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August 16th, 2020

Is the COVID-19 Virus Pathogenic Because It Depletes Specific Host MicroRNAs?

Why is the COVID-19 virus deadly, while many other coronaviruses are fairly innocuous and just cause colds? A team of University of Alabama at Birmingham (UAB) and Polish researchers propose an answer--the COVID-19 virus acts as a microRNA "sponge." This action modulates host microRNA levels in ways that aid viral replication and stymy the host immune response. This testable hypothesis results from analysis of current literature and a bioinformatic study of the COVID-19 virus and six other coronaviruses. The hypothesis was published online on August 5, 2020, as a perspective in the American Journal of Physiology-Lung Cellular and Molecular Physiology. Human microRNAs (miRNAs) are short, non-coding RNAs made up of about 22 bases. They act to regulate gene expression by their complementary pairing with specific messenger RNAs of the cell. That pairing silences the messenger RNA, preventing it from being translated into a protein. Thus, miRNAs are a fine-tuned controller of cell metabolism or the cell's response to stress and adverse challenges, such as infection by a virus. The miRNAs are only about 0.01 percent of total human cell and tissue RNA, while replicating viral RNA of a virus like the COVID-19 virus may reach 50 percent of the total cellular RNA. So, the UAB and Polish researchers say, if the COVID-19 virus has binding sites for specific miRNAs -- and these sites are different from the binding sites for miRNAs found on coronaviruses that cause colds--the more pathogenic COVID-19 virus may selectively sponge up certain miRNAs to dysregulate the cell in ways that make it a dangerous human coronavirus. The sponge idea is not novel.

August 15th

Researchers Use Organ-on-a-Chip Microsystem to Investigate How Ovarian Cancer Cells Gain Access to Platelets, an Interaction That Leads to Ovarian Cancer Metastasis

Abhishek Jain (photo), PhD, Assistant Professor in the Department of Biomedical Engineering and the Department of Medical Physiology in the College of Medicine, collaborated with researchers from the Departments of Gynecologic Oncology and Cancer Biology at MD Anderson Cancer Center to gain a better understanding of the interaction among ovarian cancer tumors, blood vessels, and platelets. The scientists found that tumors break the blood vessel barriers and this allows them to communicate with blood cells, including platelets. When these tumors come into contact with platelets, they can then metastasize. The results of this collaborative research were published online on July 27, 2020 in Blood Advances. The article is titled “OvCa-Chip Microsystem Recreates Vascular Endothelium–Mediated Platelet Extravasation in Ovarian Cancer.” Previously, researchers understood that platelets are one of the initiators of ovarian cancer metastasis but did not know what led to the introduction of the platelets to the tumor cells. Instead of struggling to view this relationship in animal models, Dr. Jain's team brought a new solution to the table: organ-on-a-chip research. Organs-on-a-chip are microfluidic medical devices the size of a USB drive. The team designed the OvCa-Chip to give researchers an easier window to view the biological processes between tumors and platelets.In an interview with the International Society on Thrombosis and Hemostasis, Dr. Jain explained that "it basically is a microenvironment where ovarian tumor cells can be co-cultured along with their blood vessels, and then they can interact with blood cells.

Gene Expressed in Oligodendrocytes May Be Possible Target for Treatment in Multiple Sclerosis (MS)

The disease multiple sclerosis (MS) attacks the central nervous system and, with time, can give rise to muscle tremors, a loss of balance, and other symptoms. Researchers at Karolinska Institutet in Sweden have now identified a gene, Gsta4, coding for glutathione S-transferase A4 (image), that protects a certain kind of cell (oligodendrocyte) in the brain from being destroyed. It is hoped that the results of the study, which were published on August13, 2020 in Nature Communications, can help to improve the treatment of this serious disease. The open-access article is titled “Gsta4 Controls Apoptosis of Differentiating Adult Oligodendrocytes During Homeostasis and Remyelination Via the Mitochondria-Associated Fas-Casp8-Bid-Axis.” “Taken together, our findings are particularly interesting for several reasons,” says corresponding author Karl Carlström, Researcher at the Department of Clinical Science at Karolinska Institutet in Sweden. “Too little is known about the mechanisms behind progressive MS, by which I mean the phase of the disease in which oligodendrocytes and neurons in the brain die without re-forming.” Brain neurons can be likened to electric wires, the protective and insulating sheathes of which are essential to their purpose. The cells that provide such insulation are called oligodendrocytes and it is these cells that the immune system attacks in an early phase of MS. Researchers at Karolinska Institutet have studied possible mechanisms influencing both how well oligodendrocytes mature into functional cells and their survival during this process. MS is a disease of the central nervous system (the brain and spinal cord) and can last for many years, leading in many cases to, among other problems, loss of sensation, tremors, difficulties walking, mood swings, and visual impairment.

Progress in Development of Oral Vaccine for Anthrax in Ranging Livestock and Wildlife

There may soon be a new weapon in the centuries-old battle against anthrax in wildlife thanks to ground-breaking work at the Texas A&M University College of Veterinary Medicine & Biomedical Sciences (CVMBS). Anthrax, a disease caused by a bacterium called Bacillus anthracis, contaminates surface soil and grasses, where it may be ingested or inhaled by livestock or grazing wildlife. This is especially common in the western Texas Hill Country, where each year the disease kills livestock and wildlife. While normally not an attention-grabbing problem, a spike of cases in 2019 made headlines around the state. According to Jamie Benn Felix, PhD, a postdoctoral research associate in the Cook Wildlife Lab led by CVMBS Department of Veterinary Pathobiology's (VTPB) Dr. Walt Cook, that spike may have been responsible for the deaths of more than 10,000 animals. "If you assume the economic value for each animal was $1,000, which is probably extremely low given the number of exotic species on some of the ranches, you're looking at an economic loss of $10 million in just a few months," she said. "And given the problems with reporting cases, it could be significantly higher than that." The good news is that there is already a vaccine for anthrax, which many livestock owners administer annually. Unfortunately, it can only be administered with an injection that is time-consuming for livestock and not feasible for wildlife. With that in mind, Dr. Benn Felix and the Cook Wildlife Lab team, in collaboration with VTPB researchers Dr. Allison Rice-Ficht and Dr. Thomas Ficht, went to work to attempt to create a formulation to deliver the vaccine orally, which would allow for potential distribution to wildlife. Dr.

August 13th

Depletion of “Reelin” Protein May Be Effective in Multiple Sclerosis, and Chronic Inflammatory Conditions Such As Psoriasis, Crohn’s Disease, and Rheumatoid Arthritis

In an animal model of multiple sclerosis (MS), decreasing the amount of a protein (“Reelin”) (image) made in the liver significantly protected against development of the disease’s characteristic symptoms and promoted recovery in symptomatic animals, scientists the University of Texas Southwestern (UTSW) Medical Center report. The findings, published online on August 12, 2020 in Science Translational Medicine, could lead to a new treatment strategy for this neurological disease and other conditions marked by chronic inflammation. The article is titled “Reelin Depletion Protects Against Autoimmune Encephalomyelitis By Decreasing Vascular Adhesion Of Leukocytes.” In 1997, researchers discovered a protein secreted in the brain called “Reelin.” Subsequent work showed that Reelin appears to help the brain organize itself during development and assists in forming connections between brain cells during adulthood. However, as researchers learned more about Reelin, they discovered that large amounts of it are produced in the liver and that cells lining blood vessels have receptors for this protein. A 2016 study by Joachim Herz, MD, Director of the UTSW’s Center for Translational Neurodegeneration Research and Professor in the Departments of Molecular Genetics, Neurology and Neurotherapeutics, and Neuroscience at UTSW, and his colleagues showed that depleting levels of circulating Reelin protected mice from atherosclerosis. Probing deeper into the mechanism behind this phenomenon, the researchers found that Reelin appears to regulate the production of adhesion molecules on blood vessel walls that capture circulating monocytes, a type of inflammation-inducing immune cell.

August 12th

45-Year Cancer Mystery Solved; Epigenetic Silencing of Key Enzyme Prevents Synthesis of “Y” Nucleotide in Phenylalanine tRNA Causes Certain Small, But Highly Aggressive Tumors

Before the first oncogene mutations were discovered in human cancer in the early 1980s, the 1970s provided the first data suggesting alterations in the genetic material of tumors. In this context, in 1975 Nature published an article describing the existence of a specific alteration in the transformed cell: a transfer RNA (tRNA) responsible for carrying the amino acid phenylalanine to build proteins was missing a piece, the enigmatic nucleotide "Y” a hypermodulated guanine (https://pubmed.ncbi.nlm.nih.gov/163007/). After that seminal observation, silence and ignorance have reigned for forty-five years on the causes and consequences of not having that correct base in that tRNA. In an article that was just published online on August 10, 2020 in PNAS by the group of Manel Esteller (photo) (https://www.carrerasresearch.org/esteller-manel_124337), MD, PhD, Director of the Josep Carreras Leukaemia Research Institute, ICREA Research Professor and Professor of Genetics at the University of Barcelona in Spain, this 45-year-old mystery appears to have been solved by results showing that in certain cancer cells the enzyme (tRNA wybutosine-synthesizing protein 2) that generates the nucleotide "Y" is epigenetically inactivated, causing small, but highly aggressive tumors. The open-access PNAS article is titled "Epigenetic Loss of the Transfer RNA-Modifying Enzyme TYW2 Induces Ribosome Frameshifts in Colon Cancer." “Since the original discovery in 1975, there has been much biochemical work to characterize the enzymes involved in the different steps that lead to the desired nucleotide ‘Y,’ a hypermodified guanine, but without connecting this characterization with its defect in tumor biology.

Key Brain Region Was “Recycled” As Humans Developed Ability to Read; Part of Visual Cortex Dedicated to Recognizing Objects Appears Predisposed to Identifying Words & Letters, MIT Study Finds

Humans began to develop systems of reading and writing only within the past few thousand years. Our reading abilities set us apart from other animal species, but a few thousand years is much too short a timeframe for our brains to have evolved new areas specifically devoted to reading. To account for the development of this skill, some scientists have hypothesized that parts of the brain that originally evolved for other purposes have been “recycled” for reading. As one example, they suggest that a part of the visual system that is specialized to perform object recognition has been repurposed for a key component of reading called orthographic processing--the ability to recognize written letters and words. A new study from MIT neuroscientists offers evidence for this hypothesis. The findings suggest that even in nonhuman primates, who do not know how to read, a part of the brain called the inferotemporal (IT) cortex is capable of performing tasks such as distinguishing words from nonsense words, or picking out specific letters from a word. “This work has opened up a potential linkage between our rapidly developing understanding of the neural mechanisms of visual processing and an important primate behavior--human reading,” says James DiCarlo, PhD, the Head of MIT’s Department of Brain and Cognitive Sciences, an investigator in the McGovern Institute for Brain Research and the Center for Brains, Minds, and Machines, and the senior author of the study. Rishi Rajalingham, PhD, an MIT postdoc, is the lead author of the study, which was published online on August 4, 2020 in Nature Communications. The open-access article is titled “The Inferior Temporal Cortex Is a Potential Cortical Precursor of Orthographic Processing in Untrained Monkeys.” Other MIT authors on this article are postdoc Kohitij Kar, PhD, and technical associate Sachi Sanghavi.

“Breakthrough Article” in Nucleic Acids Research Presents Data Supporting Full-Scale Clinical Development of Antisense Oligonucleotides (ASOs) for Possible Treatment of Prion Diseases Such As Fatal Familial Insomnia & Creutzfeldt-Jakob Disease

Research teams led by Sonia Vallabh (photo), PhD, whose mother died of the hereditary prion disease fatal familial insomnia, and Eric Minikel, PhD, at Harvard Medical School and The Broad Institute, Holly Kordasiewicz, PhD, at Ionis Pharmaceuticals, and Deborah Cabin, PhD, at McLaughlin Research Institute, have reported the results of preclinical studies of an antisense therapy against different strains of prion disorders, including mechanistic experiments and validation in animal model systems, in an article titled “Prion Protein Lowering is a Disease-modifying Therapy Across Prion Strains, Stages, and Endpoints,” and published online on August 10, 2020 in Nucleic Acids Research. This article was designated by NAR as a “Breakthrough Article,” that is, an article that “describes studies that provide exceptional new insight and understanding into an area of research that will clearly motivate and guide new research opportunities and directions.” “Breakthrough Articles” represent the top papers that NAR receives for publication, and are selected by the Editors based on nominations and subsequent recommendations by the reviewers and editorial board members. Prion diseases are rapidly fatal and currently untreatable neurodegenerative diseases. They include Creutzfeldt-Jakob disease, fatal familial insomnia, and kuru in humans, bovine spongiform encephalitis (BSE) (Mad Cow Disease) in cattle, and scrapie in sheep. These diseases are caused by disruption of the structure of a normal prion protein (PrP). The disrupted PrP is characterized by a beta-sheet structure rather than the alpha-helix structure that characterizes the normal PrP.

August 10th

CytoDyn Announces Clinically Significant Top-line Results from Its Phase 2 Trial of Leronlimab in Mild-to-Moderate COVID-19 Patients; Results “Bode Well for Leronlimab’s Activity In Patients With More Severe Illness,” Senior Science Advisor Says

On August 11, 2020, CytoDyn Inc. (OTC.QB: CYDY), a late-stage biotechnology company headquartered in Seattle, Washington, announced the Top-Line results from its recently completed, randomized, double-blind, Phase 2 trial of leronlimab for COVID-19 patients with mild-to-moderate symptoms. The primary endpoint showed early clinical improvement in symptom score at Day 3 in patients receiving leronlimab. In addition, leronlimab also demonstrated statistically significant improvement versus placebo in key secondary efficacy endpoint, National Early Warning Score 2 scale (NEWS2). The results will be reported to the United States FDA, the United Kingdom MHRA, and the European Union regulatory agency, EMA. Harish Seethamraju, MD, Lead Principal Investigator at Montefiore Medical Center, New York City, stated, “The results demonstrate that CCR5 blockade by leronlimab given as a weekly subcutaneous injection in mild-to-moderate COVID-19 patients is reasonably safe and associated with rapid improvement in viral symptoms with fewer adverse events than when compared to placebo.” Nader Pourhassan, PhD, President and Chief Executive Officer of CytoDyn, stated, “In the mild- to-moderate population, it is important to have a therapeutic option for COVID-19 in patients who are showing signs of rapid clinical deterioration. Patients receiving leronlimab showed a statistically significant improvement using NEWS2 clinical parameters. We will make a case for immediate approval of leronlimab for this population of COVID-19 patients, not only in the U.S., but also in the UK and other countries around the world.” Scott A. Kelly, MD, Chief Medical Officer of CytoDyn, said, “We are thrilled with the results of leronlimab in mild-to-moderate COVID-19 patients.

Malaria Research Suggests Targeting Key Red Blood Cell Kinases with Existing Anti-Cancer Drugs May Thwart Disease; Targeting Key Host Enzymes with Repurposed Drugs Could Have Far Wider Application, Including in Anti-Viral Treatment for COVID-19

New research into malaria suggests targeting enzymes from the human host, rather than from the pathogen itself, could offer effective treatment for a range of infectious diseases, including COVID-19. The study, conducted by an international team and led by RMIT University's Professor Christian Doerig, PhD, outlines a strategy that could save years of drug discovery research and millions of dollars in drug development by repurposing existing treatments designed for other diseases such as cancer. The approach shows so much promise it has received government funding for its potential application in the fight against COVID-19. The study, published online on August 11, 2020 in Nature Communications, demonstrated that the parasites that cause malaria are heavily dependent on enzymes in red blood cells (RBCs) where the parasites hide and proliferate. The open-access article is titled “Analysis of Erythrocyte Signalling Pathways During Plasmodium falciparum Infection Identifies Targets for Host-Directed Antimalarial Intervention.” The study also revealed that drugs developed for cancer, and which inactivate these human enzymes, known as protein kinases, are highly effective in killing the parasite and represent an alternative to drugs that target the parasite itself. Lead author, RMIT's Dr. Jack Adderley, said the analysis revealed which of the host cell enzymes were activated during infection, revealing novel points of reliance of the parasite on its human host. "This approach has the potential to considerably reduce the cost and accelerate the deployment of new and urgently needed anti-malarials," he said.