In silico analysis and molecular dynamics simulation of human superoxide dismutase 3 (SOD3) genetic variants.

Oxidative stress is a major factor in aging processes. Superoxide dismutase 3 (SOD3) plays a key role in the protection of extracellular oxidative stress. Missense mutations in SOD3 have been described to be associated with the occurrence of pulmonary, cardiovascular, and neoplastic diseases. This study aims to analyze the effects of missense mutations on the SOD3 structure and function by modeling a complete SOD3 structure as well as analyzing the differences between the wild-types and mutants using computational simulations. Here, ten algorithms were used to predict the structural and functional effects of missense mutations. A complete model of SOD3 protein was made by ab initio and comparative modeling using the Rosetta algorithm and validated by PROCHECK, Verify 3D, QMEAN, and ProSa. Molecular dynamics (MD) simulations were performed and analyzed using the GROMACS package. The deleterious potential of the A58T and R231G mutants was not predicted by the majority of the used algorithms. The analyzed mutations were predicted as destabilizing by at least one algorithm. The MD analyses indicated that protein flexibility may be increased by all of the analyzed mutations, while the protein-ligand stability may be decreased. They also suggested that the variants A91T and R231G increase the overall dimensions of SOD3 and decrease its accessible surface area. Our findings, therefore, indicated that the analyzed mutations could affect the protein structure and its ability to interact with other molecules, which may be related to the functional impairment of SOD3 upon A58T and R231G mutations, as well as their involvement in pathologies.

Fatal pulmonary embolism in hospitalized patients. Clinical diagnosis versus pathological confirmation.

OBJECTIVE: To assess the incidence of fatal pulmonary embolism (FPE), the accuracy of clinical diagnosis, and the profile of patients who suffered an FPE in a tertiary University Hospital. METHODS: Analysis of the records of 3,890 autopsies performed at the Department of General Pathology from January 1980 to December 1990. RESULTS: Among the 3,980 autopsies, 109 were cases of clinically suspected FPE; of these, 28 cases of FPE were confirmed. FPE accounted for 114 deaths, with clinical suspicion in 28 cases. The incidence of FPE was 2.86%. No difference in sex distribution was noted. Patients in the 6th decade of life were most affected. The following conditions-were more commonly related to FPE: neoplasias (20%) and heart failure (18.5%). The conditions most commonly misdiagnosed as FPE were pulmonary edema (16%), pneumonia (15%) and myocardial infarction (10%). The clinical diagnosis of FPE showed a sensitivity of 25.6%, a specificity of 97.9%, and an accuracy of 95.6%. CONCLUSION: The diagnosis of pulmonary embolism made on clinical grounds still has considerable limitations.