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Archive - Jan 2013

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January 31st

Autism Risk Linked to Prenatal Inflammation

Maternal inflammation during early pregnancy may be related to an increased risk of autism in children, according to new findings supported by the National Institute of Environmental Health Sciences (NIEHS), part of the National Institutes of Health. Researchers found this in children of mothers with elevated C-reactive protein (CRP), a well-established marker of systemic inflammation. The risk of autism among children in the study was increased by 43 percent among mothers with CRP levels in the top 20th percentile, and by 80 percent for maternal CRP in the top 10th percentile. The findings appeared online on January 22, 2013 in the journal Molecular Psychiatry and add to mounting evidence that an overactive immune response can alter the development of the central nervous system in the fetus. "Elevated CRP is a signal that the body is undergoing a response to inflammation from, for example, a viral or bacterial infection," said the lead scientist on the study, Alan Brown, M.D., professor of clinical psychiatry and epidemiology at Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, and Mailman School of Public Health. "The higher the level of CRP in the mother, the greater the risk of autism in the child." Dr. Brown cautioned that the results should be viewed in perspective because the prevalence of inflammation during pregnancy is substantially higher than the prevalence of autism. "The vast majority of mothers with increased CRP levels will not give birth to children with autism," Dr. Brown said.

Deficiencies in Two Genes Combine to Contribute to Hirschprung Disease

Mutations in single genes can cause catastrophic diseases, such as Huntington's disease or sickle cell anemia. However, many conditions, including cancer, diabetes, and birth defects are multigenic, arising from the collective failure of the function of more than one gene. Researchers know that mutations in at least twelve individual genes are associated with the congenital defect Hirschprung Disease (HSCR), in which children are born lacking nerves that innervate the large intestine. Now two companion studies published in Human Molecular Genetics by Paul Trainor, Ph.D., Investigator at the Stowers Institute for Medical Research, identify a new gene associated with HSCR and show how the migration of cells that form the gut nervous system is impeded when the combined doses of two candidate genes are low. Understanding the genetic basis of HSCR offers hope for better diagnostics and treatment for it and other developmental defects caused by failure of cell migration. The cells that go awry in HSCR are a subset of what are called neural crest cells, embryonic cells that spring from the developing brain and spinal cord in mice or humans and then travel long distances to form, among other structures, structures in the face and heart, smooth muscle, and neurons of the peripheral nervous system, including those that innervate the gut. Dr. Trainor has been interested in neural crest cells since he was a graduate student, often focusing on developmental defects caused by their malfunction. "Neural crest cells have to be born in the right place, migrate an incredibly long distance, survive the migration, multiply and then differentiate into a mature cell type," says Dr.

Diffusion Coefficients for Complete Proteome of E. coli Determined for First Time

Understanding of the chemical foundations of life requires knowledge about the rate of chemical reactions in cells. The rates of these reactions depend on how fast the molecules taking part in reactions move (diffuse) in the cytoplasm. Professor Robert Hołyst's research team from the Institute of Physical Chemistry of the Polish Academy of Sciences in Warsaw (IPC PAS) managed to determine – for the first time – the diffusion coefficients for virtually all the proteins occurring in Escherichia coli. The method developed by the researchers can also be used for other cells. The movements of molecules in cells resemble a bit what's going on in railway stations. But the differences are obvious at first glance. "Regular trains leave stations at fixed times, whereas in cells transport processes take place virtually all the time. That's why it doesn't make sense to ask what time does the train with specific molecules leave the station. But it definitely makes sense to ask how fast the train with specific molecules is moving!” explains Professor Hołyst. Transport efficiency of chemical compounds in cells became inspiring for many transport companies. There's talk of biologistics as modelling vehicle or rail transport by looking up to what's going on inside the cells. Professor Hołyst, however, has no illusions about that: "Everyone is delighted, for in cells the transport is so wonderfully resistant to perturbations. They forget, however, that the transport results from random fluctuations, in addition occurring in a small volume, where viscosity depends not only on the medium, but also on the size of the viscosity probe! I wish good luck to all those who want to transfer processes occurring in physically so different environment to our roads.

January 30th

First Artificial Enzyme Created by Evolution in a Test Tube

There’s a wobbly new biochemical structure in Dr. Burckhard Seelig’s lab at the University of Minnesota that may resemble what enzymes looked like billions of years ago, when life on earth began to evolve – long before they became ingredients for new and improved products, from detergents to foods and fuels. Dr. Seelig created the fledgling enzyme by using directed evolution in the laboratory. Working with colleague Dr. Gianluigi Veglia, graduate student Fa-An Chao, and other team members, Dr.Seelig subsequently determined the enzyme’s structure, which made its debut December 9 as an advance online publication in Nature Chemical Biology. Lab tests show that the enzyme (a type of RNA ligase, which connects two RNA molecules) functions as natural enzymes although its structure looks very different and it is flexible rather than rigid. Dr. Seelig speculates the new protein resembles primordial enzymes, before their current structures evolved. While a handful of groups worldwide are developing artificial enzymes, these groups use rational design to construct the proteins on computers. Instead, the Seelig lab employs directed evolution. "To my knowledge, our enzyme is the only entirely artificial enzyme created in a test tube by simply following the principles of natural selection and evolution," he says. Rational enzyme design relies on preconceived notions of what a new enzyme should look like and how it should function. In contrast, directed evolution involves producing a large quantity of candidate proteins and screening several generations to produce one with the desired function. With this approach, the outcome isn’t limited by current knowledge of enzyme structure. "Just as in nature, only the fittest survive after each successive generation," Dr. Seelig explains.

Ancient Snail Shell Analysis Reveals a Humid Mediterranean

An international team of researchers has shown that old wives' tales that snails can tell us about the weather should not be dismissed too hastily. While the story goes that if a snail climbs a plant or post, rain is coming, research led by the University of York goes one better: it shows snails can provide a wealth of information about the prevailing weather conditions thousands of years ago. The researchers, including scientists from the Scottish Universities Environmental Research Centre (SUERC), analyzed the chemistry of snail shells dating back 9,000 to 2,500 years recovered from Mediterranean caves, looking at humidity at different times in the past. Their findings, which were reported online on January 30, 2013 in the journal Quaternary International, reveal that when the first farmers arrived in Italy and Spain, the western Mediterranean was not the hot dry place it is now, but warmer, wetter, and stickier. The research was led by Dr. André Carlo Colonese from York’s Department of Archaeology. Dr. Colonese and his co-authors believe that land snails have great potential as a source of information about human behaviour and palaeoclimatic conditions and therefore should be given much more attention. Dr. Colonese, an EU Marie Curie Fellow in York’s Centre for Human Palaeoecology & Evolutionary Origins, said: “By putting together research on snails from multiple sites across Spain and Italy, we were able to produce a large-scale regional picture for weather conditions over the western Mediterranean area. This allowed us to observe differences in climate across the region.

January 26th

Telomerase Mutation a Driver Mutation in Melanoma

Approximately ten percent of all cases of malignant melanoma are familial cases. The genome of affected families tells scientists a lot about how the disease develops. Professor Dr. Rajiv Kumar of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) together with Professor Dr. Dirk Schadendorf from Essen University Hospital studied a family in which 14 family members were affected by malignant melanoma. The scientists analyzed the genomes of family members and found an identical mutation in the gene for telomerase, an enzyme often called the “immortality enzyme,” in all persons studied. Telomerase protects the ends of chromosomes from being lost in the process of cell division and, thus, prevents that cell from aging and dying. The inherited gene mutation leads to the formation of a binding site for protein factors in the controlling region of the telomerase gene, causing it to become overactive. As a result, mutated cells overproduce telomerase and hence become virtually immortal. The results were published online in Science on January 24, 2013. This spectacular finding of the family analysis prompted the scientists to also look for mutated telomerase genes in non-inherited (sporadic) melanoma, which is much more common than the familial variant. In most of the tissue samples of melanomas of all stages they found alterations in the telomerase gene switch, which the researchers clearly identified as typical consequences of sun exposure. Even though these mutations were not identical to those found in the melanoma family, they had the same effect: overactive telomerase. "We don't believe that the telomerase gene in melanoma is mutated by pure chance, but that it is a so-called driver mutation that drives carcinogenesis," says Dr. Kumar.

January 17th

Novel Technique Reveals Dynamics of Telomere DNA Structure

Biomedical researchers studying aging and cancer are intensely interested in telomeres, the protective caps on the ends of chromosomes. In a new study, scientists at the University of California-Santa Cruz used a novel technique to reveal structural and mechanical properties of telomeres that could help guide the development of new anti-cancer drugs. Telomeres are long, repetitive DNA sequences at the ends of chromosomes that serve a protective function analogous to that of the plastic tips on shoelaces. As cells divide, their telomeres get progressively shorter, until eventually the cells stop dividing. Telomeres can grow longer, however, through the action of an enzyme called telomerase, which is especially active in cells that need to keep dividing indefinitely, such as stem cells. Researchers have also found that most tumor cells show high telomerase activity. Dr. Michael Stone, an assistant professor of chemistry and biochemistry at UC-Santa Cruz, said his lab is particularly interested in the folding and unfolding of a DNA structure at the tail end of the telomere, known as a G-quadruplex, because it plays a key role in regulating telomerase activity. "Most cancer cells use telomerase as one mechanism to maintain uncontrolled growth, so it is an important target for anti-cancer therapeutics," Dr. Stone said. "The G-quadruplex structures of telomere DNA inhibit the function of the telomerase enzyme, so we wanted to understand the mechanical stability of this structure." Xi Long, a graduate student in Dr. Stone's lab, led the project, which involved integrating two techniques to manipulate and monitor single DNA molecules during the unfolding of the G-quadruplex structure.

Potential New Treatment for Gastrointestinal Cancers Discovered

Researchers have identified a complex of proteins that promotes the growth of some types of colon and gastric cancers, and shown that medications that block the function of this complex have the potential to be developed into a new treatment for these diseases. The complex of proteins, known as mTorc1 (mammalian target of rapamycin complex 1), has previously been implicated in the development of some other cancers, but this is the first time it has been shown to promote the growth of colon and gastric cancers that are associated with inflammation. Dr Stefan Thiem and Associate Professor Matthias Ernst from the Walter and Eliza Hall Institute’s Cell Signalling and Cell Death division made the discovery with colleagues while at the Melbourne-Parkville Branch of the Ludwig Institute for Cancer Research. Associate Professor Ernst is a Ludwig Institute Member. Their findings were published online on January 16, 2013 in the Journal of Clinical Investigation. Cancers of the digestive system are a significant cause of death in Australia. Colon (or bowel) cancer causes more than 4,000 deaths annually – more than any other cancer except lung cancer – while more than 1,000 Australians die from gastric (or stomach) cancer each year. Associate Professor Ernst said many types of colon and gastric cancer are associated with chronic inflammation. “We have previously shown that the immune system’s inflammatory response can promote the growth of tumors,” he said.

January 16th

Possible Role for Huntington’s Gene Discovered

About 20 years ago, scientists discovered the gene that causes Huntington’s disease, a fatal neurodegenerative disorder that affects about 30,000 Americans. The mutant form of the gene has many extra DNA repeats in the middle of the gene, but scientists have yet to determine how that extra length produces Huntington’s symptoms. In a new step toward answering that question, MIT biological engineers have found that the protein encoded by this mutant gene alters patterns of chemical modifications of DNA. This type of modification, known as methylation, controls whether genes are turned on or off at any given time. The mutant form of this protein, dubbed “huntingtin,” appears to specifically target genes involved in brain cell function. Disruptions in the expression of these genes could account for the neurodegenerative symptoms seen in Huntington’s disease, including early changes in cognition, says Dr. Ernest Fraenkel, an associate professor of biological engineering at MIT. Dr. Fraenkel’s lab is now investigating the details of how methylation might drive those symptoms, with an eye toward developing potential new treatments. “One could imagine that if we can figure out, in more mechanistic detail, what’s causing these changes in methylation, we might be able to block this process and restore normal levels of transcription early on in the patients,” says Dr. Fraenkel, senior author of a paper describing the findings in this week’s (January 15, 2013) issue of PNAS. Lead author of the paper is Christopher Ng, an MIT graduate student in biological engineering. Other authors are MIT postdoc Ferah Yildirim; recent graduates Yoon Sing Yap, Patricio Velez, and Adam Labadorf; technical assistants Simona Dalin and Bryan Matthews; and Dr. David Housman, the Virginia and D.K. Ludwig Professor of Biology.

January 14th

Researchers Identify Gene Fusion for Rare Cancer

It started with a 44-year-old woman with solitary fibrous tumor, a rare cancer seen in only a few hundred people each year. By looking at the entire DNA from this one patient's tumor, researchers have found a genetic anomaly that provides an important clue to improving how this cancer is diagnosed and treated. Researchers at the University of Michigan Comprehensive Cancer Center sequenced the tumor's genome through a new program called MI-ONCOSEQ, which is designed to identify genetic mutations in tumors that might be targeted with new therapies being tested in clinical trials. The sequencing also allows researchers to find new mutations. In this case, an unusual occurrence of two genes - NAB2 and STAT6 - fusing together. This is the first time this gene fusion has been identified. "In most cases, mutations are identified because we see them happening again and again. Here, we had only one case of this. We knew NAB2-STAT6 was important because integrated sequencing ruled out all the known cancer genes. That allowed us to focus on what had been changed," says lead study author Dan R. Robinson, research fellow with the Michigan Center for Translational Pathology. Once they found the aberration, the researchers looked at 51 other tumor samples from benign and cancerous solitary fibrous tumors, looking for the NAB2-STAT6 gene fusion. It showed up in every one of the samples. Results were published online January 13, 2013 in Nature Genetics. "Genetic sequencing is extremely important with rare tumors," says study co-author Scott Schuetze, M.D., associate professor of internal medicine at the U-M Medical School. "Models of rare cancers to study in the laboratory are either not available or very limited.