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Archive - Mar 16, 2014

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Novel Approach Reveals Gene Variant That Reduces Heart Attack Risk

Scientists have discovered a previously unrecognized gene variation that makes humans have healthier blood lipid levels and reduced risk of heart attacks -- a finding that opens the door to using this knowledge in testing or treatment of high cholesterol and other lipid disorders. But even more significant is how they found the gene, which had been hiding in plain sight in previous hunts for genes that influence cardiovascular risk. This region of DNA where the gene was found had been implicated as being important in controlling blood lipid levels in a report from several members of the same research team in 2008. But although this DNA region had many genes, none of them had any obvious link to blood lipid levels. The promise of an entirely new lipid-related gene took another six years and a new approach to find. In a new paper published online on March 16, 2014 in Nature Genetics, a team from the University of Michigan (U-M) and the Norwegian University of Science and Technology reports that they have zeroed in on the gene in an entirely new way. The team scanned the genetic information available from a biobank of thousands of Norwegians, focusing on variations in genes that change the way proteins function. Most of what they found turned out to be already known to affect cholesterol levels and other blood lipids. But one gene, named TM6SF2, wasn't on the radar at all. In a minority of the Norwegians who carried a particular change in the gene, blood lipid levels were much healthier and they had a lower rate of heart attacks. And when the researchers boosted or suppressed the gene in mice, they saw the same effect on the animals' blood lipid levels.

Scientists Clarify Mechanisms of Nectar Production and Secretion

Evolution is based on diversity, and sexual reproduction is key to creating a diverse population that secures competitiveness in nature. Plants had to solve a problem: they needed to find ways to spread their genetic material. Flying pollinators—insects, birds, and bats—were nature's solution. Charles Darwin's "abominable mystery" highlighted the coincidence of flowering plant and insect diversification about 120 million years ago and ascribed it to the coordinated specialization of flowers and insects in the context of insects serving as pollen carriers. To make sure the flying pollinators would come to the flowers to pick up pollen, plants evolved special organs called nectaries to attract and reward the animals. These nectaries are secretory organs that produce perfumes and sugary rewards. Yet despite the obvious importance of nectar, the process by which plants manufacture and secrete it has largely remained a mystery. New research from a team led by the Carnegie Institute of Science’s (Washinton, D.C.) Dr. Wolf Frommer, director of the Plant Biology Department, in collaboration with the Carter lab in Minnesota and the Baldwin lab in Jena, Germany, has now identified key components of the sugar synthesis and secretion mechanisms. Their work also suggests that the components were recruited for this purpose early during the evolution of flowering plants. Their work was published online on March 16, 2014 in Nature. The team used advanced techniques to search for transporters that could be involved in sugar transport and were present in nectaries. They identified the transport protein SWEET9 as a key player in three diverse flowering plant species and demonstrated that it is essential for nectar production.

MicroRNAs Target Transposons in Plant Reproductive Cells, Protecting Against Genome Damage

Reproductive cells, such as an egg and sperm, join to form stem cells that can mature into any tissue type. But how do reproductive cells arise? We humans are born with all of the reproductive cells that we will ever produce. But in plants things are very different. They first generate mature, adult cells and only later "reprogram" some of them to produce eggs and sperm. For a plant to create reproductive cells, it must first erase a key code, a series of tags attached to DNA across the genome known as epigenetic marks. These marks distinguish active and inactive genes. But the marks serve another critical role. They keep a host of damaging transposons, or "jumping genes," inactive. As the cell wipes away the epigenetic code, it activates transposons, placing the newly formed reproductive cell in great danger of sustaining genetic damage. On March 16, 2014, researchers at Cold Spring Harbor Laboratory (CSHL) in New York led by Professor and HHMI Investigator Dr. Robert Martienssen announce the discovery of a pathway that helps to keep transposons inactive even when the epigenetic code is erased. "Jumping genes" were first identified more than 50 years ago at CSHL by Nobel-prize-winning researcher Dr. Barbara McClintock. Subsequent study revealed that jumping genes (or transposable elements) are long, repetitive stretches of DNA. They resemble remnants of ancient viruses that have inserted themselves into their host DNA. When active, transposons copy themselves and jump around in the genome. They can insert themselves right in the middle of genes, thus interrupting them. Scientists have found that more than 50% of the human genome is made up of transposons. Remarkably, in plants, up to 90% of the genome is composed of these repetitive sequences.

Novel Approach to Treating Chronic Lymphocytic Leukemia (CLL)

Dartmouth researchers have developed a novel and unique approach to treating chronic lymphocytic leukemia (CLL), a form of blood cancer that often requires repeated chemotherapy treatments to which the cancer grows resistant. The researchers, led by Alexey V. Danilov, M.D., Ph.D., assistant professor at the Geisel School of Medicine at Dartmouth and hematologist-oncologist at the Norris Cotton Cancer Center, modeled in the laboratory the lymph node microenvironment where CLL cells are found. The scientists were able to disrupt the activity of a pathway (NF-kappa B) that ensures the survival and resistance of the CLL cells in such microenvironments. The study findings were published in the March 15, 2014 issue of Clinical Cancer Research. "In this in vitro microenvironment, we used MLN4924 to disrupt the activity of the NF-kappaB pathway by targeting Nedd8, which controls activation of NF-kappa B," said Dr. Danilov. "This decreased the survival of CLL cells and re-sensitized them to conventional chemotherapy as well as novel agents. Because the CLL cells used were obtained from patients with this disorder, these findings are immediately relevant to the clinic." Dr. Danilov says that unlike other novel therapies that have shown promise in the treatment of CLL, this approach is unique because it does not directly target proteins within the B-cell receptor pathway. He also notes that other research models that mimic the natural lymph node microenvironment have typically induced prolonged survival of CLL cells and made them resistant to in vitro chemotherapy. This research used novel model systems which reversed the pro-survival effects of the microenvironment. The researchers are now working to understand the intricate mechanisms of how MLN4924 decreased the survival of CLL cells.

Scientists Use Direct Coupling Analysis to Investigate Complex Molecular Machines

Open, feed, cut. Such is the humdrum life of a motor molecule, the subject of new research at Rice University, that eats and excretes damaged proteins and turns them into harmless peptides for disposal. The why is obvious: Without these trash bins, the Escherichia coli bacteria they serve would die. And thanks to Rice, the how is becoming clearer. Biophysicists at Rice used the miniscule machine – a protease called an FtsH-AAA hexameric peptidase – as a model to test calculations that combine genetic and structural data. Their goal is to solve one of the most compelling mysteries in biology: how proteins perform the regulatory mechanisms in cells upon which life depends. The Rice team of biological physicist Dr. José Onuchic and postdoctoral researchers Drs. Biman Jana and Faruck Morcos published a new paper on the work online on March 7, 2014 in a special issue of the Royal Society of Chemistry journal, Physical Chemistry Chemical Physics. The special issue edited by Rice biophysicist Dr. Peter Wolynes and Dr. Ruth Nussinov, a researcher at the National Cancer Institute and a professor at the Sackler School of Medicine at Tel Aviv University, pulls together current thinking on how an explosion of data combined with ever more powerful computers is bringing about a second revolution in molecular biology. The paper describes the Onuchic group’s first successful attempt to feed data through their computational technique to describe the complex activity of a large molecular machine formed by proteins. Ultimately, understanding these machines will help researchers design drugs to treat diseases like cancer, the focus of Rice’s Center for Theoretical Biological Physics. “Structural techniques like X-ray crystallography and nuclear magnetic resonance have worked quite well to help us understand how smaller proteins function,” Dr.