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Energy Use And Work Output By Cross-bridges In Fast- And Slow-twitch Muscles
Funder
National Health and Medical Research Council
Funding Amount
$191,177.00
Summary
All voluntary movement is produced by the action of skeletal muscles. The muscles provide the mechanical power required to move the limbs and the body. To do so, they require energy which is ultimately derived from the breakdown of food. Therefore, we can describe the fundamental process underlying muscular contraction as the conversion of energy from a chemical form into a mechanical form. This project investigates the relationship between the breakdown of molecules that provide energy and the ....All voluntary movement is produced by the action of skeletal muscles. The muscles provide the mechanical power required to move the limbs and the body. To do so, they require energy which is ultimately derived from the breakdown of food. Therefore, we can describe the fundamental process underlying muscular contraction as the conversion of energy from a chemical form into a mechanical form. This project investigates the relationship between the breakdown of molecules that provide energy and the production of mechanical energy or work. Normal contraction involves many cyclic interactions between two proteins, actin and myosin. Each cycle produces a tiny force that contributes to the shortening of the muscle. For over 30 years, it has been thought that energy required for each force producing cycle was provided by the breakdown of one energy-providing molecule, called ATP. Almost all current models of muscle contraction are based on this idea. Recently, data from studies using isolated actin and myosin and observing their interaction in vitro have indicated that many force-producing cycles may be performed with the energy from just one ATP. If this is correct, it will revolutionise our ideas about the way muscles convert chemical energy into mechanical energy. However, the interaction of proteins in a dish is far removed from a normal muscle and the aim of this project is to determine the relationship between force producing cycles and energy use in intact muscles. If multiple force-producing cycles can be powered by one ATP molecule in intact muscle too, then the current idea that the biochemical processes that release energy from ATP are intimately linked to the mechanical changes in myosin that occur as it produces force will be untenable. In short, we will have to rediscover how muscles convert chemical energy into mechanical energy and find out how that energy can be stored from one force-producing cycle to the next.Read moreRead less
A Prospective Study Of The Psychiatric & Medical Characteristics Of Post-infective Fatigue & Chronic Fatigue Syndrome.
Funder
National Health and Medical Research Council
Funding Amount
$500,000.00
Summary
This project forms the central component of a larger set of studies which investigate competing psychiatric, immunological and infective models of the causes of a number of chronic fatigue syndromes, including post-infective fatigue. The study takes place in western NSW where certain viral illnesses (Glandular Fever, Ross River Virus) and a non-viral infection (QF) are common and have been associated with prolonged fatigue states. The study follows patients from laboratory-documented infections ....This project forms the central component of a larger set of studies which investigate competing psychiatric, immunological and infective models of the causes of a number of chronic fatigue syndromes, including post-infective fatigue. The study takes place in western NSW where certain viral illnesses (Glandular Fever, Ross River Virus) and a non-viral infection (QF) are common and have been associated with prolonged fatigue states. The study follows patients from laboratory-documented infections with appropriate infective, immunological and psychological measures throughout the course of their acute illness, the early recovery period and for the next 12 months. These patients are compared with people who present to their doctor with other forms of medically-unexplained fatigue. Very few previous studies have used an appropriate prospective design and followed patients with documented illness from the onset through to the development of specific forms of chronic fatigue. Further, the study is unique in terms of the range of viral and non-viral agents being investigated. It relies on the combined psychiatric, immunological and infective disease expertise of a group of researchers with an international reputation for the successful completion of such multidisciplinary projects. The initial phase of the study has demonstrated that the research team has the capacity to complete this project. Initial results have already demonstrated the potential roles of psychological and immunological factors in causing some cases of prolonged fatigue. Further, the initial results indicate that two key symptom sets (fatigue, psychological distress) can be adequately measured during the recovery phase and are predicted by differing psychological factors. The study will result in the identification of different psychiatric risk factors to chronic fatigue, assist development of clear diagnostic guidelines for post-infective fatigue and guide relevant aetiological and treatment research.Read moreRead less
Microbiological And Immunological Determinants Of Prolonged Illness Following Q Fever.
Funder
National Health and Medical Research Council
Funding Amount
$362,036.00
Summary
Q fever is a severe, sometimes life-threatening infection acquired by individuals who work with livestock, particularly abattoir workers. At least 10% of individuals who develop Q fever experience prolonged ill-health in the form of weeks or months of debilitating fatigue, profuse night sweats, headaches, as well as muscle and joint pains. This poorly understood persistent illness is associated with substantial disability and loss of income. This research is based upon an established cohort stud ....Q fever is a severe, sometimes life-threatening infection acquired by individuals who work with livestock, particularly abattoir workers. At least 10% of individuals who develop Q fever experience prolonged ill-health in the form of weeks or months of debilitating fatigue, profuse night sweats, headaches, as well as muscle and joint pains. This poorly understood persistent illness is associated with substantial disability and loss of income. This research is based upon an established cohort study in which subjects with acute, documented Q fever are recruited shortly after the onset of symptoms and followed at regular intervals through to recovery or persistent symptoms. The aim of this research is to determine whether abnormal persistence of the causative organsim of Q fever, Coxiella burnetii, underlies the continued symptoms in those who do not recover promptly from the acute illness. Furthermore, the research is examining the host defense response against the organism via the production of cytokines or immunological hormones, to determine whether these proteins mediate the ongoing symptoms. If confirmed, these hypotheses would lead the way to diagnostic markers for the disorder and a rational treatment strategy.Read moreRead less
Treatment Of Virally-induced Cancers By RNA Interference.
Funder
National Health and Medical Research Council
Funding Amount
$389,250.00
Summary
Cancers require certain mutations and the over expression of genes to cause disease. Each cancer has a unique set of gene changes thus making it difficult to treat. However, it has become clear that the normal control mechanisms of many cancers are still intact but are repressed by the over expression of these oncogenes (or cancer genes). By turning off these oncogenes we can restore normal control to the cell and the cancer will die normally. We will use a new method of gene targeting called RN ....Cancers require certain mutations and the over expression of genes to cause disease. Each cancer has a unique set of gene changes thus making it difficult to treat. However, it has become clear that the normal control mechanisms of many cancers are still intact but are repressed by the over expression of these oncogenes (or cancer genes). By turning off these oncogenes we can restore normal control to the cell and the cancer will die normally. We will use a new method of gene targeting called RNA interference to turn off oncogenes. RNA interference involves treatment of cells with a small peice of genetic material that provides the cell with an identity pattern of the gene to be eliminated. The cell takes the pattern and turms off the genes expression. As long as the pattern only turns off the cancer gene all other genes will remain normal. We will test this using cervical cancer as a model as all these cancers are caused by infection with a virus that carries 2 oncogenes. It is these virus oncogenes that cause the cancer and therefore we know the exact target genes that need to be turned off. Most importantly these genes are not present in normal cells making it safe to target them by RNA interference. We have gathered an expert group of investigators with experience in cervical cancer and cancer genetics to address this problem. If successful we will have proven this new technique can work against cervical cancer and this method could then be applied to any cancer. We would then be able to start human trials. Cervical cancer kills over 300 women in Australia each year, is the leading cause of cancer death in Aboriginal women, is 2nd most common cancer of women in the world and is the leading cancer killer worldwide in women under 50.Read moreRead less
I am a physiologist investigating the molecular basis of normal function in skeletal muscle and the dysfunctions occurring in various muscle diseases and in fatigue. In addition, I investigate analogous dysfunction of calcium release and excitability occu
Immunopathogenesis Of Varicella Zoster Virus Infection
Funder
National Health and Medical Research Council
Funding Amount
$346,250.00
Summary
Varicella zoster virus (VZV) is a herpesvirus which infects up to 90% of the population. VZV causes chicken pox (varicella) predominantly in childhood and shingles (herpes zoster) in middle to old age people. Whilst VZV usually causes relatively mild disease in healthy individuals, VZV still causes significant morbidity in children and adults. VZV causes life-threatening disease in immunocompromised individuals such as patients who are elderly or have HIV disease. Shingles affects many elderly i ....Varicella zoster virus (VZV) is a herpesvirus which infects up to 90% of the population. VZV causes chicken pox (varicella) predominantly in childhood and shingles (herpes zoster) in middle to old age people. Whilst VZV usually causes relatively mild disease in healthy individuals, VZV still causes significant morbidity in children and adults. VZV causes life-threatening disease in immunocompromised individuals such as patients who are elderly or have HIV disease. Shingles affects many elderly individuals and a major complication is prolonged severe pain or post-herpetic neuralgia (PHN), which can be severely debilitating and often requires follow-up medical care for months or even years after the initial attack. Despite its significant impact on the community, little is known about how this virus functions and causes disease. This project aims to improve our understanding of how VZV infection affects specialised human cells in order to provide novel information for the development of therapies aimed at lessening the impact of VZV disease on the community. This project has four components: (1) We will continue studies which have shown that VZV causes programmed cell death (apoptosis) in human skin cells (fibroblasts) but not human nerve cells (neurons). We aim to identify viral genes responsible for the cell-type specific modulation of apoptosis in human neurons and fibroblasts (2) We will examine human sensory ganglia (clusters of human nerve cells) during shingles and determine what immune cells are present and whether neurons are undergoing apoptosis (3) To assess the impact of VZV infection on the ability of specialized immune cells (called dendritic cells) to mature properly (4) We have shown that VZV may actively avoid immune detection by interfering with the function of dendritic cells. We aim to identify the mechanism responsible for the virus interfering with the expression of immune molecules which are essential for our immune system.Read moreRead less
Using Single Patient Trials To Determine The Effectiveness Of Psychostimulants In Fatigue In Advanced Cancer Patients
Funder
National Health and Medical Research Council
Funding Amount
$162,563.00
Summary
The lack of good evidence in palliative care (PC) is widely acknowledged but research in PC is difficult. Methodological barriers include: difficulties in recruitment, high rates of attrition, problems with maintaining distinct and sustainable intervention strategies, poorly chosen outcomes and opposition to randomization. Organizational barriers include: lack of research infrastructure, few trained clinical researchers, prioritisation of clinical responsibilities and funding difficulties. The h ....The lack of good evidence in palliative care (PC) is widely acknowledged but research in PC is difficult. Methodological barriers include: difficulties in recruitment, high rates of attrition, problems with maintaining distinct and sustainable intervention strategies, poorly chosen outcomes and opposition to randomization. Organizational barriers include: lack of research infrastructure, few trained clinical researchers, prioritisation of clinical responsibilities and funding difficulties. The hierarchy of evidence rates RCTs as the gold standard. An alternative is the n-of-1 trial: a randomized, double-blind cross-over comparison of active drug with placebo or another drug. The patient is in effect their own control. N-of-1 trials provide an objective means of testing the effectiveness of medicines in individual patients, providing evidence stronger than RCT evidence for the efficacy of that drug in that particular individual. If multiple n-of-1 trials are conducted, the resultant data amounts to RCT evidence for that treatment in a population. We propose n-of-1 trials as a workable option for researching the benefit of drugs and other therapies in PC patients. If successful, this model could be accepted internationally as the gold standard for research in this difficult population group. This would be a world first and of great national and international significance. In advanced cancer, the prevalence of fatigue is very high at 60-90% and can be related to the treatment or the disease itself. The impact of fatigue on function (physical, mental, social and spiritual) and hence quality of life (QOL) is very significant for many palliative patients as well as their families-carers. The role of pyschostimulants in the management of fatigue in patients with advanced cancer and life limiting disease needs to be defined. We will conduct n-of-1 trials of psychostimulants (i.e. methylphenidate) for fatigue in a group of 40 patients, recruited from 5 sites around Australia through a national clinical trial network recently set up for palliative care research. Managing fatigue with treatment supported by the best possible evidence for individual patients and producing any improvement in fatigue will improve patients� functional status, and will greatly improve QOL for patients and carers.Read moreRead less
Molecular Mechanisms Of Varicella Zoster Virus Interactions With Key Target Cells
Funder
National Health and Medical Research Council
Funding Amount
$421,650.00
Summary
Varicella zoster virus (VZV) is a herpesvirus which infects up to 90% of the population. VZV causes chickenpox (varicella) predominantly in childhood and shingles (herpes zoster) in middle to old age people. Whilst VZV usually causes relatively mild disease in healthy individuals, VZV still causes significant morbidity in children and adults. VZV causes life-threatening disease in immunocompromised individuals such as patients who are elderly or have HIV disease . Herpes zoster affects many eder ....Varicella zoster virus (VZV) is a herpesvirus which infects up to 90% of the population. VZV causes chickenpox (varicella) predominantly in childhood and shingles (herpes zoster) in middle to old age people. Whilst VZV usually causes relatively mild disease in healthy individuals, VZV still causes significant morbidity in children and adults. VZV causes life-threatening disease in immunocompromised individuals such as patients who are elderly or have HIV disease . Herpes zoster affects many ederly individuals and a major complication is prolonged severe pain or post-herpetic neuralgia (PHN), both severely debilitating and which often requires follow-up medical care for months or years after the initial attack. Despite its significant impact on the community, little is known about the molecular details of how this virus functions. This project aims to improve our understanding of how VZV infection affects specialised human cells in order to make further advances in antiviral therapies as well improve vaccine design for the treatment or prevention of VZV disease and the crippling complication of PHN. This project has four components: (1) We will continue studies which have shown that VZV may actively avoid detection by the immune system. We aim to identify the mechanism and viral genes responsible for interfering with the expression of molecules which are essential for our immune system. (2) We will determine whether VZV infection of specialised immune cells (called dendritic cells) will affect their ability to function and interact with other immune cells (called T cells). (3) We will examine how VZV interacts in human nerve cells (neurons) and whether infected neurons undergo specially programmed cell death (apoptosis). (4) We will examine how different human cells change when they are infected with VZV. A new and exciting technology called DNA microarray now makes it possible to examine the expression of many thousands of genes in one experiment.Read moreRead less