A5044267250- Cardiac electrophysiology and arrhythmias
- Ion channel regulation and function
- Receptor Mechanisms and Signaling
- Insect and Pesticide Research
- Electrochemical Analysis and Applications
- Neuroscience and Neural Engineering
- Nicotinic Acetylcholine Receptors Study
- Insect Pest Control Strategies
- Probabilistic and Robust Engineering Design
- Cholinesterase and Neurodegenerative Diseases
- Redox biology and oxidative stress
- Fuel Cells and Related Materials
- Atomic and Subatomic Physics Research
- Neurobiology and Insect Physiology Research
- Analytical Methods in Pharmaceuticals
- Venomous Animal Envenomation and Studies
- Insect Resistance and Genetics
- Nanopore and Nanochannel Transport Studies
- Enzyme Structure and Function
- Glycosylation and Glycoproteins Research
- Lipid Membrane Structure and Behavior
- Electrostatic Discharge in Electronics
- Cardiac pacing and defibrillation studies
- PARP inhibition in cancer therapy
- RNA and protein synthesis mechanisms
Victor Chang Cardiac Research Institute
2016-2025
UNSW Sydney
2016-2025
St Vincent's Clinic
2016-2021
University of Technology Sydney
2008-2018
Mathematical models are increasingly being relied upon to provide quantitatively accurate predictions of cardiac electrophysiology. Many such concern the behaviour particular subcellular components (namely, ion channels) which, together, allow propagation electrical signals through heart-muscle tissue; that is, firing action potentials. In particular, I Kr , a voltage-sensitive potassium ion-channel current, is interest owing central pore its primary protein having propensity blockage by...
Abstract When using mathematical models to make quantitative predictions for clinical or industrial use, it is important that come with a reliable estimate of their accuracy (uncertainty quantification). Because complex biological systems are always large simplifications, model discrepancy arises—models fail perfectly recapitulate the true data generating process. This presents particular challenge making accurate predictions, and especially accurately quantifying uncertainty in these...
Se-ing is believing: Many proteins are cross-braced by disulfide bonds that frequently play key roles in protein structure, folding, and function. Unfortunately, the methods available for assignment of disulfide-bond connectivities technically difficult prone to misinterpretation. Now bond native can be visualized directly using 77Se NMR spectroscopy.
The hERG (human ether-a-go-go-related gene) encoded potassium ion (K+) channel plays a major role in cardiac repolarization. Drug-induced blockade of has been cause potentially lethal ventricular tachycardia termed Torsades de Pointes (TdPs). Therefore, we presented pharmacoinformatics strategy using combined ligand and structure based models for the prediction inhibition potential (IC50) new chemical entities (NCEs) during early stages drug design development. Integrated GRid-INdependent...
Current mandated preclinical tests for drug-induced proarrhythmia are very sensitive, but not sufficiently specific. This has led to concern that there is a high attrition rate of potentially safe drugs could have been beneficial patients. The comprehensive in vitro initiative proposed new metrics based around silico risk predictions, which informed, among other things, by measures human ether-à-go-go-related gene channel (hERG) block kinetics. However, high-throughput patch-clamp systems...
The Janus-faced atracotoxins are a unique family of excitatory peptide toxins that contain rare vicinal disulfide bridge. Although lethal to wide range invertebrates, their molecular target has remained enigmatic for almost decade. We demonstrate here these selective, high-affinity blockers invertebrate Ca(2+)-activated K(+) (K(Ca)) channels. atracotoxin (J-ACTX)-Hv1c, the prototypic member this toxin family, selectively blocked K(Ca) channels in cockroach unpaired dorsal median neurons with...
Current guidelines around preclinical screening for drug-induced arrhythmias require the measurement of potency block voltage-gated potassium channel subtype 11.1 (K<sub>v</sub>11.1) as a surrogate risk. A shortcoming this approach is that measured IC<sub>50</sub> K<sub>v</sub>11.1 varies widely depending on voltage protocol used in electrophysiological assays. In study, we aimed to investigate factors contribute these differences and identify whether it possible make predictions about...
We provide details of a series short voltage-clamp protocols designed for gathering large amount information on hERG (K v 11.1) ion channel gating. The have limited number steps and consist only ramps, making them easy to implement any patch clamp setup, including automated platforms. primary objective is assist with parameterisation, selection refinement mathematical models detail manual model-driven designs, together an explanation their rationale design criteria. Although the are intended...
Spider venoms are actively being investigated as sources of novel insecticidal agents for biopesticide engineering. After screening 37 theraphosid spider venoms, a family three new "short-loop" inhibitory cystine knot toxins (κ-TRTX-Ec2a, κ-TRTX-Ec2b, and κ-TRTX-Ec2c) were isolated characterized from the venom African tarantula <i>Eucratoscelus constrictus</i>. Whole-cell patch-clamp recordings cockroach dorsal unpaired median neurons revealed that, despite significant sequence homology with...
Abstract The canonical mechanistic model explaining potassium channel gating is of a conformational change that alternately dilates and constricts collar-like intracellular entrance to the pore. It based on premise K + ions maintain complete hydration shell while passing between transmembrane cavity cytosol, which must be accommodated. To put test, we locked conformation Kir prevent widening narrow collar. Unexpectedly, conduction was unimpaired in channels. In parallel, employed all-atom...
Drug block of voltage-gated potassium channel subtype 11.1 human ether-a-go-go related gene (K<sub>v</sub>11.1) (hERG) channels, encoded by the <i>KCNH2</i> gene, is associated with reduced repolarization cardiac action potential and predominant cause acquired long QT syndrome that can lead to fatal arrhythmias. Current safety guidelines require potency K<sub>V</sub>11.1 assessed in preclinical phase drug development. However, not all drugs are proarrhythmic, meaning screening on basis...
is one of the 59 medically actionable genes recommended by American College Medical Genetics for reporting incidental findings from clinical genomic sequencing. However, half reported
Hydroxychloroquine, chloroquine and azithromycin are three drugs that were proposed to treat coronavirus disease 2019 (COVID-19). While concern already existed around their proarrhythmic potential, there little data regarding how altered physiological states encountered in patients such as febrile state, electrolyte imbalances or acidosis might change risk profiles.Potency of human ether-à-go-go related gene (hERG) block was measured using high-throughput electrophysiology the presence...
Selen als Sehhilfe: Viele Proteine enthalten verbrückende Disulfidbindungen, die häufig eine wesentliche Rolle für Proteinstruktur, -faltung und -funktion spielen. Doch Methoden, um Verknüpfungsmuster von Disulfidbindungen in Proteinen zu bestimmen, sind technisch schwierig führen leicht Fehlinterpretationen. Nun ist es möglich, diese Verknüpfungen nativen direkt mithilfe der 77Se-NMR-Spektroskopie visualisieren.
Vicinal disulfide bridges, in which a bond is formed between adjacent cysteine residues, constitute an unusual but expanding class of potential allosteric disulfides. Although vicinal rings (VDRs) are relatively uncommon, they have proven to be functionally critical almost all proteins been discovered. However, it has proved difficult test whether these sterically constrained disulfides participate important redox transformations. We demonstrate that chemical replacement VDRs with dicarba or...
<ns4:p>Automated patch-clamp platforms are widely used and vital tools in both academia industry to enable high-throughput studies such as drug screening. A leak current ground occurs whenever the seal between a pipette cell (or internal solution machines) is not perfectly insulated from bath (extracellular) solution. Over 1 GΩ resistance solutions commonly quality standard for manual patch work. With automated it can be difficult obtain high intra- extra-cellular solutions. One suggested...
Mathematical models are increasingly being relied upon to provide quantitatively accurate predictions of cardiac electrophysiology. Many such concern the behaviour particular subcellular components (namely, ion channels) which, together, allow propagation electrical signals through heart-muscle tissue - namely, firing action potentials. In particular, I Kr , a voltage-sensitive potassium ion-channel current, is interest owing its central pore's propensity for blockage by various small...
Spider venoms are a rich source of insecticidal peptide toxins. Their development as bioinsecticides has, however, been hampered due to concerns about potential lack stability and oral bioactivity. We therefore systematically evaluated several synthetic strategies increase the potency potent spider-venom ω-HXTX-Hv1a (Hv1a). Selective chemical replacement disulfide bridges with diselenide bonds N- C-terminal cyclization were anticipated improve Hv1a resistance proteolytic digestion, thereby...
Automated patch-clamp platforms are widely used and vital tools in both academia industry to enable high-throughput studies such as drug screening. A leak current ground occurs whenever the seal between a pipette cell (or internal solution machines) is not perfectly insulated from bath (extracellular) solution. Over 1 GΩ resistance solutions commonly quality standard for manual patch work. With automated it can be difficult obtain high intra- extra-cellular solutions. One suggested method...