Victor Chang Cardiac Research Institute

About: Victor Chang Cardiac Research Institute is a nonprofit organization based out in Sydney, New South Wales, Australia. It is known for research contribution in the topics: Mechanosensitive channels & Heart failure. The organization has 708 authors who have published 1599 publications receiving 70035 citations.

Effect of S5P α-helix charge mutants on inactivation of hERG K+ channels

Abstract: The ether-a-go-go (EAG) family of voltage-gated K+ channels contains three subfamilies, EAG, ether-a-go-go related (ERG) and ether-a-go-go like (ELK). The human ether-a-go-go related gene (hERG) K+ channel has been of significant interest because loss of function in the hERG channel is associated with a markedly increased risk of cardiac arrhythmias. The hERG channel has unusual kinetics with slow activation and deactivation but very rapid and voltage-dependent inactivation. The outer pore region of the hERG K+ channel is predicted to be different from that of other members of the voltage-gated K+ channel family. HERG has a much longer linker between the fifth transmembrane domain (SS) and the pore helix (S5P linker) compared to other families of voltage-gated K+ channels (43 amino acids compared to 14–23 amino acids). Further, the S5P linker contains an amphipathic α-helix that in hERG channels probably interacts with the mouth of the pore to modulate inactivation. The human EAG and rat ELK2 channels (hEAG and rELK2) show reduced or no inactivation in comparison to hERG channels, yet both channels are predicted to contain a similarly long S5P linker to that of hERG. In this study, we have constructed a series of chimaeric channels consisting of the S1–S6 of hERG but with the S5P α-helical region of either hEAG or rELK2, and one consisting of the S1–S6 of rELK2 but with the S5P α-helical region of hERG to investigate the role of the S5P linker in inactivation. Our studies show that charged residues on the α-helix of the S5P linker contribute significantly to the differences in inactivation characteristics of the EAG family channels. Further, individually mutating each of the hydrophilic residues on the S5P α-helix of hERG to a charged residue had significant effects on the voltage dependence of inactivation and the two residues with the greatest affect when mutated to a lysine, N588 and Q592, both lie on the same face of the S5P α -helix. We suggest that inactivation of hERG involves the interaction of this face of the S5P α-helix with a charged residue on the remainder of the outer pore domain of the channel.

Oligoastrocytomas: throwing the baby out with the bathwater?

Abstract: biology, clinical trial design, and future treatment deci-sions. OA should not be ignored in the proposed new clas-sification guidelines [2].Sahm and colleagues studied 43 cases diagnosed as OA based on histology. But in 30 of these cases, immunostain-ing for IDH1 (R132H) mutation was restricted to oligo-dendroglial areas only. The astrocytic component of these tumours was re-interpreted to be reactive in nature [4], and they were reclassified as oligodendroglioma. We propose that this finding indicates that ‘true’ OAs (i.e. tumours com-posed of two distinct

On-line Synthesis of the Human Ascending Aortic Pressure Pulse From the Finger Pulse

Abstract: Although systolic pressure in the ascending aorta (AA) can be determined accurately from the radial arterial waveform using a single generalized transfer function (TF) of the upper limb, a better on-line methods is needed for accurate noninvasive synthesis of the AA pressure contour to characterize left ventricular contractile function and ventricular-vascular coupling. AA, tonometric carotid (CA), and photoplethysmographic finger (FA) arterial pressure waveforms were recorded in 12 subjects (10 male, aged 59.1+/-10.3 years, mean+/-SD) during cardiac catheterization. The AA-FA TF was estimated using (1) a single generalized TF (GAA), (2) individualized TFs directly determined from CA-FA recordings in each patient (DAA), and (3) individualized TFs computed from CA-FA recordings in each patient with a mathematical model of the human upper limb (MAA). AA pressure waveforms were synthesized from FA recordings in real time using convolution windows derived from these TFs. Under steady state conditions, the root mean square error (RMSE) between measured and synthesized AA was lower by DAA (3.3+/-1.3 mm Hg) and MAA (3.9+/-1.2 mmHg) than by GAA (4.8+/-2.0 mm Hg, P<.05). During dynamic load alteration induced by the Valsalva maneuver, however, the MAA method performed better (5.4+/-2.8 mm Hg) than both the GAA (5.8+/-3.3 mm Hg, P<.05) and DAA (6.5+/-2.7 mm Hg, P<.01) methods. The beat-to-beat AA contour can be accurately and noninvasively synthesized on-line using individualized TFs. During dynamic load alteration, individualized TFs derived with an upper limb arterial model provide greater accuracy.