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Archive - Feb 2015

February 23rd

C2H2 Zinc Finger Proteins (Over 700 in Number and 3% of Human Proteome) Have Evolved from Inhibitors of Endogenous Retro-Elements (EREs) to Transcription Factors

University of Toronto scientists have discovered how viral remnants helped shape control of our genes. If genes were lights on a string of DNA, the genome would appear as an endless flicker, as thousands of genes come on and off at any given time. Dr. Tim Hughes, a Professor at the University of Toronto's Donnelly Centre, has been focused on unraveling the rules behind this tightly orchestrated light-show, because, when it fails, disease can occur. Genes are switched on or off by proteins called transcription factors. These proteins bind to precise sites on the DNA that serve as guideposts, telling transcription factors that their target genes are nearby. In an article published online on February 18, 2015 in Nature Biotechnology, Dr. Hughes and his team describe the first systematic study of the largest group of human transcription factors, called C2H2-Zinc Finger (C2H2-ZF) transcription factors (image shows the general structure of these transcription factors). The Nature Biotechnology article is titled “C2H2 Zinc Finger Proteins Greatly Expand the Human Regulatory Lexicon.” Despite their important roles in development and disease, these proteins have remained largely uninvestigated because they posed a formidable challenge to researchers. C2H2-ZF transcription factors constitute a group of over 700 proteins, approximately 3 per cent of all human genes. To make matters more complicated, most human C2H2-ZF transcription factors are very different from C2H2-ZF transcription factors in other organisms, such as those in mice, for example. This means that scientists can not apply insights gained from animal studies to human C2H2-ZFs. In their new work, Dr.

February 21st

RNA Markers in Saliva May Reveal Deadly Diseases Early Enough to Treat Them, UCLA Scientists Analyze 165 Million Genetic Sequences from Saliva; Fluid Found to Be Surprisingly Rich Source of microRNA, piRNA, and circRNA

UCLA research could lead to a simple saliva test capable of diagnosing — at an early stage — diabetes and cancer, and perhaps neurological disorders and autoimmune diseases. The study, the most comprehensive analysis ever conducted of RNA molecules in human saliva, demonstrates that saliva contains many of the same disease-revealing molecules that are contained in blood. It was published online today by the peer-reviewed journal Clinical Chemistry and was published Clinical Chemistry’s January 2015 special print issue, “Molecular Diagnostics: A Revolution in Progress.” “If we can define the boundaries of molecular targets in saliva, then we can ask what the constituents in saliva are that can mark someone who has pre-diabetes or the early stages of oral cancer or pancreatic cancer — and we can utilize this knowledge for personalized medicine,” said Dr. David Wong, a senior author of the research and UCLA’s Felix and Mildred Yip Endowed Professor in Dentistry. Dr. Wong said the test also holds promise for diagnosing Type 2 diabetes, gastric cancer, and other diseases. “If you don’t look in saliva, you may miss important indicators of disease,” Dr. Wong said. “There seems to be treasure in saliva, which will surprise people.” RNA, widely known as a cellular messenger that makes proteins and carries out DNA’s instructions to other parts of the cell, is now understood to perform sophisticated chemical reactions and is believed to perform an extraordinary number of other functions, at least some of which are unknown. Dr. Wong’s research over the past decade has focused on identifying biomarkers in saliva.

Dental Researchers Develop New Model for Studying How T-Cells Cause Inflammation; Model Based on Oral Yeast Infection, Th17 Cells, Immunodeficient Mice; Use May Lead to Development of New Anti-Fungal Agents

Dental researcher Dr. Pushpa Pandiyan (photo) and colleagues have discovered a new way to model how infection-fighting T-cells cause inflammation in mice. The hope is that the discovery will lead to new therapies and/or drugs that jump-start weakened or poorly functioning immune systems, said Dr. Pandiyan, an Assistant Professor at Case Western Reserve University (CWRU) School of Dental Medicine. Dr. Pandiyan believes the process could lead to identifying and testing new drugs to replace anti-fungal medicines that have become ineffective as the fungi develop a resistance to them. Dr. Pandiyan's findings are explained and demonstrated in the Journal of Visualized Experiments (JoVE) article "Th17 Inflammation Model of Oropharyngeal Candidiasis in Immunodeficient Mice," published online on February 18, 2015. The research advances Dr. Pandiyan's previous work on isolating different types of oral T-cells for study. T-cells are a type of white blood cell that is critical to the body's immune system. In the newest research, she used T-cells and injected them into mice genetically engineered to have no immunity in order to test how the cells function when fighting a common thrush-like yeast infection found in the mouth, called Candida albicans. When the infection-fighting cells are not controlled properly, they caused inflammation. According to Dr. Pandiyan, approximately 60 percent of the population has the fungus, but a healthy immune system keeps it under control. In humans with weak immune systems, the fungal growth appears as a white coating on the tongue. Individuals with the infection report a painful burning sensation in the mouth. As the infection spreads, it causes inflammation of the mouth area, tongue, and gums. Left untreated, it can spread to the throat and the esophagus.

Natively Folded Chemokine (CCL28) Linked to Development of Asthma; Exploiting Unique Structural Features of CCL28 May Lead to Creation of Potent and Specific CCL28 Inhibitors

Researchers at the Medical College of Wisconsin (MCW) have linked a specific protein to the development of post-viral infection asthma, which is the first step in generating a novel type of asthma therapy designed to prevent development of post-viral asthma in young children. The findings were published in the February 13, 2015 issue of the Journal of Biological Chemistry. The article was titled “Structure-Function Analysis of CCL28 in the Development of Post-Viral Asthma. Brian F. Volkman, Ph.D., Professor of Biochemistry; and Mitchell H. Grayson, M.D., Associate Professor of Allergy and Immunology; are the lead researchers on the study. Asthma is a chronic disease of the airways that affects more than 300 million people worldwide. It is the number-one illness leading to school absences in children, and accounts for more than 1.8 million emergency room visits annually. There is no cure; all current therapies focus on providing symptomatic relief, and reducing the number and severity of attacks. "Understanding the molecular mechanisms by which asthma develops and establishes itself as a chronic disease is key to elucidating alternative and potentially curative therapies," said Dr. Grayson. The researchers had previously found evidence linking a human chemokine (protein) called CCL28 ( to the development of chronic asthma. This study is the first, however, that examines structural analysis and its impact on disease development. "We found that even in the absence of a viral infection, CCL28 can play a role in the induction of asthma pathology--when the protein is natively folded. If unfolded, it does not," explained Dr. Volkman. "We propose that by exploiting the unique structural features of CCL28, potent and specific CCL28 inhibitors may be developed.

Bacteria Use Their Cas9 Enzyme Not Only to Cut, But Also to Create Immunological Memories of, Viral DNA

Bacteria may not have brains, but they do have memories, at least when it comes to viruses that attack them. Many bacteria have a molecular immune system that allows these microbes to capture and retain pieces of viral DNA that they have encountered in the past, in order to recognize and destroy that viral DNA when it shows up again. Research at Rockefeller University, published online on February 18, 2015 in Nature, offers new insight into the mysterious process by which this system works to encode viral DNA in a microbe's genome for later use as guides for virus-cutting enzymes. The title of the Nature article is "Cas9 Specifies Functional Viral Targets during CRISPR–Cas Adaptation." "Microbes, like vertebrates, have immune systems capable of adapting to new threats. Cas9, one enzyme employed by these systems, uses immunological memories to guide cuts to viral genetic code. However, very little is known about how these memories are acquired in the first place," says Assistant Professor Luciano Marraffini, head of the Laboratory of Bacteriology at Rockefeller. "Our work shows that Cas9 also directs the formation of these memories among certain bacteria." These memories are embedded in the bacterial equivalent of an adaptive immune system capable of discerning helpful from harmful viruses. This is called the CRISPR (clustered regularly interspaced short palindromic repeats) system. It works by altering the bacterium's genome, adding short viral sequences called spacers in between the repeating DNA sequences. These spacers form the memories of past invaders. They serve as guides for enzymes encoded by CRISPR-associated genes (Cas), which seek out and destroy those same viruses should they attempt to infect the bacterium again.

February 20th

Powerful Neutralizing Dengue Antibody Found

A new Duke-National University of Singapore (Duke-NUS)-led study has identified a super-potent human monoclonal antibody that requires just a minute amount to neutralize the dengue virus. This significant advance, published online on February 20, 2015, in an open-access article in Nature Communications, shows how a newly identified antibody, 5J7, is highly effective in killing dengue virus; only 10-9 g of antibody is needed to stop the infection of dengue serotype 3 virus (DENV-3). The authors report that DENV-specific antibody 5J7 is exceptionally potent, neutralizing 50% of virus at nanogram-range antibody concentration. This new finding gives hope for the development of effective dengue treatments. The authors further report that cryo-electron microscopy analysis of the Fab 5J7–DENV complex shows that a single Fab molecule binds across three envelope proteins and engages three functionally important domains, each from a different envelope protein. These domains are critical for receptor binding and fusion to the endosomal membrane. The ability to bind to multiple domains allows the 5J7 antibody to fully coat the dengue virus surface with only 60 copies of Fab, that is, half the amount compared with other potent antibodies. The authors say that their study of 5J7 reveals a highly efficient and unusual mechanism of molecular recognition by an antibody. Their article is titled “A Highly Potent Human Antibody Neutralizes Dengue Virus Serotype 3 by Binding across Three Surface Proteins.” Over the last 50 years, the incidence of dengue virus infection has increased by 30 times worldwide. The virus causes fever, rashes, and joint pain and, in severe cases, bleeding and shock. It is estimated to be endemic in 100 countries and is a huge burden on healthcare systems.

Bacteria Specifically Adapt Their Metabolism to Host Genotype; Results Imply Form of Bacterial “Memory”

Bacteria are masters at adapting to their environment. This adaptability contributes to the bacteria’s survival inside the host. Researchers at the Vetmeduni Vienna in Austria have now demonstrated that the bacterial pathogen Listeria monocytogenes adapts its metabolism specifically to the host genotype. The bacterial metabolic fingerprint correlated with the susceptibility of the infected mouse strain. The researchers published their results online in the open-access journal PLOS ONE on December 26, 2014. The title of the article is “Deciphering Host Genotype-Specific Impacts on the Metabolic Fingerprint of Listeria monocytogenes by FTIR Spectroscopy.” Understanding such adaptation mechanisms is crucial for the development of effective therapeutics. Dr, Monika Ehling-Schulz’s group from the Institute of Microbiology, together with Dr. Mathias Müller’s group at the Institute of Animal Breeding and Genetics studied the influence of host organisms on bacterial metabolism. The researchers infected three different lineages of mice with the bacteria Listeria monocytogenes. The mouse strains showed significant differences in their response to the infection and in the severity of their clinical symptoms. The researchers isolated the bacteria days after infection and analyzed them for changes in their metabolism. The scientists used a specific infrared spectroscopy method (FTIR) (see below) to monitor metabolic changes. The chemometric analysis of the bacterial metabolic fingerprints revealed host genotype specific imprints and adaptations of the bacterial pathogen. “Our findings may have implications on how to treat infectious diseases in general. Every patient is different and so are their bacteria,” first author Dr. Tom Grunert states.

Powerful New Scanning Transmission Electron Microscope (STEM) Can See and Pinpoint Single Atoms

A new super-powerful electron microscope that can pinpoint the position of single atoms, and will help scientists push boundaries even further, in fields such as advanced materials, healthcare, and power generation, was unveiled February 19, 2015 by the Engineering and Physical Sciences Research Council (EPSRC). The £3.7 million Nion Hermes Scanning Transmission Electron Microscope, one of only three in the world, will be sited at the EPSRC SuperSTEM facility at the Daresbury laboratory complex near Warrington, UK, which is part of the Science and Technology Facilities Council (STFC). The new microscope not only allows imaging of unprecedented resolution of objects a million times smaller than a human hair, but also analysis of materials. This means that researchers will not only be able to clearly identify the atoms, but observe the strength of the bonds between them. This will improve understanding of their electronic properties when in bulk and how they may perform when used. Minister for Universities, Science, and Cities, Greg Clark, said: “The UK is a world leader in the development and application of STEM (Scanning Transmission Electron Microscope) techniques, and this new super-powerful microscope will ensure we remain world-class. From developing new materials for space travel to creating a better, cheaper treatment for anaemia, this new super-powerful microscope lets UK scientists examine how materials behave at a level a million times smaller than a human hair. This exciting research will help lead to breakthroughs that will benefit not only our health but the environment too.” Professor Philip Nelson, EPSRC’s Chief Executive said: “This EPSRC investment in state-of-the-art equipment is an investment in UK science and engineering.

February 19th

Study in Myanmar Confirms Artemisinin-Resistant Malaria Close to Border with India

The spread of malaria parasites that are resistant to the drug artemisinin, the front-line treatment against malaria infection, into neighboring India would pose a serious threat to the global control and eradication of malaria. If drug resistance spreads from Asia to the African sub-continent, or emerges in Africa independently as we've seen several times before, millions of lives will be at risk. The collection of samples from across Myanmar and its border regions was led by Dr. Kyaw Myo Tun of the Defense Services Medical Research Centre, Napyitaw, Myanmar and coordinated by the Mahidol-Oxford Tropical Medicine Research Unit (MORU) in Bangkok, Thailand. The researchers examined whether parasite samples collected at 55 malaria treatment centres across Myanmar carried mutations in specific regions of the parasite's kelch gene (K13), a known genetic marker of artemisinin drug resistance. The team confirmed resistant parasites in Homalin, Sagaing Region located only 25 kilometers from the Indian border. The article describing these findings is to be published online on February 20, 2015 in Lancet Infectious Diseases. The article is titled “Spread of Artemisinin-Resistant Plasmodium falciparum in Myanmar: a Cross-Sectional Survey of the K13 Molecular Marker. "Myanmar is considered the front line in the battle against artemisinin resistance as it forms a gateway for resistance to spread to the rest of the world," says Dr. Charles Woodrow from the Mahidol-Oxford Tropical Medicine Research Unit and senior author of the current study at Oxford University. "With artemisinins we are in the unusual position of having molecular markers for resistance before resistance has spread globally.

Karolinska Scientists Use Single-Cell RNA-Seq Analysis to Map and Identify 47 Different Types of Cell in the Brain

Using a process known as single-cell sequencing, scientists at Karolinska Institutet have produced a detailed map of cortical cell types and the genes active within them. The study, which was published online on February 19, 2015 in Science, marks the first time this method of analysis has been used on such a large scale on such complex tissue. The article was titled “Cell Types in the Mouse Cortex and Hippocampus Revealed by Single-Cell RNA-seq.” The team studied over three thousand cells, one at a time, and even managed to identify a number of hitherto unknown types. “If you compare the brain to a fruit salad, you could say that previous methods were like running the fruit through a blender and seeing what color juice you got from different parts of the brain,” says Dr. Sten Linnarsson, Senior Researcher in the Department of Medical Biochemistry and Biophysics. “But in recent years we’ve developed much more sensitive methods of analysis that allow us to see which genes are active in individual cells. This is like taking pieces of the fruit salad, examining them one by one and then sorting them into piles to see how many different kinds of fruit it contains, what they’re made up of, and how they interrelate.” The knowledge that all living organisms are built up of cells is almost 200 years old. Since the discovery was made by a group of 19th century German scientists, we have also learnt that the nature of a particular body tissue is determined by its constituent cells, which are, in turn, determined by which genes are active in their DNA. However, little is still known about how this happens in detail, especially as regards the brain, the body’s most complex organ.