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July 22nd, 2009

Gene Linked to Restless Legs Syndrome

Researchers at the Mayo Clinic, together with collaborators, have identified what is believed to be the first gene mutation linked to restless legs syndrome. The scientists identified the mutation (in the MEIS1 gene) in a family with six members. Three who had restless legs syndrome had the mutation and the other three without the disease did not. "The presence of the mutation in all affected individuals supports a pathogenic role for the MEIS1 gene, and we now need to confirm this finding with other international research groups who study restless legs syndrome," said Dr. Carles Vilariño-Güell, the lead author of the study. "The mutation we found is in a portion of the protein that is identical in species as distinct to human as frogs and fish, which tells us that this portion is very important for the proper function of the protein and that the mutation has a very high chance of causing disease," he said. The researchers doubt that a large proportion of the millions of people who suffer from the syndrome have this mutated MEIS1 gene. They point out, however, that understanding the function of both the normal gene and the abnormal gene will likely provide some insights into this mysterious disorder. Restless legs syndrome is estimated to affect between 5 and 11 percent of the population in Europe and in North America. The condition is characterized by unpleasant sensations in the legs at rest, especially in the evening, that are temporarily relieved by movement. Because restless legs syndrome often interrupts sleep, people commonly are diagnosed after they consult a sleep specialist for assistance. This research was reported in the July 21 issue of Neurology.

Wild Chimpanzees Can Die from AIDS-Like Illness

Although the AIDS virus entered the human population via chimpanzees, scientists have long believed that chimpanzees do not develop AIDS. Now, however, an international team of researchers, including Dr. Jane Goodall, has shown that wild chimpanzees infected with simian immunodeficiency virus (SIV) (the precursor of HIV-1) can, in fact, contract and die from an AIDS-like illness. The authors report that infected chimpanzees in their study group were 10-16 times more likely to die than those that were uninfected. The team also found that infected females were less likely to give birth and infants born to infected mothers were unlikely to survive. The virus, the researchers learned, was transmitted sexually and through mother's milk. Examination of tissue samples from dead chimpanzees revealed a loss of CD4+ T-cells (which are vital to immunity) in SIV-infected chimpanzees. Loss of these cells renders victims susceptible to many other infections--the classic indication of AIDS. “We hope this will lead to a better understanding of the virus that will benefit both humans and chimpanzees," commented Dr. Goodall. Dr. Beatrice Hahn was the senior author of this report, which appeared in the July 23 issue of Nature. [Press release 1] [Press release 2] [Nature News] [Nature abstract]

July 21st

Sea Lamprey Jettisons One-Fifth of Its DNA During Development

Early in embryonic development, the sea lamprey discards 20 percent of its DNA and dramatically remodels its genome. This remarkable finding was reported by researchers at the University of Washington and the Benaroya Research Institute. This is believed to be the first recorded observation of a vertebrate extensively reorganizing its genome as a normal part of development. The sea lamprey is a primitive fish that emerged from jawless fish first appearing 500 million years ago. It is essentially a living fossil from around the time that vertebrates originated. Sea lampreys have a long juvenile life as larvae in fresh water, where they eat on their own. Their short adult lives are normally spent in the sea as blood-sucking parasites. Their round, jawless mouths stick like suction cups to other fish. Several circular rows of teeth rasp through the skin of their unlucky hosts. Their appetite is voracious. Later, as they return to streams and rivers along the northern Atlantic seaboard, sea lampreys atrophy until they are little more than vehicles for reproduction. After mating, they perish. The scientists don't know how the lamprey’s large-scale genome reorganization happens, or why. The lead author said that his favorite hypothesis, yet unproven, is that the extra genetic material might play a role in the proliferation of precursor cells for sperm and eggs, and in early embryonic development. The genetic material might then be discarded either when it is no longer needed or to prevent abnormal growth. This work was reported in the July 7 issue of PNAS. [Press release] [PNAS abstract]

Drug-Dispensing Contact Lens Developed

Taking eye drops multiple times a day can be difficult to do, and, because of blinking and tearing, as little as 1 to 7 percent of the dose is actually absorbed by the eye. Now, researchers at Children’s Hospital Boston and collaborating institutions have developed a special contact lens that can gradually dispense a constant amount of medication to the eye, at adjustable rates. In laboratory testing, the prototype lens dispensed ciprofloxacin (an antibiotic often used in eye drops) for 30 days, the longest duration for which contact lenses are currently approved by the FDA; in some tests, the lens continued releasing drug for up to 100 days. The amounts dispensed were sufficient to kill pathogens in a laboratory assay. The researchers see applications in conditions such as glaucoma and dry-eye which require frequent daily eye drops. They have begun to test the prototype lens in animals and plan to begin human testing as soon as possible. The technology recently won the Life Sciences track in MIT's 100K Entrepreneurship Competition. This work was reported in the July issue of Investigative Ophthalmology and Visual Science. [Press release] [IOVS abstract]

July 20th

Puzzle Solution Points to Possible Treatment for Aggressive Alzheimer’s Disease

The puzzling behavior of a key enzyme has been explained and this may pave the way toward a possible treatment for a rapidly progressing form of Alzheimer’s disease (AD). Butyrylcholinesterase (BChE) breaks down the neurotransmitter acetylcholine and is associated with the neurofibrillary tangles and amyloid plaques that characterize AD. People with a particular mutation of the BChE gene, called the BChE-K mutation, are prone to more rapid development of AD than are those with the normal gene. This has been a puzzle because, in theory, the carriers of the mutated gene should be more protected from the devastating effects of the disease, because the mutated BChE breaks down acetylcholine at a slower rate than does the normal BChE. The result is that the mutation carriers maintain higher levels of this neurotransmitter, so they should, in principle, be protected from AD, in which acetylcholine levels decrease. In the current work, researchers at the Hebrew University of Jerusalem, and collaborating institutions, found that the mutation in the BChE-K gene damages the very end, or tail, of the resultant mutant protein. This tail is the part of BChE which is important for protection from the AD plaques. The tail does this by interacting with the AD beta-amyloid protein and preventing it from precipitating and forming the AD plaques. Thus, it seems that the K mutation can be both neuroprotective by sustaining acetylcholine levels and neurodegenerative by inefficiently interfering with the formation of AD plaques. To compare the normal protein to the K mutant, the researchers used synthetic tails of the normal and the K proteins, as well as engineered human BChE produced in the milk of transgenic goats. The goat-produced protein is prepared for the U.S. military as protection from nerve gas poisoning.

July 16th

Genetic Origin of Short Legs in Dogs

A single genetic event (a DNA insertion) is responsible for the origin of short, curved legs in dachshunds, corgis, basset hounds, and at least 16 other breeds of dogs. Researchers from the National Human Genome Research Institute, and collaborators, reported this finding online in Science on July 16. Specifically, the researchers found that, in contrast to other dog breeds, all short-legged dog breeds have an extra copy of the gene that codes for a growth-promoting protein called fibroblast growth factor 4 (FGF4). Although functional, the extra gene lacks certain parts of the DNA code, called introns, found in normal genes. These characteristics led researchers to conclude that the extra gene is a so-called “retrogene” that was inserted into the dog genome some time after the ancestor of modern dog breeds diverged from wolves. In the case of short-legged dogs, the inserted retrogene results in the overproduction of the FGF4 protein, which researchers hypothesized might turn on key growth receptors at the wrong times during fetal development. Veterinary researchers already know that in certain dog breeds the development of long bones is curtailed due to calcification of growth plates, resulting in short legs with a curved appearance. The trait, called disproportional dwarfism, or chondrodysplasia, is an American Kennel Club standard for more than a dozen domestic dog breeds, including the dachshund, corgi, Pekingese, and basset hound. This trait is distinct from the uniformly miniature size of toy breeds, such as the toy poodle. "Our findings suggest that retrogenes may play a larger role in evolution than has been previously thought, especially as a source of diversity within species," said the study's first author, Dr. Heidi Parker.

July 15th

Genome of Schistosomiasis Parasite Sequenced

Scientists have sequenced the genome of the parasitic flatworm (Schistosoma mansoni) that causes intestinal schistosomiasis (also called snail fever), a devastating tropical disease that afflicts more than 200 million people in the developing world. "We have used state-of-the-art genetic and computational approaches to decipher the genome of this pathogen and to facilitate drug discovery," said Dr. Najib El-Sayed, senior author of the paper. "Many promising leads for drug development targets have emerged." Schistosomiasis is one of several neglected tropical diseases prevalent across much of Africa, Asia, and South America and affects mainly poor populations living in areas where water is unsafe, sanitation inadequate, and basic health care unavailable. It impacts adults’ and children's capacity to work and learn, and often leads to death. With knowledge of this parasite's genome sequence, scientists will now possibly be able to develop much-needed new treatments for schistosomiasis, for which a vaccine does not yet exist. The drug commonly used to treat this parasitic infection does not prevent re-infection, and there are growing reports of drug resistance and treatment failures. The term “snail fever” comes from part of the S. mansoni parasite’s complex life cycle. The parasite's eggs hatch in water, enter into snail hosts, and then travel to human hosts through contaminated water sources, such as bathing and swimming areas. The mature worm grows in the human blood vessel system, depositing eggs around the bladder or intestines, which triggers the formation of excess connective tissue in those regions. The parasite's eggs are passed to the liver or exit through the urine or feces, continuing the cycle of infection. The genome sequencing of S.

Citrus Chemical Prevents Obesity in Mice

Researchers have reported that a particular flavonoid (naringenin) derived from citrus fruit shows promise for preventing weight gain and other signs of metabolic syndrome, which can lead to type 2 diabetes and increased risk of cardiovascular disease. Metabolic syndrome is characterized by a group of metabolic risk factors present in one person. These risk factors include abdominal obesity, blood fat disorders, elevated blood pressure, and insulin resistance or glucose intolerance. In the current study, one group of mice was fed a high-fat (western) diet to induce the symptoms of metabolic syndrome. A second group was fed the exact same diet and treated with naringenin. Naringenin corrected the elevations in triglyceride and cholesterol, prevented the development of insulin resistance, and completely normalized glucose metabolism. The researchers found that naringenin worked by genetically reprogramming the liver to burn up excess fat, rather than store it. "Furthermore, the marked obesity that develops in these mice was completely prevented by naringenin," said Dr. Murray Huff, senior author of the study. "What was unique about the study was that the effects were independent of caloric intake, meaning the mice ate exactly the same amount of food and the same amount of fat. There was no suppression of appetite or decreased food intake, which are often the basis of strategies to reduce weight gain and its metabolic consequences,” Dr. Huff said.

Animal Evidence That Dietary Supplement May Help Prevent, Treat Cataracts

New evidence, obtained in a rat model, supports earlier suggestions that the dietary supplement carnosine might be effective in preventing and treating cataracts. Cataracts are a clouding of the lens of the eye and are a leading cause of vision loss worldwide. Cataracts develop when the main structural protein in the lens, alpha-crystallin, forms abnormal clumps. The clumps make the lens cloudy and impair vision. Previous studies had hinted that carnosine might help block the formation of these clumps. In the current work, scientists from the University of Catania in Italy, and colleagues, exposed tissue cultures of healthy rat lenses to either guanidine, a substance known to induce the formation of cataracts, or to a combination of guanidine and carnosine. The guanidine lenses became completely cloudy, while the guanidine/carnosine lenses developed 50 to 60 percent less cloudiness. Carnosine also restored most of the clarity to clouded lenses. The results demonstrate the potential of using carnosine for preventing and treating cataracts, the scientists said. The study is scheduled to be published in the July 28 edition of Biochemistry. [Press release]

July 13th

Enzyme Deletion Preserves Thymus Function, Extends Lifespan

Researchers have shown, in a mouse model, that deletion of the gene for a particular enzyme [pregnancy-associated plasma protein A (PAPPA)] can preserve thymus function throughout life and extend lifespan by as much as 30 percent. The so-called PAPPA “knockout” mice also showed a significantly lower occurrence of spontaneous tumors than typical mice. It is suggested that preservation of thymus function permits the mice to maintain a robust immune system that contributes to healthy longevity. In all normal mammals, the thymus―the organ that produces T-cells to fight disease and infection―degenerates with age. PAPPA controls the availability in tissues of a hormone known as insulin-like growth factor (IGF) that is a promoter of cell division. Hence, IGF is required for normal embryonic and postnatal growth. But IGF also is associated with tumor growth, inflammation, and cardiovascular disease in adults. By deleting PAPPA, the researchers were able to control the availability of IGF in tissues and dampen its many ill effects. In the thymus, deletion of PAPPA maintained just enough IGF to sustain production of T cells without consuming precursor cells, thereby preventing the degeneration of the thymus. "Controlling the availability of IGF in the thymus by targeted manipulation of PAPPA could be a way to maintain immune protection throughout life," study leader Dr. Abbe de Vallejo said. "This study has profound implications for the future study of healthy aging and longevity." The results were published in the July 7 issue of PNAS. [Press release] [PNAS article]