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Archive - Mar 2011

March 30th

Mystery of 22nd Amino Acid Production Is Solved

The most recently discovered amino acid, pyrrolysine, is produced by a series of just three chemical reactions with a single precursor – the amino acid lysine, according to new research. Scientists at Ohio State University used mass spectrometry and a series of experiments to discover how cells make the amino acid, a process that until now had been unknown. They confirmed that pyrrolysine is made from enzymatic reactions with two lysine molecules – a surprising finding, given that some portions of its structure suggested to researchers that it might have more complex origins. The research is published in the March 31 issue of the journal Nature. Pyrrolysine is rare and so far is known to exist in about a dozen organisms. But its discovery in 2002 as a genetically encoded amino acid in methane-producing microbes raised new questions about the evolution of the genetic code. Pyrrolysine is among 22 amino acids that are used to create proteins from the information stored in genes. Proteins are essential to all life and perform most of the work inside cells. This information about how pyrrolysine is produced – its biosynthetic pathway – offers a more complete understanding of how amino acids are made. And because of its rarity, this molecule is emerging as a handy tool for manipulating proteins in biomedical research. With its production mechanism identified, scientists can use that information to devise ways to mass-produce similar or identical synthetic molecules for a variety of research purposes. The Ohio State scientists had a genuine "ah-ha" moment over the course of the study. As part of their experimentation, they combined lysine with one other amino acid and some enzymes and expected this to produce what is called an intermediate – essentially, a piece of an amino acid that is generated in the biosynthesis process.

Scientists Seek to Selectively Starve Kidney Cancer Cells

Researchers at the University of Texas Southwestern Medical Center have discovered genetic pathways to selectively starve kidney cancer cells. Two separate studies indicate that both rare and common cases of kidney cancer may be susceptible to a new class of drugs that inhibits cancer cells from generating the energy needed to survive. In one study, available online and scheduled for the May 5 issue of the journal Oncogene, researchers found that inactivating the gene von Hippel-Lindau (VHL) in mice blocked cells from using oxygen to provide energy to the cell, forcing them to use another method of energy generation, namely glycolysis – the conversion of glucose to lactic acid. Because the VHL gene is inactive in about 90 percent of clear-cell renal cell carcinomas, the most common type of kidney cancer in humans, the study provides a rationale for the evaluation of glycolytic inhibitors in fighting kidney cancer, said Dr. James Brugarolas, assistant professor of internal medicine and developmental biology and the study's senior author. "It would be expected to kill cancer cells preferentially and spare most normal cells that would still have mitochondrial respiration to rely on," said Dr. Brugarolas. An estimated 58,000 new cases of kidney cancer were reported in the U.S. in 2010, and 13,040 died of the disease. Based on incidence of this cancer from 2005 to 2007, 1 in 67 people will be diagnosed with cancer of the kidney or renal pelvis during his or her lifetime. The study also revealed that the effect of VHL loss was mediated by hypoxia-inducible factors (HIF), a family of proteins that binds to specific DNA sequences and responds to decreases in oxygen, known as hypoxia. "We discovered that simultaneous inactivation of HIF rescued the mice from the effects of VHL inactivation," Dr. Brugarolas said.

54 Beneficial Compounds Found in Pure Maple Syrup

University of Rhode Island researcher Dr. Navindra Seeram has discovered 34 new beneficial compounds in pure maple syrup and confirmed that 20 compounds discovered last year in preliminary research play a key role in human health. On March 30, 2011, at the 241st American Chemical Society's National Meeting in Anaheim, California, the URI assistant pharmacy professor told scientists from around the world that his URI team has now isolated and identified 54 beneficial compounds in pure maple syrup from Quebec, five of which have never been seen in nature. "I continue to say that nature is the best chemist, and that maple syrup is becoming a champion food when it comes to the number and variety of beneficial compounds found in it," Dr. Seeram said. "It's important to note that in our laboratory research we found that several of these compounds possess anti-oxidant and anti-inflammatory properties, which have been shown to fight cancer, diabetes, and bacterial illnesses." These discoveries of new molecules from nature can also provide chemists with leads that could prompt synthesis of medications that could be used to fight fatal diseases, Dr. Seeram said. "We know that the compounds are anti-inflammatory agents and that inflammation has been implicated in several chronic diseases, such as heart disease, diabetes, certain types of cancers and neurodegenerative diseases, such as Alzheimer's," Dr. Seeram said. As part of his diabetes research, Dr. Seeram has collaborated with Dr. Chong Lee, professor of nutrition and food sciences in URI's College of the Environment and Life Sciences. The scientists have found that maple syrup phenolics, the beneficial anti-oxidant compounds, inhibit two carbohydrate hydrolyzing enzymes that are relevant to Type 2 diabetes management. The irony of finding a potential anti-diabetes compound in a sweetener is not lost on Dr. Seeram.

Scientists Sequence Protein from 600,000-Year-Old Mammoth

Researchers from the University of York and Manchester have successfully extracted protein from the bones of a 600,000-year-old mammoth, paving the way for the identification of ancient fossils. Using an ultra-high resolution mass spectrometer, bio-archaeologists were able to produce a near complete collagen sequence for the West Runton Elephant, a Steppe Mammoth skeleton which was discovered in cliffs in Norfolk, UK, in 1990. The remarkable 85 percent complete skeleton - the most complete example of its species ever found in the world - is preserved by the Norfolk Museums and Archaeology Service in Norwich. Bio-archaeologist Professor Matthew Collins, from the University of York’s Department of Archaeology, said: “The time depth is absolutely remarkable. Until several years ago we did not believe we would find any collagen in a skeleton of this age, even if it was as well-preserved as the West Runton Elephant. We believe protein lasts in a useful form ten times as long as DNA which is normally only useful in discoveries of up to 100,000 years old in Northern Europe. The implications are that we can use collagen sequencing to look at very old extinct animals. It also means we can look through old sites and identify remains from tiny fragments of bone.” Dr Mike Buckley, from the Faculty of Life Sciences at the University of Manchester, said: “What is truly fascinating is that this fundamentally important protein, which is one of the most abundant proteins in most (vertebrate) animals, is an ideal target for obtaining long lost genetic information." The collagen sequencing was carried out at the Centre for Excellence in Mass Spectrometry at the University of York and it is arguably the oldest protein ever sequenced; short peptides (chains of amino acids) have controversially been reported from dinosaur fossils.

March 29th

Nanobioconjugate Targets Deadly Breast Cancer Cells

Throwing stones at castle walls is one way to attack an enemy, but sneaking inside makes the target much more vulnerable. Researchers at Cedars-Sinai's Maxine Dunitz Neurosurgical Institute have employed a similar strategy using a mouse model to target important mechanisms inside the most challenging breast cancer cells. Earlier studies at Cedars-Sinai found a similar approach effective in attacking malignant brain tumor targets. Unlike other drugs that target cancer cells from outside and often injure normal cells as a side effect, this therapy consists of multiple drugs chemically bonded to a "transport vehicle." The drugs bypass healthy cells, accumulate inside tumor cells and attack molecular targets that enable cancer cells to grow and spread. Studies using a mouse model show this highly targeted approach, using combinations of drugs, to be more effective than standard treatment methods. This research targeted HER2-positive breast cancer – a type that, due to a genetic mutation, makes excessive amounts of a protein that promotes the growth of cancer cells. HER2-positive breast cancers tend to be more aggressive and less responsive to treatment than other breast cancers. One commonly used antitumor drug, trastuzumab (Herceptin®), is sometimes beneficial, but with advantages and disadvantages. It is an antibody to the HER2 antigen, which means it naturally seeks out this protein in cancers. But its effectiveness as a treatment usually is limited because in 66 to 88 percent of patients, the tumors become resistant within the first year of treatment. Herceptin also can injure normal organs it contacts. The researchers reported in their recent studies, published in the February 19, 2011 issue of Cancer Research, that the new drug carried multiple molecular components, each with a distinct role.

Irish Hare Threatened

Researchers at Queen’s University Belfast in Northern Ireland have issued a stark warning about the future of the Irish hare and the threat it faces from the European ‘brown’ hare, which has set up home in Mid-Ulster and West Tyrone. Dr. Neil Reid from Quercus (Queen’s University’s Centre for Biodiversity and Conservation Science), said: “In March 2011, the Northern Ireland Assembly voted to outlaw hare coursing in Northern Ireland to protect the future of the Irish hare. But our native hare remains vulnerable to another serious threat – that of the invading European hare.” European hares are found in Britain and continental Europe, but they have been highly successful in invading many countries beyond their native range in south-west Europe and parts of Asia. There have been many studies on their impact on native species. Dr. Reid reviewed these studies to get a clearer picture of how much of a threat the invading species might be to the Irish hare. The study, published in the March 2011 issue of the international journal Biological Invasions, suggested that European hares exhibit strong competition for habitat space and food resources with native species, most notably other hare species. It also warns that disease and parasite transmission and climate change may give the invading European hare an edge over the native species. Dr. Reid added: “The Irish hare represents an evolutionary unique lineage, which is restricted to Ireland where it has been present since before the last glacial maximum, making it one of our few native mammal species. Hence, it has been isolated for 30,000-60,000 years.

Apoptosis-Targeted Drug May Prove Useful in Multiple Cancers

Researchers at the University of Michigan Comprehensive Cancer Center have developed a new drug called AT-406 with potential to treat multiple types of cancer. A study published online on March 28, 2011, in the Journal of Medicinal Chemistry showed that AT-406 effectively targets proteins that block normal cell death from occurring. Blocking these proteins caused tumor cells to die, while not harming normal cells. The researchers believe the drug could potentially be used alone or in combination with other treatments. The normal cell death process, called apoptosis, is what keeps normal cells in check. When apoptosis is disrupted, cells reproduce uncontrollably, which is a hallmark of human cancer. "Removing key apoptosis blockades in tumor cells is a completely new cancer therapeutic approach and could have benefit for the treatment of many types of human tumors," said study senior author Dr. Shaomeng Wang, Warner-Lambert/Parke-Davis Professor in Medicine and director of the Cancer Drug Discovery Program at the U-M Comprehensive Cancer Center. Dr. Wang's laboratory has been pursuing new cancer treatments aimed at this cell death pathway since 2003. His team designed and made AT-406 and tested it in the laboratory in 2006. The small-molecule drug homes in directly on the proteins – called inhibitor of apoptosis proteins or IAPs – that block cell death. The researchers found that AT-406 destroyed these proteins in cancer cells. Meanwhile, the drug had little to no effect on normal cells. In animal models, the drug shrank tumors but caused few side effects. The drug is designed to be taken by mouth, which researchers say will make it easier than traditional intravenous chemotherapies to administer.

Cancer Drug Gleevec Shows Promise for Treating Sclerodoma

A drug approved to treat certain types of cancer has shown promising results in the treatment of patients with scleroderma, according to results from an open-label Phase II trial. While the drug's efficacy must be demonstrated in a Phase III trial, the gold standard for testing a drug, researchers are optimistic that Gleevec (imatinib) could potentially be a weapon against the chronic connective tissue disease for which a treatment has remained elusive. "This trial showed Gleevec has acceptable safety and tolerability, and there are hints of efficacy or suggestions the drug may work," said Robert Spiera, M.D., an associate attending rheumatologist at Hospital for Special Surgery who led the study. "This study strongly suggests that a randomized placebo-controlled trial is warranted." The study appeared online on March 11, 2011, in Annals of the Rheumatic Diseases. Systemic scleroderma affects not only the skin, but also underlying blood vessels, and often muscles and joints, as well as the gastrointestinal tract, kidneys, lungs and heart. According to the Scleroderma Foundation, roughly 300,000 individuals have scleroderma in the United States and roughly a third of these have the systemic kind. The disease typically strikes in the prime of patients' lives, when they are 30-50 years old. To date, there has never been a drug that has been shown to be effective for scleroderma. For the study, investigators at Hospital for Special Surgery enrolled 30 patients with diffuse scleroderma, a widespread severe form of the disease, and gave them 400 mg of Gleevec per day. Patients were evaluated monthly for 12 months during treatment and were seen for follow-up three months after discontinuing the drug.

New Imaging Capability for Chemical Mapping of Nanoscale Materials

Scientists at Berkeley Lab’s Molecular Foundry and colleagues have pioneered a new chemical mapping method that provides unprecedented insight into materials at the nanoscale. Moving beyond traditional static imaging techniques, which provide a snapshot in time, these new maps will guide researchers in deciphering molecular chemistry and interactions at the nanoscale—critical for artificial photosynthesis, biofuels production, and light-harvesting applications such as solar cells. “This new technique allows us to capture very high-resolution images of nanomaterials with a huge amount of physical and chemical information at each pixel,” said Dr. Alexander Weber-Bargioni, a postdoctoral scholar in the Imaging and Manipulation of Nanostructures Facility at the Foundry. “Usually when you take an image, you just get a picture of what this material looks like, but nothing more. With our method, we can now gain information about the functionality of a nanostructure with rich detail.” The Molecular Foundry is a U.S. Department of Energy (DOE) Office of Science nanoscience center and national user facility. With the Foundry’s state-of-the-art focused ion beam tool at its disposal, Dr. Weber-Bargioni and his team designed and fabricated a coaxial antenna capable of focusing light at the nanoscale, – a harnessing of light akin to wielding a sharp knife in a thunderstorm, Dr. Weber-Bargioni said. Consisting of gold wrapped around a silicon nitride atomic force microscope tip, this coaxial antenna serves as an optical probe for structures with nanometer resolution for several hours at a time. What’s more, unlike other scanning probe tips, it provides enough enhancement, or light intensity, to report the chemical fingerprint at each pixel while collecting an image (typically 256 pixels x 256 pixels).

March 28th

Scientists ID Gene Region Associated with Attempted Suicide

A genome-wide association study of thousands of people with bipolar disorder suggests that genetic risk factors may influence the decision to attempt suicide. Johns Hopkins scientists and an international team of collaborators, reporting online on March 22, 2011, in the journal Molecular Psychiatry, have identified a small region on chromosome 2 that is associated with increased risk for attempted suicide. This small region contains four genes, including the ACP1 gene, and the researchers found above normal levels of the ACP1 protein in the brains of people who had committed suicide. This protein is thought to influence the same biological pathway as lithium, a medication known to reduce the rate of suicidal behavior. The researchers said the findings could lead to better suicide prevention efforts by providing new directions for research and drug development. "We have long believed that genes play a role in what makes the difference between thinking about suicide and actually doing it," said study leader Dr. Virginia L. Willour, Ph.D., an assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. Dr. Willour and her colleagues studied DNA samples from nearly 2,700 adults with bipolar disorder, 1,201 of them with a history of suicide attempts and 1,497 without. They found that those with one copy of a genetic variant in the region of chromosome 2 where ACP1 is located were 1.4 times more likely to have attempted suicide, and those with two copies were almost 3 times as likely. Dr. Willour and her colleagues were able to replicate their findings in another group of samples: This one comprised DNA from more than 3,000 people with bipolar disorder.