Split conformation of Chaetomium thermophilum Hsp104 disaggregase.

Hsp104 and its bacterial homolog ClpB form hexameric ring structures and mediate protein disaggregation. The disaggregated polypeptide is thought to thread through the central channel of the ring. However, the dynamic behavior of Hsp104 during disaggregation remains unclear. Here, we reported the stochastic conformational dynamics and a split conformation of Hsp104 disaggregase from Chaetomium thermophilum (CtHsp104) in the presence of ADP by X-ray crystallography, cryo-electron microscopy (EM), and high-speed atomic force microscopy (AFM). ADP-bound CtHsp104 assembles into a 65 left-handed spiral filament in the crystal structure at a resolution of 2.7 Å. The unit of the filament is a hexamer of the split spiral structure. In the cryo-EM images, staggered and split hexameric rings were observed. Further, high-speed AFM observations showed that a substrate addition enhanced the conformational change and increased the split structure's frequency. Our data suggest that split conformation is an off-pathway state of CtHsp104 during disaggregation.

Usefulness of a combination of systolic function by left ventricular ejection fraction and diastolic function by E/E' to predict prognosis in patients with heart failure.

Left ventricular (LV) ejection fraction (EF) was known as a conventional predictor of heart failure (HF). However, early transmitral flow velocity (E)/early diastolic velocity of mitral annulus (E') correlated well with LV end-diastolic pressure, and E/E' ratio >15 was an excellent predictor of adverse outcomes in patients with HF. This study was designed to determine the prognostic value of a new combined index, E/E' ratio and LVEF, in patients with HF. One hundred twenty-six consecutive patients hospitalized with HF underwent comprehensive echocardiographic-Doppler study when ready for discharge. Patients were divided into the 4 groups of group I (LVEF >40% and E/E' ratio <15), group II (EF >40% and E/E' ratio >or=15), group III (EF or=15). The ability of this index to determine the primary end point (rehospitalization for HF or cardiac death) was assessed. Patients with significant valvular disease were excluded. Of 126 patients, 110 met the inclusion criteria. Follow-up was complete for 108 of 110 patients at 351 +/- 252 days after discharge. There were 27, 30, 21, and 30 patients in groups I, II, III, and IV, respectively. There were 52 patients with the primary end point. On univariate analysis, E/E' ratio, group IV, E', and age were significant predictors. In multivariable analysis, the most powerful independent prognostic indicator of events was group IV (hazard ratio 12.6, 95% confidence interval 2.2 to 74.2, p = 0.005). In conclusion, a new index, a combination of LVEF and E/E' ratio, allowed the identification of patients at higher risk of readmission and cardiac death in patients with HF.