Modulation of the slow/common gating of CLC channels by intracellular cadmium.

Members of the CLC family of Cl(-) channels and transporters are homodimeric integral membrane proteins. Two gating mechanisms control the opening and closing of Cl(-) channels in this family: fast gating, which regulates opening and closing of the individual pores in each subunit, and slow (or common) gating, which simultaneously controls gating of both subunits. Here, we found that intracellularly applied Cd(2+) reduces the current of CLC-0 because of its inhibition on the slow gating. We identified CLC-0 residues C229 and H231, located at the intracellular end of the transmembrane domain near the dimer interface, as the Cd(2+)-coordinating residues. The inhibition of the current of CLC-0 by Cd(2+) was greatly enhanced by mutation of I225W and V490W at the dimer interface. Biochemical experiments revealed that formation of a disulfide bond within this Cd(2+)-binding site is also affected by mutation of I225W and V490W, indicating that these two mutations alter the structure of the Cd(2+)-binding site. Kinetic studies showed that Cd(2+) inhibition appears to be state dependent, suggesting that structural rearrangements may occur in the CLC dimer interface during Cd(2+) modulation. Mutations of I290 and I556 of CLC-1, which correspond to I225 and V490 of CLC-0, respectively, have been shown previously to cause malfunction of CLC-1 Cl(-) channel by altering the common gating. Our experimental results suggest that mutations of the corresponding residues in CLC-0 change the subunit interaction and alter the slow gating of CLC-0. The effect of these mutations on modulations of slow gating of CLC channels by intracellular Cd(2+) likely depends on their alteration of subunit interactions

Assessment of density functional methods with correct asymptotic behavior

Long-range corrected (LC) hybrid functionals and asymptotically corrected (AC) model potentials are two distinct density functional methods with correct asymptotic behavior. They are known to be accurate for properties that are sensitive to the asymptote of the exchange-correlation potential, such as the highest occupied molecular orbital energies and Rydberg excitation energies of molecules. To provide a comprehensive comparison, we investigate the performance of the two schemes and others on a very wide range of applications, including the asymptote problems, self-interaction-error problems, energy-gap problems, charge-transfer problems, and many others. The LC hybrid scheme is shown to consistently outperform the AC model potential scheme. In addition, to be consistent with the molecules collected in the IP131 database [Y.-S. Lin, C.-W. Tsai, G.-D. Li, and J.-D. Chai, J. Chem. Phys., 2012, 136, 154109], we expand the EA115 and FG115 databases to include, respectively, the vertical electron affinities and fundamental gaps of the additional 16 molecules, and develop a new database AE113 (113 atomization energies), consisting of accurate reference values for the atomization energies of the 113 molecules in IP131. These databases will be useful for assessing the accuracy of density functional methods.Comment: accepted for publication in Phys. Chem. Chem. Phys., 46 pages, 4 figures, supplementary material include

Simultaneous rota-stenting and transcatheter aortic valve implantation for patients with heavily calcified coronary stenosis and aortic stenosis

AbstractGiven that coronary artery disease (CAD) in octogenarians undergoing transcatheter aortic valve implantation (TAVI) often presents with more complex lesions and extensive calcification, rotational atherectomy (RA) may be needed in some cases before stenting. However, data regarding the feasibility and safety of simultaneous RA during TAVI using the Medtronic CoreValve (MCV; Medtronic, Minneapolis, MN, USA) system are lacking. Three out of 107 (2.8%) patients (2 females, average age 85.6 years, mean aortic valve area 0.5 cm2, mean left ventricular ejection fraction 39%, mean Logistic EuroScore 70%), with complex, heavily calcified coronary stenosis, and severe valvular aortic stenosis (AS) were treated with TAVI and RA due to high surgical risk. After balloon valvuloplasty, all coronary lesions were successfully treated with RA and stenting, immediately followed by transfemoral TAVI with a self-expandable MCV. Our data suggested that in the very elderly patients with severe and heavily calcified CAD and AS who were turned down for cardiac surgery, RA and stenting followed by TAVI may be performed successfully in a combined, single-stage procedure