizing an objective function that contains the difference between observed and calculated dam displacements. The optimization problem of minimizing objective function is solved with genetic algorithm. The calculated dam displacements are simulated by using finite element method according to water level change acting on dam upstream. The practical dam displacements are observed on the dam crest. The investigation shows that the forecasted dam displacements agree well with observed ones. The effectiveness of proposed inversion procedure is validated.

Based on plastic-damage constitutive model of concrete, the developing process of damage domains is simulated for the earthquake analysis of concrete dam by taking account of the change of strain speed and stiffness degradation effect caused by material damage. The plastic-damage constitutive model is applied and the dam-reservoir dynamic interaction resulting from the transverse component of ground motion is modeled using the developed and generalized Westergaard formula added mass technique. Numerical simulation results show that the damaged domains mainly distribute at the change in geometry of upper part of the dam and vertical construction joints. The damaged domains of dam are same as the maximum tensile stress because the tensile strength of concrete is less its compress strength.