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Archive - Sep 2013


September 13th

New "Urzyme" Findings Challenge “RNA World” Assumptions on Origin of Life

Before there was life on Earth, there were molecules. A primordial soup. At some point a few specialized molecules began replicating. This self-replication, scientists agree, kick-started a biochemical process that would lead to the first organisms. But exactly how that happened — how those molecules began replicating — has been one of science's enduring mysteries. Now, research from University of North Carolina (UNC) School of Medicine biochemist Charles Carter, Ph.D., and colleagues, appearing in the September 13, 2013 issue of the Journal of Biological Chemistry, offers an intriguing new view on how life began. The paper was selected as one of the JBC’s papers of the week. Dr. Carter's work is based on lab experiments during which his team recreated ancient protein enzymes that likely played a vital role in helping create life on Earth. Dr. Carter's finding flies in the face of the widely-held theory that ribonucleic acid (RNA) self-replicated without the aid of simple proteins and eventually led to life as we know it. In the early 1980s, researchers found that ribozymes — RNA enzymes — act as catalysts. It was evidence that RNA can be both the blueprints and the chemical catalysts that put those blueprints into action. This finding led to the "RNA World" hypothesis, which posits that RNA alone triggered the rise of life from a sea of molecules. But for the hypothesis to be correct, ancient RNA catalysts would have had to copy multiple sets of RNA blueprints nearly as accurately as do modern-day enzymes. That's a hard sell; scientists calculate that it would take much longer than the age of the universe for randomly generated RNA molecules to evolve sufficiently to achieve the modern level of sophistication.

New Research Points to Promising Treatment for Macular Degeneration

Researchers at the University of North Carolina (UNC) School of Medicine, together with colleaguesat other institutions, have published new findings in the hunt for a better treatment for macular degeneration. In studies using mice, a class of drugs known as MDM2 inhibitors proved highly effective at causing the regression of the abnormal blood vessels responsible for the vision loss associated with the disease. “We believe we may have found an optimized treatment for macular degeneration,” said senior study author Sai Chavala, M.D., director of the Laboratory for Retinal Rehabilitation and assistant professor of Ophthalmology and Cell Biology & Physiology at the UNC School of Medicine. “Our hope is that MDM2 inhibitors would reduce the treatment burden on both patients and physicians.” The research was published online in an open-access article on September 9, 2013 in the Journal of Clinical Investigation. As many as 11 million Americans have some form of macular degeneration, which is the most common cause of central vision loss in the western world. Those with the disease find many daily activities such as driving, reading, and watching TV increasingly difficult. Currently, the best available treatment for macular degeneration is an antibody called anti-VEGF that is injected into the eye. Patients must visit their doctor for a new injection every 4-8 weeks, adding up to significant time and cost. “The idea is we’d like to have a long-lasting treatment so patients wouldn’t have to receive as many injections,” said Dr. Chavala. “That would reduce their overall risk of eye infections, and also potentially lower the economic burden of this condition by reducing treatment costs.” Dr. Chavala practices at the Kittner Eye Center at UNC Health Care in Chapel Hill and New Bern.

September 12th

“Zone in with Zon”—Cytosine, the “Wild Card” Base in Epigenetics

Dr. Gerald Zon’s latest “Zone in with Zon” blog post, dated September 9, 2013, compares the curious chemical biology of cytosine in epigenetics with the “curiouser and curiouser” happenings that Alice discovered after following the White Rabbit down a large rabbit hole. Dr. Zon begins this fascinating treatment by first offering a brief discussion of the basics of epigenetics, particularly the role of 5-methylated cytosine (5mC). Dr. Zon notes that in mammals 5mC is required for allele-specific expression of imprinted genes, transcriptional repression of retrotransposons, and for X chromosome inactivation in females. He also describes “passive” and “active” demethylation. He noted that so-called 5mC “erasers” have been sought for a long time. In 2011, it was indeed shown that oxidation of 5mC by TET (ten, eleven translocation) enzymes followed by TDG (thymine-DNA glycosylase)-mediated base excision of 5caC (5-carboxycytosine) constitutes a pathway for active DNA methylation. Dr. Zon further noted that additional independent work in 2011 showed that 5hmC (5-hydroxymethylcytosine) can be converted to 5hmU (5-hydroxymethyluracil), which can be a good substrate for TDG and may thus provide another mechanism for active cytosine demethylation in mammals. Dr. Zon pointed out that the oxidation-deamination mechanism in active cytosine demethylation was challenged in 2012 by Nabel et al. However, in 2013, Lie et al. cautioned that such deamination may occur in specific cellular contexts. Dr. Zon says that 5hmU in DNA is called “Base J.” It is present in all kinetoplastid flagellates studied—including Trypanosoma and Leishmania—but absent from other eukaryotes, prokaryotes, and viruses. Dr.

September 7th

DNA Used to Assemble Transistor from Graphene

DNA is the blueprint for life. Could it also become the template for making a new generation of computer chips based not on silicon, but on an experimental material known as graphene? That’s the theory behind a process that Stanford chemical engineering professor Dr. Zhenan Bao revealed online on August 30, 2013 in Nature Communications. Dr. Bao and her co-authors, former post-doctoral fellows Dr. Anatoliy Sokolov and Dr. Fung Ling Yap, hope to solve a problem clouding the future of electronics: consumers expect silicon chips to continue getting smaller, faster and cheaper, but engineers fear that this cycle could grind to a halt. Why has to do with how silicon chips work. Everything starts with the notion of the semiconductor, a type of material that can be induced to either conduct or stop the flow of electricity. Silicon has long been the most popular semiconductor material used to make chips. The basic working unit on a chip is the transistor. Transistors are tiny gates that switch electricity on or off, creating the zeroes and ones that run software. To build more powerful chips, designers have done two things at the same time: they’ve shrunk transistors in size and also swung those gates open and shut faster and faster. The net result of these actions has been to concentrate more electricity in a diminishing space. So far that has produced small, faster, and cheaper chips. But at a certain point, heat and other forms of interference could disrupt the inner workings of silicon chips. "We need a material that will let us build smaller transistors that operate faster using less power," Dr. Bao said. Graphene has the physical and electrical properties to become a next-generation semiconductor material – if researchers can figure out how to mass-produce it. The image depicts the assembly process.

September 5th

Molecular Marker Predicts Patients Most Likely to Benefit Longest from Two Popular Cancer Drugs

Johns Hopkins scientists and collaborators have identified a molecular marker called "Mig6" (mitogen-inducible gene 6) that appears to accurately predict longer survival -- up to two years -- among patients prescribed two of the most widely used drugs in a class of anticancer agents called EGFR inhibitors. The U.S. Food and Drug Administration-approved drugs, gefitinib (Iressa) and erlotinib (Tarceva), are prescribed for lung and pancreatic cancer patients, but only a few who have mutations in the EGFR gene usually benefit with a prolonged reduction of tumor size. The two drugs block the gene's ramped-up protein production, but patients' responses to the drug vary widely – from no survival benefit to several years. The average is several months. "Clinicians have had no reliable method for distinguishing patients who are not likely to respond to EGFR inhibitors and those who will respond very well," says David Sidransky, M.D., professor of otolaryngology, oncology, pathology, urology, and genetics at Johns Hopkins. Looking at the precise level of protein production from the EGFR gene alone in specific patients was not proven to be a good indicator of patients' response to EGFR-blocking drugs, but the presence or absence of Mig6 might be, he adds. In a preliminary study,publishe on July 31, 2013 in the online open-access journal, PLOS ONE, the Johns Hopkins scientists found the genetic marker in a series of experiments that began with laboratory-derived lung and head and neck cancer cell lines resistant to EGFR-inhibitor drugs. In the cell lines, the team found very high levels of protein production from the Mig6 gene -- up to three times the level in sensitive cell lines. Mig6 is one of the molecules that controls the activity of the EGFR protein.

Study Offers New Insight into How Cheetahs Catch Their Prey

A new research study has revealed that the cheetah, the world’s fastest land animal, matches and may even anticipate the escape tactics of different prey when hunting, rather than just relying on its speed and agility as previously thought. The study, which has just been published in the Royal Society Journal Biology Letters was carried out by a team of researchers from Queen’s University Belfast, in collaboration with other institutions in the UK (University of Aberdeen, University of Swansea, Institute of Zoology, Zoological Society of London, University of Oxford), and elsewhere (North Carolina State University, The Lewis Foundation, South African National Parks, Earth and OCEAN Technologies, Kiel, Germany). The research team used GPS and accelerometer data loggers deployed on cheetahs, along with traditional observation methods. The study was funded by a Royal Society International Joint Project grant, a NERC New Investigator award and the Lewis Foundation. Explaining the team’s findings, lead researcher Dr Michael Scantlebury, from the School of Biological Sciences at Queen’s University Belfast, said: “The more we understand about the physiology and the hunting tactics of this charismatic animal, the more we are able to ensure its continuing existence. Our study found that whilst cheetahs are capable of running at exceptionally high speeds, the common adage that they simply ‘outrun’ their prey does not explain how they are able to capture more agile animals. Previous research has highlighted their incredible speed and acceleration and their ability to turn after escaping prey. We have now shown that hunt tactics are prey-specific. In other words, we now know that rather than a simple maximum speed chase, cheetahs first accelerate towards their quarry before slowing down to mirror prey-specific escaping tactics.

New Gene Identified for NPH, a Cystic Kidney Disease of Children

Sylvia Hoff, a graduate student from the Spemann Graduate School of Biology and Medicine (SGBM), has identified a new gene that causes cystic kidneys in children and young adults. The work by the Ph.D. student Hoff and her international collaboration of partners was published in the August 2013 issue of Nature Genetics. The research group’s results lead to the identification of novel insights into the molecular mechanism underlying nephronophthisis (NPH), which is a prerequisite for developing pharmacological targets and new therapies for children with NPH. NPH is the most common inherited kidney disease that leads to renal failure in children. It is an autosomal recessive disease. The kidneys of affected children develop cysts, and as there is no approved therapy yet, patients need dialysis and renal transplantation. In addition, NPH often affects other organs apart from the kidney, such as the eyes, the liver, or the brain. Hoff, together with Dr. Soeren Lienkamp of the Nephrology Department at the Freiburg University Medical Center headed by Professor Gerd Walz, analyzed the function of NPH proteins during early developmental processes. They found that the ANKS6 protein has functions similar to those of some of the known NPH proteins. In collaboration with research groups in France, USA, Denmark, Switzerland, Egypt, the Netherlands, and Germany, they succeeded in identifying mutations in the ANKS6 gene of children with NPH. This confirmed that ANKS6 is a novel NPH-disease gene. The patients suffered from early-onset cystic kidney disease and structural heart abnormalities. Further analysis revealed that ANKS6 also forms a protein network with three other NPH proteins (INVS, NPHP3, and NEK8) at the cilium, a hair-like structure on the surface of many cells.

September 4th

Kruppel-Like Factors Established As Master Regulators of Vascular Health

Case Western Reserve researchers have identified a genetic factor that blocks the blood vessel inflammation that can lead to heart attacks, strokes, and other potentially life-threatening events. The breakthrough involving Kruppel-like factor (KLF) 15 is the latest in a string of discoveries from the laboratory of professor of medicine Mukesh K. Jain, M.D., F.A.H.A., that involves a remarkable genetic family. Kruppel-like factors appear to play prominent roles in everything from cardiac health and obesity to metabolism and childhood muscular dystrophy. School of Medicine instructor Yuan Lu, M.D., a member of Dr. Jain’s team, led the study involving KLF-15 and its role in inflammation, which was published online on Sepember 3, 2013 in the Journal of Clinical Investigation. Dr. Lu and colleagues observed that KLF-15 blocks the function of a molecule called NF-kB, a dominant factor responsible for triggering inflammation. This finding reveals a new understanding of the origins of inflammation in vascular diseases, and may eventually lead to new, targeted treatment options. “It had been suspected that smooth muscle cells were related to inflammation, but it hadn’t been pinpointed and specifically linked to disease,” said Dr. Jain, Ellery Sedgwick Jr. Chair and director, Case Cardiovascular Research Institute at Case Western Reserve School of Medicine. Dr. Jain also is chief research officer for the Harrington Heart & Vascular Institute at University Hospitals Case Medical Center. “This work provides cogent evidence that smooth muscle cells can initiate inflammation and thereby promote the development of vascular disease.” Smooth muscle cells are only one of two major cell types within blood vessels walls. The other cell type, endothelium, has traditionally taken the blame for inflammation, but Dr.

Study Reveals How Signals from Defective Neurons Are Squelched by Quality Control System

Biologists at the University of California (UC), San Diego, have identified a new component of the cellular mechanism by which humans and animals automatically check the quality of their nerve cells to assure they’re working properly during development. In a paper published in the September 4, 2013 issue of the journal Neuron, the scientists report the discovery in the laboratory roundworm C. elegans of a “quality check” system for neurons that uses two proteins to squelch the signals from defective neurons and marks them for either repair or destruction. “To be able to see, talk, and walk, nerve cells in our body need to communicate with their right partner cells,” explains Dr. Zhiping Wang, the lead author in the team of researchers headed by Dr. Yishi Jin, a professor of neurobiology in UC San Diego’s Division of Biological Sciences and a professor of cellular and molecular medicine in its School of Medicine. “The communication is mediated by long fibers emitting from neurons called axons, which transmit electric and chemical signals from one cell to the other, just like cables connecting computers in a local wired network. In developing neurons, the journey of axons to their target cells is guided by a set of signals. These signals are detected by ‘mini-receivers’—proteins called guidance receptors—on axons and translated into ‘proceed,’ ‘stop,’ ‘turn left’ or ‘turn right.’ Thus, the quality of these receivers is very important for the axons to interpret the guiding signals.” Dr. Jin, who is also an Investigator of the Howard Hughes Medical Institute, says defective protein products and environmental stress, such as hyperthermia, can sometimes jeopardize the health and development of cells. “This may be one reason why pregnant women are advised by doctors to avoid saunas and hot tubs,” she adds.

Angiomotin Protein Newly Linked to Initial Tumor Growth in Several Cancers

A team led by scientists from The Scripps Research Institute (TSRI) has shown that a protein once thought to inhibit the growth of tumors is instead required for initial tumor growth. The findings could point to a new approach to cancer treatment. The study was published as the cover article of the September 3, 2013 issue of the journal Science Signaling. The focus of the study was angiomotin, a protein that coordinates cell migration, especially during the start of new blood vessel growth and proliferation of other cell types. “We were the first to describe angiomotin’s involvement in cancer,” said Dr. Joseph Kissil, a TSRI associate professor who led the studies. “ And while some following studies found it to be inhibiting, we wanted to clarify its role by using both cell studies and animal models. As a result, we have now found that it is not an inhibitor at all, but instead is required for Yap to produce new tumor growth.” Yap (yes-associated-protein) is a potent oncogene that is over-expressed in several types of tumors. In addition to identifying angiomotin’s critical role in tumor formation, Dr. Kissil and his colleagues found the protein is active within the cell nucleus. Earlier cell studies focused on the function of the protein at the cell membrane. “This pathway, which was discovered less than a decade ago, appears to regulate processes that are closely linked to cancer,” Dr. Kissil said. “The more we study it, the more we see its involvement.” The first authors of the study are Dr. Chunling Yi of Georgetown University Medical Center and Dr. Zhewei Shen of the University of Pennsylvania. Other authors include Dr. Anat Stemmer-Rachamimov of Massachusetts General Hospital; Drs. Noor Dawany, Louise C. Showe and Qin Liu of The Wistar Institute; Dr. Scott Troutman of TSRI; Dr. Akihiko Shimono of TransGenic, Inc.; Dr.