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Archive - 2012

February 9th

Most Lethal Known Species of Prion Identified

Scientists from the Florida campus of The Scripps Research Institute have identified a single prion protein that causes neuronal death similar to that seen in “mad cow” disease, but which is at least 10 times more lethal than larger prion species. This toxic single molecule or “monomer” challenges the prevailing concept that neuronal damage is linked to the toxicity of prion protein aggregates called “oligomers.” The study was published online on February 7, 2012 in PNAS. “By identifying a single molecule as the most toxic species of prion proteins, we’ve opened a new chapter in understanding how prion-induced neurodegeneration occurs,” said Scripps Florida Professor Corinne Lasmézas, who led the new study. “We didn’t think we would find neuronal death from this toxic monomer so close to what normally happens in the disease state. Now we have a powerful tool to explore the mechanisms of neurodegeneration.” In the study, the newly identified toxic form of abnormal prion protein, known as TPrP, caused several forms of neuronal damage ranging from apoptosis (programmed cell death) to autophagy, the self-eating of cellular components, as well as molecular signatures remarkably similar to that observed in the brains of prion-infected animals. The study found the most toxic form of prion protein was a specific structure described as alpha-helical. In addition to the insights it offers into prion diseases such as “mad cow” and a rare human form called Creutzfeldt-Jakob disease, the study opens the possibility that similar neurotoxic proteins might be involved in neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. In prion disease, infectious prions (short for proteinaceous infectious particles), thought to be composed solely of protein, have the ability to reproduce, despite the fact that they lack DNA and RNA.

February 6th

Hopkins Releases Free Software for Mutation Analysis

DNA sequencing to detect genetic mutations can aid in the diagnosis and selection of treatment for cancer. Current methods of testing DNA samples, specifically, Sanger sequencing and pyrosequencing, occasionally produce complex results that can be difficult or impossible to interpret. Scientists at the Johns Hopkins University School of Medicine have developed a free software program, Pyromaker, that can more accurately identify such complex genetic mutations. Pyromaker is a web-based application that produces simulated pyrograms based on user input, including the percentage of tumor and normal cells, the wild-type sequence, the dispensation order, and any number of mutant sequences. Pyromaker calculates the relative mutant and wild-type allele percentages and then uses these to generate the expected signal at each point in the dispensation sequence. The final result is a virtual trace of the expected pyrogram. The researchers validated Pyromaker against actual pyrograms containing common mutations in the KRAS gene, which plays an important role in the pathogenesis of a variety of tumors. The actual pyrograms and virtual pyrograms were quantitatively identical for all mutations tested. They then demonstrated that all codon 12 and 13 single and complex mutations generate unique pyrograms. However, some complex mutations were indistinguishable from single base mutations, indicating that complex mutations may be underreported.

February 5th

Genetic Variant Increases Risk of Common Form of Stroke

A genetic variant that increases the risk of a common type of stroke has been identified by scientists in a study published online in Nature Genetics on February 5, 2012. This is one of the few genetic variants to date to be associated with risk of stroke and the discovery opens up new possibilities for treatment. Stroke is the second leading cause of death worldwide (more than one in ten of all deaths, and over six million deaths annually), and also in developed countries is a major cause of chronic disability. As the world's populations age, the impact of stroke on wellbeing is likely to increase further. Several different mechanisms underlie strokes. One of the most common types is when blood flow is impaired because of a blockage to one or more of the large arteries supplying blood to the brain – large artery ischemic stroke. This accounts for over a third of all strokes. Researchers from St George's, University of London and Oxford University, working with scientists from Europe, America, and Australia, in one of the largest genetic studies of stroke to date, compared the genetic make-ups of 10,000 people who had suffered from a stroke with those of 40,000 healthy individuals. The study was funded by the Wellcome Trust. The researchers discovered an alteration in a gene called HDAC9 which affects a person's risk of large artery ischemic stroke. This variant occurs on about 10 per cent of human chromosomes. Those people who carry two copies of the variant (one inherited from each parent) have nearly twice the risk for this type of stroke compared to those with no copies of the variant. The protein produced by HDAC9 is already known to play a role in the formation of muscle tissue and heart development. However, the exact mechanism by which the genetic variant increases the risk of stroke is not yet known.

Possible Biomarker Reported for Osteoarthritis

Henry Ford Hospital researchers in Detroit, Michigan, together with collaborators, have identified for the first time two molecules that together hold promise as a biomarker for measuring cartilage damage associated with osteoarthritis. Researchers say the concentrations of two molecules called non-coding RNAs in blood were associated with mild cartilage damage in 30 patients who were one year removed from reconstruction surgery to repair an anterior cruciate ligament, or ACL, injury. The findings are described as significant in the ongoing and tedious search for biomarkers for osteoarthritis, the most common form of arthritis that afflicts an estimated 27 million Americans aged 25 and older. It is caused by the normal aging process or wear and tear of a joint. The study was presented February 4, 2012 at the annual Orthopaedic Research Society conference in San Francisco. "Our results suggest we have identified a long-awaited biomarker for this leading cause of disability," says Dr. Gary Gibson, director of Henry Ford's Bone and Joint Center and the study's lead author. "For various pathology reasons associated with the variability of the disease and challenging blood biochemistry, developing a biomarker for osteoarthritis has been very elusive. But we believe our work shows great promise. The next step is to expand the number of patients studied and determine whether the degree in blood concentration can determine if the cartilage damage will worsen over time. Our ultimate goal is to develop a biomarker that can be used in the development of future treatments to prevent the progression of the disease," he added. The study, a collaboration of Henry Ford, the University of Guelph in Ontario, and University of Toronto, involved 121 Canadian patients from 2006-2011.

DNA Methylation in Brain’s Executive Hub Tracked Across Lifetime

For the first time, scientists have tracked the activity, across the lifespan, of an environmentally responsive regulatory mechanism that turns genes on and off in the brain's executive hub. Among key findings of the study by National Institutes of Health (NIH) scientists: genes implicated in schizophrenia and autism turn out to be members of a select club of genes in which regulatory activity peaks during an environmentally-sensitive critical period in development. The mechanism, called DNA methylation, abruptly switches from off to on within the human brain's prefrontal cortex during this pivotal transition from fetal to postnatal life. As methylation increases, gene expression slows down after birth. Epigenetic mechanisms like methylation leave chemical instructions that tell genes what proteins to make –what kind of tissue to produce or what functions to activate. Although not part of our DNA, these instructions are inherited from our parents. But they are also influenced by environmental factors, allowing for change throughout the lifespan. "Developmental brain disorders may be traceable to altered methylation of genes early in life," explained Dr. Barbara Lipska, a scientist in the NIH's National Institute of Mental Health (NIMH) and lead author of the study. "For example, genes that code for the enzymes that carry out methylation have been implicated in schizophrenia. In the prenatal brain, these genes help to shape developing circuitry for learning, memory, and other executive functions which become disturbed in the disorders. Our study reveals that methylation in a family of these genes changes dramatically during the transition from fetal to postnatal life – and that this process is influenced by methylation itself, as well as genetic variability.

February 4th

Extremely Long-Lived Proteins May Provide Insight into Cell Aging

One of the big mysteries in biology is why cells age. Now scientists at the Salk Institute for Biological Studies report that they have discovered a weakness in a component of brain cells that may explain how the aging process occurs in the brain. The scientists discovered that certain proteins, called extremely long-lived proteins (ELLPs), which are found on the surface of the nucleus of neurons, have a remarkably long lifespan. While the lifespan of most proteins totals two days or less, the Salk Institute researchers identified ELLPs in the rat brain that were as old as the organism, a finding they reported on February 2, 2012 in Science. The Salk scientists are the first to discover an essential intracellular machine whose components include proteins of this age. Their results suggest the proteins can last an entire lifetime, without being replaced. ELLPs make up the transport channels on the surface of the nucleus; gates that control what materials enter and exit. Their long lifespan might be an advantage if not for the wear-and-tear that these proteins experience over time. Unlike other proteins in the body, ELLPs are not replaced when they incur aberrant chemical modifications and other damage. Damage to the ELLPs weakens the ability of the three-dimensional transport channels that are composed of these proteins to safeguard the cell's nucleus from toxins, says Dr. Martin Hetzer, a professor in Salk's Molecular and Cell Biology Laboratory, who headed the research. These toxins may alter the cell's DNA and thereby the activity of genes, resulting in cellular aging. Funded by the Ellison Medical Foundation and the Glenn Foundation for Medical Research, Dr. Hetzer's research group is the only lab in the world that is investigating the role of these transport channels, called the nuclear pore complex (NPC), in the aging process.

Whole-Exome Sequencing ID’s Cause of Metabolic Disease

Sequencing a patient’s entire genome to discover the source of his or her disease is not routine – yet. But geneticists are getting close. A case report, published February 2, 2012 in the American Journal of Human Genetics, shows how researchers can combine a simple blood test with an “executive summary” scan of the genome to diagnose a type of severe metabolic disease. Researchers at Emory University School of Medicine and Sanford-Burnham Medical Research Institute used “whole-exome sequencing” to find the mutations causing a glycosylation disorder in a boy born in 2004. Mutations in the gene (called DDOST) that is responsible for the boy’s disease had not been previously seen in other cases of glycosylation disorders. Whole-exome sequencing is a cheaper, faster, but still efficient strategy for reading the parts of the genome scientists believe are the most important for diagnosing disease. The report illustrates how whole-exome sequencing, which was first offered commercially for clinical diagnosis in 2011, is entering medical practice. Emory Genetics Laboratory is now gearing up to start offering whole-exome sequencing as a clinical diagnostic service. It is estimated that most disease-causing mutations (around 85 percent) are found within the regions of the genome that encode proteins, the workhorse machinery of the cell. Whole-exome sequencing reads only the parts of the human genome that encode proteins, leaving the other 99 percent of the genome unread. The boy in the case report was identified by Dr. Hudson Freeze and his colleagues. Dr. Freeze is director of the Genetic Disease Program at Sanford-Burnham Medical Research Institute. A team led by Dr. Madhuri Hegde, associate professor of human genetics at Emory University School of Medicine and director of the Emory Genetics Laboratory, identified the gene responsible.

February 3rd

New Technology Tackles Treatment-Resistant Cancers

Free-flowing cancer cells have been mapped with unprecedented accuracy in the bloodstream of patients with prostate, breast, and pancreatic cancer, using a brand-new approach, in an attempt to assess and control the disease as it spreads in real time through the body, and to solve the problem of predicting response and resistance to therapies. In comparison to a previous generation of systems, the researchers state their test showed a significantly greater number of high-definition circulating tumor cells (HD-CTCs), in a higher proportion of patients, by using a computing-intensive method that enables them to look at millions of normal cells and find the rare cancer cells among them. Their results, published on February 3, 2012, in Physical Biology, could help reveal the mechanisms behind the spread of solid tumours from one organ or tissue to another – mechanisms that have, until now, remained a mystery. Dr Jorge Nieva, an oncologist at Billings Clinic (Billings, Montana) leading the study, said: "This technology will allow scientists to move away from mouse and cell culture systems and speed the delivery of cures for cancer in people. This is the technology we have been waiting for to solve the problem of resistance to chemotherapy drugs." Senior technology author of the study, Professor Peter Kuhn, said: "In the future, our fluid biopsy can effectively become the companion to the patient for life. If we can assess the disease in real time, we can make quantitative treatment decisions in real time.

New RNA-Based Therapeutic Strategies for Controlling Gene Expression

Small RNA-based nucleic acid drugs represent a promising new class of therapeutic agents for silencing abnormal or overactive disease-causing genes, and researchers have discovered new mechanisms by which RNA drugs can control gene activity. A comprehensive review article in Nucleic Acid Therapeutics, a peer-reviewed journal published by Mary Ann Liebert, Inc., details these advances. Short strands of nucleic acids, called small RNAs, can be used for targeted gene silencing, making them attractive drug candidates. These small RNAs block gene expression through multiple RNA interference (RNAi) pathways, including two newly discovered pathways in which small RNAs bind to Argonaute proteins or other forms of RNA present in the cell nucleus, such as long non-coding RNAs and pre-mRNA. Dr. Keith T. Gagnon and Dr. David R. Corey, University of Texas Southwestern Medical Center, in Dallas, Texas, review common features shared by RNAi pathways for controlling gene expression and focus in detail on the potential for Argonaute-RNA complexes in gene regulation and other exciting new options for targeting emerging forms of non-coding RNAs and pre-mRNAs in the review. "The field of RNA-mediated control of gene expression is rapidly evolving and the article by Gagnon and Corey provides a highly informative and up-to-date review of this exciting and often surprising area of biomedical research. We are delighted to publish this important review for the field," says Co-Editor-in-Chief Dr. Bruce A. Sullenger, Duke Translational Research Institute, Duke University Medical Center, Durham, North Carolina. [Press release] [Nucleic Acid Therapeutics artcle]

February 2nd

Alzheimer’s Disease May Spread by “Jumping” from One Brain Region to Another

For decades, researchers have debated whether Alzheimer’s disease starts independently in vulnerable brain regions at different times, or if it begins in one region and then spreads to neuroanatomically connected areas. A new study by Columbia University Medical Center (CUMC) researchers strongly supports the latter, demonstrating that abnormal tau protein, a key feature of the neurofibrillary tangles seen in the brains of those with Alzheimer’s, propagates along linked brain circuits, “jumping” from neuron to neuron. The findings, published February 1, 2012 in the online journal PloS One, open new opportunities for gaining a greater understanding of Alzheimer’s disease and other neurological diseases and for developing therapies to halt its progression, according to senior author Dr. Karen E. Duff, professor of pathology (in psychiatry and in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain) at CUMC and at the New York State Psychiatric Institute. Alzheimer’s disease, the most common form of dementia, is characterized by the accumulation of plaques (composed of amyloid-beta protein) and fibrous tangles (composed of abnormal tau protein) in brain cells called neurons. Postmortem studies of human brains and neuroimaging studies have suggested that the disease, especially the neurofibrillary tangle pathology, begins in the entorhinal cortex, which plays a key role in memory. Then, as Alzheimer’s progresses, the disease appears in anatomically linked higher brain regions. “Earlier research, including functional MRI studies in humans, have also supported this pattern of spread,” said study coauthor Dr. Scott A. Small, professor of neurology in the Sergievsky Center and in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at CUMC.