Monash Biomedicine Discovery Institute

Clayton, Australia

Monash Biomedicine Discovery Institute

Clayton, Australia

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News Article | May 16, 2017
Site: www.eurekalert.org

An international study led by Monash University has discovered the molecular mechanism by which the potentially deadly superbug 'Golden Staph' evades antibiotic treatment, providing the first important clues on how to counter superbug antibiotic resistance. 'Superbugs' are bacteria that are resistant to commonly used antibiotics, presenting a global health threat. To tackle this global challenge, researchers from Monash's Biomedicine Discovery Institute (BDI) are collaborating with Israel's Weizmann Institute of Science, and the NTU Institute of Structural Biology in Singapore. Now, the Monash BDI researchers have identified the first important clues on how to 'retool' antibiotics to counter the strategies bacteria enlist to evade the life-saving drugs, with the findings published in the journal mBio. Researchers used the latest generation electron microscopes at the Monash Ramaciotti Centre for Electron Microscopy to image at the molecular level -- for the first time -- the changes that take place in superbugs that have become resistant to the most modern antibiotics. Examining bacterial samples of antibiotic-resistant Staphylococcus aureus or 'Golden Staph' taken from a hospital patient, they compared data of a non-resistant strain with their counterparts overseas. These included Shashi Bhushan from NTU, and Zohar Eyal and Nobel Laureate, Professor Ada Yonath from the Weizmann Institute who won the Nobel Prize for Chemistry in 2009. "Using the combined data we could rationalise how the bacteria escapes drug treatment by a really important hospital antibiotic and describe in molecular detail how it becomes like a superbug," said Monash BDI scientist and lead researcher Dr Matthew Belousoff. "The bacteria mutates or evolves to change the shape of the molecule to which the antibiotic would bind so the drug can no longer fit there," Dr Belousoff said. "Knowing what your enemy is doing is the first step to the next phase of new drug design," he said. "We've developed a technique that others can use that might help us speed up the arms race of antibiotic development." Dr Belousoff said Monash BDI researchers are now using this new tool to investigate other drug-resistant bacteria. The research, involving the expertise of Monash microscopist Dr Mazdak Radjainia and mentoring of Professor Trevor Lithgow, was supported by the Australian National Health and Medical Research Council (NHMRC). Read the full paper titled Structural basis for linezolid binding site rearrangement in the Staphylococcus aureus ribosome Committed to making the discoveries that will relieve the future burden of disease, the newly established Monash Biomedicine Discovery Institute at Monash University brings together more than 120 internationally-renowned research teams. Our researchers are supported by world-class technology and infrastructure, and partner with industry, clinicians and researchers internationally to enhance lives through discovery. The World Health Organisation has warned that new antibiotics were urgently needed to counter the growing threat of superbugs. It predicted that deaths from antimicrobial resistance could rise to 10 million by 2050, surpassing the total deaths caused by cancer and diabetes combined. If antibiotics lose their effectiveness, surgery and even treatment of wounds could become life-threatening.


News Article | May 18, 2017
Site: www.eurekalert.org

Findings from new research led by the Monash Biomedicine Discovery Institute (BDI) and University College London may finally resolve, and potentially provide answers, as to why older women have higher incidences of miscarriage and have babies with chromosomal abnormalities. Female fertility declines rapidly after the age of 37 -- with women over 42 having only a five per cent chance of having a baby without fertility treatment. The problem is that as a woman ages, her eggs also age -- increasing the chances of chromosomal abnormalities. This leads to an increase in conditions such as Down's syndrome, where the egg has three copies of chromosome 21. However most chromosomal abnormalities in eggs lead to embryos that either fail to implant in the womb, or miscarry soon after implantation. In women over 40 most miscarriages are caused by the wrong number of chromosomes being present in the egg. In a paper published today in Nature Communications, Professor John Carroll from the Monash BDI, together with an international team of collaborators, reveal a fault in how the egg controls the levels of a protein called securin. In the final stages of egg development just before ovulation, it undergoes two specialised cell divisions known as meiosis I and meiosis II. Securin is important for both divisions but in old eggs, it appears that there is insufficient securin remaining to ensure meiosis II takes place normally. Most chromosome abnormalities occur in the first egg division (meiosis I) but it is known that a substantial number of abnormalities also occur during meiosis II. Dr Ibtissem Nabti and Professor Carroll's experiments help explain why things go wrong in this second division. In these older women the chromosomes in their eggs start to fall apart because there is insufficient securin to control the process. Dr Nabti, formerly from University College London, is currently at the Abu Dhabi campus of New York University. The discovery opens the way to improving an older woman's chances of having eggs with fewer chromosomal abnormalities through regulating the processes that control securin levels in the two divisions of the egg or controlling the protein that securin regulates (a protein called separase). According to Professor Carroll, new therapeutic approaches to improving egg quality in older women is very important at a time when the age at which women are having their first baby is increasing. "It is immensely challenging because any treatments need to be safe for the egg and subseqents embryo and would usually need to be applied while the egg is in the ovary," Professor Carroll said. "It may one day be possible to perform treatments in-vitro (in the laboratory) but human in-vitro egg maturation is not yet very successful." The research team is working with Monash IVF to improve in vitro maturation and identify new targets that may be able to better control prevent the degradation of Securin, according to Professor Carroll. "Now that we have an idea of at least one of the causes of the increased incidence of chromosomal abnormalities and miscarriages in older women, we can attempt to find ways to prevent this happening," Professor Carroll said. Committed to making the discoveries that will relieve the future burden of disease, the newly established Monash Biomedicine Discovery Institute at Monash University brings together more than 120 internationally-renowned research teams. Our researchers are supported by world-class technology and infrastructure, and partner with industry, clinicians and researchers internationally to enhance lives through discovery.


News Article | May 18, 2017
Site: www.sciencedaily.com

Findings from new research led by the Monash Biomedicine Discovery Institute (BDI) and University College London may finally resolve, and potentially provide answers, as to why older women have higher incidences of miscarriage and have babies with chromosomal abnormalities. Female fertility declines rapidly after the age of 37 -- with women over 42 having only a five per cent chance of having a baby without fertility treatment. The problem is that as a woman ages, her eggs also age -- increasing the chances of chromosomal abnormalities. This leads to an increase in conditions such as Down's syndrome, where the egg has three copies of chromosome 21. However most chromosomal abnormalities in eggs lead to embryos that either fail to implant in the womb, or miscarry soon after implantation. In women over 40 most miscarriages are caused by the wrong number of chromosomes being present in the egg. In a paper published today in Nature Communications, Professor John Carroll from the Monash BDI, together with an international team of collaborators, reveal a fault in how the egg controls the levels of a protein called securin. In the final stages of egg development just before ovulation, it undergoes two specialised cell divisions known as meiosis I and meiosis II. Securin is important for both divisions but in old eggs, it appears that there is insufficient securin remaining to ensure meiosis II takes place normally. Most chromosome abnormalities occur in the first egg division (meiosis I) but it is known that a substantial number of abnormalities also occur during meiosis II. Dr Ibtissem Nabti and Professor Carroll's experiments help explain why things go wrong in this second division. In these older women the chromosomes in their eggs start to fall apart because there is insufficient securin to control the process. Dr Nabti, formerly from University College London, is currently at the Abu Dhabi campus of New York University. The discovery opens the way to improving an older woman's chances of having eggs with fewer chromosomal abnormalities through regulating the processes that control securin levels in the two divisions of the egg or controlling the protein that securin regulates (a protein called separase). According to Professor Carroll, new therapeutic approaches to improving egg quality in older women is very important at a time when the age at which women are having their first baby is increasing. "It is immensely challenging because any treatments need to be safe for the egg and subseqents embryo and would usually need to be applied while the egg is in the ovary," Professor Carroll said. "It may one day be possible to perform treatments in-vitro (in the laboratory) but human in-vitro egg maturation is not yet very successful." The research team is working with Monash IVF to improve in vitro maturation and identify new targets that may be able to better control prevent the degradation of Securin, according to Professor Carroll. "Now that we have an idea of at least one of the causes of the increased incidence of chromosomal abnormalities and miscarriages in older women, we can attempt to find ways to prevent this happening," Professor Carroll said.


News Article | May 23, 2017
Site: www.eurekalert.org

Inflammation is the process by which the body responds to injury or infection but when this process becomes out of control it can cause disease. Monash Biomedicine Discovery Institute (BDI) researchers, in collaboration with the Monash Institute of Pharmaceutical Sciences (MIPS), have shed light on a key aspect of the process. Their findings may help guide the development of new treatments of inflammatory diseases such as atherosclerosis, which can lead to heart attack or stroke, and type 2 diabetes. Published today in the journal Science Signaling, the research reveals how certain proteins cause the white blood cells that play a central role in inflammatory responses to behave in different ways. White blood cells are beneficial in helping to eliminate invading microorganisms or repair damaged tissue, but they can prolong the response and damage healthy tissues, leading to disease. The proteins, called chemokines, are secreted into blood vessels and activate chemokine receptors embedded in the outer membranes of the white blood cells. While it was previously thought that this occurred like an on-off switch, the scientists found that the chemokine receptor can behave more like a 'dimmer switch' with one chemokine giving a strong signal and another giving a weaker signal. They found that different responses can be caused by different chemokines activating the same receptor. This explained for the first time the mechanism by which white blood cells produced varying responses: a strong short-lived response (acute inflammation) or a steady, longer-lived response (chronic inflammation). "Until now, we did not understand how this was possible," said co-lead author Associate Professor Martin Stone. "Our work has identified the specific features of chemokines and receptors that are involved in their inflammatory activity," Associate Professor Stone said. "The ultimate goal is to develop anti-inflammatory drugs that target these molecules," he said. The findings, which Associate Professor Stone presented at an international conference on cell signalling last week, will have wide implications as the proteins involved are essential to all inflammatory diseases. Associate Professor Stone, who heads a laboratory in the Infection and Immunity Program at the Monash BDI collaborated closely with co-lead author Dr Meritxell Canals from MIPS. First author was PhD student Mrs Zil E. Huma. This research was supported by the Australian National Health and Medical Research Council, the Australian Research Council, Monash University and ANZ Trustees. Read the full paper titled Key determinants of selective binding and activation by the monocyte chemoattractant proteins at the chemokine receptor CCR2 Committed to making the discoveries that will relieve the future burden of disease, the newly established Monash Biomedicine Discovery Institute at Monash University brings together more than 120 internationally-renowned research teams. Our researchers are supported by world-class technology and infrastructure, and partner with industry, clinicians and researchers internationally to enhance lives through discovery.


News Article | May 25, 2017
Site: www.sciencedaily.com

Inflammation is the process by which the body responds to injury or infection but when this process becomes out of control it can cause disease. Monash Biomedicine Discovery Institute (BDI) researchers, in collaboration with the Monash Institute of Pharmaceutical Sciences (MIPS), have shed light on a key aspect of the process. Their findings may help guide the development of new treatments of inflammatory diseases such as atherosclerosis, which can lead to heart attack or stroke, and type 2 diabetes. Published today in the journal Science Signaling, the research reveals how certain proteins cause the white blood cells that play a central role in inflammatory responses to behave in different ways. White blood cells are beneficial in helping to eliminate invading microorganisms or repair damaged tissue, but they can prolong the response and damage healthy tissues, leading to disease. The proteins, called chemokines, are secreted into blood vessels and activate chemokine receptors embedded in the outer membranes of the white blood cells. While it was previously thought that this occurred like an on-off switch, the scientists found that the chemokine receptor can behave more like a 'dimmer switch' with one chemokine giving a strong signal and another giving a weaker signal. They found that different responses can be caused by different chemokines activating the same receptor. This explained for the first time the mechanism by which white blood cells produced varying responses: a strong short-lived response (acute inflammation) or a steady, longer-lived response (chronic inflammation). "Until now, we did not understand how this was possible," said co-lead author Associate Professor Martin Stone. "Our work has identified the specific features of chemokines and receptors that are involved in their inflammatory activity," Associate Professor Stone said. "The ultimate goal is to develop anti-inflammatory drugs that target these molecules," he said. The findings, which Associate Professor Stone presented at an international conference on cell signalling last week, will have wide implications as the proteins involved are essential to all inflammatory diseases. Associate Professor Stone, who heads a laboratory in the Infection and Immunity Program at the Monash BDI collaborated closely with co-lead author Dr Meritxell Canals from MIPS. First author was PhD student Mrs Zil E. Huma.


News Article | May 24, 2017
Site: www.medicalnewstoday.com

Inflammation is the process by which the body responds to injury or infection but when this process becomes out of control it can cause disease. Monash Biomedicine Discovery Institute (BDI) researchers, in collaboration with the Monash Institute of Pharmaceutical Sciences (MIPS), have shed light on a key aspect of the process. Their findings may help guide the development of new treatments of inflammatory diseases such as atherosclerosis, which can lead to heart attack or stroke, and type 2 diabetes. Published in the journal Science Signaling, the research reveals how certain proteins cause the white blood cells that play a central role in inflammatory responses to behave in different ways. White blood cells are beneficial in helping to eliminate invading microorganisms or repair damaged tissue, but they can prolong the response and damage healthy tissues, leading to disease. The proteins, called chemokines, are secreted into blood vessels and activate chemokine receptors embedded in the outer membranes of the white blood cells. While it was previously thought that this occurred like an on-off switch, the scientists found that the chemokine receptor can behave more like a 'dimmer switch' with one chemokine giving a strong signal and another giving a weaker signal. They found that different responses can be caused by different chemokines activating the same receptor. This explained for the first time the mechanism by which white blood cells produced varying responses: a strong short-lived response (acute inflammation) or a steady, longer-lived response (chronic inflammation). "Until now, we did not understand how this was possible," said co-lead author Associate Professor Martin Stone. "Our work has identified the specific features of chemokines and receptors that are involved in their inflammatory activity," Associate Professor Stone said. "The ultimate goal is to develop anti-inflammatory drugs that target these molecules," he said. The findings, which Associate Professor Stone presented at an international conference on cell signalling last week, will have wide implications as the proteins involved are essential to all inflammatory diseases. Associate Professor Stone, who heads a laboratory in the Infection and Immunity Program at the Monash BDI collaborated closely with co-lead author Dr Meritxell Canals from MIPS. First author was PhD student Mrs Zil E. Huma. This research was supported by the Australian National Health and Medical Research Council, the Australian Research Council, Monash University and ANZ Trustees. Article: Key determinants of selective binding and activation by the monocyte chemoattractant proteins at the chemokine receptor CCR2, Martin J. Stone et al., Science Signaling, doi: 10.1126/scisignal.aai8529, published 23 May 2017.


News Article | May 8, 2017
Site: www.eurekalert.org

An international study led by researchers at Monash University' Biomedicine Discovery Institute (BDI) has shone light on the way the Hepatitis C Virus (HCV) hijacks the communication systems in the host cells it infects, uncovering potential new therapeutic targets for the disease. HCV affects about two per cent of the world's population. Infection can lead to chronic hepatitis, which can progress to liver cirrhosis and carcinoma. Importantly, the approach used by the scientists - which led to the identification of a drug-like molecule that stopped the virus from replicating within cells - may have broader application to other infectious diseases. This is because all intracellular pathogens rely on their host cell signalling system to replicate. The study, published in Nature Communications today, focused on protein kinases, enzymes that are key regulators of cellular processes. It built on previous ground-breaking work on malaria published in 2011 by author Monash Professor Christian Doerig, and others, who found that if host cell protein kinases were prevented from working it would kill malaria parasites. The Monash BDI researchers worked in collaboration with Canadian-based company Kinexus, and used an antibody microarray to simultaneously investigate hundreds of factors involved in cell signalling that were modulated by HCV replication, including human protein kinases. "This antibody microarray allowed us to find a number of new cell signalling pathways that were activated or suppressed by an HCV infection," Professor Doerig said. First author Dr Reza Haqshenas said the researchers then used gene silencing technology to determine whether the genes' cell factors identified using the antibody microarray were indeed important for HCV replication and therefore potential targets for anti-HCV compounds. They were then able to use a compound recently discovered by Harvard University investigator Professor Nathanael Gray to block the activity of one of the kinases important in HCV replication, MAP4K2. "Nathanael sent us his new molecule, and we put it in our host cells, infected them with HCV and found that while the cells were fine, they didn't support virus replication anymore," Dr Reza Haqshenas said. Professor Doerig said the study provided a compelling "proof of concept." "The platform we have established can be adopted to identify new anti-infective compounds against any pathogen including, viruses, bacteria and parasites, that invade mammalian cells," he said. "Importantly, fighting a pathogen by hitting an enzyme from the host cell is likely to slow the emergence of drug resistance, because the pathogen cannot easily escape through the selection of target mutations," Professor Doerig said. The researchers will now extend their work in studies on the Zika virus and toxoplasmosis. The study, which included Monash BDI Professor Roger Daly, was carried out in collaboration with the Peter MacCallum Cancer Centre (Associate Professor Kaylene Simpson) and the Garvan Institute (bioinformatician Dr Jianmin Wu), Associate Professor Hans Netter, and the French National Institute of Health and Medical Research INSERM (Professor Thomas Baumert). It was supported with funding from the Australian Centre for HIV and Hepatitis Virology Research (ACH2). Read the full paper (DOI: 10.1038/NCOMMS15158 - active once embargo lifts), titled Signalome-wide assessment of host cell response to Hepatitis C virus, published today in Nature Communications. Committed to making the discoveries that will relieve the future burden of disease, the newly established Monash Biomedicine Discovery Institute at Monash University brings together more than 120 internationally-renowned research teams. Our researchers are supported by world-class technology and infrastructure, and partner with industry, clinicians and researchers internationally to enhance lives through discovery


News Article | December 7, 2016
Site: www.eurekalert.org

Every 18 seconds someone dies from tuberculosis (TB). It is the world's most deadly infectious disease. Mycobacterium tuberculosis, the causative agent of TB, has infected over one-third of the entire human population with an annual death toll of approximately 1.5 million people. For the first time, an international team of scientists from Monash and Harvard Universities have seen how, at a molecular level, the human immune system recognises TB infected cells and initiates an immune response. Their findings, published in Nature Communications, are the first step toward developing new diagnostic tools and novel immunotherapies. Lead author, Professor Jamie Rossjohn says one of the main reasons for our current lack of knowledge comes down to the complexity of the bacterium itself. Working with Professor Branch Moody's team at Harvard, they have begun to gain key insight into how the immune system can recognise this bacterium. Crucial to the success of M. tuberculosis as a pathogen is its highly unusual cell wall that not only serves as a barrier against therapeutic attack, but also modulates the host immune system. Conversely, its cell wall may also be the "Achilles' heel" of mycobacteria as it is essential for the growth and survival of these organisms. This unique cell wall is comprised of multiple layers that form a rich waxy barrier, and many of these lipid -- also known as fatty acids -- components represent potential targets for T-cell surveillance. Specifically, using the Australian Synchrotron, the team of scientists have shown how the immune system recognises components of the waxy barrier from the M. tuberculosis cell wall. "With so many people dying from TB every year, any improvements in diagnosis, therapeutic design and vaccination will have major impacts," Professor Moody says. "Our research is focussed on gaining a basic mechanistic understanding of an important biomedical question. And may ultimately provide a platform for designing novel therapeutics for TB and treat this devastating disease," Professor Rossjohn concludes. Professor Jamie Rossjohn is a Chief Investigator on the Australian Research Council Centre of Excellence in Advanced Molecular Imaging. The $39 million ARC-funded Imaging CoE develops and uses innovative imaging technologies to visualise the molecular interactions that underpin the immune system. Featuring an internationally renowned team of lead scientists across five major Australian Universities and academic and commercial partners globally, the Centre uses a truly multi scale and programmatic approach to imaging to deliver maximum impact. The Imaging CoE is headquartered at Monash University with four collaborating organisations - La Trobe University, the University of Melbourne, University of New South Wales and the University of Queensland. Professor Rossjohn is also a researcher at the Monash Biomedicine Discovery Institute. Committed to making the discoveries that will relieve the future burden of disease, the newly established Monash Biomedicine Discovery Institute at Monash University brings together more than 120 internationally-renowned research teams. Our researchers are supported by world-class technology and infrastructure, and partner with industry, clinicians and researchers internationally to enhance lives through discovery.


News Article | February 21, 2017
Site: www.eurekalert.org

Monash University (Australia) and Cardiff University (UK) researchers have come a step further in understanding how the human immunodeficiency virus (HIV) evades the immune system. Declared a pandemic in 1987 by the World Health Organization, HIV infection has been responsible for 39 million deaths over the last 30 years. It remains one of the world's most significant public health challenges and thus a greater understanding of how HIV functions is urgently needed so that researchers can design better therapies to target this devastating pathogen. Published today in Nature Structural and Molecular Biology, the Monash-Cardiff team has made an important finding in understanding how HIV-I can evade the immune system. They demonstrated, in molecular detail, how mutations within HIV can lead to differing ways in which key immune molecules, termed the Major Histocompatibility Complex (MHC), display fragments of the virus and how this results in the HIV remaining "hidden" from the immune system. Principal author of the study, Dr Julian Vivian, said the team was yet to develop a complete understanding of how HIV outmanoeuvred our immune system. "This work uncovers a novel mechanism for HIV immune escape, which will be important to incorporate into future vaccine development and may have broader implications for immune recognition of MHC molecules," he said. The recent finding is part of a much larger international alliance between the two Universities, with the Systems Immunity Research Institute (SIURI) at Cardiff University and Monash Biomedicine Discovery Institute (BDI), having signed a Memorandum of Understanding. The five year mutual agreement recognises a number of highly productive joint projects already being conducted around inflammation and immunity, and provides a mechanism for enabling additional innovative projects and student exchange in the areas of protective immunity, metabolism, autoimmunity and cancer. A chief Investigator on the ARC CoE for Advanced Molecular Imaging, based at Monash BDI, Professor Jamie Rossjohn, said the find was exciting and unexpected. "These result were only possible because of the close collaborative ties between Monash and Cardiff researchers." Cardiff University Vice-Chancellor, Professor Colin Riordan, said the signing of the MoU called for a celebration. "Formalising this collaboration is another step forward in what will continue to be a highly successful exchange program and transfer of knowledge between the two countries for the benefit of all." Monash BDI Director, Professor John Carroll, said the research demonstrated the power of international collaboration. "We are bringing together excellence in molecular and systems level immunity in this partnership, and I know it will lead to many more great discoveries." The $39 million ARC-funded Imaging CoE develops and uses innovative imaging technologies to visualise the molecular interactions that underpin the immune system. Featuring an internationally renowned team of lead scientists across five major Australian Universities and academic and commercial partners globally, the Centre uses a truly multi scale and programmatic approach to imaging to deliver maximum impact. The Imaging CoE is headquartered at Monash University with four collaborating organisations - La Trobe University, the University of Melbourne, University of New South Wales and the University of Queensland. Committed to making the discoveries that will relieve the future burden of disease, the newly established Monash Biomedicine Discovery Institute at Monash University brings together more than 120 internationally-renowned research teams. Our researchers are supported by world-class technology and infrastructure, and partner with industry, clinicians and researchers internationally to enhance lives through discovery.


News Article | October 31, 2016
Site: www.sciencedaily.com

A team of researchers from Cardiff University and Monash Biomedicine Discovery Institute has succeeded in creating a three-dimensional mammary gland model that will pave the way for a better understanding of the mechanisms of breast cancer. Using a cocktail of growth factors, scientists were able to grow mouse mammary cells into three-dimensional mammary tissue. Known as an 'organoid', the model mimics the structure and function of a real mammary gland. This enables researchers to increase their understanding of how breast tissue develops, and provides an active model for the study of disease and drug screening. As well as determining how to grow these life-like mammary glands, researchers also discovered how to maintain them in culture to allow ongoing experimentation -- the first time this has been developed in a laboratory. Professor Trevor Dale of Cardiff University School of Biosciences explains the significance of this research: "Much of how breast tissues respond to external stimuli such as hormones is, as yet, unknown. In order to fully tackle the mechanisms that lie behind breast cancer we first need to understand how healthy breast tissue develops. As such, developing a model of a normal breast with the actual architecture of a mammary gland has long been a 'Holy Grail' for cancer researchers." Dr Thierry Jarde, from the Monash Biomedicine Discovery Institute, adds: "This model allows us to really study the basic biology of how the breast develops -- how hormones work, what are the genetic influences. Further down the track we hope to use this model in tandem with models of breast cancer in order to carry out effective drug-screening." The research is published in the journal Nature Communications.

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