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Archive - 2013

February 3rd

Scientists Capture Key Moments in Cell Death

Scientists at the Walter and Eliza Hall Institute have for the first time visualized the molecular changes in a critical cell death protein that force cells to die. The finding provides important insights into how cell death occurs, and could lead to new classes of medicines that control whether diseased cells live or die. Controlled cell death, called apoptosis, is important for controlling the number of cells in the body. Defects in cell death have been linked to the development of diseases such as cancer and neurodegenerative conditions. Insufficient cell death can cause cancer by allowing cells to become immortal while excessive cell death of neurons may be a cause of neurodegenerative conditions. Dr. Peter Czabotar, Professor Peter Colman, and colleagues in the institute's Structural Biology division, together with Dr. Dana Westphal from the institute's Molecular Genetics of Cancer division, made the discovery which is published in the January 31, 2013 edition of the journal Cell. Dr. Czabotar said activation of the protein Bax had long been known to be an important event leading to apoptosis, but until now it was not known how this activation occurred. "One of the key steps in cell death is that holes are punched into a membrane in the cell, the mitochondrial membrane," Dr Czabotar said. "Once this happens the cell is going to go on and die. Bax is responsible for punching the holes in the mitochondrial membrane and visualizing its activation brings us a step closer to understanding the mechanics of cell death." Using the Australian Synchrotron, Dr. Czabotar and colleagues were able to obtain detailed three-dimensional images of Bax changing shape as it moved from its inactive to active form. The active form ruptures mitochondrial membranes, removing the cell's energy supply and causing cell death.

February 1st

Researchers Develop Automated Breast Density Test Linked To Cancer Risk

Researchers at the Moffitt Cancer Center in Tampa, Florida, and colleagues at the Mayo Clinic in Rochester, Minnesota, have developed a novel computer algorithm to easily quantify a major risk factor for breast cancer based on analysis of a screening mammogram. Increased levels of mammographic breast density have been shown in multiple studies to be correlated with elevated risk of breast cancer, but the approach to quantifying this parameter has been limited to the laboratory setting where measurement requires highly skilled technicians. This new discovery opens the door for translation to the clinic where the algorithm can be used to identify high-risk women for tailored treatment. “We recently developed an automated method to estimate mammographic breast density that assesses the variation in grayscale values in mammograms,” explained study lead author John J. Heine, Ph.D., associate member of the Cancer Epidemiology Program and Cancer Imaging and Metabolism Department at Moffitt. According to the authors, mammographic breast density, or the proportion of fibroglandular tissue pictured on the mammogram, is an established risk factor for breast cancer. Women with high mammographic breast density have a greater risk of developing breast cancer. However, mammographic breast density has not been used in clinical settings for risk assessments due in large part to the lack of an automated and standardized measurement. Using their new method, the researchers compared the accuracy and reliability of their measurements of variation in breast density with the performance of tests that use the degree of dense breast tissue in a mammogram to assess breast cancer risk. A study describing their novel method and its utility was first published online on July 3, 2012 in the Journal of the National Cancer Institute.

New Methods for Quantifying Antisense Drug Delivery to Target Cells and Tissues

Powerful antisense drugs that target disease-associated genes to block their expression can be used to treat a broad range of diseases. Though antisense therapy has been proven effective, challenges remain in ensuring that the drugs reach their intended targets. Two new methods for detecting and measuring the levels of antisense drugs in cells that could accelerate the development of improved antisense drugs are described in a fast-track 2013 article in BioResearch Open Access, a bimonthly peer-reviewed journal. In the article, Drs. Frederick Schnell, Stacy Crumley, Dan Mourich, and P.L. Iversen, from Sarepta Therapeutics and Oregon State University (Corvallis, OR), describe two fast and sensitive methods for detecting a promising type of antisense therapeutic called a phosphorodiamidate morpholine oligomer, or PMO. Using these novel methods the scientists were able to detect PMO delivery to individual cells and quantify how much PMO resides in a particular tissue in the body, such as the lung. For example, the authors describe the measurement of intranasally delivered PMO in lung tissue and, more specifically, in different cell types in the lung. They were able to measure the clearance kinetics of the PMO and determine if it stayed in the lung tissue. "The development of novel, rapid PMO detection techniques such as these will advance the field of PMO research in a significant way, providing valid alternatives to the current time-consuming and labor-intensive methods," says BioResearch Open Access Editor-in-Chief Jane Taylor, Ph.D., MRC Centre for Regenerative Medicine, University of Edinburgh, Scotland. [Press release] [BioResearch Open Access article]

Cats and Humans Suffer from Similar Forms of Epilepsy

Epilepsy arises when the brain is temporarily swamped by uncoordinated signals from nerve cells. Research at the Vetmeduni Vienna has now uncovered a cause of a particular type of epilepsy in cats. Surprisingly, an incorrectly channelled immune response seems to be responsible for the condition, which closely resembles a form of epilepsy in humans. The work is published in the January/February 2013 issue of the Journal of Veterinary Internal Medicine. There is something sinister about epilepsy: the disease affects the very core of our being, our brain. Epileptic attacks can lead to seizures throughout the body or in parts of it. Clouding of consciousness or memory lapses are also possible. The causes are still only partially understood, but in some cases brain tumors, infections, inflammations of the brain, or metabolic diseases have been implicated. Epilepsy is not confined to humans and many animals also suffer from it. Together with partners in Oxford and Budapest, Dr. Akos Pakozdy and his colleagues at the University of Veterinary Medicine, Vienna, have managed to identify the cause of a certain form of epilepsy in cats, in which the cat’s own immune system attacks particular proteins in the cell membranes of nerve cells. The symptoms include twitching facial muscles, a fixed stare, chewing motions, and heavy dribbling. Based on their clinical experience, the researchers believe that this form of epilepsy is fairly widespread in cats. Interestingly, a highly similar type of epilepsy occurs in humans: an inflammation in the brain, known as limbic encephalitis, leads to epileptic seizures that generally manifest themselves in the arm and the facial muscles on only one side of the body. Dr.

Genetically Modified Tobacco Plants Produce Economic Antibodies to Treat Rabies

Smoking tobacco might be bad for your health, but a genetically altered version of the plant might provide a relatively inexpensive cure for infection with the deadly rabies virus. In a new research report appearing online on January 31, 2013 in The FASEB Journal, scientists produced a monoclonal antibody in transgenic tobacco plants that was shown to neutralize the rabies virus. This new antibody works by preventing the virus from attaching to nerve endings around the bite site and keeps the virus from traveling to the brain. "Rabies continues to kill many thousands of people throughout the developing world every year and can also affect international travelers," said Leonard Both, M.Sc., a researcher involved in the work from the Hotung Molecular Immunology Unit at St. George's, University of London, in the United Kingdom. "An untreated rabies infection is nearly 100 percent fatal and is usually seen as a death sentence. Producing an inexpensive antibody in transgenic plants opens the prospect of adequate rabies prevention for low-income families in developing countries." To make this advance, Both and colleagues "humanized" the sequences for the antibody so people could tolerate it. Then, the antibody was produced using transgenic tobacco plants as an inexpensive production platform. The antibody was purified from the plant leaves and characterized with regards to its protein and sugar composition. The antibody was also shown to be active in neutralizing a broad panel of rabies viruses, and the exact antibody docking site on the viral envelope was identified using certain chimeric rabies viruses. "Although treatable by antibodies if caught in time, rabies is bad news," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal.

January 31st

Autism Risk Linked to Prenatal Inflammation

Maternal inflammation during early pregnancy may be related to an increased risk of autism in children, according to new findings supported by the National Institute of Environmental Health Sciences (NIEHS), part of the National Institutes of Health. Researchers found this in children of mothers with elevated C-reactive protein (CRP), a well-established marker of systemic inflammation. The risk of autism among children in the study was increased by 43 percent among mothers with CRP levels in the top 20th percentile, and by 80 percent for maternal CRP in the top 10th percentile. The findings appeared online on January 22, 2013 in the journal Molecular Psychiatry and add to mounting evidence that an overactive immune response can alter the development of the central nervous system in the fetus. "Elevated CRP is a signal that the body is undergoing a response to inflammation from, for example, a viral or bacterial infection," said the lead scientist on the study, Alan Brown, M.D., professor of clinical psychiatry and epidemiology at Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, and Mailman School of Public Health. "The higher the level of CRP in the mother, the greater the risk of autism in the child." Dr. Brown cautioned that the results should be viewed in perspective because the prevalence of inflammation during pregnancy is substantially higher than the prevalence of autism. "The vast majority of mothers with increased CRP levels will not give birth to children with autism," Dr. Brown said.

Deficiencies in Two Genes Combine to Contribute to Hirschprung Disease

Mutations in single genes can cause catastrophic diseases, such as Huntington's disease or sickle cell anemia. However, many conditions, including cancer, diabetes, and birth defects are multigenic, arising from the collective failure of the function of more than one gene. Researchers know that mutations in at least twelve individual genes are associated with the congenital defect Hirschprung Disease (HSCR), in which children are born lacking nerves that innervate the large intestine. Now two companion studies published in Human Molecular Genetics by Paul Trainor, Ph.D., Investigator at the Stowers Institute for Medical Research, identify a new gene associated with HSCR and show how the migration of cells that form the gut nervous system is impeded when the combined doses of two candidate genes are low. Understanding the genetic basis of HSCR offers hope for better diagnostics and treatment for it and other developmental defects caused by failure of cell migration. The cells that go awry in HSCR are a subset of what are called neural crest cells, embryonic cells that spring from the developing brain and spinal cord in mice or humans and then travel long distances to form, among other structures, structures in the face and heart, smooth muscle, and neurons of the peripheral nervous system, including those that innervate the gut. Dr. Trainor has been interested in neural crest cells since he was a graduate student, often focusing on developmental defects caused by their malfunction. "Neural crest cells have to be born in the right place, migrate an incredibly long distance, survive the migration, multiply and then differentiate into a mature cell type," says Dr.

Diffusion Coefficients for Complete Proteome of E. coli Determined for First Time

Understanding of the chemical foundations of life requires knowledge about the rate of chemical reactions in cells. The rates of these reactions depend on how fast the molecules taking part in reactions move (diffuse) in the cytoplasm. Professor Robert Hołyst's research team from the Institute of Physical Chemistry of the Polish Academy of Sciences in Warsaw (IPC PAS) managed to determine – for the first time – the diffusion coefficients for virtually all the proteins occurring in Escherichia coli. The method developed by the researchers can also be used for other cells. The movements of molecules in cells resemble a bit what's going on in railway stations. But the differences are obvious at first glance. "Regular trains leave stations at fixed times, whereas in cells transport processes take place virtually all the time. That's why it doesn't make sense to ask what time does the train with specific molecules leave the station. But it definitely makes sense to ask how fast the train with specific molecules is moving!” explains Professor Hołyst. Transport efficiency of chemical compounds in cells became inspiring for many transport companies. There's talk of biologistics as modelling vehicle or rail transport by looking up to what's going on inside the cells. Professor Hołyst, however, has no illusions about that: "Everyone is delighted, for in cells the transport is so wonderfully resistant to perturbations. They forget, however, that the transport results from random fluctuations, in addition occurring in a small volume, where viscosity depends not only on the medium, but also on the size of the viscosity probe! I wish good luck to all those who want to transfer processes occurring in physically so different environment to our roads.

January 30th

First Artificial Enzyme Created by Evolution in a Test Tube

There’s a wobbly new biochemical structure in Dr. Burckhard Seelig’s lab at the University of Minnesota that may resemble what enzymes looked like billions of years ago, when life on earth began to evolve – long before they became ingredients for new and improved products, from detergents to foods and fuels. Dr. Seelig created the fledgling enzyme by using directed evolution in the laboratory. Working with colleague Dr. Gianluigi Veglia, graduate student Fa-An Chao, and other team members, Dr.Seelig subsequently determined the enzyme’s structure, which made its debut December 9 as an advance online publication in Nature Chemical Biology. Lab tests show that the enzyme (a type of RNA ligase, which connects two RNA molecules) functions as natural enzymes although its structure looks very different and it is flexible rather than rigid. Dr. Seelig speculates the new protein resembles primordial enzymes, before their current structures evolved. While a handful of groups worldwide are developing artificial enzymes, these groups use rational design to construct the proteins on computers. Instead, the Seelig lab employs directed evolution. "To my knowledge, our enzyme is the only entirely artificial enzyme created in a test tube by simply following the principles of natural selection and evolution," he says. Rational enzyme design relies on preconceived notions of what a new enzyme should look like and how it should function. In contrast, directed evolution involves producing a large quantity of candidate proteins and screening several generations to produce one with the desired function. With this approach, the outcome isn’t limited by current knowledge of enzyme structure. "Just as in nature, only the fittest survive after each successive generation," Dr. Seelig explains.

Ancient Snail Shell Analysis Reveals a Humid Mediterranean

An international team of researchers has shown that old wives' tales that snails can tell us about the weather should not be dismissed too hastily. While the story goes that if a snail climbs a plant or post, rain is coming, research led by the University of York goes one better: it shows snails can provide a wealth of information about the prevailing weather conditions thousands of years ago. The researchers, including scientists from the Scottish Universities Environmental Research Centre (SUERC), analyzed the chemistry of snail shells dating back 9,000 to 2,500 years recovered from Mediterranean caves, looking at humidity at different times in the past. Their findings, which were reported online on January 30, 2013 in the journal Quaternary International, reveal that when the first farmers arrived in Italy and Spain, the western Mediterranean was not the hot dry place it is now, but warmer, wetter, and stickier. The research was led by Dr. André Carlo Colonese from York’s Department of Archaeology. Dr. Colonese and his co-authors believe that land snails have great potential as a source of information about human behaviour and palaeoclimatic conditions and therefore should be given much more attention. Dr. Colonese, an EU Marie Curie Fellow in York’s Centre for Human Palaeoecology & Evolutionary Origins, said: “By putting together research on snails from multiple sites across Spain and Italy, we were able to produce a large-scale regional picture for weather conditions over the western Mediterranean area. This allowed us to observe differences in climate across the region.