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Archive - 2011 - Story

November 4th

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.

Scientists ID Neurons That Keep Us Awake; Implications for Sleep Disorders and Depression

Bright light arouses us. Bright light makes it easier to stay awake. Very bright light not only arouses us, but is known to have antidepressant effects. Conversely, dark rooms can make us sleepy. It's the reason some people use masks to make sure light doesn't wake them while they sleep. Now researchers at UCLA have identified the group of neurons that mediates whether light arouses us — or not. Dr. Jerome Siegel, a professor of psychiatry at the Semel Institute for Neuroscience and Human Behavior at UCLA, and colleagues report in the October 26, 2011 edition of the Journal of Neuroscience that the cells necessary for a light-induced arousal response are located in the hypothalamus, an area at the base of the brain responsible for, among other things, control of the autonomic nervous system, body temperature, hunger, thirst, fatigue — and sleep. These cells release a neurotransmitter called hypocretin, Dr. Siegel said. The researchers compared mice with and without hypocretin and found that those that didn't have it were unable to stay awake in the light, while those who had it showed intense activation of these cells in the light but not while they were awake in the dark. This same UCLA research group earlier determined that the loss of hypocretin was responsible for narcolepsy and the sleepiness associated with Parkinson's disease. But the neurotransmitter's role in normal behavior was, until now, unclear. "This current finding explains prior work in humans that found that narcoleptics lack the arousing response to light, unlike other equally sleepy individuals, and that both narcoleptics and Parkinson's patients have an increased tendency to be depressed compared to others with chronic illnesses," said Dr.

APBs Play Key Role in Alternative Mechanism of Telomere Lengthening

Scientists of the German Cancer Research Center have discovered an alternative mechanism for the extension of the telomere repeat sequence by DNA repair enzymes. The ends of the chromosomes, the telomeres, are repetitive DNA sequences that shorten every time a cell divides during the process of duplicating its genome. Once the telomeres become very short the cell stops dividing. Thus, telomeres work like a cellular clock that keeps an eye on the number of cell divisions. And once the cell's time is over it can no longer divide. Circumventing this control mechanism is crucial for tumor cells in order to proliferate without limits. In the majority of tumors this is accomplished by reactivating telomerase, an enzyme that normally extends the telomeres only in embryonic cells, and thus resets the cellular clock during development. However, a 10-15% fraction of tumors keeps on dividing without telomerase by making use of what is called the ALT-mechanism for "Alternative Lengthening of Telomeres". The hallmark of ALT cancer cells is a special type of complexes of promyelocytic leukemia (PML) protein at the telomeres that are termed ALT-associated PML nuclear bodies or APBs. ALT-tumors can be identified by the presence of APBs on fluorescence microscopy images since normal cells do not have these structures. However, the function of APBs has remained mysterious. In a recent study, Dr. Inn Chung and Dr. Karsten Rippe from the German Cancer Research Center, together with Dr. Heinrich Leonhard from the LMU in Munich, applied a novel approach to study APBs. They succeeded in artificially making APBs in living cells by tethering PML and other APB proteins to the telomeres.

November 2nd

Phase III Drug Trial Shows Significant Lung Function Improvement in Genetic Subset of Cystic Fibrosis Patients

A new study has confirmed that the drug, ivacaftor, significantly improves lung function in some people with cystic fibrosis (CF). The results of the phase III clinical trial study, "A CFTR Potentiator in Patients with Cystic Fibrosis and the G551D Mutation," led by Dr. Bonnie W. Ramsey of Seattle Children's Research Institute and the University of Washington, were published in the November 3, 2011 issue of the New England Journal of Medicine. Ivacaftor, also known as VX-770, was developed by Vertex Pharmaceuticals with financial support from the Cystic Fibrosis Foundation. The oral medicine targets the defective protein produced by the gene mutation called G551D that can cause CF. Researchers found that CF patients carrying the G551D mutation – approximately four per cent of all CF patients – who were treated with VX-770 showed a 17 per cent relative improvement in lung function that was sustained over the course of 48 weeks. Additionally, patients with G551D treated with VX-770 showed improvements in other areas critically important to the health of people with CF. Study participants experienced significant reductions in sweat chloride levels indicating an improvement in the body's ability to carry salt in and out of cells – a process, which when defective, leads to CF. They also experienced decreased respiratory distress symptoms and improved weight gain. Those who received VX-770 gained on average seven pounds compared to those in the placebo group who gained approximately one pound. This is significant because many people with CF have difficulty gaining and maintaining weight due to reduced lung function and chronic infection. "Our study shows that we are now able to improve the quality of life for cystic fibrosis patients with the G551D mutation with the administration of VX-770," said Dr.