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.

The C-H Peripheral Stalk Base: A Novel Component in V1-ATPase Assembly

Abstract: Vacuolar ATPases (V-ATPases) are molecular machines responsible for creating electrochemical gradients and preserving pH-dependent cellular compartments by way of proton translocation across the membrane. V-ATPases employ a dynamic rotary mechanism that is driven by ATP hydrolysis and the central rotor stalk. Regulation of this rotational catalysis is the result of a reversible V1Vo-domain dissociation that is required to preserve ATP during instances of cellular starvation. Recently the method by which the free V1-ATPase abrogates the hydrolytic breakdown of ATP upon dissociating from the membrane has become increasingly clear. In this instance the central stalk subunit F adopts an extended conformation to engage in a bridging interaction tethering the rotor and stator components together. However, the architecture by which this mechanism is stabilized has remained ambiguous despite previous work. In an effort to elucidate the method by which the rotational catalysis is maintained, the architecture of the peripheral stalks and their respective binding interactions was investigated using cryo-electron microscopy. In addition to confirming the bridging interaction exuded by subunit F for the first time in a eukaryotic V-ATPase, subunits C and H are seen interacting with one another in a tight interaction that provides a base for the three EG peripheral stalks. The formation of a CE3G3H sub-assembly appears to be unique to the dissociated V-ATPase and highlights the stator architecture in addition to revealing a possible intermediate in the assembly mechanism of the free V1-ATPase.

Heart transplantation following donation after circulatory death: Expanding the donor pool.

Abstract: Heart transplantation from donation after circulatory death (DCD) donors is a rapidly expanding practice. In this review, we describe the history and challenges of DCD heart transplantation and overview the procurement protocols and methods of limiting ischemic injury, current outcomes, and future directions. There are now at least three protocols that permit resuscitation and viability assessment of the DCD heart either in situ or ex situ. While the retrieval protocol for hearts from DCD donors will depend on local regulations, the outcomes of DCD heart transplant recipients reported to date are excellent regardless of the retrieval protocol and are comparable to the outcomes of heart transplant recipients from donation after brain death (DBD) donors. In the two centers with the largest published experience, DCD heart transplantation now accounts for one third of their heart transplant activity. With international trends indicating that there is an increasing utilisation of the DCD pathway, it is expected that DCD donors will become a major source of heart donation worldwide.

Nkx2.5 marks angioblasts that contribute to hemogenic endothelium of the endocardium and dorsal aorta

Abstract: As an animal embryo develops, it establishes a circulatory system that includes the heart, vessels and blood. Vessels and blood initially form in the yolk sac, a membrane that surrounds the embryo. These yolk sac vessels act as a rudimentary circulatory system, connecting to the heart and blood vessels within the embryo itself. In older embryos, cells in the inner layer of the largest blood vessel (known as the dorsal aorta) generate blood stem cells that give rise to the different types of blood cells. A gene called Nkx2.5 encodes a protein that controls the activity of a number of complex genetic programs and has been long studied as a key player in the development of the heart. Nkx2.5 is essential for forming normal heart muscle cells and for shaping the primitive heart and its surrounding vessels into a working organ. Interfering with the normal activity of the Nkx2.5 gene results in severe defects in blood vessels and the heart. However, many details are missing on the role played by Nkx2.5 in specifying the different cellular components of the circulatory system and heart. Zamir et al. genetically engineered chick and mouse embryos to produce fluorescent markers that could be used to trace the cells that become part of blood vessels and heart. The experiments found that some of the cells that form the blood and vessels in the yolk sac originate from within the membranes surrounding the embryo, outside of the areas previously reported to give rise to the heart. The Nkx2.5 gene is active in these cells for only a short period of time as they migrate toward the heart and dorsal aorta, where they give rise to blood stem cells These findings suggest that Nkx2.5 plays an important role in triggering developmental processes that eventually give rise to blood vessels and blood cells. The next step following on from this work will be to find out what genes the protein encoded by Nkx2.5 regulates to drive these processes. Mapping the genes that control the early origins of blood and blood-forming vessels will help biologists understand this complex and vital tissue system, and develop new treatments for patients with conditions that affect their circulatory system. In the future, this knowledge may also help to engineer synthetic blood and blood products for use in trauma and genetic diseases.

Concentration dependent effect of GsMTx4 on mechanosensitive channels of small conductance in E. coli spheroplasts

Abstract: The spider peptide GsMTx4, at saturating concentration of 5 muM, is an effective and specific inhibitor for stretch-activated mechanosensitive (MS) channels found in a variety of eukaryotic cells. Although the structure of the peptide has been solved, the mode of action remains to be determined. Because of its amphipathic structure, the peptide is proposed to interact with lipids at the boundaries of the MS channel proteins. In addition, GsMTx4 has antimicrobial effects, inhibiting growth of several species of bacteria in the range of 5-64 microM. Previous studies on prokaryotic MS channels, which serve as model systems to explore the principle of MS channel gating, have shown that various amphipathic compounds acting at the protein-lipid interface affect MS channel gating. We have therefore analyzed the effect of different concentrations of extracellular GsMTx4 on MS channels of small conductance, MscS and MscK, in the cytoplasmic membrane of wild-type E. coli spheroplasts using the patch-clamp technique. Our study shows that the peptide GsMTx4 exhibits a biphasic response in which peptide concentration determines inhibition or potentiation of activity in prokaryotic MS channels. At low peptide concentrations of 2 and 4 microM the gating of the prokaryotic MS channels was hampered, manifested by a decrease in pressure sensitivity. In contrast, application of peptide at concentrations of 12 and 20 microM facilitated prokaryotic MS channel opening by increasing the pressure sensitivity.