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June 16th, 2015

“Breakthrough Article” in Nucleic Acids Research: Powerful FDF-PAGE Technique Reveals Previously Undetected Small RNAs Hidden by Complementary Transcripts

Investigators working in the Plant Sciences Department of Cambridge University and the School of Biological Sciences, Edinburgh University, led by Dr. David Baulcombe, have identified shortcomings in current methods for detecting small RNAs (between 18 nucleotides and 30 nucleotides in length) and have used a new approach to identify small RNAs that might be under the control of competing endogenous RNAs (ceRNAS). This new work has been awarded the status of “Breakthrough Article” by the Nucleic Acids Research (NAR) journal and was published online in the open-access NAR on June 13, 2015. The article is titled “FDF-PAGE: A Powerful Technique Revealing Previously Undetected Small RNAs Sequestered by Complementary Transcripts.” FDF-PAGE is the abbreviation for “fully denaturing formaldehyde-polyacrylamide gel electrophoresis.” Small RNA sequencing is a powerful approach for investigating the regulation of gene expression inside cells. Millions of sequence “reads” can be obtained, providing clues to the control of thousands of genes. The data, however, are limited by the quality of the RNA used as the raw material for sequencing. Dr. Baulcombe and coworkers show that it is likely that some small RNAs will hybridize to complementary sequences and that this binding will reduce their detection. To overcome this problem, the authors add a procedure for separating complementary strands to the protocol for RNA preparation prior to sequencing. This method provides a more robust and accurate profile of cellular RNAs and is likely to find wide application in the sequencing of small RNAs. Reviewers and editors at NAR who have examined this new study describe its results as an important advance for understanding small RNAs and reducing biases that lead to incorrect hypotheses. One reviewer noted “This is the next step.

Pronounced Expression of AF1q Gene Promotes Breast Cancer Aggression and Metastasis

A particular human gene variant makes breast cancer cells more aggressive. Not only are these cells more resistant to chemotherapy, but they also leave the primary tumor and establish themselves in other parts of the body in the form of metastases. An international group of researchers led by Dr. Lukas Kenner of MedUni Vienna in Austria has now identified a gene, AF1q, as being substantially responsible for this aggressive breast cancer behavior and recognized this gene as a possible starting point for more accurate diagnosis and potential targeted therapeutic approaches. The human AF1q gene was originally discovered in a chromosomal abnormality and recognized as an important factor in the development of leukemia. Elevated AF1q levels were also found in particularly aggressive forms of acute myeloid leukemia (AML). The exact function of AF1q in the body is not yet fully understood but the current study shows that AF1q is an important key protein in the TCF7/Wnt signaling pathway and controls the behavior of cancer cells. Increased AF1q expression promotes the development and growth of tumor cells and prevents natural cellular death. Patients suffering from breast cancer who have pronounced AF1q expression have a much poorer prognosis than those who do not. Furthermore, "AF1q-positive" cancer cells are more resistant to forms of chemotherapy. It was further demonstrated in model experiments that increased expression of AF1q in breast cancer cells encourages metastasis to the liver and also to the lung. When the research group compared samples of primary tumor with samples of metastases, they found that AF1q-positive cancer cells had left the primary tumor and established themselves in other areas of the body as metastases.

Study Identifies Promising New Drug Target in Huntington’s Disease; Blocking Function of Striatal-Enriched GTPase Rhes Protein May Halt Initiation of HD

Huntington’s disease attacks the part of the brain that controls movement, destroying nerves with a barrage of toxicity, yet leaves other parts relatively unscathed. Scientists from the Florida campus of The Scripps Research Institute (TSRI) have established conclusively that an activating protein, called “Rhes,” plays a pivotal role in focusing the toxicity of Huntington’s disease in the striatum, a smallish section of the forebrain that controls body movement and is potentially involved in other cognitive functions such as working memory. “Our study definitively confirms the role of Rhes in Huntington’s disease,” said TSRI Assistant Professor Dr. Srinivasa Subramaniam, who led the study. “Our next step should be to develop drugs that inhibit its action.” The study was published online on June 3, 2015 in the journal Neurobiology of Disease. The article is titled ““Ectopic Expression of the Striatal-Enriched GTPase Rhes Elicits Cerebellar Degeneration and an Ataxia Phenotype in Huntington Disease.” In an earlier study, Dr. Subramaniam and his colleagues showed that Rhes binds to a series of repeats in the huntingtin protein (named for its association with Huntington’s disease), increasing the death of neurons. The new study shows that deleting Rhes significantly reduces behavioral problems in animal models of the disease. In addition, the study took the research further and revealed the effects of adding Rhes to the cerebellum, a brain region normally not affected in Huntington’s. Remarkably, Huntington disease animals injected with Rhes experienced an exacerbation of motor issues, including loss of balance and coordination. Dr.

June 14th

Harvard Scientists Transplant “Biological Clock” from Cyanobacteria to E. coli, Which Normally Does Not Have Circadian Rhythm; “Circadian” E. coli May Ultimately Be Used in Creation of Precisely-Timed Drug Release Medications and Jet Lag Prevention

Often referred to as the "body clock," circadian rhythm controls what time of day people are most alert, hungry, tired, or physically primed due to a complex biological process that is not unique to humans. Circadian rhythms, which oscillate over a roughly 24-hour cycle in adaptation to the Earth's rotation, have been observed in most of the planet's plants, animals, fungi, and cyanobacteria, and are responsible for regulating many aspects of organisms' physiological, behavioral and metabolic functions. Now, scientists, led by the pioneering Harvard synthetic biologist Pamela Silver, Ph.D., have harnessed the circadian mechanism found in cyanobacteria to transplant the circadian wiring into a common species of bacteria that is naturally non-circadian. The novel work, which for the first time demonstrates the transplant of a circadian rhythm, is described in an open-access article published online on June 12, 2015 in Science Advances. "By looking at systems in nature as modular, we think like engineers to manipulate and use biological circuits in a predictable, programmable way," said Dr. Silver, who is a Core Faculty member at the Wyss Institute for Biologically Inspired Engineering at Harvard University and a Professor in the Department of Systems Biology at Harvard Medical School. Dr. Silver's team used this methodology to successfully transplant a circadian rhythm into the bacterial species E. coli, which is widely used as a "workhorse" cell species by biologists due to how well it is understood and the ease with which E. coli can be genetically altered. The genetically engineered circadian E.

Possibly Effective Drug Treatment to Halt Progression of, or Reverse, Pulmonary Fibrosis & Pulmonary Hypertension, Two Rapidly Fatal Lung Diseases; Triciribine Drug Inhibits Production of Akt1 Protein and Halts or Reverses These Diseases in Mouse Models

Researchers at the University of Georgia have discovered that the drug triciribine may reverse or halt the progression of pulmonary fibrosis (image) and pulmonary hypertension, two respiratory diseases that are almost invariably fatal. The scientitst published their findings online on May 29, 2015 in the British Journal of Pharmacology. The article is titled “Akt Inhibitor, Triciribine, Ameliorates Chronic Hypoxia-Induced Vascular Pruning and TGFβ-Induced Pulmonary fFbrosis.” Pulmonary fibrosis occurs when lung tissue becomes scarred, leading to loss of lung function and reduced oxygen supply to the blood. Pulmonary hypertension involves an increase of blood pressure in the arteries of the lung that can lead to heart failure. Although no definitive cause for the disease has been identified, pulmonary fibrosis affects nearly 130,000 people in the U.S., with about 48,000 new cases diagnosed annually, according to the Coalition for Pulmonary Fibrosis. Pulmonary hypertension is rare--with only about 15 to 50 cases per million people--but the total number of deaths attributed to the disease increased by more than 40 percent in the U.S. between 1980 and 2002, according to the Centers for Disease Control and Prevention. "The average life expectancy for people with these diseases is only about five years after diagnosis, and while the drug treatments we currently have may help improve quality of life, they don't reduce mortality," said Dr. Somanath Shenoy, co-author of the paper and associate professor in UGA's College of Pharmacy.

June 13th

Free Webinar on Exosome Biogenesis Scheduled for June 25; Seminar Will Discuss Hypothesis That HIV and Other Retroviruses Exploit the Exosomal Machinery in Budding from the Cell Membrane

Exosomes are small secreted vesicles that have a diameter of ~50-200 nm. Exosomes are typically enriched for a specific subset of host-derived proteins, nucleic acids, lipids, and carbohydrates, though they also incorporate most host cell molecules at baseline levels. Various models of exosome biogenesis have been proposed, but the field lacks the robust mechanistic studies that are needed to obtain a molecular understanding of vesicle secretion. Beckman Coulter is sponsoring a new educational webinar, “Exosome Biogenesis and the Budding of Proteins and Viruses,” with Stephen Gould, Ph.D., as speaker. The seminar, which is scheduled for June 25, 2015, will describe a cargo-based approach in which the lab focuses on the cis-acting signals that are necessary and sufficient for the budding of specific proteins. These studies have revealed that exosomal proteins are targeted to sites of vesicle budding by a combination of (1) high-order oligomerization and (2) binding to the plasma membrane. In addition, the work supports the hypothesis that the plasma membrane is a major site of exosome budding. In support of this research, it is known that HIV and other retroviruses have the same topology, size, and array of host cell molecules as exosomes, raising the possibility that retroviruses bud from infected cells by an exosomal pathway. This hypothesis is supported by the fact that retroviral Gag proteins, their main structural protein, are targeted to sites of exosome budding, bud from cells in association with exosomal cargo proteins, form high-order oligomeric complexes that bind the plasma membrane, and require plasma membrane binding in order to bud from cells.

NIH Awards $1.7 Million Grant to Exosome Start-Up Company Seeking to Develop Anti-Cancer Therapeutic Technology Using Exosomes; Grant “Validates Significant Potential of Exosome-Based Cancer Therapeutics”

The National Institutes of Health (NIH) National Cancer Institute has awarded a five-year, $1.7 million grant to the University of New Mexico (UNM) Health Sciences Center to advance the development of new, exosome-based technology that empowers the body’s own natural defenses to fight cancer. Exovita Biosciences, Inc. ( , a company in Albuquerque, New Mexico, formed by the New Mexico Startup Factory, holds the option to an exclusive, worldwide license for the patent-pending technology developed by Kristina Antonia Trujillo, Ph.D., a research assistant professor in UNM’s Department of Biochemistry and Molecular Biology. Exovita executed a Sponsored Research Agreement in February 2015 with UNM. The agreement will fund the development of the exosome-based technology as a therapeutic, while the NIH grant will fund the mechanistic investigation of how the exosomes exert their anti-cancer properties. The data generated through these awards will be the foundation for eventual cancer-fighting therapeutics. Richard Larson, M.D., Ph.D., Executive Vice Chancellor and Vice Chancellor for Research at the Health Sciences Center, said the NIH grant validates the significant potential of exosome-based cancer therapeutics. “Exosomes are small, fluid-filled packets that allow our cells to communicate with each other,” Dr. Larson said. “The therapeutic approach being taken by Exovita and Dr. Trujillo represents a new way of using our own natural biological process to fight cancer.” Dr. Trujillo, the principal investigator for the NIH RO1 grant, has identified specific cells that produce exosomes, which kill cancer cells without harming healthy cells.

June 11th

Exosome Role in Cancer Featured in June 11 NEJM Article on Clinical Applications of Basic Research

The June 11, 2015, issue of the New England Journal of Medicine featured an article titled “Expanding on Exosomes and Ectosomes in Cancer” in the journal’s section on Clinical Applications of Basic Research. The article was authored by Lorraine O’Driscoll, Ph.D., Director of Research and Associate Professor of Pharmacology, School of Pharmacy & Pharmaceutical Sciences, at Trinity College Dublin in Ireland. Dr. O’Driscoll began by noting that up until recently exosomes were considered to have no biological significance. Now, however, these nanosized vesicles are believed to be mini-maps of their cells of origin, with physiological and pathologic relevance. In cancer, she said, exosomes have been implicated in the transfer of “undesirable” information from one cell to another, with consequences that include stimulating the proliferation, motility, and invasive properties of the recipient cell, transferring drug resistance, inducing the formation of endothelial tubules (e.g., in angiogenesis), and attracting cancer cells to secondary sites within living organisms. Although our understanding of exosomes remains “rudimentary,” Dr. O’Driscoll said that four recent studies (all published in 2014) lend strong support to the concept that exosomes derived from cancer cells are dynamic mini-factories that actively contribute to the progression of disease. These studies have focused on the microRNA (miRNA) content of exosomes, she said. In one study, conducted by Dr. Sonia Melo and colleagues, the researchers worked with exosomes from breast-cancer cell lines and exosomes from non-tumorigenic breast-cell lines (

June 10th

Worm Study Suggests Innate Immune Response to Mutant ALS Proteins Drives Neurodegeneration in ALS; Blocking of Response May Be Treatment Possibility

A previously unknown link between the immune system and the death of motor neurons in amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, has been discovered by scientists at the CHUM Research Centre and the University of Montreal. The finding paves the way to a whole new approach for finding a drug that can cure, or at least slow the progression, of such neurodegenerative diseases as ALS, Alzheimer's, Parkinson's, and Huntington's diseases. The study, published online on June 10, 2015 in Nature Communications, shows that the immune system in the animal model C. elegans, a tiny 1 mm-long roundworm, plays a critical role in the development of this animal model ALS. “An imbalance of the immune system can contribute to the destruction of motor neurons and trigger the disease,” said Dr. Alex Parker, CRCHUM researcher and Associate Professor in the Department of Neuroscience at the University of Montreal. The article is titled “Neurodegeneration in C. elegans Models of ALS Requires TIR-1/Sarm1 Immune Pathway Activation in Neurons.” ALS is a neuromuscular disease that attacks neurons and the spinal cord. Those affected gradually become paralyzed and typically die within five years of the onset of symptoms. No effective remedy currently exists for this devastating affliction. Riluzole, the only approved medication, only extends the patient's life by a few months. More than a dozen genes are related to ALS. If a mutation occurs in one of them, the person develops the disease. Scientists introduced a mutated human ALS gene (TDP-43 or FUS) into C. elegans, a nematode worm widely used for genetic experiments. The worms became paralyzed within approximately 10 days. The challenge was to find a way of saving them from certain death.

Study Reveals Roles for Fragile X Syndrome Proteins (FMRP and FXRP2) in Controlling GluA1 Expression and Neuronal Maturation

Fragile X syndrome is the most common inherited intellectual disability and the greatest single genetic contributor to autism. Unlocking the mechanisms underlying fragile X syndrome could reveal significant new information about about the brain. In a new study, published online on June, 4, 2015 in the journal Cell Reports, researchers from the University of Wisconsin-Madison’s Waisman Center and Department of Neuroscience show that two proteins implicated in fragile X syndrome play a crucial role in the proper development of neurons in mice. They also show that while the two proteins act through distinct mechanisms in the formation of new neurons, they also share some duties. The Cell Reports article is titled “Fragile X Proteins FMRP and FXR2P Control Synaptic GluA1 Expression and Neuronal Maturation via Distinct Mechanisms.” “This is the first demonstration of the additive function of fragile X proteins in neuronal development,” says study corresponding author and Waisman Center and Department of Neuroscience Professor Xinyu Zhao. Relatively little is known about the underlying mechanisms that lead to the cognitive and learning deficits in fragile X syndrome, Dr. Zhao says, making it difficult to devise effective therapies. She studies the two fragile X proteins, FMRP (fragile X mental retardation protein) and FXR2P (the autosomal paralog of FMRP), because doing so could yield new information that might ultimately lead to effective treatment for fragile X syndrome, as well as for other disorders marked by defects in neuronal development, such as autism and schizophrenia. For instance, while FXR2P has been shown to be important in autism, the function of the protein and its contribution to fragile X syndrome has been unclear, Dr. Zhao says.