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.

Real-Time Bioimpedance Sensing of Antifibrotic Drug Action in Primary Human Cells

Abstract: Fibrotic diseases are among the most serious health issues with severe burdens due to their chronic nature and a large number of patients suffering from the debilitating effects and long-term sequelae. Collagenase treatment is a nonsurgical option but has limited results. To date, there is no potent noninvasive solution for fibrosis. Part of the reason for this is the lack of appropriate in vitro live cell screening tools to assess the efficacy of new therapeutical agents. Here, we demonstrate the utility of a cell-based electrochemical impedance biosensor platform to screen the efficacy of potential antifibrotic compounds. The platform employs a label-free and noninvasive strategy to detect the progression of fibrosis and the potency of the antifibrotic molecules in real-time. The fundamental principle that governs this novel system is that dynamic changes in cell shape and adhesion during fibrosis can be measured accurately by monitoring the changes in the impedance. This is achieved by growing the cell...

High-Frequency Echocardiography - Transformative Clinical and Research Applications in Humans, Mice, and Zebrafish.

Abstract: Echocardiography is an invaluable tool for characterizing cardiac structure and function in vivo. Technological advances in high-frequency ultrasound over the past 3 decades have increased spatial and temporal resolution, and facilitated many important clinical and basic science discoveries. Successful reverse translation of established echocardiographic techniques, including M-mode, B-mode, color Doppler, pulsed-wave Doppler, tissue Doppler and, most recently, myocardial deformation imaging, from clinical cardiology into the basic science laboratory has enabled researchers to achieve a deeper understanding of myocardial phenotypes in health and disease. With high-frequency echocardiography, detailed evaluation of ventricular systolic function in a range of small animal models is now possible. Furthermore, improvements in frame rate and the advent of diastolic strain rate imaging, when coupled with the use of select pulsed-wave Doppler parameters, such as isovolumic relaxation time and E wave deceleration, have enabled nuanced interpretation of ventricular diastolic function. Comparing pulsed-wave Doppler indices of atrioventricular inflow during early and late diastole with parameters that describe the simultaneous myocardial deformation (e.g., tissue Doppler e and a, global longitudinal strain rate and global longitudinal velocity) may yield additional insights related to myocardial compliance. This review will provide a historical perspective of the development of high-frequency echocardiography and consider how ongoing innovation will help future-proof this important imaging modality for 21st century translational research.

Structural Dynamics of the MscL C-terminal Domain.

Abstract: The large conductance mechanosensitive channel (MscL), acts as an osmoprotective emergency valve in bacteria by opening a large, water-filled pore in response to changes in membrane tension. In its closed configuration, the last 36 residues at the C-terminus form a bundle of five α-helices co-linear with the five-fold axis of symmetry. Here, we examined the structural dynamics of the C-terminus of EcMscL using site-directed spin labelling electron paramagnetic resonance (SDSL EPR) spectroscopy. These experiments were complemented with computational modelling including molecular dynamics (MD) simulations and finite element (FE) modelling. Our results show that under physiological conditions, the C-terminus is indeed an α-helical bundle, located near the five-fold symmetry axis of the molecule. Both experiments and computational modelling demonstrate that only the top part of the C-terminal domain (from the residue A110 to E118) dissociates during the channel gating, while the rest of the C-terminus stays assembled. This result is consistent with the view that the C-terminus functions as a molecular sieve and stabilizer of the oligomeric MscL structure as previously suggested.

Hydrophobic interactions between the voltage sensor and pore mediate inactivation in Kv11.1 channels

Abstract: Kv11.1 channels are critical for the maintenance of a normal heart rhythm. The flow of potassium ions through these channels is controlled by two voltage-regulated gates, termed “activation” and “inactivation,” located at opposite ends of the pore. Crucially in Kv11.1 channels, inactivation gating occurs much more rapidly, and over a distinct range of voltages, compared with activation gating. Although it is clear that the fourth transmembrane segments (S4), within each subunit of the tetrameric channel, are important for controlling the opening and closing of the activation gate, their role during inactivation gating is much less clear. Here, we use rate equilibrium free energy relationship (REFER) analysis to probe the contribution of the S4 “voltage-sensor” helix during inactivation of Kv11.1 channels. Contrary to the important role that charged residues play during activation gating, it is the hydrophobic residues (Leu529, Leu530, Leu532, and Val535) that are the key molecular determinants of inactivation gating. Within the context of an interconnected multi-domain model of Kv11.1 inactivation gating, our REFER analysis indicates that the S4 helix and the S4–S5 linker undergo a conformational rearrangement shortly after that of the S5 helix and S5P linker, but before the S6 helix. Combining REFER analysis with double mutant cycle analysis, we provide evidence for a hydrophobic interaction between residues on the S4 and S5 helices. Based on a Kv11.1 channel homology model, we propose that this hydrophobic interaction forms the basis of an intersubunit coupling between the voltage sensor and pore domain that is an important mediator of inactivation gating.