Syndicate content

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.

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.

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.

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.

Screening for Genetic High Cholesterol (Familial Hypercholinesterolemia) Could Help Patients and Families Avoid Heart Attack

Genetic high cholesterol is underdiagnosed and undertreated, according to research presented on September 1, 2019 at the ESC (European Society of Cardiology) Congress 2019 together with the World Congress of Cardiology in Paris, France (August 31-September 4). The presentation abstract was titled "Prevalence and Severity of Coronary Disease In Patients with Familial Hypercholesterolemia Hospitalized for an Acute Myocardial Infarction: Data from the RICO Survey.” Screening could identify patients and family members affected by the condition so that lifestyle changes and treatments can be started to prevent heart attack and stroke. Heterozygous familial hypercholesterolaemia (FH) is a life-threatening genetic condition linked with a high risk of premature cardiovascular disease, including heart attack and stroke. FH is one of the most common potentially fatal family disorders, with a prevalence estimated at 1/250 to 1/200, corresponding to 3.6 to 4.5 million individuals in Europe. Patients with FH have high levels of "bad" cholesterol (low-density lipoprotein; LDL) due to a mutation in genes that clear cholesterol from the body. LDL particles accumulate in the blood and can ultimately build up in the coronary artery walls. Children of patients with heterozygous FH have a 50% chance of inheriting the disorder. As LDL cholesterol levels are elevated as early as birth, the risk of heart attack in patients with FH is 10 to 13 times greater than that of the general population. Elevated LDL cholesterol plus family or personal history of early heart disease are key criteria for diagnosis, which may be confirmed by genetic testing. Management of FH includes a healthy lifestyle and medication.

Lung Cancer in Dogs Is Associated with HER2 Gene Mutation Seen In Human Breast Cancer; Clinical Trial of Drug (Neratinib) Effective in Human Breast Cancer Now Being Planned for Dogs with Lung Cancer; Possible Implications for Humans Who Have Never Smoked

Despite those velvet paintings of poker-playing dogs smoking pipes, cigars, and cigarettes, our canine friends really do not use tobacco. But, like many humans who have never smoked, dogs still get lung cancer. And, as many women who develop a particular type of breast cancer, the same gene -- HER2 -- also appears to be the cause of lung cancer in many dogs, according to a promising new study of pet dogs led by the Translational Genomics Research Institute (TGen), an affiliate of the City of Hope (California), and The Ohio State University. Published online on August 20, 2019 in the journal Clinical Cancer Research, this study could have significant implications, not only for dogs, but also for people who have never smoked. The article is titled “Identification of Recurrent Activating HER2 Mutations in Primary Canine Pulmonary Adenocarcinoma.” TGen and Ohio State found that neratinib -- a drug that has successfully been used to battle human breast cancer -- might also work for many of the nearly 40,000 dogs in the U.S. that annually develop the most common type of canine lung cancer, known as canine pulmonary adenocarcinoma (CPAC). Neratinib inhibits a mutant cancer-causing form of the gene HER2, which is common to both CPAC and HER2-positive human breast cancer patients. "With colleagues at Ohio State, we found a novel HER2 mutation in nearly half of dogs with CPAC. We now have a candidate therapeutic opportunity for a large proportion of dogs with lung cancer," said Will Hendricks, PhD, an Assistant Professor in TGen's Integrated Cancer Genomics Division, Director of Institutional Research Initiatives, and the study's senior author. Based on the results from this study, a clinical trial using neratinib is planned for dogs with naturally occurring lung cancer that have the HER2 mutation.

UW-Madison Leads Effort to Associate Multiple Maladies with FMR1 Premutation That Many Thought Harmless in Carriers; Full Mutation Causes Fragile X Syndrome; Landmark Study Demonstrates Power of Keeping & Mining Electronic Health Records

It was long believed that the so-called FMR1 premutation — an excessive number of trinucleotide repeats (55-200 repeats; normal number of repeats is 5 to 40) in the FMR1 gene — had no direct effect on the people who carry it. Until recently, the only recognized effect on the carriers of the flawed gene was the risk of having offspring with fragile X syndrome (>200 of the trinucleotide repeats), a rare but serious form of developmental disability. In recent years, however, at least two clinical conditions have been well documented in the carriers themselves: an age-dependent neurodegenerative disorder and, in female carriers, early menopause. Now, a team of researchers from the University of Wisconsin (UW)–Madison and Wisconsin’s Marshfield Clinic has found that there may be a much broader health risk to carriers, with potentially dozens of clinical conditions that can be ascribed directly to carrying the premutation. The researchers employed machine learning, a form of artificial intelligence (AI), to mine decades of electronic health records (EHRs) of nearly 20,000 individuals in order to make this landmark discovery. In a study published online on August 21, 2019 in Science Advances, the team led by Marsha Mailick (photo), PhD, a researcher and Professor at UW–Madison’s Waisman Center, and Emeritus Vice Chancellor for Research and Graduate Education at UW-Madison, together with UW–Madison graduate student Arezoo Movaghar, provides a better understanding of the previously disputed relationship between this well-known genetic premutation and a wide range of clinical conditions. At the same time, the interdisciplinary study richly illustrates the power of data-driven discovery.

Protein (FLRT3) with Roles In Neuron Development & Cell Adhesion May Be a Key Factor in Generation of Neuropathic Pain; Blocking FLRT3 Activity May Offer Possible Avenue to Reducing Such Pain

Researchers from Japan's Osaka University have made an important leap in our understanding of how chronic pain conditions develop. In a study published online on July 25, 2019 in the Journal of Neuroscience, the team explains how a protein previously implicated in neuron growth and cell adhesion is also critical for the development of pain sensitization (see image below). The article is titled “Increased Expression of Fibronectin Leucine-Rich Transmembrane Protein 3 in the Dorsal Root Ganglion Induces Neuropathic Pain in Rats.” Neuropathic pain is a chronic condition arising from previous nerve injury or certain diseases, including diabetes, cancer, and multiple sclerosis. Affected patients often display hypersensitivity to normally non-painful stimuli such as touch or repetitive movement, with pain commonly manifesting as shooting burning sensations, numbness, or pins and needles. In many cases, the pain cannot be relieved with analgesics. In humans, the spinal cord dorsal horn acts as a sorting station for pain stimuli. Signals coming in from peripheral areas of the body are processed and then transmitted via secondary neurons to the brain. Importantly, this is a key region in the development of neuropathic pain; studies have linked the condition to abnormal neuronal excitability in the spinal cord dorsal horn. However, what causes these neurons to become overly excited remains a mystery. FLRT3 (fibronectin leucine-rich transmembrane protein-3) is a protein commonly found in both embryonic and adult nervous systems. And while researchers don't know exactly what role it plays in adult tissues, FLRT3 has been implicated in synapse formation and cell adhesion in the developing brain.

Syndicate content