Quantitative Brain Dynamics. This proposal will benefit Australia through unique and fundamental contributions to understanding brain dynamics via the development of innovative approaches and technologies. It will contribute to the national priority goals of Breakthrough Science, Frontier Technologies, and Promoting an Innovation Culture and Economy. Science outcomes will include improved understanding and probing of brain self-organization, dynamics, and function, including unique contributio ....Quantitative Brain Dynamics. This proposal will benefit Australia through unique and fundamental contributions to understanding brain dynamics via the development of innovative approaches and technologies. It will contribute to the national priority goals of Breakthrough Science, Frontier Technologies, and Promoting an Innovation Culture and Economy. Science outcomes will include improved understanding and probing of brain self-organization, dynamics, and function, including unique contributions to understanding alertness and the foundations of vision. These outcomes will be applied to develop new technologies for brain imaging and monitoring.Read moreRead less
Membrane-associated structure and the effect of metals on Abeta peptide from Alzheimer's disease. Alzheimer's disease currently affects 5% of Australians over 65, and will triple by year 2050 without an effective therapy. Much research to understand the causes of the disease has focused on the distinctive amyloid deposits found in patients' cerebral tissue. Recent evidence suggests that nerve cell death is actually directly caused by soluble forms of the protein fragments and metals that form th ....Membrane-associated structure and the effect of metals on Abeta peptide from Alzheimer's disease. Alzheimer's disease currently affects 5% of Australians over 65, and will triple by year 2050 without an effective therapy. Much research to understand the causes of the disease has focused on the distinctive amyloid deposits found in patients' cerebral tissue. Recent evidence suggests that nerve cell death is actually directly caused by soluble forms of the protein fragments and metals that form these deposits. We will investigate the specific molecular structure of these fragments with metals in relation to vesicles which mimic the nerve cell surface. This information may facilitate future biomedical efforts work to develop therapies, as well as develop general techniques to study similar structural problems.Read moreRead less
Characterisation of two-pore domain potassium channels: structure-function studies of the M1-P1 loops of TASK channels. TWIK-related Acid Sensitive K+ (TASK) channels are members of the novel class of two-pore domain potassium channel family. They are potently inhibited by local anaesthetics and have been implicated as having important roles in many pathophysiological conditions such as heart arrythmias, stroke, epilepsy, breast and other cancers. The in depth structural and functional character ....Characterisation of two-pore domain potassium channels: structure-function studies of the M1-P1 loops of TASK channels. TWIK-related Acid Sensitive K+ (TASK) channels are members of the novel class of two-pore domain potassium channel family. They are potently inhibited by local anaesthetics and have been implicated as having important roles in many pathophysiological conditions such as heart arrythmias, stroke, epilepsy, breast and other cancers. The in depth structural and functional characterisation of this class of potassium channels is of great importance as they are interesting targets for new therapeutic developments. Advancement of knowledge in the structure and function of these channels will underpin drug targeting that will aid preventative healthcare, allowing Australians to age well and age productively.Read moreRead less
Parametric Brain Imaging via Modeling and Analysis of Electroencephalographic Signals. Parameters of brain function and physiology will be spatially imaged with high time resolution via their effects on electroencephalographic (EEG) signals, a form of imaging that is impossible with existing methods. This will be achieved by improving existing physiologically-based models of the generation of EEGs and developing analysis tools based on fitting of model predictions to multielectrode EEG data. T ....Parametric Brain Imaging via Modeling and Analysis of Electroencephalographic Signals. Parameters of brain function and physiology will be spatially imaged with high time resolution via their effects on electroencephalographic (EEG) signals, a form of imaging that is impossible with existing methods. This will be achieved by improving existing physiologically-based models of the generation of EEGs and developing analysis tools based on fitting of model predictions to multielectrode EEG data. The results will be used to probe spatiotemporal features of EEGs in normal subjects to explore the underlying fundamental mechanisms and to infer novel parameter variations of practical relevance.Read moreRead less
Electro-active and migratory peptides in lipid bilayers: NMR and biophysical studies. All living things are characterized by the separation of inner space from the surrounding medium by a self-assembling membrane. Selective entry and exit of water, ions and solutes is a defining feature of each type of cell. Some proteins sense the voltage difference across the cell membrane and open or close in response to voltage changes. Others, like bacterial toxins assemble in the membrane as pores, while o ....Electro-active and migratory peptides in lipid bilayers: NMR and biophysical studies. All living things are characterized by the separation of inner space from the surrounding medium by a self-assembling membrane. Selective entry and exit of water, ions and solutes is a defining feature of each type of cell. Some proteins sense the voltage difference across the cell membrane and open or close in response to voltage changes. Others, like bacterial toxins assemble in the membrane as pores, while other peptides migrate across the membrane piggy-backing their peptide cargo. The aim is to understand the molecular mechanisms in examples of these membrane-active peptides and proteins with a view to enabling rational intervention into their operation in situ in normal and disease states.Read moreRead less
NMR studies of membrane proteins and peptides in novel amphiphilic mesophases. Membrane proteins are the next frontier in structural biology. Our goal is the structural and mechanistic characterization of the proteins and peptides from platypus venom and a cardiac potassium ion channel, HERG, that has a particular role in the suppression of cardiac arrhythmias. To do this we will refine and develop methods using amphiphilic mesophases and micelles and state-of-the-art NMR spectroscopy. Electrop ....NMR studies of membrane proteins and peptides in novel amphiphilic mesophases. Membrane proteins are the next frontier in structural biology. Our goal is the structural and mechanistic characterization of the proteins and peptides from platypus venom and a cardiac potassium ion channel, HERG, that has a particular role in the suppression of cardiac arrhythmias. To do this we will refine and develop methods using amphiphilic mesophases and micelles and state-of-the-art NMR spectroscopy. Electrophysiological analysis of ion channels and interactions with toxins will relate NMR structures to function. The NMR methodologies we develop will have broad applicability to membrane proteins in general.
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Protein chips for the high-throughput study of immune complexes by mass spectrometry. Mass spectrometry is a core enabling technology for proteomics with proteins identified by molecular weight, mass maps and sequencing within the confines of a mass spectrometer. We have found conditions under which it is possible to preserve and detect protein complexes by matrix-assisted laser desorption ionization (MALDI) mass spectrometry that has promising implications for the high-throughput screening of p ....Protein chips for the high-throughput study of immune complexes by mass spectrometry. Mass spectrometry is a core enabling technology for proteomics with proteins identified by molecular weight, mass maps and sequencing within the confines of a mass spectrometer. We have found conditions under which it is possible to preserve and detect protein complexes by matrix-assisted laser desorption ionization (MALDI) mass spectrometry that has promising implications for the high-throughput screening of protein-protein interactions. Technologies pioneered by the applicant will be advanced to achieve the high-throughput analysis of antibody complexes with native gel recovered protein antigens across emerging strains of the influenza virus by means of miniature protein chips.Read moreRead less
In-situ Scanning Probe Microscopy of biological redox processes: nanoscale structure and morphology. The science behind this project underpins the development of nanobiotechnology. Immediate applications foreseen, are the development of biosensors and diagnostic devices based on our intimate knowledge of the nature of the protein attachment to a surface. Use of synthetic membranes to create biomimetic surfaces will impact significantly on our understanding of the role and contribution membranes ....In-situ Scanning Probe Microscopy of biological redox processes: nanoscale structure and morphology. The science behind this project underpins the development of nanobiotechnology. Immediate applications foreseen, are the development of biosensors and diagnostic devices based on our intimate knowledge of the nature of the protein attachment to a surface. Use of synthetic membranes to create biomimetic surfaces will impact significantly on our understanding of the role and contribution membranes have on protein structure, function hence disease.Read moreRead less
Nuclear magnetic resonance (NMR) studies of complex cellular responses: isotopomer sub-spaces, 'lost' ATP and 'tunable' anisotropy. Red blood cells (RBCs) transport oxygen around the body but they have other roles that are mediated by complex interconnecting metabolic pathways that generate myriad metabolites including ATP. A longstanding conundrum is the inability to account for ~60% of ATP turnover in human RBCs. Processes that may consume this 'lost' ATP, include autonomous motion of the cel ....Nuclear magnetic resonance (NMR) studies of complex cellular responses: isotopomer sub-spaces, 'lost' ATP and 'tunable' anisotropy. Red blood cells (RBCs) transport oxygen around the body but they have other roles that are mediated by complex interconnecting metabolic pathways that generate myriad metabolites including ATP. A longstanding conundrum is the inability to account for ~60% of ATP turnover in human RBCs. Processes that may consume this 'lost' ATP, include autonomous motion of the cell membrane called 'flickering', and maintenance of the biconcave-disc shape. NMR spectroscopy of quadrupolar nuclei in chiral aligned media, and isotopomer analysis will be used to define the kinetics of metabolism and membrane processes and thus help define the molecular basis of major blood disorders. Read moreRead less
Ionic Dispersion Forces in Physical Chemistry: Implications for pH, Electrochemistry, Nanoparticle Formation and Organic Synthesis. Our current understanding of charged systems in solution is deeply flawed . Existing theories are not predictive, mainly because they concentrate entirely on electrostatics. This proposal aims to partially rectify this by including the effects of previously neglected dispersion forces in a number of problems. These forces are responsible for much of the behaviou ....Ionic Dispersion Forces in Physical Chemistry: Implications for pH, Electrochemistry, Nanoparticle Formation and Organic Synthesis. Our current understanding of charged systems in solution is deeply flawed . Existing theories are not predictive, mainly because they concentrate entirely on electrostatics. This proposal aims to partially rectify this by including the effects of previously neglected dispersion forces in a number of problems. These forces are responsible for much of the behaviour seen in the following systems: the theory of electrolytes; electrochemistry pH and buffers; self energy effects in organic chemistry; and zeolite and nano-particle synthesis. The main outcome will be accurate and predictive theories for these systems.Read moreRead less