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Archive - Feb 2015

February 11th

Order of Acquired Gene Mutations Can Have Huge Impact on Cancer Progression; Pioneering Research Offers Powerful New Insights into Origins of Cancer

The order in which genetic mutations are acquired determines how an individual cancer behaves, according to research from the University of Cambridge, published today, February 11, 2015, in the New England Journal of Medicine. The article was entitled, “The Impact of Mutation Order on Myeloproliferative Neoplasms.” Most of the genetic mutations that cause cancer result from environmental “damage” (for example, through smoking or as a result of over-exposure to sunlight) or from spontaneous errors occurring as cells divide. In a study published today, researchers in the Department of Hematology, the Cambridge Institute for Medical Research and the Wellcome Trust/Medical Research Council Stem Cell Institute show, for the first time, that the order in which such mutations occur can have an impact on disease severity and response to therapy. The researchers examined genetically distinct single stem cells taken from patients with myeloproliferative neoplasms (MPNs), a group of bone marrow disorders that are characterized by the over-production of mature blood cells, together with an increased risk of both blood clots and leukemia. These disorders are identified at a much earlier stage than most cancers because the increased number of blood cells is readily detectable in blood counts taken during routine clinical check-ups for completely different problems. Approximately one in ten of MPN patients carry mutations in both the JAK2 gene and the TET2 gene. By studying these individuals, the research team was able to determine which mutation came first and to study the effect of mutation order on the behavior of single blood stem cells.

Nova Scotia Research Team Analyzes Structure of Spider Silk’s AcSp1's Repeat Sequence at Very High Resolution; Repeat Units Behave in Modular Fashion; Findings Advance Development of Artificial Silks

Incredibly tough, slightly stretchy spider silk is a lightweight, biodegradable wonder material with numerous potential biomedical applications. But although humans have been colonizing relatively placid silkworms for thousands of years, harvesting silk from territorial and sometimes cannibalistic spiders has proven impractical. Instead, labs hoping to harness spider silk's mechanical properties are using its molecular structure as a template for their own biomimetic silks. A team of researchers from Dalhousie University in Nova Scotia is focusing on the toughest of the spider's seven types of silk--aciniform silk, used to wrap up prey that blunders into the spider’s web. Over the past few years, the scientists have gradually unraveled its protein architecture and begun to understand the connection between its structure and its function. The researchers presented their latest findings in a poster session during the 59th meeting of the Biophysical Society, held Feb. 7-11 in Baltimore, Maryland. The poster, "Roles of Spider Wrapping Silk Protein Domains in Fibre Properties" by Lingling Xu, Marie-Laurence Tremblay, Kathleen E. Orrell, Xiang-Qin Liu and Jan K. Rainey, was displayed on Tuesday, February 10, 2015. The first step in creating artificial spider silk is to replicate the proteins that make up the natural version, in this case, by recombinantly expressing them in E. coli. The key protein in aciniform silk, AcSp1, has three parts. Most of the protein is a repeated sequence of about two hundred amino acids. Two tails called the N- and C-terminal domains hang off each end of the protein chain.

Alligator Peptides Could Protect Humans Against Wound infection

Sophisticated germ fighters found in alligator blood may help future soldiers in the field fend off infection, according to new research by George Mason University. The study, published Feb. 11 in the scientific journal PLOS One, is the result of a fundamental research project supported by the Defense Threat Reduction Agency (DTRA) to find bacterial infection-defeating compounds in the blood of the crocodilian family of reptiles, which includes American alligators. The project is about to start its fourth year and has received $6 million in funding to date from DTRA. If fully funded over five years, the project will be worth $7.57 million. Alligators live in bacteria-filled environments and dine on carrion. Yet this ancient reptile rarely falls ill. "If you look at nature, sometimes we can find pre-selected molecules to study," says study co-author Dr. Monique van Hoek. "I was surprised to find peptides that were as effective as they are in fighting bacteria. I was really impressed." Discoveries made by George Mason's 17-member, multidisciplinary research team could eventually find their way to the battlefield to protect fighters from wound infections and potential exposure to biothreat agents. Researchers believe this work could benefit civilians too. "We hope that these could be the basis [upon which] to develop new treatments," says Dr.van Hoek, a Professor in the School of Systems Biology and the National Center for Biodefense and Infectious Diseases at George Mason. Dr. Van Hoek and lead co-authors Dr. Barney Bishop and Dr. Joel Schnur from the College of Science suspected the xxxx germ-fighting ability could be in the form of anti-microbial peptides.

Transcriptomics Identifies Genes & Signaling Pathways That May Regulate Neurodegeneration

Massive elimination of neurons is a critical aspect of normal nervous system development, but also represents a defining feature of neurodegenerative pathologies, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis(ALS or Lou Gehrig’s disease). Although the molecular events that trigger neuronal death in each of these neurodegenerative diseases are distinct, the downstream apoptotic process through which neurons die in these pathologies are thought to share commonalities to each other, as well as to developmentally-regulated neuronal death. Identifying genes that promote or prevent neuronal death would thus be an important step in understanding both developmentally-regulated neuronal death as well as the mechanisms underlying degenerative brain disorders. Scientists at Southern Methodist University (SMU), led by Professor and Chair of Biological Sciences Dr. Santosh D'Mello, have used RNA-Seq to conduct transcriptome profiling of gene expression changes in dying neurons. This study, reported [online] in the February 2015 issue of Experimental Biology and Medicine, utilized cultured cerebellar granule neurons, one of the most widely used models to study neuronal death. Other labs have used DNA microarray analysis to characterize gene expression changes in this model. However, microarray analysis is only capable of measuring the status of known transcripts, and expression of low-abundance mRNAs is often not detected by the hybridization-based approach. While changes in the expression of several hundred genes were detected by microarray analyses, in the study by Dr. D'Mello and colleagues, over 4,000 genes displayed significantly altered expression. Most affected were genes functioning in cell death and survival regulation, cell growth and proliferation, and molecular transport.

IBS Testing Using Digenome-Seq Technique Confirms Safety of CRISPR-Cas9 Technology

The Institute for Basic Science (IBS) research team (Center for Genome Engineering) has successfully confirmed that CRISPR-Cas9 has accurate on-target effects in human cells. This result was achieved through joint research with the Seoul National University College of Medicine and ToolGen, Inc. There has been great interest in CRISPR-Cas9 as a tool to develop anti-cancer cell therapies and/or to correct genetic defects that cause hereditary xxxx in stem and somatic cells. However, because there has been no reliable and sensitive method to measure the accuracy of CRISPR-Cas9 genome-wide, its safety has remained in question. Consequently, it has been difficult to eliminate the possibility that CRISPR-Cas9 may induce mutations in off-target sequences that are similar to on-target sequences. Off-target mutations in tumor suppressor genes, for example, can cause cancer. The researchers have developed a technique termed “Digenome-Seq” to locate both on-target and off-target sequences that can be mutated by CRISPR-Cas9 via genome sequencing. The scientists digested human genomic DNA using Cas9 nucleases in a test tube. This digested DNA was then subjected to whole-genome sequencing. This in vitro digest yielded a unique pattern at both on-target and off-target sequences that can be computationally identified. Furthermore, by adding guanine nucleotides at the end of sgRNA (single-guided RNA) that composes CRISPR-Cas9, they have successfully created this highly-developed programmable nuclease, which has no measurable off-target effects in the human genome. Dr. Jin-Soo Kim, Director of the Center for Genome Engineering at IBS, as well as Professor in the Department of Chemistry at Seoul National University, says, “If CRISPR-Cas9 truncates off-target DNA sequences, it might induce unwanted mutations.

New Variant of Rabbit Hemorrhagic Disease Virus (RHDV) Endangers Iberian Lynx

A study led by the Hunting Resources Research Institute demonstrates the effects that a new variant of the rabbit hemorrhagic disease virus (RHDV) is having on wild rabbits on the Iberian Peninsula. The virus threatens the survival of its predator, the Iberian lynx. Scientists have identified a new variant of RHDV throughout the entire Iberian Peninsula, including the areas where the Iberian lynx lives, such as the Sierra Morena mountains. A study published in the December 2014 issue of Emerging Infectious Diseases addresses the problem of this new outbreak of the virus for wild populations, which has caused a high number of mortalities on farms. The studfy is titled, “Ecosystem Effects of Variant Rabbit Hemorrhagic Disease Virus, Iberian Peninsula." "Very little is still known about this new variant, so it is difficult to say whether it is more serious than the previous one. Nevertheless, a significant difference is that it affects very young individuals, ten or eleven days old, which was not happening before," declares Dr. Delibes-Mateos, co-author of the study by the Hunting Resources Research Institute (CSIC-UCLM-JCCM) to SINC. Dr. Delibes-Mateos currently works for the Centre for Research into Biodiversity and Genetic Resources (University of Porto) (http://cibio.up.pt/) and the Institute for Advanced Social Sciences (CSIC) (http://www.iesa.csic.es/iesa/index/lng/en), both in Portugal.This new outbreak of RHDV could harm the rounding up of young individuals and put their dynamics at risk.

Toxin in Coral Snake Venom Binds Extremely Tightly to GABA(A) Receptors; New Finding May Offer Clues to Epilepsy, Schizophrenia, and Chronic Pain

For more than a decade, a vial of rare snake venom refused to give up its secret formula for lethality; its toxins had no effect on the proteins that most venoms target. Finally, an international team of researchers has figured out its recipe: a toxin that permanently activates a crucial type of nerve cell protein, preventing the cells from resetting and causing deadly seizures in prey. The details were presented in an article published online on February 9, 2015 in PNAS. "What we found are the first known animal toxins, and by far the most potent compounds, to target GABA(A) receptors," says Frank Bosmans, Ph.D., Assistant Professor of Physiology and Neuroscience at the Johns Hopkins University School of Medicine. "Once they bind to the receptors, they don't let go." Biochemical studies revealed the identity of the venom's active ingredient: it's actually twin proteins, dubbed micrurotoxins (MmTX) after their serpentine source, the reclusive coral snake Micrurus mipartitus. Most toxins in snake venoms target specialized nicotinic acetylcholine receptors on the surface of nerve cells that make muscles contract, paralyzing the snakes' victims. But when the researchers tested MmTX on lab-grown cells saturated with nicotinic acetylcholine receptors, nothing happened. This was puzzling because, in mice, MmTX was known to cause a repeating pattern of relaxation and seizures, similar to what's seen in epilepsy. By tagging the protein with a radioactive label, the team at Aix Marseille University in xxx was able to find out what protein it acted on. To the team's surprise, MmTX binds to GABA(A) receptors, pores on nerve cells in the brain and spinal cord. The function of GABA(A) receptors is to respond to the molecule GABA by opening to allow negatively charged chloride ions to flow into a nerve cell that has just fired.

Newly Funded AdaptoSCOPE Project Will Examine the Molecular Basis of Darwinian Adaptation When the Polygenic Basis of Adaptation Is Considered; Completely Novel View of Adaptive Landscapes Will Be Provided

Professor Juliette de Meaux from the Botanical Institute of the University of Cologne has received a Consolidator Grant from the European Research Council for her project AdaptoSCOPE, which explores the molecular basis of Darwinian adaptation. The project will run for five years and will receive up to 1.6 million euros in funding. The goal of this project is to demonstrate that novel aspects of the molecular basis of Darwinian adaptation can be discovered if the polygenic basis of adaptation is taken into account. Specifically, it will study the adaptation of the plant Arabidopsis thaliana to different climatic surroundings. This species is found at diverse latitudes and shows signs of local adaptation to different climates. Its molecular structures are optimized in the course of this adaptation. The research project will identify the molecular pathways subjected collectively to natural selection. Moreover, it will clarify if Arabidopsis lyrata, a close relative of A. thaliana, is subject to similar modifications of its molecular systems in its adaptation to different climates. The project will provide a completely novel view on adaptive landscapes and examine whether local adaptation occurs by convergent evolution of the molecular systems in plants. This approach has the potential to find broad applications in ecology and agriculture. Dr. de Meaux received her training as a botanist at the Ecole Normale Supérieure in Lyon and the Université Pierre and Marie Curie in Paris. She completed her Ph.D. at the Université d’Orsay in 2002. From 2010 to 2014, she was Professor of Plant Molecular Evolution at the University of Münster. Since 2015, she has held the Chair for Plant Molecular Ecology at the University of Cologne.

[Press release 2015]

First Kobuviruses Described from Africa; In Spotted Hyena, Side-Striped Jackal and Golden Jackal, and Local Domestic Dog; Kobuviruses Now Seem Less Host-Specific Than First Thought

An international team of researchers led by scientists at the German Leibniz Institute for Zoo and Wildlife Research (IZW) have genetically described the first kobuviruses to be reported from Africa. The results show that the viruses are less host-specific than previously assumed. The study has been published in Virology. The title of the Virology article is "Molecular Characterization of Canine Kobuvirus in Wild Carnivores and the Domestic Dog in Africa." Current knowledge of the recently described genus Kobuvirus is limited. In humans and livestock, kobuviruses are known to cause gastroenteritis and, hence are important for both health and economic reasons. To date, canine kobuvirus is known to infect domestic dogs in Europe, the USA, and Asia. Before the current study, the only wild carnivore known to be infected with canine kobuvirus was the red fox in Europe, and Kobuvirus infection had not been reported from Africa. A team of researchers from the Tanzanian Wildlife Research Institute, the Ecosystem Alliance (USA), and the IZW investigated Kobuvirus infection in wild carnivores in the Serengeti National Park (NP) in Tanzania, East Africa, and in domestic dogs living in villages outside the Serengeti NP. Using state-of-the-art molecular techniques, the scientists were able to provide the complete Kobuvirus genome from three wild carnivore species: the spotted hyena, the side-striped jackal and golden jackal, and the local domestic dog. These species were infected with canine kobuvirus strains genetically distinct from those in geographical regions outside Africa. Interestingly, the strains infecting wild carnivores inside the Serengeti NP were genetically distinct from those infecting domestic dogs outside the park, and genetically distinct strains were detected in domestic dogs from different villages.

Scientists at Biophysical Society Annual Meeting Describe Mapping Localization Pattern of Nearly Every Protein in a E. coli Cell for Its Entire Cell Cycle

Not unlike an urban restaurant, the success of a bacterial cell depends on three things: localization, localization, and localization. But the complete set of controls by which bacteria control the movement of proteins and other essential biological materials globally within the confines of their membrane walls has been something of a mystery. Now, researchers at the University of Washington have parsed out the localization mechanisms that E. coli use to sort through and organize their subcellular components. "Despite their small size and relative simplicity, bacterial cells appear to possess a robust and complex level of subcellular organization, both spatially and temporally, that was once thought to only exist in more complex organisms," said Dr. Nathan Kuwada, a postdoctoral fellow in the laboratory of Dr. Paul Wiggins at the University of Washington. "We wanted to know how many mechanisms bacteria possess to localize subcellular components, and, to answer this question, we set out to image the localization pattern of nearly every protein in a bacterial cell for the entire cell cycle." Dr. Kuwada described the group's findings on Sunday (February 8, 2015) at the Biophysical Society's 59th annual meeting in Baltimore, Maryland (February 7-11, 2015). E. coli localize nearly one-fifth of their proteins to specific subcellular sites, but until now, the cell-cycle localization behavior of only a small subset of proteins had been characterized in detail. Dr. Kuwada and his colleagues sought to remedy this by imaging an existing library of green-fluorescent protein fusions in E. coli by use of a high-throughput, live-cell imaging scheme. This allowed them to image close to a thousand individual protein fusions in growing cells for 6-8 hours, providing them with hundreds of complete cell cycles for each protein.