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Archive - Feb 2013

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February 10th

24 New Genes for Short-Sightedness Identified

An international team of scientists led by a group at King's College London has discovered 24 new genes that cause refractive errors and myopia (short-sightedness). Myopia is a major cause of blindness and visual impairment worldwide, and currently there is no cure. These findings, published online on February 10, 2013 in Nature Genetics, reveal genetic causes of the trait, which could lead to finding better treatments or ways of preventing the condition in the future. Thirty per cent of Western populations and up to 80 per cent of Asian people suffer from myopia. During visual development in childhood and adolescence the eye grows in length, but in myopes it grows too long, and light entering the eye is then focused in front of the retina rather than on it. This results in a blurred image. This refractive error can be corrected with glasses, contact lenses or surgery. However, the eye remains longer, the retina is thinner, and this may lead to retinal detachment, glaucoma, or macular degeneration, especially with higher degrees of myopia. Myopia is highly heritable, although up to now, little was known about the genetic background. To find the genes responsible, researchers from Europe, Asia, Australia, and the United States collaborated as the Consortium for Refraction and Myopia (CREAM). They analyzed genetic and refractive error data for over 45,000 people from 32 different studies, and found 24 new genes for this trait, and confirmed two previously reported genes. Interestingly, the genes did not show significant differences between the European and Asian groups, despite the higher prevelance among Asian people. The new genes include those which function in brain and eye tissue signalling, the structure of the eye, and eye development.

Old Drug May Lead to New Treatments for Diabetes and Obesity

Researchers at the University of Michigan's (U-M) Life Sciences Institute have found that amlexanox, an off-patent drug currently prescribed for the treatment of asthma and other uses, also reverses obesity, diabetes, and fatty liver in mice. The findings from the lab of Dr. Alan Saltiel, the Mary Sue Coleman director of the Life Sciences Institute, were published online on February 10, 2013 in Nature Medicine. "One of the reasons that diets are so ineffective in producing weight loss for some people is that their bodies adjust to the reduced calories by also reducing their metabolism, so that they are 'defending' their body weight," Dr. Saltiel said. "Amlexanox seems to tweak the metabolic response to excessive calorie storage in mice." Different formulations of amlexanox are currently prescribed to treat asthma in Japan and canker sores in the United States. Dr. Saltiel is teaming up with clinical trial specialists at U-M to test whether amlexanox will be useful for treating obesity and diabetes in humans. He is also working with medicinal chemists at U-M to develop a new compound based on the drug that optimizes its formula. The study appears to confirm and extend the notion that the genes IKKE and TBK1 play a crucial role for maintaining metabolic balance, a discovery published by the Saltiel lab in 2009 in the journal Cell. "Amlexanox appears to work in mice by inhibiting two genes—IKKE and TBK1—that we think together act as a sort of brake on metabolism," Dr. Saltiel said. "By releasing the brake, amlexanox seems to free the metabolic system to burn more, and possibly store less, energy." Using high-throughput chemical screening at LSI's Center for Chemical Genomics to search for compounds that inhibit IKKE and TBK1, the researchers hit upon an approved off-patent drug: amlexanox.

February 9th

Evolutionary Rates Could Shed Light on Functions of Uncharacterized Genes

Genes that have roles in the same biological pathways change their rate of evolution in parallel, a finding that could be used to discover their functions, said a researcher at the University of Pittsburgh School of Medicine in the February 1, 2013 issue of GENETICS. Humans have nearly 21,000 genes that make as many proteins, but the functions of most of those genes have not been fully determined, said lead investigator Nathan Clark, Ph.D., assistant professor of computational and systems biology at the Pitt School of Medicine. Knowing what a particular gene does could help unravel the workings of the body, foster understanding of disease processes, and identify targets for new drugs. "For our study, we took a close look at the way genes evolved between species and we found an interesting signature," he said. "Genes that perform biological functions together have similar evolutionary histories in that the rates at which they change parallel each other. This could allow us to identify partner genes that we might never have suspected to work together in biochemical pathways." The researchers studied the evolving genomes of 18 yeast species and 22 mammalian species, looking particularly at genes that are involved in meiosis, a cell division process, and in DNA repair. They found parallel changes, such as acceleration or deceleration, in evolutionary rates among not only genes encoding proteins that physically interact with each other, but also among those that had no direct contact but still participated in meiosis or DNA repair pathways. All genes mutate over time, which can be beneficial, harmful, or meaningless. Some yeast species evolved a different method of reproduction and meiosis stopped as it was no longer essential for survival, Dr. Clark said.

February 7th

Study Reexamines Role of IGF-1R As Therapeutic Target in Ewing Sarcoma

First author Alison O'Neill, then an undergraduate at Georgetown University and now a first-year medical student at Georgetown, and a team of scientists from Johns Hopkins, Boston Children's Hospital, Memorial Sloan-Kettering Cancer Center, and Georgetown's Lombardi Cancer Center (including senior author Dr. Jeffrey Toretsky), have found evidence that the insulin-like growth factor 1 receptor (IGF-1R) may require reevaluation as a therapeutic target in Ewing sarcoma (ES). The group’s findings, published online on January 29, 2013 in the open-access journal Sarcoma, contribute to a growing body of work that calls into question the longstanding high hopes for anti-IGF-1R therapy in light of the actual nature of IGF-1R’s role in Ewing sarcoma biology. The authors noted that IGF-1R has been the subject of more than 20 years of research as a potential therapeutic target in ES. These investigations have included the role of IGF-1R in the initiation of ES, in vitro and in vivo effects of blocking IGF-1R, and the expression of signaling components in patients with ES. As a result of these data, patients with ES were thought to be ideal candidates for therapy directed towards the IGF-1R axis. ES patients were thus enrolled in early clinical trials of humanized monoclonal antibodies against IGF-1R with the expectation of significant antitumor effects. The phase II studies showed objective response rates that ranged from 8 to 15%, with the vast majority being partial responses measured in weeks to months. The authors said that anti-IGF-1R therapy clearly benefits a subset of patients, and it will be essential to find markers to identify those patients most likely to respond.

February 5th

Iron Transporter Discovery Offers Promise of New Treatments for Iron Deficiency and Parasitic Worm Infections

Humans survive by constantly recycling iron, a metal that is an essential component of red blood cells, but which is toxic outside of those cells. More than 90 percent of the iron in an adult human's 25 trillion life-sustaining red blood cells is recycled from worn-out cells. Almost 50 years ago scientists first began hypothesizing that our bodies must have a special protein 'container' to safely transport heme -- the form of iron found in living things – during the breakdown and recycling of old red blood cells and other types of heme metabolism. Now a team of scientists from the University of Maryland, Harvard Medical School, the National Institutes of Health and the University of Utah School of Medicine have identified this long-sought heme-iron transporter and shown that it is the same HRG1 protein that a common microscopic worm, C. elegans, uses to transport heme. In humans, the iron in heme is the component that allows hemoglobin in red blood cells to carry the oxygen needed for life. The team's findings are based on studies in human, mouse, zebrafish, and yeast systems, and are published in the February 5, 2013 issue of Cell Metabolism. "Our current work reveals that the long-sought heme transporter that permits humans to recycle over 5 million red blood cells per second in our spleen and liver, is the same HRG1 transporter protein that my students and I discovered in worms in 2008, and which we showed at that time is used by C. elegans to safely carry heme-iron that it obtains from dirt into its intestine," says team leader and corresponding author Dr. Iqbal Hamza, a University of Maryland associate professor in the Department of Animal & Avian Sciences. "Moreover, we show in this current study that mutations in the gene for HRG1 can be a causative agent for genetic disorders of iron metabolism in humans," he says.

Fitness-Reducing Interaction Between Nuclear and Mitochondrial DNA Mutations

Plant and animal cells contain two genomes: one in the nucleus and one in the mitochondria. When mutations occur in each, they can become incompatible, leading to disease. To increase understanding of such illnesses, scientists at Brown University and Indiana University have recently traced one example in fruit flies down to the individual errant nucleotides and the mechanism by which the flies become sick. Diseases from a mutation in one genome are complicated enough, but some illnesses arise from errant interactions between two genomes: the DNA in the nucleus and the DNA in the mitochondria. Scientists want to know more about how such genomic disconnects cause disease. In a step in that direction, scientists at Brown University and Indiana University have traced one such incompatibility in fruit flies down to the level of individual nucleotide mutations and describe how the genetic double whammy makes the flies sick. “This has relevance to human disease but it’s also relevant to all organisms because these two genomes are in all animals and all plants,” said Dr. David Rand, professor of biology at Brown and senior author of the study published online on January 31, 2013 in PLOS Genetics. “There are a lot of metabolic diseases that are mitochondrial in origin and they have peculiar genetic tracking — a two-part system needs to be considered.” Five years ago at Brown, Dr. Rand and two postdoctoral researchers — Dr. Colin Meiklejohn, of Brown and Indiana University, and Dr. Kristi Montooth, now an assistant professor at Indiana University — began searching for an example in the convenient testbed of fruit flies.

February 4th

Researchers Reveal Mechanism to Halt Cancer Cell Growth, Discover Potential Therapy

University of Pittsburgh Cancer Institute (UPCI) researchers have uncovered a technique to halt the growth of cancer cells, a discovery that led them to a potential new anti-cancer therapy. When deprived of a key protein, some cancer cells are unable to properly divide, a finding described in the cover story of the February 2013 issue of the Journal of Cell Science and first published online on .September 26, 2012 in that journal. "This is the first time anyone has explained how altering this protein at a key stage in cell reproduction can stop cancer growth," said Bennett Van Houten, Ph.D., the Richard M. Cyert Professor of Molecular Pharmacology at UPCI and senior author of the research paper. "Our hope is that this discovery will spur the development of a new type of cancer drug that targets this process and could work synergistically with existing drugs." All cells have a network of mitochondria, which are tiny structures inside cells that are essential for energy production and metabolism. Dynamin-related protein 1 (Drp1) helps mitochondria undergo fission, a process by which they split themselves into two new mitochondria. In breast or lung cancer cells made to be deficient in Drp1, the researchers observed a huge network of highly fused mitochondria. These cancer cells appear to have stalled during a stage in cell division called G2/M. Unable to divide into new cells, the cancer growth stops. Those cells that do try to divide literally tear their chromosomes apart, causing more stress for the cell. The cover of the Journal of Cell Science includes a colorful image of a breast cancer cell deficient in Drp1 that is stuck during the process of separating its chromosomes into two identical sets to be divided among two new cells. Lead author Wei Qian, Ph.D., a postdoctoral fellow in Dr.

Study Suggests Taking Insulin for Type 2 Diabetes Could Expose Patients to Greater Risk of Health Complications

Patients with type 2 diabetes treated with insulin could be exposed to a greater risk of health complications including heart attack, stroke, cancer, and eye complications, a new study has found. Examining the UK Clinical Practice Research Datalink (CPRD) - data that characterises about 10% of the UK population - a team of researchers from Cardiff University's School of Medicine looked at the risk of death for patients taking insulin compared with other treatments designed to lower blood glucose levels in people with type 2 diabetes. The team's epidemiological study found people have greater risk of individual complications associated with diabetes such as heart attack, stroke, eye complications, and renal disease when compared with patients treated with alternative glucose-lowering treatments. The report was published online on January 31, 2013 in The Journal of Clinical Endocrinology & Metabolism. "Insulin treatment remains the most longstanding blood-glucose-lowering therapies for people with type 2 diabetes, with its use growing markedly in recent years," according to Professor Craig Currie from Cardiff University's School of Medicine, who led the study. "However, with new diabetes therapies and treatments emerging there has been a new spotlight on treatments to ensure what the best and safest form of diabetes treatment is. By reviewing data from CPRD between 1999 and 2011 we've confirmed there are increased health risks for patients with type 2 diabetes who take insulin to manage their condition," he adds. The study adds to previous findings which identified potential health risks of insulin in this specific group of people. Initial concerns were first raised regarding the use of insulin in type 2 diabetes from a population-based study in Canada, which reported a three-fold increase in mortality.

Predator Wasps Breed at the Expense of Spider Juveniles

Two wasp species, Calymmochilus disparand Gelis apterus, have been recorded as parasitoids on ant-eating spiders in a study published online on February 1, 2013 in the open-access journal ZooKeys. The host spider,Zodarion styliferum, belongs to the largest genus of predominantly ant-eating spiders. Their distribution area includes Europe, Asia, and North Africa, significantly, with at least 35 species reported for the Iberian Peninsula only, marking a record in numbers in Portugal, where this study was conducted. Available data on the biology of the host spider shows that all species of the genus Zodarion are compulsory ant eaters. What is interesting is that these spiders perform aggressive mimicry, i.e., disguise as ants to help them in their hunt and to capture their prey. These crafty hunters are often nocturnal wanderers and mainly active in twilight. During the day, these spiders remain hidden in carefully built igloo-shaped stone retreats that are attached to the underside of rocks or dead wood. The igloos provide protection against unfavourable environmental conditions and enemies such as ants. Despite these evolutionary advancements in the fight for survival, however, the Z. styliferum spider turns out to be an easy victim for wasp species in their efforts striving for reproduction. The predatory wasp attacks during daylight when the spiders are inactive. The females of the parasitoid wasp species attack the hosts in the shelter of their igloo, penetrating the walls with their long ovipositors. When collected for this study, the wasp larvae were attached to the abdomen of an immobilized spider juvenile, which they used as food for their own development. Apart from feeding on the juveniles, the peculiar home of the ant-eating host provides another convenience for the parasites. The larva of G.

February 3rd

Recreating Natural Complex Gene Regulation

By reproducing in the laboratory the complex interactions that cause human genes to turn on inside cells, Duke University bioengineers have created a system they believe can benefit gene therapy research and the burgeoning field of synthetic biology. This new approach should help basic scientists as they tease out the effects of "turning on" or "turning off" many different genes, as well as clinicians seeking to develop new gene-based therapies for human disease. "We know that human genes are not just turned on or off, but can be activated to any level over a wide range. Current engineered systems use one protein to control the levels of gene activation," said Dr. Charles Gersbach, assistant professor of biomedical engineering at Duke's Pratt School of Engineering and member of Duke's Institute for Genome Sciences and Policy. "However, we know that natural human genes are regulated by interactions between dozens of proteins that lead to diverse outcomes within a living system. In contrast to typical genetics studies that dissect natural gene networks in a top-down fashion, we developed a bottom-up approach, which allows us to artificially simulate these natural complex interactions between many proteins that regulate a single gene," Dr. Gersbach said. "Additionally, this approach allowed us to turn on genes inside cells to levels that were not previously possible." The results of the Duke experiments, which were conducted by Dr. Pablo Perez-Pinera, a senior research scientist in Gersbach's laboratory, were published online on February 3, 2013 in the journal Nature Methods. Human cells have about 20,000 genes that produce a multitude of proteins, many of which affect the actions of other genes. Being able to understand these interactions would greatly improve the ability of scientists in all areas of biomedical research.