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March 18th, 2019

Scientists Characterize, Target, & Manipulate Critical Subset of Neurons Responsible for Excessive Drinking; Major Breakthrough in Identifying Key Brain Cells May Open Door to Developing Drug Therapies or Even Gene Therapies for Alcohol Addiction

Scientists at Scripps Research Institute (La Jolla, California) have found that they can reverse the desire to drink in alcohol-dependent rats--with the flip of a switch. The researchers were able to use lasers to temporarily inactivate a specific neuronal population, reversing alcohol-seeking behavior and even reducing the physical symptoms of withdrawal. "This discovery is exciting--it means we have another piece of the puzzle to explain the neural mechanism driving alcohol consumption," says Olivier George, PhD, an Associate Professor at Scripps Research and senior author of the new study, published on March 18, 2019 in Nature Communications. The open-access article is titled “Inactivation of a CRF-Dependent Amygdalofugal Pathway Reverses Addiction-Like Behaviors in Alcohol-Dependent Rats.” Although the laser treatment is far from ready for human use, Dr. George believes identifying these neurons opens the door to developing drug therapies or even gene therapies for alcohol addiction. "We need compounds that are specific to this neuronal circuitry," Dr. George says. According to the National Institute on Alcohol Abuse and Alcoholism, more than 15.1 million adults in the United States suffer from alcohol use disorder. Previous work at Scripps Research has shown that transitioning from casual drinking to dependent drinking occurs alongside fundamental changes in how the brain sends signals. These signals drive the intense cravings that make it so difficult for many people to scale back their alcohol consumption. Dr. George and his colleagues have been hunting for the brain cells that driving drinking in an alcohol-addicted rat model. In 2016, they reported that they had found a possible source: a neuronal "ensemble," or group of connected cells in a brain region called the central nucleus of the amygdala (CeA).

Inflammation Links Heart Disease & Depression, New Study Finds

People with heart disease are more likely to suffer from depression, and the opposite is also true. Now, scientists at the University of Cambridge (UK) believe they have identified a link between these two conditions: inflammation - the body's response to negative environmental factors, such as stress. While inflammation is a natural response necessary to fight off infection, chronic inflammation (which may result from psychological stress as well as lifestyle factors such as smoking, excessive alcohol intake, physical inactivity, and obesity) is harmful. The link between heart disease and depression is well documented. People who have a heart attack are at a significantly higher risk of experiencing depression. Yet, scientists have been unable to determine whether this is due to the two conditions sharing common genetic factors or whether shared environmental factors provide the link. "It is possible that heart disease and depression share common underlying biological mechanisms, which manifest as two different conditions in two different organs--the cardiovascular system and the brain," says Dr Golam Khandaker (, PhD, a Wellcome Trust Intermediate Clinical Fellow at the University of Cambridge in the UK. "Our work suggests that inflammation could be a shared mechanism for these conditions." In a study published on March 19, 2019 in Molecular Psychiatry, Dr. Khandaker and colleague Dr Stephen Burgess led a team of researchers from Cambridge who examined this link by studying data relating to almost 370,000 middle-aged participants of UK Biobank.

New Evidence Supports Suggestion That Narcolepsy Is Autoimmune Disease; Cytotoxic Autoreactive CD8 T Cells Found in Patients with Narcolepsy

Researchers from the University of Copenhagen have discovered autoreactive cells in persons suffering from narcolepsy. This is a new, important proof that the sleep disorder is an autoimmune disease. This knowledge may lead to better treatment of the chronic condition, the researchers behind the new discovery believe. For many years, scientists have suspected that the sleep disorder narcolepsy is an autoimmune disease, though without being able to prove it conclusively. Now, researchers from the Faculty of Health and Medical Sciences at the University of Copenhagen, together with the Technical University of Denmark and Rigshospitalet, have found a new, important proof that their presumptions were correct. The new research results were on February 19, 2019 in Nature Communications. The open-access article is titled “CD8+ T Cells from Patients with Narcolepsy and Healthy Controls Recognize Hypocretin Neuron-Specific Antigens.” “We have found autoreactive cytotoxic CD8 T cells in the blood of narcolepsy patients. That is, the cells recognize the neurons that produce hypocretin, which regulates a person's waking state. It does not prove that they are the CD8 T cells are the ones that killed the neurons, but it is an important step forward. Now we know what the cells are after,” says the article’s senior author, Associate Professor Birgitte Rahbek Kornum (photo), PhD, from the Department of Neuroscience at the University of Copenhagen. The immune system is designed to recognize viruses and bacteria. When its cells are autoreactive - which is the case in autoimmune diseases - the immune system recognizes the body's own cells as foreign and attacks them. That the immunr cells are cytotoxic means that they are capable of killing other cells.

Blood Test Using Vibrational Spectroscopy Accurately Spots Molecular Signature of Fibromyalgia; “Could Lead to Better, More Directed Treatment for Patients," Lead Researcher Says; Unusual Collaboration with Food Science Group Key to Advance

For the first time, researchers have evidence that fibromyalgia can be reliably detected in blood samples -- work they hope will pave the way for a simple, fast diagnosis. In a study published in the February 15, 2019 issue of the Journal of Biological Chemistry, researchers from The Ohio State University report success in identifying biomarkers of fibromyalgia and differentiating it from a handful of other related diseases. Their article is titled “Metabolic Fingerprinting for Diagnosis of Fibromyalgia and Other Rheumatologic Disorders.” The discovery could be an important turning point in care of patients with a disease that is frequently misdiagnosed or undiagnosed, leaving them without proper care and advice on managing their chronic pain and fatigue, said lead researcher Kevin Hackshaw (photo), MD, an Associate Professor in Ohio State's College of Medicine and a rheumatologist at the University's Wexner Medical Center. Identification of biomarkers of the disease - a "metabolic fingerprint" like that discovered in the new study - could also open up the possibility of targeted treatments, he said. To diagnose fibromyalgia, doctors now rely on patient-reported information about a multitude of symptoms and a physical evaluation of a patient's pain, focusing on specific tender points, he said. But there's no blood test - no clear-cut, easy-to-use tool to provide a quick answer. "We found clear, reproducible metabolic patterns in the blood of dozens of patients with fibromyalgia. This brings us much closer to a blood test than we have ever been," Dr. Hackshaw said.

March 14th

Huntington Disease Rate of Progression Determined by Length of Uninterrrupted CAG Repeats in DNA, Not Length of Polyglutamine Segment of Mutant Huntingtin Protein; Results Point to Importance of DNA Maintenance Mechanisms

HIn a preprint posted on January 24, 2019 by Cold Spring Harbor Laboratory’s bioRxiv, the Genetic Modifiers of Huntington’s Disease Consortium (GeM-HD), including such prominent HD experts as James Gusella, PhD, and Marcy MacDonald, PhD, both of the Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital; and Jane Paulsen, PhD, Departments of Psychiatry and Neurology, University of Iowa, make the provocative suggestion that some property of the uninterrupted CAG repeat segment in exon 1 of the huntingtin-coding gene (HTT), distinct from the resulting too-lengthy polyglutamine segment of the huntingtin protein, determines the rate at which HD develops. The article is titled “Huntington's Disease Onset Is Determined by Length of Uninterrupted CAG, Not Encoded Polyglutamine, and Is Modified by DNA Maintenance Mechanisms” (( According to the article abstract, “The timing of onset shows no significant association with HTT cis-eQTLs, but is influenced, sometimes in a sex-specific manner, by polymorphic variation at multiple DNA maintenance genes, suggesting that the special onset-determining property of the uninterrupted CAG repeat is a propensity for length instability that leads to its somatic expansion. Additional naturally-occurring genetic modifier loci, defined by GWAS, may influence HD pathogenesis through other mechanisms.

Heart Uses Exosomes to Send SOS Signal to Bone Marrow (BM) Cells After Heart Attack; In BM, Exosomes Release Heart-Specific MicroRNAs That Down-Regulate CXCR4 & Stimulate BM Progenitor Cells to Enter Blood Stream & Travel to Heart to Attempt Repairs

Human cells release exosomes. These tiny, membrane-bound vesicles can carry cargo for cell-to-cell communication, with the ability to ferry diverse loads of proteins, lipids, and/or nucleic acids. Researchers at the University of Alabama at Birmingham (UAB) and in China now report that exosomes are key to the SOS signal that the heart muscle sends out after a heart attack. After the heart attack, the exosomes in the bloodstream carry greatly increased amounts of heart-specific microRNAs — an observation seen in both mice and humans. These exosomes preferentially carry the microRNAs to progenitor cells in the bone marrow. Inside those progenitor cells, the microRNAs turn off a specific gene that allows the progenitor cells to leave the bone marrow and enter the bloodstream. The cells then travel to the heart to attempt repairs. The investigators say discovery of this novel pathway — a signal from the damaged heart to a systemic response by the reparative bone marrow cells — can now be leveraged to improve cell-based cardiovascular repair after heart attacks. The study — led by Gangjian Qin, MD, Professor in the UAB Department of Biomedical Engineering and Director of the Molecular Cardiology Program, and Min Cheng, MD, PhD, Huazhong University of Science and Technology, Wuhan, China — was published online on February 27, 2019 in Nature Communications. The open-access article is titled “Circulating Myocardial MicroRNAs from Infarcted Hearts Are Carried in Exosomes and Mobilize Bone Marrow Progenitor Cells.” For 15 years, it had been known that progenitor cells are released from the bone marrow after a heart attack. These cells move to the damaged heart muscle to attempt repairs. However, many efforts to improve that repair have yielded only modest efficacies, at best.

March 13th

New Genetic Data on 50,000 UK Biobank Participants Made Available to Global Health Research Community—"“We Believe This Is the Largest Open-Access Resource of Exome Sequence Data Linked to Robust Health Records in the World," Regeneron SVP Says

A vast tranche of new UK Biobank genetic data became available to health researchers on March 11, 2019, offering an unprecedented resource to enhance understanding of human biology and aid in therapeutic discovery. The exome sequence data of 50,000 UK Biobank participants was generated at the Regeneron Genetics Center through a collaboration among UK Biobank, Regeneron (US), and GSK (GlaxoSmithKline - UK) and are linked to detailed health records, imaging, and other health-related data. Regeneron is also leading a consortium of biopharma companies (including Abbvie, Alnylam, AstraZeneca, Bristol-Myers Squibb, Biogen, Pfizer, and Takeda) to complete exome sequencing of the remaining 450,000 UK Biobank participants by 2020. In addition, GSK has committed a £40 million (~$53 million) investment to initiatives, such as UK Biobank, that harness advances in genetic research in the development of new medicines. Consistent with the founding principles of UK Biobank, the first tranche of data has now been incorporated back into the UK Biobank resource for the global health research community to use. It follows a brief exclusive research period for Regeneron and GSK. Additional tranches of data will similarly be released over the next two years. All sequencing and analyses activities are undertaken on a de-identified basis, with the utmost consideration and respect for participant privacy and confidentiality principles. This major enhancement to UK Biobank would have been unimaginable when the study began recruiting participants in 2006, and makes it one of the most important studies of population health in the world.

Large New Study (Over 35,000 Individuals with Late-Onset AD, Over 94,000 Total) Identifies Five Additional Genes That Put People at Greater Risk of Alzheimer’s Disease—Dr. Francis Collins Comments in NIH Director’s Blog

Predicting whether someone will get Alzheimer’s disease (AD) late in life, and how to use that information for prevention, has been an intense focus of biomedical research. The goal of this work is to learn, not only about the genes involved in AD, but how they work together, and with other complex biological, environmental, and lifestyle factors to drive this devastating neurological disease. It’s good news to be able to report that an international team of researchers, partly funded by NIH, has made more progress in explaining the genetic component of AD. Their analysis, involving data from more than 35,000 individuals with late-onset AD, has identified variants in five genes that put people at greater risk of AD. It also points to molecular pathways involved in AD as possible avenues for prevention, and offers further confirmation of 20 other genes that had been implicated previously in AD. The results of this largest-ever genomic study of AD suggest key roles for genes involved in the processing of beta-amyloid peptides, which form plaques in the brain recognized as an important early indicator of AD. The results also offer the first evidence for a genetic link to proteins that bind tau, the protein responsible for tell-tale tangles in the AD brain that track closely with a person’s cognitive decline. The Nature Genetics article summarizing this work was published online on February 28, 2019, and is titled “Genetic Meta-Analysis of Diagnosed Alzheimer’s Disease Identifies New Risk Loci and Implicates Aβ, Tau, Immunity, and Lipid Processing.”

March 12th

“Join the the R-EV-olution!” Highlights from 3rd Annual Mid-Atlantic Extracellular Vesicle (EV) Scientific Symposium

(BY RACHEL DERITA, PhD,Thomas Jefferson University, Department of Cancer Biology). The field of extracellular vesicles (EVs) is expanding rapidly and this was never more evident than when a group of prominent leaders in the field, and scientists more recently entering the field, all came to The Wistar Institute in Philadelphia, Pennsylvania for the 3rd Annual Mid-Atlantic Extracellular Vesicle Scientific Symposium on February 26, 2019. The Symposium provided an opportunity for veteran EV researchers from different backgrounds, and scientists who have more recently entered the field, to both present their research and network with each other to exchange insights on this exciting and accelerating field that seems more important in more different areas almost every week. The Symposium began with a talk by Kenneth Witwer, PhD, Associate Professor of Molecular and Comparative Pathobiology at Johns Hopkins University, and a Co-Chair of the Symposium, who is also Executive Chair of the International Society of Extracellular Vesicles (ISEV). Recently, Dr. Witwer and Clotilde Thery, PhD, INSERM Director of Research at the Institut Curie, and over 380 other contributing ISEV members, published the “Minimal Information for Studies of Extracellular Vesicles 2018 (MISEV 2018) in the Journal of Extracellular Vesicles. This is an update to guidelines first published in 2014 in response to a need for increased methodologic understanding and rigor in the EV field. Dr. Witwer highlighted some of the most important updates made to MISEV since 2014. The most prominent of these was in the nomenclature of EVs.

Gene (MT-ATP6) Behind Long-Recognized Mitochondrial Disease Has Highly Varied Effects; CHOP Researchers Find More Than 30 Variations in MT-ATP6 Gene with Broadly Variable Clinical Symptoms and Biochemical Features

For more than two decades, mutations in a gene located in the DNA of mitochondria have been classified as a mitochondrial disease and linked to a particular set of symptoms. However, according to new findings from researchers at Children's Hospital of Philadelphia (CHOP), mutations in this gene, which encodes an essential part of the mitochondrial motor known as ATP synthase that generates cellular energy, are much more variable than previously thought. This prompts the need to develop more precise clinical tests that can better determine the course of treatment for patients affected by mitochondrial disorder. The study was published online on February 14. 2019 in the journal Human Mutation. The article is titled “"MT-ATP6 Mitochondrial Disease Variants: Phenotypic and Biochemical Features Analysis in 218 Published Cases and Cohort of 14 New Cases." Mitochondria are structures found within human and animal cells that are responsible for energy production. Mitochondria contain 37 genes encoded in their own DNA (mtDNA) that are separate from the DNA found inside the nucleus of the cell. Variations in more than 350 different genes located across both nuclear and mitochondrial DNA are responsible for causing mitochondrial diseases, which can typically cause more than 16 different symptoms in each patient and affect multiple organs. Mutations in the mtDNA-encoded ATP synthase membrane subunit 6 gene (MT-ATP6) are found in between 10 and 20 percent of cases of Leigh syndrome, a progressive brain disorder long recognized as a form of mitochondrial disease, and another recognizable condition known as neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome.