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Archive - Feb 2017

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February 8th

“Goldilocks” CNV Genes That Tell the Tale of Human Evolution Hold Clues to Variety of Diseases

Geneticists from Trinity College Dublin in Ireland have used our evolutionary history to shine light on a plethora of neurodevelopmental disorders and diseases. Their findings isolate a relatively short list of genes as candidates for many diverse conditions including autism spectrum disorders, schizophrenia, ADHD, intellectual disability, developmental delay, and epilepsy. The geneticists' findings were published in February 8, 2017 in Nature Communications. The open-access article is titled “Dosage Sensitivity Is a Major Determinant of Human Copy Number Variant Pathogenicity.” There are over 20,000 genes in the human genome that contain the all-important codes used to produce specific proteins in the body. In their study, the Trinity geneticists focused on regions of the genome that are duplicated or deleted in some individuals. These regions, termed “copy number variants” (CNVs), are abundant in humans. Not all CNVs result in noticeable differences between individuals -- sometimes the genes within them function similarly regardless of the number of copies present. However, variations in other CNVs are implicated in a variety of debilitating disorders and diseases. These disease CNVs are large, and a major challenge is to identify which genes within the regions are causing the problems. Professor in Genetics at Trinity, Aoife McLysaght, Ph.D., said: "Our idea was that there must be some genes within these regions with 'Goldilocks' properties: too much or too little duplication, and things don't work properly. The number of copies must be just right." The Trinity team looked back over our evolutionary history to discover which genes don't tolerate increases or decreases over evolutionary time. This segment of their work suggested that the key is in the presence of these Goldilocks genes within the disease-causing CNVs.

February 7th

Overcoming Hurdles in CRISPR Gene Editing to Improve Treatment

More and more scientists are using the powerful new gene-editing tool known as CRISPR/Cas9, a technology isolated from bacteria, that holds promise for new treatment of such genetic diseases as cystic fibrosis, muscular dystrophy, and hemophilia. But to work well, the new gene-clipping tool must be delivered safely across the cell membrane and into its nucleus, a difficult process that can trigger the cell's defenses and "trap" CRISPR/Cas9, greatly reducing its treatment potential. Now, researchers in nanochemistry expert Dr. Vincent Rotello's laboratory at the University of Massachusetts Amherst have designed a delivery system using nanoparticles to assist CRISPR/Cas9 across the membrane and into the cell nucleus while avoiding entrapment by cellular machinery. Details wrepublished online on January 27, 2017 in ACS Nano. The article is titled “Direct Cytosolic Delivery of CRISPR/Cas9-Ribonucleoprotein for Efficient Gene Editing.” The lab's experiment leader, Dr. Rubul Mout, says, "CRISPR has two components: a scissor-like protein called Cas9, and an RNA molecule called sgRNA that guides Cas9 to its target gene. Once the Cas9-sgRNA pair gets to the destination gene in the nucleus, it can interrogate its genetic mistakes and correct them with the help of the host cell's repair machinery." He points out that bcause CRISPR's potential was first discovered in 2012, gene editing or genome engineering has quickly become an intense research topic in biology and medicine. The goal is to treat otherwise incurable genetic diseases by manipulating diseased genes. "However, to achieve this, biotech and pharmaceutical companies are constantly searching for more efficient CRISPR delivery methods," he adds.

Adjusting Levels of Kynurenic Acid Can Have Significant Effects on Schizophrenic-Like Behavior in Mice

A new study by University of Maryland School of Medicine researchers, and collaborators, has found that in mice, adjusting levels of a compound called kynurenic acid (image) can have significant effects on schizophrenia-like behavior. The study was published online on December 16, 2016 in Biological Psychiatry. In recent years, scientists have identified kynurenic acid as a potential key player in schizophrenia. The article is titled “Adaptive and Behavioral Changes in Kynurenine 3-Monooxygenase Knockout Mice: Relevance to Psychotic Disorders.” People with schizophrenia have higher than normal levels of kynurenic acid in their brains. KYNA, as it is known, is a metabolite of the amino acid tryptophan; it decreases glutamate, and research has found that people with this illness tend to have less glutamate signaling than people without the disease. Scientists have theorized that this reduction in glutamate activity, and therefore the higher KYNA levels seen in patients, might be connected with a range of symptoms seen in schizophrenia, especially cognitive problems. For several years, Robert Schwarcz, Ph.D., a Professor in the Department of Psychiatry at the University of Maryland School of Medicine (UM SOM), who in 1988 was the first to identify the presence of KYNA in the brain, has studied the role of KYNA in schizophrenia and other neuropsychiatric diseases. For the new study, Dr. Schwarcz and his team collaborated closely with scientists at the Karolinska Institute in Stockholm, Sweden, the University of Leicester in the United Kingdom, and KynuRex, a biotech company in San Francisco. "This study provides crucial new support for our longstanding hypothesis," Dr. Schwarcz said. "It explains how the KYNA system may become dysfunctional in schizophrenia."

Over 40 Years of Research on Critically Endangered Nimba Toad Summarized in New Paper; Nimba Toad Is Known for Its Exceptional Reproductive Biology

The critically endangered Nimba toad has long been known for its exceptional reproductive biology. The females of this unique species give live birth to fully developed juveniles, having for nine months continuously provided nutrition to the fetuses in the womb (matrotrophy). While live birth (viviparity) among frogs and toads is rather an exception than a common characteristic, matrotrophy, in place of alternatives such as the fetus being fed with yolk, unfertilized eggs, or smaller siblings, is what makes the Nimba toad one of a kind. However, more than 40 years of research had not been comprehensively, accessibly, and completely summarized. The gap has recently been filled with a new paper, published on February 3, 2017 in the open-access journal Zoosystematics and Evolution by German scientists Drs. Laura Sandberger-Loua and Mark-Oliver Rödel, both affiliated with Museum für Naturkunde, Berlin, and Dr. Hendrik Müller, Friedrich-Schiller-Universität Jena. The article is titled “A Review of the Reproductive Biology of the Only Known Matrotrophic Viviparous Anuran, the West African Nimba Toad, Nimbaphrynoides occidentalis.” Studying the phenomenon, the scientists went through the literature published over four decades to gather the scattered details. They have also discussed the relationship between the toad's reproductive biology and its specific habitat of merely 4 km² of high altitude grasslands located at a minimum of 1,200 meters in the Nimba mountains, West Africa. The climate of the area is characterized by a rainy season lasting from April to October and a dry season from November to February/March. These seasons are found to determine the activity of the Nimba toads.

February 6th

Exosome Diagnostics Enters Agreement with Merck KGaA, Darmstadt, Germany

On February 6, 2017, Exosome Diagnostics, Inc., announced that it has entered into an agreement with Merck KGaA, Darmstadt, Germany, a leading science and technology company, to help further the company’s drug development efforts in oncology and other therapeutic areas, utilizing the full breadth of Exosome Diagnostics’ proprietary technology platforms. The platforms span across both nucleic acid and protein, including Shahky™, Exosome Diagnostics’ exosomal protein capture and quantitative analysis instrument. This agreement represents the first publicly announced partnership that grants access to Exosome Diagnostics’ recently unveiled point-of-care protein detection instrument. The instrument, Shahky, which has the ability to generate a high signal above the noise by selectively targeting disease-specific exosomes and removing background that is non-relevant to the disease in question, was tested and its performance validated in a leading Boston Hospital in early January of 2017. The instrument’s capabilities will make it a powerful technology for discovering, assessing, and validating clinical biomarkers, on a system that has been developed, and overseen by Exosome’s Regulatory Department, with design control and engineering practices that are in accordance with FDA and other applicable regulations. “We are excited to bring first-of-its-kind technologies, such as Shahky, to our partners. The Shahky instrument represents a disruptive technology for drug development and ultimately the clinic,” stated Mario Morken, Head of Business Development for Exosome Diagnostics.

“Landmark” Gene Therapy Work Significantly Restores Hearing in Genetically Deaf Mice

In the summer of 2015, a team at Boston Children's Hospital and Harvard Medical School reported restoring rudimentary hearing in genetically deaf mice using gene therapy. Now the Boston Children's research team reports restoring a much higher level of hearing -- down to 25 decibels, the equivalent of a whisper -- using an improved gene therapy vector developed at Massachusetts Eye and Ear. The new vector and the mouse studies are described in two back-to-back papers in Nature Biotechnology (published online on February 6, 2017). The first article is titled “A Synthetic AAV Vector Enables Safe and Efficient Gene Transfer to the Mammalian Inner Ear,” and the second is titled “Gene Therapy Restores Auditory and Vestibular Function in a Mouse Model of Usher Syndrome Type 1c.” While previous vectors have only been able to penetrate the cochlea's inner hair cells, the first Nature Biotechnology study showed that a new synthetic vector, Anc80, safely transferred genes to the hard-to-reach outer hair cells when introduced into the cochlea. This study's three Harvard Medical School senior investigators were Jeffrey R. Holt Ph.D., of Boston Children's Hospital; Konstantina Stankovic, M.D., Ph.D., of Massachusetts Eye and Ear and Luk H. Vandenberghe, Ph.D., who led Anc80's development in 2015 at Massachusetts Eye and Ear's Grousbeck Gene Therapy Center. "We have shown that Anc80 works remarkably well in terms of infecting cells of interest in the inner ear," says Stankovic, M.D., an otologic surgeon at Massachusetts Eye and Ear and Associate Professor of Otolaryngology at Harvard Medical School.

February 5th

Discovery Helps Explain Why Only Some People Develop Life-Threatening Dengue Infections

For most people who contract it, dengue fever is a relatively mild disease—at least the first time around. For some, however, a subsequent infection by the virus unleashes a vicious and potentially deadly illness. New research from a team based at The Rockefeller University in New York has begun to reveal why certain people are more vulnerable to these dangerous secondary infections. Their latest findings, described online on January 26, 2017 in Science, could lead to better strategies to identify and better treat those most at risk. The article is titled “IgG Antibodies to Dengue Enhanced for FcγRIIIA Binding Determine Disease Severity.” “Patients with severe secondary disease have high levels of a particular type of antibody that triggers a forceful immune response. This distinctive signature did not show up in patients with more mild illness,” says senior author Dr. Jeffrey V. Ravetch, Theresa and Eugene M. Lang Professor and Head of the Leonard Wagner Laboratory of Molecular Genetics and Immunology at The Rockefeller. “Our work sheds new light on the way in which the dengue virus co-opts antibodies produced as a result of the previous infection, using them to inflict more damage the second time around,” Dr. Ravetch adds. Known as “breakbone fever” for the intense aches it causes, dengue is transmitted by mosquitos in the tropics and subtropics. In the more severe form of the disease, which typically occurs among people who have been infected before, patients can develop hemorrhagic fever, which causes them to leak fluid from their blood vessels and bleed abnormally, sometimes from the nose, gums, and under the skin. In extreme cases, people lose so much blood that they develop a critical condition known as shock.

February 4th

Red “Color Channel” May Aid in Screening for Diabetic Eye Disease

In photographs of the eye used to screen for diabetes-related eye disease, separating out the red color channel can help show some abnormalities -- especially in racial/ethnic minority patients, suggests a study in the February 2017 issue of Optometry and Vision Science, official journal of the American Academy of Optometry. The open-access article is titled “Comparison of Cysts in Red and Green Images for Diabetic Macular Edema.” Inspecting the channel for red (long-wavelength) reflected light can improve the ability to detect diabetic macular edema, a complication of diabetes that can lead to blindness. Using the red color channel of these images may have a special advantage in detecting macular edema in racial/ethnic minority patients -- in whom natural pigments in back of the eye tend to be darker. The lead author of the new study was Mastour A. Alhamami, Ph.D., of Indiana University School of Optometry, Bloomington. The researchers analyzed standard color fundus photographs obtained from 2,047 adult patients with diabetes. Ninety percent of patients identified themselves as racial/ethnic minorities (other than non-Hispanic white). The study was performed in a medically under-served group, most without access to routine eye care. For patients with diabetes, regular dilated eye examinations (at least once yearly) are recommended to detect early signs of diabetic eye disease. One major finding in diabetic eye disease is macular edema (a fluid accumulation in the retina) resulting from leaky blood vessels in the back of the eye. This condition is a leading cause of vision loss among working-age adults with diabetic eye disease. The retinal photographs showed clinically significant macular edema in 148 patients.

Study Investigates Changes in Microbiota During Space Flight Using Twin Astronauts, One in Space and One on Earth

Northwestern University researchers studying the gut bacteria of Scott (photo) and Mark Kelly, NASA astronauts and identical twin brothers, as part of a unique human study have found that changes to certain gut "bugs" occur in space. The Northwestern team is one of ten NASA-funded research groups studying the Kelly twins to learn how living in space for a long period of time -- such as a mission to Mars -- affects the human body. While Scott spent nearly a year in space, his brother, Mark, remained on Earth, as a ground-based control. "We are seeing changes associated with spaceflight, and they go away upon return to Earth," said Dr. Fred W. Turek, the Charles E. and Emma H. Morrison Professor of Biology in the Weinberg College of Arts and Sciences at Northwester. He is a co-leader of the study. "It's early in our analysis, so we don't know yet what these changes mean," said Dr. Martha H. Vitaterna, study co-leader and Research Associate Professor of Neurobiology at Northwestern. "We don't know what it is about spaceflight that is driving the changes in gut microbes." The research team includes collaborators from Rush University Medical School and the University of Illinois at Chicago. "We will be working closely with the other Twins Study teams to piece together a more complete picture of the effects of long space missions," Dr. Turek said. "What we learn will help us safeguard the health of astronauts, and it will also help us improve human health on Earth." Dr. Turek reported his team's preliminary research results at NASA's Human Research Program's annual Investigators' Workshop, held last week in Galveston, Texas. This was the first meeting where the researchers with the 10 Twins Study teams, which are looking at different aspects of the twins' physiology, could share their data with each other.

February 3rd

How Ribosomal Protein L4 Is Protected by Chaperone

For proteins, this would be the equivalent of the red-carpet treatment: each protein belonging to the complex machinery of ribosomes -- components of the cell that produce proteins -- has its own chaperone to guide it to the right place at the right time and protect it from harm. In a new Caltech study, researchers are learning more about how ribosome chaperones work, showing that one particular chaperone binds to its protein client in a very specific, tight manner, almost like a glove fitting a hand. The researchers used X-ray crystallography to solve the atomic structure of the ribosomal protein bound to its chaperone. "Making ribosomes is a bit like baking a cake. The individual ingredients come in protective packaging that specifically fits their size and shape until they are unwrapped and blended into a batter," says Dr. André Hoelz, Professor of Chemistry at Caltech, a Heritage Medical Research Institute (HMRI) Investigator, and Howard Hughes Medical Institute (HHMI) Faculty Scholar." What we have done is figure out how the protective packaging fits one ribosomal protein, and how it comes unwrapped." Dr. Hoelz is the principal investigator behind the study published online on February 2, 2017, in the Nature Communications. The finding has potential applications in the development of new cancer drugs designed specifically to disable ribosome assembly. In all cells, genetic information is stored as DNA and transcribed into mRNAs that code for proteins. Ribosomes translate the mRNAs into amino acids, linking them together into polypeptide chains that fold into proteins. More than a million ribosomes are produced per day in an animal cell.