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Archive - 2011

November 6th

Pigeonpea Genome Sequenced; Should Speed Development of High-Yield Varieties

Once referred to as an "orphan crop" grown mainly by poor farmers, pigeonpea is now joining the world's league of major food crops with the completion of its genome sequence. The completed genome sequence of pigeonpea is featured as an advance online publication on November 6, 2011 on the website of the journal Nature Biotechnology. The paper provides an overview of the structure and function of the genes that define the pigeonpea plant. It also reveals clues on how the genomic sequence can be useful to crop improvement for sustainable food production particularly in the marginal environments of Asia and sub-Saharan Africa. Years of genome analysis by a global research partnership led by the International Crops Research Institute for the Semi-Arid Tropics (ICRISAT) based in Hyderabad, India have resulted in the identification of 48,680 pigeonpea genes. A couple of hundreds of these genes were found unique to the crop in terms of drought tolerance, an important trait that can be transferred to other similar crops like soybean, cowpea, or common bean that belong to the same family. In the fight against poverty and hunger amid the threat of climate change, highly nutritious, drought-tolerant crops are the best bets for smallholder farmers in marginal environments to survive and improve their livelihoods. Pigeonpea, grown on about 5 million hectares in Asia, sub-Saharan Africa, and South-Central America, is a very important food legume for millions of the poor in the semi-arid regions of the world. Known as the "poor people's meat" because of its high protein content, it provides a well-balanced diet when accompanied with cereals. "The mapping of the pigeonpea genome is a breakthrough that could not have come at a better time.

Common Bacterial Pathogen Contributes to Some Colon Tumors

Working with lab cultures and mice, Johns Hopkins scientists have found that a strain of the common gut pathogen Bacteroides fragilis causes colon inflammation and increases activity of a gene called spermine oxidase (SMO) in the intestine. The effect is to expose the gut to hydrogen peroxide – the caustic, germ-fighting substance found in many medicine cabinets -- and cause DNA damage, contributing to the formation of colon tumors, say the scientists. "Our data suggest that the SMO gene and its products may be one of the few good targets we have discovered for chemoprevention," says Dr. Robert Casero, professor of oncology at the Johns Hopkins Kimmel Cancer Center. In a study, Casero and his colleagues introduced B. fragilis to two colon cell lines and measured SMO gene activity. In both cell lines, SMO gene activity increased two to four times higher than in cells not exposed to the bacteria. The scientists also observed similar increases in enzymes produced by the SMO gene. The scientists successfully prevented DNA damage in these cells by blocking SMO enzyme activity with a compound called MDL 72527. The Johns Hopkins team also tested their observations in a mouse model, created by Hopkins infectious disease specialist Dr. Cynthia Sears to develop colon tumors. Mice exposed to the bacteria had similar increases in SMO. Mice treated with MDL 72527 had far fewer tumors and lower levels of colon inflammation than untreated mice. Results of the experiments were published on September 13, 2011 in the Proceedings of the National Academy of Sciences. Dr. Casero says hydrogen peroxide can freely distribute through and into other cells. "It roams around, and can damage the DNA in cells," he says. Rising levels of hydrogen peroxide and DNA damage in the colon are clear steps to tumor development, says Dr.

November 5th

N-Terminal Acetylation Promotes Some Protein Interactions; Cancer Drug Implications

Research led by St. Jude Children's Research Hospital scientists has identified an unexpected mechanism facilitating some protein interactions that are the workhorses of cells and, in the process, identified a potential new cancer drug development target. The discovery involves a chemical known as an acetyl group. An estimated 85 percent of human proteins have this chemical added to the amino acid at one end of the protein. The addition comes in a process known as N-terminal acetylation. N-terminal acetylation occurs shortly after proteins are assembled. Although it has long been known that proteins are N-terminally acetylated, until now it was unknown how such acetylation could serve specific functions. The findings came from scientists studying a system cells use to regulate the fate and function of proteins. The researchers showed that much like a key must fit precisely to work a lock, the acetylated end of one enzyme fits perfectly into a deep pocket on the surface of another protein. The connection helps accelerate the activity of a protein complex that is involved in regulating cell division and that has been linked to cancer. The research appears in the November 4, 2011 issue of the journal Science. The findings have potential implications for drug discovery and for understanding basic mechanisms governing the interaction of possibly thousands of proteins, said the study's senior author, Dr. Brenda Schulman, a member of the St. Jude Department of Structural Biology and a Howard Hughes Medical Institute investigator. "The work presents a major new concept in protein-protein interactions," she said.

Blocking Key Enzyme May Protect Against Kidney Disease in Diabetes

The enzyme arginase-2 plays a major role in kidney failure, and blocking the action of this enzyme might lead to protection against renal disease in diabetes, according to researchers. "We believe these arginase inhibitors may be one of the new targets that can slow down the progression of, or even prevent the development of, end-stage renal disease," said Dr. Alaa S. Awad, assistant professor of nephrology, Penn State College of Medicine. In the United States, diabetes is the leading cause of end-stage renal disease -- kidney failure -- causing nearly 45 percent of all cases. Currently the treatment for diabetic patients likely to develop end-stage renal disease includes blood pressure and glucose control therapy and life-style changes. The researchers tested two different sets of diabetic mice to try to prevent kidney failure. They gave one set of mice -- genetically diabetic -- a potent arginase inhibitor; the other set of mice -- induced to be diabetic -- were genetically unable to produce arginase-2. Both sets of mice showed no signs of kidney failure during the test period. The body naturally produces varieties of arginase. The liver produces arginase-1, while the kidneys produce arginase-2, which leads to kidney failure. The researchers did not detect arginase-1 in the kidneys of the mice, and they have not yet developed an arginase inhibitor that can differentiate between the two forms of the enzyme. "These findings indicate that arginase-2 plays a major role in induction of diabetic renal injury and that blocking arginase-2 activity or expression could be a novel therapeutic approach for treatment of diabetic nephropathy," the researchers report in the November 2011 issue of Diabetes. One of the symptoms of diabetic nephropathy is albuminuria -- losing protein in the urine.

November 4th

Protein Protects Against Cerebral Palsy-Like Brain Damage in Mice

Scientists at Washington University School of Medicine in St. Louis have shown that a particular protein may help prevent the kind of brain damage that occurs in babies with cerebral palsy. Using a mouse model that mimics the devastating condition in newborns, the researchers found that high levels of the protective protein, Nmnat1 (NAD-synthesizing enzyme nicotinamide mononucleotide adenylyl transferase 1), substantially reduce damage that develops when the brain is deprived of oxygen and blood flow. The finding offers a potential new strategy for treating cerebral palsy as well as strokes, and perhaps Alzheimer's, Parkinson's, and other neurodegenerative diseases. The research was reported online on November 4, 2011 in the Proceedings of the National Academy of Sciences. "Under normal circumstances, the brain can handle a temporary disruption of either oxygen or blood flow during birth, but when they occur together and for long enough, long-term disability and death can result," says senior author Dr. David M. Holtzman, the Andrew and Gretchen Jones Professor and head of the Department of Neurology. "If we can use drugs to trigger the same protective pathway as Nmnat1, it may be possible to prevent brain damage that occurs from these conditions as well as from neurodegenerative diseases." The researchers aren't exactly sure how Nmnat1 protects brain cells, but they suspect that it blocks the effects of the powerful neurotransmitter glutamate. Brain cells that are damaged or oxygen-starved release glutamate, which can overstimulate and kill neighboring nerve cells. The protective effects of Nmnat1 were first identified five years ago by Dr. Jeff Milbrandt, the James S.

Research Reveals Exit Strategy of Measles Virus

Measles virus is perhaps the most contagious virus in the world, affecting 10 million children worldwide each year and accounting for 120,000 deaths. An article published online on November 2, 2011 in Nature explains why this virus spreads so rapidly. The discovery by Dr. Roberto Cattaneo, at the Mayo Clinic in Rochester, Minnesota, in collaboration with Dr. Veronika von Messling, at the Centre INRS–Institut Armand-Frappier and research teams at several other universities opens up promising new avenues in cancer treatment. Measles virus spreads from host to host primarily by respiratory secretions. This mode of transmission explains why the virus spreads so quickly and how it resists worldwide vaccination programs to eradicate it. The study in Nature shows for the first time how the measles virus "exits" its host via nectin-4, which is found in the trachea. While viruses generally use cellular receptors to trigger and spread infection in the body, measles virus uses one host protein to enter the host and another protein expressed at a strategic site to get out. Nectin-4 is a biomarker for certain types of cancer, such as breast, ovarian, and lung cancers. Clinical trials are currently under way using a modified measles virus. Because measles virus actively targets nectin-4, measles-based cancer therapy may be more successful in patients whose cancers express nectin-4. Such therapy could be less toxic than chemotherapy or radiation. [Press release] [Nature abstract]

Chemical Breakthrough May Revolutionize PET Scans

A new chemical process developed by a team of Harvard researchers, and collaborators at Massachusetts General Hospital, greatly increases the utility of positron emission tomography (PET) in creating real-time 3-D images of chemical process occurring inside the human body. The work is described in the November 4, 2011 issue of Science. This new work by Dr. Tobias Ritter, Associate Professor of Chemistry and Chemical Biology, and colleagues holds out the tantalizing possibility of using PET scans to peer into any number of functions inside the bodies of living patients by simplifying the process of creating "tracer" molecules used to create the 3-D images. For example, imagine a pharmaceutical company developing new treatments by studying the way "micro-doses" of drugs behave in the bodies of living humans. Imagine researchers using non-invasive tests to study the efficacy of drugs aimed at combatting disorders such as Alzheimer's disease, and to identify the physiological differences in the brains of patients suffering from schizophrenia and bipolar disorder. The process is a never-before-achieved way of chemically transforming fluoride into an intermediate reagent, which can then be used to bind a fluorine isotope to organic molecules, creating the PET tracers. Often used in combination with CT scans, PET imaging works by detecting radiation emitted by tracer atoms, which can be incorporated into compounds used in the body or attached to other molecules. "It's extremely exciting," Dr. Ritter said, of the breakthrough. "A lot of people said we would never achieve this, but this allows us to now make tracers that would have been very challenging using conventional chemistry." The new process builds on Dr.

AP-1 Protein Controls the Formation of Varicose Veins

Varicose veins, sometimes referred to as "varices" in medical jargon, are usually just a cosmetic problem if they occur as spider veins. In their advanced stage, however, they pose a real health threat. In people with this widespread disorder, the blood is no longer transported to the heart unhindered, but instead pools in the veins of the leg. This is because the vessel walls or venous valves no longer function adequately. Dr. Thomas Korff and his group at the Division of Cardiovascular Physiology (Director: Professor Markus Hecker) of Heidelberg University's Institute of Physiology and Pathophysiology have now shown that the pathological remodeling processes causing varicose veins are mediated by a single protein (AP-1). As a response to increased stretching of the vessel wall, this protein triggers the production of several molecules promoting changes in wall architecture. The paper, published in the October 2011 issue of The FASEB Journal, may offer a possibility for using drugs to decelerate the formation of, or even prevent, new varicose veins. Previously, no suitable experimental systems existed for studying the way in which these changes in the cells of the blood vessels are controlled. For their studies, Dr. Korff and his team took advantage of the fact that blood vessels in the mouse ear are clearly visible and are also easily accessible for minor surgical procedures. In order to artificially set off processes that are similar to the formation of varicose veins, they tied off a vein with a thin thread. The elevated pressure in the vessels caused by the pooled blood led to the recognizable remodeling characteristic of varicose veins. In addition, in the affected veins, the cell proliferation rate and the production of MMP-2 increased.

Two Genes Identified for Congenital Heart Defects in Down Syndrome

A novel study involving fruit flies and mice has allowed biologists to identify two critical genes responsible for congenital heart defects in individuals with Down syndrome, a major cause of infant mortality and death in people born with this genetic disorder. In a paper published on November 3, 2011 in the open-access journal PLoS Genetics, researchers from the University of California (UC)-San Diego, the Sanford-Burnham Medical Research Institute in La Jolla, California, and the University of Utah report the identification of two genes that, when produced at elevated levels, work together to disrupt cardiac development and function. Down syndrome, the most common genetic cause of cognitive impairment, is a disorder that occurs in one in 700 births when individuals have three, instead of the usual two, copies of human chromosome 21. “Chromosome 21 is the shortest human chromosome and intensive genetic mapping studies in people with Down syndrome have identified a small region of this chromosome that plays a critical role in causing congenital heart defects,” said Dr. Ethan Bier, a biology professor at UC-San Diego and one of the principal authors of the study. “This Down syndrome region for congenital heart disease, called the ‘DS-CHD critical region,’ contains several genes that are active in the heart which our collaborator, Julie Korenberg, had suspected of interacting with each other to disrupt cardiac development or function when present in three copies. But exactly which of these half dozen or so genes are the culprits? Identifying the genes within the DS-CHD critical region contributing to congenital heart defects is challenging to address using traditional mammalian experimental models, such as mice,” added Dr.

November 3rd

Researchers Attempt to Unravel Evolutionary Secrets of Tomato Pathogen

For decades, scientists and farmers have attempted to understand how a bacterial pathogen continues to damage tomatoes despite numerous agricultural attempts to control its spread. Pseudomonas syringae pv. tomato is the causative agent of bacterial speck disease of tomato (Solanum lycopersicum), a disease that occurs worldwide and causes severe reduction in fruit yield and quality, particularly during cold and wet springs. In the spring of 2010, for example, an outbreak in Florida and California devastated the harvest in those areas. "There is not much that can be done from a farming standpoint," said Dr. Boris Vinatzer, associate professor of plant pathology, physiology and weed science, and an affiliated faculty member with the Fralin Life Science Institute at Virginia Tech. "First, farmers try to use seed that is free of the pathogen to prevent disease outbreaks. Then, there are some disease-resistant tomato cultivars, but the pathogen has overcome this resistance by losing the gene that allowed these resistant plants to recognize it and defend themselves. For the rest, there are pesticides, but the pathogen has become resistant against them." So how exactly has the pathogen evolved to consistently evade eradication efforts? This is where science steps in, and a copy of the bacterial pathogen's game plan is crucial. Thanks to the collaborative work of Dr. Vinatzer, Virginia Bioinformatics Institute computer scientist Dr. Joao Setubal, assistant professor of statistics Dr. Scotland Leman, and their students, the genomes of several Pseudomonas syrinage pv. tomato isolates have been sequenced in order to track the bacterial pathogen's ability to overcome plant defenses and to develop methods to prevent further spread.