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September 16th, 2019

Cause of Rare, Fatal Disorder (Krabbe Disease) in Young Children Pinpointed; Proof-of-Concept Drug Therapy Benefits Mouse Model of Disease

Scientists at Washington University School of Medicine in St. Louis appear to have solved a decades-long mystery regarding the precise biochemical pathway leading to a fatal genetic disorder in children that results in seizures, developmental regression and death, usually around age 3. Studying a mouse model with the same human illness -- called Krabbe disease -- the researchers also identified a possible therapeutic strategy. The research was published online on September 16, 2019 in PNAS. The article is titled “Genetic Ablation of Acid Ceramidase In Krabbe Disease Confirms the Psychosine Hypothesis and Identifies a New Therapeutic Target.” Patients with infantile globoid cell leukodystrophy, also known as Krabbe disease, gradually lose the protective covering that insulates axons, the wiring of the nervous system. The rare condition -- affecting approximately 1 in 100,000 births -- is typically diagnosed before age 1 and progresses rapidly. Scientists have long suspected that nerve insulation is destroyed in this disorder because of a buildup of a toxic compound called psychosine. Patients with the inherited disorder are missing an important protein involved in breaking down psychosine. But the source of psychosine in Krabbe disease has been elusive, making the problem impossible to correct. "Krabbe disease in infancy is invariably fatal," said senior author Mark S. Sands, PhD, a Professor of Medicine. "It's a heartbreaking neurodegenerative disease first described more than a century ago, but we still have no effective treatments. For almost 50 years, we have assumed the psychosine hypothesis was correct -- that a toxic buildup of psychosine is the cause of all the problems. But we've never been able to prove it." Surprisingly, Dr.

September 16th

Acute Chikungunya Infection Studied at Molecular Level in Brazilian Patients; Using Systems Biology Approach, Researchers Identify Several Genes That Can Be Explored As Therapeutic Targets and As Biomarkers of Predispositiont to Chronic Joint Pain

Computational tools applied to biology are revolutionizing the study of what happens inside cells during an infection, helping scientists to understand disease mechanisms and contributing to the identification of potential therapeutic targets. An example is a study published online on June 18, 2019 in PLOS Pathogens describing how Brazilian researchers analyzed blood cells from patients infected with chikungunya virus (image). With the aid of techniques such as complex network analysis, artificial intelligence, and machine learning, the group identified gene signatures associated with the disease - sets of genes whose expression is altered by interaction with the virus. They then investigated the role played in cells by the involved genes and determined the importance of these genes to efforts to combat the virus. The open-access article is titled “Systems Analysis of Subjects Acutely Infected with the Chikungunya Virus.” Conducted in Brazil, the research was supported by São Paulo Research Foundation (FAPESP). The principal investigator was Helder Nakaya, PhD, a professor at the University of São Paulo's School of Pharmaceutical Sciences (FCF-USP). Researchers at the same university's Biomedical Science Institute (ICB-USP) and its Ribeirão Preto Medical School (FMRP-USP), as well as colleagues at Butantan Institute and the Public Health Central Laboratory of Sergipe, among others, also contributed. "We also identified a set of genes that show during the acute phase whether the patient is likely to develop chronic arthralgia [joint pain and inflammation], a relatively common condition in people infected with chikungunya. However, this finding has yet to be confirmed by future research based on a larger number of samples," Dr. Nakaya said.

Multiple Disease Agents Present in Many Ticks

In a study published online in mBio, a journal of the American Society for Microbiology, Jorge Benach, PhD, and Rafal Tokarz, PhD, and their co-authors at Stony Brook University and Columbia University respectivly, reported on the prevalence of multiple agents capable of causing human disease that are present in three species of ticks in Long Island, New York. The open-acess article is titled “ Polymicrobial Nature of Tick-Borne Diseases.” Tick-borne diseases have become a worldwide threat to public health. In the United States, cases more than doubled, from 22,000 in 2004 to more than 48,000 in 2016, according to the U.S. Centers for Disease Control. Tick-borne diseases range from subclinical to fatal infections with disproportionate incidence in children or the elderly. Moreover, some infections can also be transmitted by blood transfusions and cause severe disease in patients with underlying disorders. While public attention has focused on Lyme disease, in recent years, scientists have uncovered evidence that ticks can carry several different pathogens capable of several different tick-borne diseases, sometimes in a single tick. In the new study, researchers collected ticks from multiple locations throughout Suffolk county in the central and eastern part of Long Island, where seven diseases caused by microbes transmitted by ticks are present. In total, they scientists examined 1,633 individual ticks for 12 separate microbes. They found that more than half of the Ixodes (deer ticks) (image) were infected with the Lyme disease agent, followed by infections with the agents of babesiosis and anaplasmosis. Importantly, nearly one-quarter of these ticks are infected with more than one agent, resulting in the possibility of simultaneous transmission from a single tick bite.

Vitamin E Found to Prevent Muscle Damage After Heart Attack

Heart attack is a leading cause of death worldwide and new treatment strategies are highly sought after. Unfortunately, lasting damage to the heart muscle is not uncommon following such an event. Published in the September 2019 issue of Redox Biology, a pre-clinical study sheds new light on the potential of the acute therapy with α-TOH (vitamin E) in patients presenting with heart attack, and may ultimately offer an effective low-cost treatment. "One of the most effective anti-oxidant and anti-inflammatory agents is vitamin E and its derivatives," said Professor Karlheinz Peter, the Baker Institute's (Melbourne, Australia) Deputy Director, Basic and Translational Science and senior author of the study. The open-access article is titled “α-Tocopherol Preserves Cardiac Function by Reducing Oxidative Stress and Inflammation in Ischemia/Reperfusion Injury "Our treatment regimen reflects clinical conditions, where patients could receive their first application of vitamin E in the ambulance or upon their arrival in the emergency department, before reopening and stenting the blocked vessel and the following days in hospital before discharge. Our next step is to test an already approved formulation of Vitamin E in patients admitted with a heart attack," said Professor Peter. "We plan to prove that heart function is preserved using sensitive magnetic resonance imaging. Thereby, we hope to establish an inexpensive and effective therapy for patients with heart attack. "Nutritional scientist and vitamin specialist from Jena University in Germany, Dr.

September 5th

Early Progression to Active TB Is Associated with Highly Heritable Variant in Gene Related to Monocyte Function in Infected Peruvian Populations

While the vast majority of the 1.8 billion people infected with the TB bacterium never experience active disease, an estimated 5 to 15 percent do develop full-blown infections--roughly half of them within 18 months of exposure. Why do some people develop overt disease soon after infection, while others harbor silent infections for decades and remain apparently healthy? It's a question that has continued to mystify microbiologists, infectious disease specialists, and public health experts on the forefront of the fight against TB, which continues to claim more lives globally than any other infectious pathogen. Now, a study by scientists from Harvard Medical School, Brigham and Women's Hospital, the Broad Institute of MIT and Harvard, Socios en Salud in Peru, and other institutions offers an answer: some of the risk for early disease progression is driven by several gene variants, at least one of which controls key immune functions. The research, published online on August 21, 2019 in Nature Communications, is believed to be the first large-scale study to explore the genetic underpinnings of early TB progression among people living in the same households with confirmed active and latent infections. This was a particular strength of the study, the research team said, because it ensured a meaningful and direct comparison allowing scientists to distinguish between infected progressors and infected non-progressors. The open-acess article is titled “Early Progression to Active Tuberculosis Is a Highly Heritable Trait Driven by 3q23 In Peruvians.” To be sure, researchers added, this is not the whole story, and more genes will likely be uncovered as drivers of early disease progression.

September 4th

Scientists Identify Four Genetic Regions Associated with Left-Handedness

A new study has, for the first time, identified regions of the genome associated with left-handedness in the general population and linked their effects with brain architecture. The study linked these genetic differences with the connections between areas of the brain related to language. It was already known that genes have a partial role in determining handedness - studies of twins have estimated that 25% of the variation in handedness can be attributed to genes - but which genes these are had not been established in the general population. The new study, led by researchers at the University of Oxford who were funded by the Medical Research Council and Wellcome, was published online on September 5, 2019 in Brain. The study identified some of the genetic variants associated with left-handedness by analyzing the genomes of approximately 400,000 people from UK Biobank, which included 38,332 left-handers. The open-access article is titled “'Handedness, Language Areas, and Neuropsychiatric Diseases: Insights from Brain Imaging and Genetics,” Of the four genetic regions the scientists identified, three of these were associated with proteins involved in brain development and structure. In particular, these proteins were related to microtubules, which are part of the scaffolding inside cells, called the cytoskeleton, which guides the construction and functioning of the cells in the body. Using detailed brain imaging from approximately 10,000 of these participants, the researchers found that these genetic effects were associated with differences in brain structure, in white matter tracts - which contain the cytoskeleton of the brain - that joins language-related regions.

September 4th

Immune Cells (Neutrophils) Drive Gallstone Formation; Finding May Open Door to New Therapeutic Interventions

Sticky meshworks of DNA and proteins extruded by white blood cells called neutrophils act as the glue that binds together calcium and cholesterol crystals during gallstone formation, researchers in Germany report in an article published online on August 15, 2019 in Immunity. The article is titled “"Neutrophil Extracellular Traps Initiate Gallstone Formation.” Both genetic and pharmacological approaches that inhibited the formation of these so-called neutrophil extracellular traps (NETs) reduced the formation and growth of gallstones in mice. "Neutrophils have long been considered the first line of defense against infection and have been shown to generate NETs that entangle and kill pathogens," says senior study author Martin Herrmann, MD, PhD, an immunologist at Universitätsklinikum Erlangen in Germany. "Here, we provide additional evidence for the double-edged-sword nature of these NETs by showing that they play an important role in the assembly and growth of gallstones. Targeting neutrophils and NET formation may become an attractive instrument to prevent gallstones in high-risk populations." Gallstones (image) are hard, pebble-like pieces of material that may be as small as a grain of sand or as large as a golf ball. They form in a pear-shaped organ called the gallbladder, which releases bile to the small intestine through the bile ducts during meals to help break down fat. Although most people with gallstones do not have symptoms, they can cause abdominal pain, nausea, and vomiting, and they are a leading cause of hospital admissions worldwide. Surgery to remove the gallbladder is one of the most common operations performed on adults in the United States.

Normal Cells Show Transient Induction of Telomerae Just Before Cell Death, Mediating Senescence and Reducing Tumorigenesis

New research from the University of Maryland (UMD) and the National Institutes of Health reveals a new role for the enzyme telomerase. Telomerase's only known role in normal tissue was to protect certain cells that divide regularly, such as embryonic cells, sperm cells, adult stem cells, and immune cells. Scientists thought telomerase was turned off in all other cells, except in cancerous tumors where it promotes unlimited cell division. The new study found that telomerase reactivates in normal adult cells at a critical point in the aging process. Just before cell death, a burst of telomerase buffers cells from the stresses of aging, slowing the process and reducing DNA damage that could lead to cancer. The study was published in the Proceedings of the National Academy of Sciences on September 2, 2019. The open-access article is titled” Transient Induction of Telomerase Expression Mediates Senescence and Reduces Tumorigenesis in Primary Fibroblasts.” "This study reshapes the current understanding of telomerase's function in normal cells,"said Kan Cao, PhD, senior author of the study and an Associate Professor of Cell Biology and Molecular Genetics at UMD. "Our work shows, for the first time, that there is a role for telomerase in adult cells beyond promoting tumor formation. We can now say that regulated activation of telomerase at a critical point in a cell's life cycle serves an important function." Telomerase prevents the shortening of telomeres--a specialized DNA-protein structure at the end of a cell's chromosomes that protect the chromosomes from damage (shown lighted up in image). Telomerase plays a critical role during embryonic development and stem cell differentiation, when cells divide profusely.

September 2nd

Scientists Locate RNA of Persistent Arthritis-Causing Chikungunya Virus Hidden in Dermal and Muscle Fibroblasts and Skeletal Myofibers

Since chikungunya virus emerged in the Americas in 2013, it has infected millions of people, causing fever, headache, rash, and muscle and joint pain. For some people, painful, debilitating arthritis lasts long after the other symptoms have resolved. Researchers have suspected that the virus or its genetic material - in this case, RNA - persist in the body undetected, but they have been unable to find its hiding places. Now, researchers at Washington University School of Medicine in St. Louis have figured out a way to detect cells infected with chikungunya virus that survive the infection. The scientists genetically modified the virus such that it activated a fluorescent tag within cells during infection. Months after the initial infection, the researchers could detect glowing red cells still harboring viral RNA. The study, in mice, opens up new ways to understand the cause of - and find therapies for - chronic viral arthritis. The findings were published August 29, 2019 in PLOS Pathogens. The open-access article is titled “Dermal and Muscle Fibroblasts and Skeletal Myofibers Survive Chikungunya Virus Infection and Harbor Persistent RNA.” Senior author Deborah Lenschow, MD, PhD, an Associate Professor of Medicine and of Pathology and Immunology, and co-first author and graduate student Marissa Locke answered questions about the research, which was conducted in collaboration with co-first author Alissa Young, PhD, co-author Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine, and others. How common is chronic arthritis caused by chikungunya infection? Dr. Lenschow: Between 30% and 60% of people infected with chikungunya virus go on to develop chronic arthritis that can last up to three or four years after infection.

Promising Gene Replacement Therapy for Niemann-Pick Type A Disease Moves Forward at Ohio State

Research led by Krystof Bankiewicz (photo), MD, PhD, who recently joined The Ohio State University College of Medicine, shows that gene replacement therapy for Niemann-Pick type A disease is safe for use in nonhuman primates and has therapeutic effects in mice. These research findings were published online on August 21, 2019, in the journal Science Translational Medicine. The article is titled “Adeno-Associated Viral Vector Serotype 9–Based Gene Therapy for Niemann-Pick Disease Type A.” Prior to joining Ohio State as a Professor of Neurosurgery, Dr. Bankiewicz conducted this translational gene therapy research at the University of California at San Francisco, in conjunction with researchers in New York, Massachusetts, and Spain. Niemann-Pick disease type A (NPD-A) is a lysosomal storage disorder characterized by neurodegeneration and early death. It is caused by loss-of-function mutations in the gene coding for the enzyme acid sphingomyelinase (ASM), which hydrolyzes sphingomyelin into ceramide. With this disease, the body's ability to metabolize fat within cells is affected, causing these cells to malfunction and, eventually, die. This inherited disease can affect the brain, nerves, liver, spleen, bone marrow, and lungs. The three main types of Niemann-Pick disease are types A, B and C. The signs and symptoms experienced depend on the type and severity of the condition. Some infants with type A will show signs and symptoms within the first few months of life. Those with type B may not show signs for years and have a better chance of surviving to adulthood. People with type C may not experience any symptoms until adulthood. Dr.