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Lost in Translation: Researchers Discover Surprising Amount of Variation in tRNA Genes; Suggest Possible Role in Disease

A molecule called transfer ribonucleic acid (tRNA), is an essential component of the human genome that acts as a translator. It reads the genetic code and translates it into proteins - one of the key building blocks of the human body. When researchers and clinicians investigate the genome's relation to disease, they have traditionally focused on mutations in the code for proteins. But now researchers at Western University in Canada have shown that the genes encoding tRNAs can also have mutations that cause the code to be misread, and in greater numbers than previously thought. Think of it like a translator app on your phone - if it has errors in its software, the output is going to be all wrong, even if the original text is correct. The results of the new study were published online on August 13, 2019 in RNA Biology. The article is titled “Targeted Sequencing Reveals Expanded Genetic Diversity of Human Transfer RNAs.” "This actually changes the way we think about the genetic code," said lead author Mathew Berg, a PhD Candidate at Western's Schulich School of Medicine & Dentistry.

Researchers ID Possible Target Matrix Protein (Perlecan) in Effort to Halt Spread of Pancreatic Cancer

An international team of researchers has revealed how aggressive pancreatic cancer cells change their environment to enable easy passage to other parts of the body (metastasis) - the main cause of pancreatic cancer-related death. The researchers discovered that some pancreatic tumors produce more of a molecule called “perlecan” to remodel the environment around them, which helps cancer cells spread more easily to other parts of the body, and also protects them against chemotherapy. In a mouse model, the researchers showed that lowering the levels of perlecan reduced the spread of pancreatic cancer and improved response to chemotherapy. Led by Associate Professor Paul Timpson, PhD, Head of the Invasion and Metastasis Laboratory, and Thomas Cox, PhD, Leader of the Matrix and Metastasis Group, both at the Garvan Institute of Medical Research in Australia, the research may provide a promising new path to more effective treatment options for individuals with pancreatic and other cancers. The findings were published online on August 12, 2019 in Nature Communications. The open-access article is titled “CAF Hierarchy Driven by Pancreatic Cancer Cell p53-Status Creates a Pro-Metastatic and Chemoresistant Environment via Perlecan.”"Pancreatic cancer is very aggressive, and, by the time most cases are diagnosed, the tumor is often inoperable," says Associate Professor Timpson. "What we've discovered in this study is a two-pronged approach for treating pancreatic cancer that we believe will improve the efficiency of chemotherapy and may help reduce tumor progression and spread." Pancreatic cancer is one of the most lethal forms of cancer, with a five-year survival of ~9% in Australia.

Enterovirus Antibodies Detected in CSF of Acute Flaccid Myelitis (AFM) Patients; New Study Adds to Knowledge About Rare Condition

A new study analyzing samples from patients with and without acute flaccid myelitis (AFM) provides additional evidence for an association between the rare, but often serious, condition that causes muscle weakness and paralysis, and infection with non-polio enteroviruses. The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, funded the research, which was conducted by collaborating investigators at Columbia University's Center for Infection and Immunity, the Centers for Disease Control and Prevention (CDC), and the University of California San Diego (UCSD). The findings were reported online on August 13, 2019 in the online journal mBio. The open-access article is titled “Antibodies to Enteroviruses in Cerebrospinal Fluid of Patients with Acute Flaccid Myelitis.” There have been 570 confirmed cases since the CDC began tracking AFM in August 2014. AFM outbreaks were reported to the CDC in 2014, 2016 and 2018. AFM affects the spinal cord and is characterized by the sudden onset of muscle weakness in one or more limbs. Spikes in AFM cases, primarily in children, have coincided in time and location with outbreaks of one enterovirus (EV) EV-D68 (image) and a related enterovirus, EV-A71. Both of these viruses typically cause mild respiratory illness from which most people recover fully. Despite the epidemiological link between enterovirus circulation and AFM cases, evidence of direct causality has not been found. The researchers first looked for direct evidence of enterovirus infection in the cerebrospinal fluid (CSF) of 13 children and one adult diagnosed with AFM in 2018. They also examined five CSF samples taken from people with other central nervous system diseases.

Long-Term, Anti-Rejection-Drug-Free Tolearance of Pancreas Islets Cells Induced by Apoptotic Donor Leukocytes in Non-Human Primates; Anti-Rejection Drugs Completely Discontinued 21 Days After Transplant

For decades, immunologists have been trying to train the transplant recipient's immune system to accept transplanted cells and organs without the long-term use of anti-rejection drugs. New University of Minnesota preclinical research shows that this is now possible. In a study published online on August 2, 2019 in Nature Communications, researchers at the University of Minnesota Medical School's Department of Surgery and Schulze Diabetes Institute, collaborating with colleagues at Northwestern University, have maintained long-term survival and function of pancreatic islet transplants despite complete discontinuation of all anti-rejection drugs on day 21 after the transplant. The open-access article is titled “Long-Term Tolerance of Islet Allografts in Nonhuman Primates Induced by Apoptotic Donor Leukocytes.” This study was performed in a stringent preclinical transplant setting in nonhuman primates, one step away from humans. For many patients with end-stage organ failure, transplantation is the only effective and remaining treatment option. To prevent transplant rejection, recipients must take medications long-term that suppress the body's immune system. These immunosuppressive drugs are effective at preventing rejection over the short term; however, because anti-rejection drugs suppress all of the immune system nonspecifically, people taking these drugs face the risk of serious infections and even cancer. Additionally, non-immunological side effects of immunosuppression, such as hypertension, kidney toxicity, diarrhea, and diabetes diminish the benefits of transplantation.

Self-Sterilizing Polymer Proves Effective Against Drug-Resistant Pathogens

Researchers from North Carolina (NC) State University have found that an elastic polymer possesses broad-spectrum antimicrobial properties, allowing it to kill a range of viruses and drug-resistant bacteria in just minutes - including methicillin-resistant Staphylococcus aureus (MRSA). "We were exploring a different approach for creating antimicrobial materials when we observed some interesting behavior from this polymer and decided to explore its potential in greater depth," says Rich Spontak, PhD, co-corresponding author of a paper on the work and Distinguished Professor of Chemical and Biomolecular Engineering at NC State. "And what we found is extremely promising as an alternate weapon to existing materials-related approaches in the fight against drug-resistant pathogens. This could be particularly useful in clinical settings - such as hospitals or doctor's offices - as well as senior-living facilities, where pathogen transmission can have dire consequences." The polymer's antimicrobial properties stem from its unique molecular architecture, which attracts water to a sequence of repeat units that are chemically modified (or functionalized) with sulfonic acid groups. "When microbes come into contact with the polymer, water on the surface of the microbes interacts with the sulfonic acid functional groups in the polymer - creating an acidic solution that quickly kills the bacteria," says Reza Ghiladi, PhD, an Associate Professor of Chemistry at NC State and co-corresponding author of the paper. "These acidic solutions can be made more or less powerful by controlling the number of sulfonic acid functional groups in the polymer." The work was published online on July 17, 2019 in Materials Horizon.

Discovery of Maturation Plasticity in Acute Myeloid Leukemia Cells May Redirect Research

Approximately 22,000 people will be diagnosed this year in the US with acute myeloid leukemia (AML), the second most common type of leukemia diagnosed in adults and children, and the most aggressive of the leukemias. Less than one third of AML patients survive five years beyond diagnosis. Researchers from Australia's Monash University have discovered a key reason why this disease is so difficult to treat and therefore cure. The study, led by Associate Professor Ross Dickins from the Australian Centre for Blood Diseases, was published online on August 1, 2019 in Cell Stem Cell. The article is titled “Interconversion Between Tumorigenic and Differentiated States in Acute Myeloid Leukemia.” The paper identifies an important new concept relevant to clinicians involved in the diagnosis and treatment of AML patients. AML is characterised by an overproduction of immature white blood cells that fail to mature properly. These leukemia cells crowd the bone marrow, preventing it from making normal blood cells. In turn this causes anemia, infections, and if untreated, death. AML remains a significant health problem, with poor outcomes despite chemotherapy and stem cell transplantation. For decades it has been thought that AML growth is driven by a sub-population of immature cancer cells called “leukemia stem cells,” which lose their cancerous properties when they mature. Hence, there has been growing international interest in developing therapies aimed at forcing immature cancer cells to “grow up.” Using genetically engineered mouse models and human AML cells, Associate Professor Dickins and his Monash-led team have found that maturation of AML cells is not unidirectional as originally thought, but can instead be reversible.

TB Mycobacteria Can Use Carbon Monoxide for Survival

Carbon monoxide is an infamous and silent killer that can cause death in minutes. But while it is deadly for us, some microorganisms actually thrive on it, by using this gas as an energy source. Associate Professor Chris Greening and his team of microbiologists from the School of Biological Sciences, Monash University in Australia have discovered that some pathogens depend on carbon monoxide to survive when other nutrients are not available. The research focused on mycobacteria, a bacterial group that causes killer diseases such as tuberculosis (TB), leprosy, and Buruli ulcer. During infection, these microbes are in a hostile environment with very few nutrients to go around, meaning that anything they can do to get extra energy can be hugely advantageous. "When microbial cells are starved of their preferred energy sources, one way they subsist is by scavenging gases such as carbon monoxide," said Monash PhD student Paul Cordero, the co-lead author of the study. "They breakdown this gas into its fundamental components, which provide the cells just enough energy to persist." The researchers showed that an enzyme called carbon monoxide dehydrogenase is what allows mycobacteria to obtain energy from this gas. While the energy gained is not enough to allow for growth, the researchers found that carbon monoxide consumption allowed mycobacteria to survive for longer periods of time. The study was published online on July 29,2019 in the ISME Journal. The open-access article is titled “Atmospheric Carbon Monoxide Oxidation Is a Widespread Mechanism Supporting Microbial Survival.” The group's findings suggest that Mycobacterium tuberculosis might be able to survive inside the human host by using carbon monoxide. Present in humans since ancient times, TB remains a major global health burden.

Study Reveals Intracellular Release Mechanism for ASCT2-Transportd Nutrient Amino Acid Glutamine; Study May Lay Groundwork for Development of Small Molecules to Inhibit Growth of Cancer Cells

In order to sustain fast growth, cancer cells need to take up nutrients at a faster rate than healthy cells. The human glutamine transporter ASCT2 allows the amino acid glutamine to enter cells and ASCT2 (image) is upregulated in many types of cancer cells, which need more glutamine. It is a potential target for new anti-cancer drugs. Researchers at the University of Groningen in the Netherlands have now elucidated a structure of the human ASCT2 that provides unprecedented insight into the workings of this protein, and may aid the development of drugs. The results were published in Nature Communications on July 31, 2019. The open-access article is titled “A One-Gate Elevator Mechanism for the Human Neutral Amino Acid Transporter ASCT2.” This work allowed the researchers to solve a long-lasting riddle. It was known that these transporters work like an elevator, where the substrate glutamine is engulfed by the protein, and then carried over a long distance through the cell membrane from the outside to the inside of the cell. While it was known how the substrate enters the elevator on the outside, it remained enigmatic what happens on the inside. This study now shows, for the first time, how the transported glutamine is released into the cytoplasm of the cell. The release mechanism is surprisingly similar to its catch mechanism on the outside of the cell. The same gate - a.k.a. elevator door - is used on either side of the membrane. "Hence, we have named the transport mechanism a 'one-gate elevator,” which sets it apart from the more commonly observed mechanisms that use two different gates for entry and release,” author Dr. Dirk Slotboom says. Senior author Dr. Cristina Paulino said, "This observation is of great fundamental interest, but also has potential implications for drug design.

International OCD Foundation (IOCDF) Holds 26th Annual OCD Conference (2019) in Austin, Texas, July 19-21; Over 2,000 Attend from 49 States and 24 Countries

The 26th Annual OCD Conference was held in Austin, Texas, July 19-21. Organized by the International OCD Foundation (IOCDF), headquartered in Boston, the Conference informs and empowers members of the obsessive compulsive disorder community by bringing together health professionals, researchers, individuals with OCD, and their loved ones, with the goal of educating all attendees about the latest treatments, research, and practice in OCD and related disorders. This year, attendance broke 2,000, with attendees coming from 49 states and 24 different countries to learn more about how to help friends, families, or patients who are struggling with this troubling and variable problem. A warm welcoming statement was made to meeting attendees by Susan Boaz, President, Board of Directors, IOCDF. “One of the most unique things about the Conference is the experience of having so many diverse groups mingling, all of whom help each other find hope and support for OCD. Our researchers have the opportunity to share their latest discoveries about the causes and treatment of OCD and they value the opportunity to hear from the front lines about what is really occurring in the community of OCD sufferers. Parents meet each other and form lifetime friendships. Kids and adults with OCD learn that they are not alone. Everyone is willing to answer questions, provide information, make friends, and share hope. Our wish is that you experience kindness and inspiration at our Annual OCD Conference.” The IOCDF’s Annual OCD Conference is the only international event focused solely on serving the OCD and related disorders community.

Compound (Resveratrol) Found In Red Wine and Grape & Berry Skins & Seeds May Open Door to New Treatments for Depression & Anxiety; Research Lays Groundwork for Use of Resveratrol in Novel Anti-Depressants

Like to unwind with a glass of red wine after a stressful day? Don't give alcohol all the credit. New research has revealed that the plant compound resveratrol, which is found in red wine, displays anti-stress effects by blocking the expression of an enzyme related to the control of stress in the brain, according to a University at Buffalo (UB)-led study. The findings shed light onto how resveratrol impacts neurological processes. According to the Anxiety and Depression Association of America, depression and anxiety disorders affect 16 and 40 million people respectively in the United States. "Resveratrol may be an effective alternative to drugs for treating patients suffering from depression and anxiety disorders," says Ying Xu, MD, PhD, co-lead author and research associate professor in the UB School of Pharmacy and Pharmaceutical Sciences. The study, published in the July 15, 2019 issue of the journal Neuropharmacology, was also led by Xiaoxing Yin, PhD, Professor at Xuzhou Medical University in China. The article is titled “The antidepressant- and anxiolytic-like effects of resveratrol: Involvement of phosphodiesterase-4D inhibition.” Resveratrol, which has been linked to a number of health benefits, is a compound found in the skin and seeds of grapes and berries. While research has identified resveratrol to have antidepressant effects, the compound's relationship to phosphodiesterase 4 (PDE4), an enzyme influenced by the stress hormone corticosterone, was unknown. Corticosterone regulates the body's response to stress. Too much stress, however, can lead to excessive amounts of the hormone circulating in the brain and, ultimately, to the development of depression and/or other mental disorders.

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