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Archive - Feb 2018

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February 9th

Liver Cells with Whole Genome Duplications Protect Against Cancer in Mice

Researchers at the Children's Medical Center Research Institute (CRI) at the University of Texas (UT) Southwestern have discovered that cells in the liver with whole genome duplications, known as polyploid cells, can protect the liver against cancer. The study, published online on February 8, 2018 in Developmental Cell, addresses a long-standing mystery in liver biology and could stimulate new ideas to prevent cancer. The article is titled “The Polyploid State Plays a Tumor-Suppressive Role in the Liver.” Most human cells are diploid, carrying only one set of matched chromosomes that contain each person's genome. Polyploid cells carry two or more sets of chromosomes. Although rare in most human tissues, these cells are prevalent in the hearts, blood, and livers of mammals. Polyploidization also increases significantly when the liver is exposed to injury or stress from fatty liver disease or environmental toxins that could cause liver cancer later in life. It is unknown, however, whether these increases in polyploidization have functional importance. Previous research into the exact function of polyploid liver cells has been limited, in part because it has been difficult to change the number of sets of chromosomes in a cell, or ploidy, without introducing permanent mutations in genes that may also affect other cellular activities, such as division, regeneration, or cancer development. Because of this, there were many ideas as to why the liver is polyploid, but little experimental evidence. CRI researchers have discovered a new approach. "Our lab has developed new methods to transiently and reversibly alter ploidy for the first time. This was an important advance because it allowed us to separate the effects of ploidy from the effects of genes that change ploidy.

New Study Provides First 3D Visualization of Dynein-Dynactin Complex Bound to Microtubules

On the cellular highway, motor proteins called dyneins rule the road. Dyneins "walk" along structures called microtubules to deliver cellular cargo, such as signaling molecules and organelles, to different parts of a cell. Without dynein on the job, cells cannot divide and people can develop neurological diseases. Now, a new study, which was published on February 7, 2018 in Nature Structural & Molecular Biology, provides the first three-dimensional (3D) visualization of the dynein-dynactin complex bound to microtubules. The article is titled “Cryo-Electron Tomography Reveals That Dynactin Recruits a Team of Dyneins for Processive Motility.” The study leaders from The Scripps Research Institute (TSRI) report that a protein called dynactin hitches two dyneins together, like a yoke locking together a pair of draft horses. "If you want a team of horses to move in one direction, you need to line them up," says Gabriel C. Lander, PhD, a TSRI Associate Professor and senior author of the study. "That's exactly what dynactin is doing to dynein molecules." Understanding how the dynein-dynactin complex is assembled and organized provides a critical foundation to explain the underlying causes of several dynein-related neurodegenerative diseases such as spinal muscular atrophy (SMA) and Charcot-Marie-Tooth (CMT) disease. Researchers knew that dynactin is required for dynein to move cargo, but they struggled to get a complete picture of how the different parts of the complex worked together. "We knew that dynein only becomes active when it binds with a partner called dynactin. The problem was that, historically, it was difficult to solve this structure because it is very flexible and dynamic," explains Danielle Grotjahn, a TSRI graduate student and co-first author of the study.

Clock Protein Rev-erbα Represses Transcription by Loosening Chromosome Loops

It is well known that the human body functions on a 24-hour, or circadian, schedule. The up-and-down daily cycles of a long-studied clock protein called Rev-erb coordinates the ebb and flow of gene expression by tightening and loosening loops in chromosomes, according to new research from the Perelman School of Medicine at the University of Pennsylvania. The findings were published online on February 8, 2018 in Science. The article is titled “Rev-erbα Dynamically Modulates Chromatin Looping to Control Circadian Gene Transcription.” Over the last 15-plus years, a team led by the new study's senior author Mitchell A. Lazar, MD, PhD, Director of Penn's Institute for Diabetes, Obesity, and Metabolism, has been teasing out the versatile role of Rev-erb in maintaining daily cycles of the body's molecular clock, metabolism, and even brain health. "Many studies, including this one, point to a link between the human internal clock and such metabolic disorders as obesity and diabetes," Dr. Lazar said. "Proteins such as Rev-erb are the gears of the clock and understanding their role is important for investigating these and many other diseases." Human physiology works on a 24-hour cycle of gene expression (when the chromosome coding region is translated by RNA and then transcribed to make protein) and is controlled by the body's molecular clock. Core clock proteins activate or repress protein complexes that physically loop one part of a chromosome to become adjacent to a distant part of the same chromosome. The Penn team showed that daily oscillations of Rev-erb control gene expression in the mouse liver via interactions between on-and-off regions on the same chromosome.

Scientists Describe On-Off Switch for Inflammasomes; Finding May Advance Understanding of Inflammation in Many Diseases, Including Alzheimer’s

A discovery by Queensland scientists in Australia could be the key to stopping damage caused by uncontrolled inflammation in a range of common diseases including liver disease, Alzheimer's, and gout. University of Queensland (UQ) researchers have uncovered how an inflammation process automatically switches off in healthy cells, and are now investigating ways to stop it manually when it goes awry. UQ's Institute for Molecular Bioscience (IMB) researcher Associate Professor Kate Schroder (photo) said this inflammation pathway drove many different diseases. "Now that we understand how this pathway naturally turns off in health, we can investigate why it doesn't turn off in disease -- so it's very exciting," Dr. Schroder said. Her work at IMB's Centre for Inflammation and Disease Research focuses on inflammasomes, which are machine-like protein complexes at the heart of inflammation and disease. "These complexes form when an infection, injury, or other disturbance is detected by the immune system, and they send messages to immune cells to tell them to respond," Dr. Schroder said. "If the disturbance can't be cleared, such as in the case of amyloid plaques in Alzheimer's, these molecular machines continue to fire, resulting in neurodegenerative damage from the sustained inflammation." Dr. Schroder's team, led by Dr. Dave Boucher, discovered that inflammasomes normally work with an in-built timer switch, to ensure they only fire for a specific length of time once triggered. "The inflammasome initiates the inflammation process by activating a protein that functions like a pair of scissors, and cuts itself and other proteins," Dr. Schroder said.

February 8th

A Possible Mechanism by Which Viruses Can Establish Chronic Infections; Some Viruses Drive Production of Cytokine That Inhibits Function of CD8+ T-Cells

How do viruses that cause chronic infections, such as those caused by HIV or hepatitis c virus, manage to outsmart their hosts' immune systems? The answer to that question has long eluded scientists, but new research from McGill University has uncovered a molecular mechanism that may be a key piece of the puzzle. The discovery could provide new targets for treating a wide range of diseases. Fighting off infections depends largely on our bodies' capacity to quickly recognize infected cells and destroy them, a job carried out by a class of immune cells known as CD8+ T-cells. These soldiers get some of their orders from chemical mediators known as cytokines that make them more or less responsive to outside threats. In most cases, CD8+ T-cells quickly recognize and destroy infected cells to prevent the infection from spreading. "When it comes to viruses that lead to chronic infection, immune cells receive the wrong set of marching orders, which makes them less responsive," says Martin Richer, PhD, an Assistant Professor at McGill's Department of Microbiology & Immunology and senior author of the study, published online on January 23, 2018 Immunity. The article is titled “Interleukin-10 Directly Inhibits CD8+ T Cell Function by Enhancing N-Glycan Branching to Decrease Antigen Sensitivity.” The research, conducted in Dr. Richer's lab by graduate student Logan Smith, revealed that certain viruses persist by driving the production of a cytokine (IL-10, image shown here) that leads to modification of glycoproteins on the surface of the CD8+ T-cells, making the cells less functional. That maneuver buys time for the pathogen to outpace the immune response and establish a chronic infection. Importantly, this pathway can be targeted to restore some functionality to the T-cells and enhance the capacity to control infection.

Researchers Test Antibiotics Produced by Ants

Ants, like humans, deal with disease. To deal with the bacteria that cause some of these diseases, some ants produce their own antibiotics. A new comparative study identified some ant species that make use of powerful antimicrobial agents - but found that 40 percent of ant species tested didn't appear to produce antibiotics. The study has applications regarding the search for new antibiotics that can be used in humans. The paper, "External Immunity in Ant Societies: Sociality and Colony Size Do Not Predict Investment in Antimicrobials," was published online on February 7, 2018 in the journal Royal Society Open Science. "These findings suggest that ants could be a future source of new antibiotics to help fight human diseases," says Clint Penick, PhD, an Assistant Research Professor at Arizona State University and former postdoctoral researcher at North Carolina State University, who is lead author of the study. "One species we looked at, the thief ant (Solenopsis molesta) (photo), had the most powerful antibiotic effect of any species we tested - and until now, no one had even shown that they made use of antimicrobials," says Adrian Smith, PhD, co-author of the paper, an Assistant Research Professor of Biological Sciences at NC State and head of the NC Museum of Natural Sciences' Evolutionary Biology & Behavior Research Lab. "But the fact that so many ant species appear to have little or no chemical defense against microbial pathogens is also important,” Dr. Penick said. That's because the conventional wisdom has long been that most, if not all, ant species carry antimicrobial agents. But this work indicates that the conventional wisdom is wrong. "We thought every ant species would produce at least some type of antimicrobial," Dr. Penick says.

February 7th

Celltex Therapeutics and Texas A&M Institute for Regenerative Medicine Announce Research Agreement Focused on Use of MSC-Derived Exosomes to Treat Alzheimer’s Disease

On February 6, 2018, Houston-based biotechnology company, Celltex Therapeutics Corporation, and Texas A&M University Health Science Center College of Medicine Institute for Regenerative Medicine announced an intellectual property license acquisition and research agreement. The announcement signals the first year of a multi-year research study investigating potential therapies for Alzheimer’s disease using autologous mesenchymal stem cell (MSC)-derived exosomes. Celltex, a pioneer in autologous stem cell technology, is known for its proprietary stem cell process, which yields adult MSCs in quantities never before possible for use in therapy for vascular, autoimmune, and degenerative diseases, as well as injuries. Celltex’s acquisition of the exclusive license adds to its portfolio of cellular and exosomes intellectual property. As part of the research agreement, Darwin J. Prockop, MD, PhD, the Stearman Chair in Genomic Medicine, Director of the Texas A&M Institute for Regenerative Medicine, and Professor at the Texas A&M College of Medicine, and his lab will prepare adult MSCs and use them to derive anti-inflammatory exosomes, which are tiny vesicles that can deliver anti-inflammatory agents to the brain. Ashok K. Shetty, PhD, a Professor at the Department of Molecular and Cellular Medicine at the Texas A&M College of Medicine, Associate Director of the Institute for Regenerative Medicine and Research Career Scientist at the Olin E. Teague Veterans’ Medical Center, and his team will test the efficiency of these exosomes to reduce brain inflammation and assist in repair of neuronal damage related to Alzheimer’s disease.

Small Molecule Prevents Cartilage Damage and Promotes Cartilage Repair; Scientists Will Pursue Further Investigation of Possible Treatment for Arthritis

Will there come a time when a patient with arthritis can forgo joint replacement surgery in favor of a shot? Keck School of Medicine of USC scientist Denis Evseenko, MD, PhD, has reason to be optimistic. In an article published online on February 7, 2018 in the Annals of Rheumatic Diseases, Dr. Evseenko's team describes the promise of a new molecule named "Regulator of Cartilage Growth and Differentiation," or RCGD 423 for short. The article is titled “Drug-Induced Modulation of Gp130 Signaling Prevents Articular Cartilage Degeneration and Promotes Repair.” The RCGD 423 molecule was identified in high-throughput screening of 170,000 small molecule compounds. As its name implies, RCGD 423 enhances regeneration while curbing inflammation. When RCGD 423 was applied to joint cartilage cells in the laboratory, the cells proliferated more and died less, and when injected into the knees of rats with damaged cartilage, the animals could more effectively heal their injuries. RCGD 423 exerts its effects by communicating with a specific molecule in the body. This molecule, called the glycoprotein 130 (Gp130) receptor, receives two very different types of signals: those that promote cartilage development in the embryo, and those that trigger chronic inflammation in the adult. RCGD 423 amplifies the Gp130 receptor's ability to receive the developmental signals that can stimulate cartilage regeneration, while blocking the inflammatory signals that can lead to cartilage degeneration over the long term. Given these auspicious early results, the team is already laying the groundwork for a clinical trial to test RCGD 423 or a similar molecule as a treatment for osteoarthritis or juvenile arthritis.

Two-Step Process of Enzyme Inhibition and Drug Treatment Inhibits Liver Cancer Cell Growth in Lab Tests

Scientists at the University of Delaware (UD) and the University of Illinois at Chicago (UIC) have found a new way to kill liver cancer cells and inhibit tumor growth. First, they silence a key cellular enzyme, and then they add a powerful drug. They describe their methods in an open-access article published online on January 31, 2018 in Nature Communications. The article is titled “Hexokinase-2 Depletion Inhibits Glycolysis and Induces Oxidative Phosphorylation in Hepatocellular Carcinoma and Sensitizes to Metformin.” This research could accelerate the development of new treatments for liver cancer, which is currently difficult to cure. Often surgery is not an option for liver cancer, and the available drugs are only modestly effective. More than 82 percent of liver cancer patients die within five years of diagnosis, according to the National Institutes of Health. This project originated in labs at the UIC, where researchers grew liver cancer cells and manipulated their expression of an enzyme called hexokinase-2. Then, the cells were treated with metformin, a diabetes drug that decreases glucose production in the liver. The research group of Maciek R. Antoniewicz, PhD, Centennial Professor of Chemical and Biomolecular Engineering at the University of Delaware (UD), designed a set of experiments to measure how cancer cells respond to the loss of hexokinase-2, an enzyme that helps cells metabolize glucose, their food source. Dr. Antoniewicz is an expert in metabolic flux analysis, a technique for studying metabolism in biological systems. His research group is one of only a few in the world with expertise in a technique called 13C metabolic flux analysis of cancer cells, and he recently published a paper in Experimental & Molecular Medicine describing his methods.

Venus Fly Traps Rarely Consume Insects That Pollinate Them

While most people are familiar with Venus flytraps and their snapping jaws, there is still much that scientists don't know about the biology of these carnivorous plants. Researchers have for the first time discovered which insects pollinate the rare plants in their native habitat - and discovered that the flytraps don't eat these pollinator species. Venus flytraps (Dionaea muscipula) are in a genus all their own, and are native to a relatively small area, restricted to within a 100-mile radius of Wilmington, North Carolina. "These findings answer basic questions about the ecology of Venus flytraps, which is important for understanding how to preserve a plant that is native to such a small, threatened ecosystem," says Elsa Youngsteadt, a research associate at North Carolina State University and lead author of a paper on the work. "It also illustrates the fascinating suite of traits that help this plant interact with insects as both pollinators and prey." The paper, "Venus Flytrap Rarely Traps Its Pollinators," was published online on February 5, 2018 in the journal American Naturalist. "Everybody's heard of Venus flytraps, but nobody knew what pollinated them - so we decided to find out," says Clyde Sorenson, PhD, co-author of the paper describing the work and Alumni Distinguished Undergraduate Professor of Entomology at NC State. To that end, researchers captured insects found on Venus flytrap flowers at several sites during the plant's five-week flowering season. The researchers identified each insect and checked to see if they were carrying Venus flytrap pollen - and, if they were carrying pollen, how much.