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Congenital Blindness Reversed in Mice by Müller Glia-Driven Regenerative Therapy

Researchers funded by the National Eye Institute (NEI) of the NIH have reversed congenital blindness in mice by changing supportive cells in the retina called Müller glia into rod photoreceptors. The findings advance efforts toward regenerative therapies for blinding diseases such as age-related macular degeneration and retinitis pigmentosa. A report of the findings was published online on August 15, 2018 in Nature. The article is titled “Restoration of Vision After De Novo Genesis of Rod Photoreceptors in Mammalian Retinas.” "This is the first report of scientists reprogramming Müller glia to become functional rod photoreceptors in the mammalian retina," said Thomas N. Greenwell, PhD, NEI Program Director for Retinal Neuroscience. "Rods allow us to see in low light, but they may also help preserve cone photoreceptors, which are important for color vision and high visual acuity. Cones tend to die in later-stage eye diseases. If rods can be regenerated from inside the eye, this might be a strategy for treating diseases of the eye that affect photoreceptors." Photoreceptors are light-sensitive cells in the retina in the back of the eye that signal the brain when activated. In mammals, including mice and humans, photoreceptors fail to regenerate on their own. Like most neurons, once mature, they don't divide. Scientists have long studied the regenerative potential of Müller glia because in other species, such as zebrafish, these cells divide in response to injury and can turn into photoreceptors and other retinal neurons. The zebrafish can thus regain vision after severe retinal injury. In the lab, scientists can coax mammalian Müller glia cells to behave more as they do in the fish. But it requires injuring the tissue.

New Form of Genome Analysis (Polygenic Risk Scoring) May Enable Risk Prediction for Five Common Deadly Diseases, Including Breast Cancer, Type 2 Diabetes, and Coronary Artery Disease

A research team at the Broad Institute of MIT and Harvard, Massachusetts General Hospital (MGH), and Harvard Medical School reports a new kind of genome analysis that could identify large fractions of the population who have a much higher risk of developing serious common diseases, including coronary artery disease, breast cancer, atrial fibrillation, inflammatory bowel disease, or type 2 diabetes. These tests, which use information from millions of places in the genome to ascertain risk for five diseases, can flag greater likelihood of developing the potentially fatal conditions well before any symptoms appear. While the study was conducted with data from the UK, it suggests that up to 25 million people in the US may be at more than triple the normal risk for coronary artery disease, and millions more may be at similar elevated risk for the other conditions, based on genetic variation alone. The genomic information could allow physicians to focus particular attention on these individuals, perhaps enabling early interventions to prevent disease. The research raises important questions about how this method, called polygenic risk scoring, should be further developed and used in the medical system. In addition, the authors note that the genetic tests are largely based on information from individuals of European descent, and the results underscore the need for larger studies of other ethnic groups to ensure equity. The study was published online on August 13, 2018 in Nature Genetics and has already received significant attention from the popular press (see links below).

First Study on Physical Properties of Giant Cancer Cells May Inform New Treatments

Polyploidal cancer cells--cells that have more than two copies of each chromosome--are much larger than most other cancer cells, are resistant to chemotherapy and radiation treatments, and are associated with disease relapse. A new study by Brown University researchers is the first to reveal key physical properties of these "giant" cancer cells. The research, published online on August 9, 2018 in Scientific Reports, shows that the giant cells are stiffer and have the ability to move further than other cancer cells, which could help explain why they're associated with more serious disease. The open-access article is titled “Dysregulation in Actin Cytoskeletal Organization Drives Increased Stiffness and Migratory Persistence in Polyploidal Giant Cancer Cells.” "I think these polyploidal giant cancer cells (PGCCs) are the missing link for why tumors become so complex and heterogeneous so quickly," said Dr. Michelle Dawson, an Assistant Professor of Molecular Pharmacology, Physiology and Biotechnology at Brown and the study's corresponding author. "By understanding the physical properties of this weird population of cells we might identify a new way to eliminate them. Patients will benefit from that." Dr. Dawson, who is also an Assistant Professor of Engineering with an appointment in Brown's Center for Biomedical Engineering, worked with graduate student Botai Xuan and two undergraduate students on the study, which focused on a common strain of triple-negative breast cancer, an extremely aggressive and hard-to-eradicate kind of breast cancer. The researchers found that 2-5 percent of cells from this breast cancer strain were PGCCs with four, eight, or sixteen copies of each chromosome, instead of the normal two copies.

$2 Million for Study of Targeted Exosomes to Aid Bone & Tisssue Regeneration

According to an August 13, 2018 UIC press release, University of Illinois at Chicago (UIC) researchers have received approximately $2 million in funding from the National Institutes of Health to develop a better way to regenerate bone or tissues that have been lost to disease or injury. The UIC work will pursue the use of engineered exosomes to aid regeneration. Currently, most treatments rely on the use of growth factors or other chemical agents to stimulate stem cells, which have the ability to grow into any type of cell in the body, to regenerate what has been lost. But this approach has many limitations, including side effects and uncontrolled abnormal growths due to dosing and toxicity, which have caused complications and prevented regulatory organizations from approving the treatments for use in humans. "We need a replacement for growth factor-based interventions so that we can reduce side effects and advance these therapies to the bedside," said Dr. Sriram Ravindran, co-principal investigator of the project. "We need therapies that better mimic the body's natural processes, so the body is better able to tolerate treatment." Bone is the second most transplanted organ in the human body, after blood. Grafting and regeneration procedures are performed by health care providers to treat anything from complex bullet wounds and spinal injuries to gum disease. Dr. Ravindran, research assistant professor of oral biology, and his colleague, Dr. Praveen Gajendrareddy, jointly run a lab at the UIC College of Dentistry that develops biomimetic tools -- those that mimic natural biology -- for tissue regeneration.

Disrupted Nitrogen Metabolism Might Signal Cancer

Nitrogen is a basic building block of all the body's proteins, RNA, and DNA, so cancerous tumors are greedy for this element. Researchers at the Weizmann Institute of Science in Israel, in collaboration with colleagues from the National Cancer Institute (NCI) and elsewhere, have now shown that, in many cancers, the patient's nitrogen metabolism is altered, producing detectable changes in the body fluids and contributing to the emergence of new mutations in cancerous tissue. The study's findings, published online on August 9, 2018 in Cell, may in the future facilitate early detection of cancer and help predict the success of immunotherapy. The article is titled “Urea Cycle Dysregulation Generates Clinically Relevant Genomic and Biochemical Signatures.” When the body makes use of nitrogen, it generates from the leftovers a nitrogenous waste substance called urea in a chain of biochemical reactions that take place in the liver, which are known as the “urea cycle.” As a result of this cycle, urea is expelled into the bloodstream, and is later excreted from the body in the urine. In previous research, Dr. Ayelet Erez of Weizmann's Biological Regulation Department showed that one of the enzymes in the urea cycle has been inactivated within many cancerous tumors, increasing the availability of nitrogen for the synthesis of an organic substance called pyrimidine, which, in turn, supports RNA and DNA synthesis and cancerous growth. In the new study, conducted with Professor Eytan Ruppin of the NCI and other researchers, Dr. Erez's team identified a number of precisely defined alterations in additional enzymes of the urea cycle, which together increase the availability of nitrogenous compounds for pyrimidine synthesis. These alterations lead to increased pyrimidine levels in the tumor and predispose the cancer to mutations.

Report Highlights Feasibility of Generating DNA Sequence Data in the Developing World

Globally, biodiversity is concentrated around the equator, but the scientific institutions generating DNA sequence data to study that biodiversity tend to be clustered in developed countries toward the poles. However, the rapidly decreasing cost of DNA sequencing has the potential to change this dynamic and create a more equitable global distribution of genetic research. In a review article published online on July 13, 2018 in Applications in Plant Sciences, Dr. Gillian Dean (photo), from the Department of Botany at the University of British Columbia, and colleagues show the feasibility of producing high-quality sequence data at a laboratory in Indonesia. The open-access article is titled “Generating DNA Sequence Data with Limited Resources for Molecular Biology: Lessons from a Barcoding Project in Indonesia.” For many laboratories in the developing world, a lack of funding and practical experience are major hurdles to generating their own DNA sequence data. However, the financial, technical, and logistical burden of producing DNA sequence data has dropped precipitously in recent years. DNA sequencing is increasingly done at centralized "core" facilities dedicated to producing high-quality sequence data from prepared samples at high volume and low cost. This means that laboratories need only do initial processing of tissue to prepare DNA samples to be sent to a sequencing core facility. Molecular techniques like DNA extraction, purification, and PCR, which are necessary to prepare samples for sequencing, are now quite well established, with protocols that are relatively simple using fairly inexpensive reagents (ingredients).

Idiopathic Pulmonary Fibrosis (IPF) Associated with Increase in Extracellular Vesicles (Exosomes)* Relaying WNT5A Signaling Molecules in Lung Cells

Idiopathic pulmonary fibrosis (IPF) is an incurable lung disease of unknown origin with limited treatment options. Research suggests that the signaling molecule WNT5A plays a key role in the pathogenic process. Now, a group of scientists from Helmholtz Zentrum München in Germany, working with colleagues from the University of Denver, has taken a further step towards uncovering the mechanisms responsible for the development of fibrosis: they have shown that IPF is associated with the increase of extracellular vesicles (EVs) (sometimes called exosomes)* that relay WNT5A signals to cells in the lungs. The study, published online on July 25, 2018 in the American Journal of Respiratory and Critical Care Medicine, proposes a further pharmacological biomarker (the EVs) and a possible therapeutic approach (reducing the number of these EVs). The article is titled “Increased Extracellular Vesicles Mediate WNT-5A Signaling in Idiopathic Pulmonary Fibrosis.” Pulmonary fibrosis is associated with the increased formation of connective tissue in the lungs, resulting in scarring (fibrosis) of functional lung tissue. This leads to a decrease in the inner surface of the extremely fine alveoli and the extensibility of the lungs, which, in turn, impedes the intake of oxygen and the release of carbon dioxide. The result is impaired lung function. IPF is a particularly aggressive form of pulmonary fibrosis that cannot yet be attributed to a specific cause. The symptoms worsen rapidly. Existing drugs can slow progression of the disease, but are unable to stop it permanently. Research is therefore continuing to focus on elucidating the mechanisms underlying the pathological tissue changes associated with IPF.

New Results Suggest Glaucoma May Be Autoimmune Disease Prompted by T-Cell Reaction to Heat Shock Proteins from Commensal Microflora; Findings Suggest Possible New Avenues of Treatment & Even Prevention

Glaucoma, a disease that afflicts nearly 70 million people worldwide, remains a significant mystery. Little is known about the origins of the disease, which damages the retina and optic nerve and can lead to blindness. A new study from MIT and Massachusetts Eye and Ear has found that glaucoma may, in fact, be an autoimmune disorder. In a study of mice, the researchers showed that the body's own T-cells are responsible for the progressive retinal degeneration seen in glaucoma. Furthermore, these T-cells appear to be primed to attack retinal neurons as the result of previous interactions with bacteria (and other microflora) that normally live in our body. The discovery suggests that it could be possible to develop new treatments for glaucoma by blocking this autoimmune activity, the researchers say. "This opens a new approach to prevent and treat glaucoma," says Dr. Jianzhu Chen, an MIT Professor of Biology, a member of MIT's Koch Institute for Integrative Cancer Research, and one of the senior authors of the study, which was published online on August 10, 2018 in Nature Communications. The open-access article is titled “Commensal Microflora-Induced T Cell Responses Mediate Progressive Neurodegeneration in Glaucoma.” Dr. Dong Feng Chen, an Associate Professor of Ophthalmology at Harvard Medical School and the Schepens Eye Research Institute of Massachusetts Eye and Ear, is also a senior author of the study. The paper's lead authors are Massachusetts Eye and Ear researchers Dr. Huihui Chen, Dr. Kin-Sang Cho, and Dr. T.H. Khanh Vu. One of the biggest risk factors for glaucoma is elevated pressure in the eye, which often occurs as people age and the ducts that allow fluid to drain from the eye become blocked.

Study of Brain Cell Firing Reveals Clues to Understanding Epilepsy; Specific Interaction Between Two Proteins Found to Be Key

New therapies could be on the horizon for people living with epilepsy or anxiety, thanks to a breakthrough discovery by University of Nevada-Lasd Vegas (UNLV), Tufts University School of Medicine, and an international team of researchers studying how proteins interact to control the firing of brain cells. The study, published online on August 7, 2018 in Nature Communications, provides new insight into ways to regulate a specialized "compartment" of cells in the brain that controls their signaling. If scientists and doctors can influence that compartment, they can control the firing of brain cells, which may in turn stop or prevent seizures, among other things. UNLV neuroscientist and lead author Dr. Rochelle Hines said controlling patterns of activity are very important to the brain's function. "If we can better understand how the brain patterns activity, we can understand how it might go wrong in a disorder like epilepsy, where brain activity becomes uncontrolled," Dr. Hines said. "And if we can understand what is important for this control, we can come up with better strategies for treating and improving the quality of life for people with epileptic seizures and maybe other types of disorders as well, such as anxiety or sleep disorders." The article is titled “Developmental Seizures and Mortality Result from Reducing GABAA Receptor α2-Subunit Interaction with Collybistin.” The six-year project moved one step closer to answering decades-old questions about brain wave control, by quantitatively defining how two key proteins -- the GABAA receptor 2 subunit and collybistin -- interact. When the interaction was disrupted in rodent models, EEG tests showed brain waves moving out of control, mimicking patterns seen in humans with epilepsy and anxiety.

Epigenetic Reprogramming of Human Hearts Found in Congestive Heart Failure--Changes Likely Affect Energy Metabolism

Congestive heart failure is a terminal disease that affects nearly 6 million Americans. Yet its management is limited to symptomatic treatments because the causal mechanisms of congestive heart failure -- including its most common form, ischemic cardiomyopathy -- are not known. Ischemic cardiomyopathy is the result of restricted blood flow in coronary arteries, as occurs during a heart attack, which starves the heart muscle of oxygen. Researchers at the University of Alabama at Birmingham (UAB) have now described an underlying mechanism that reprograms the hearts of patients with ischemic cardiomyopathy, a process that differs from patients with other forms of heart failure, collectively known as dilated (non-ischemic) cardiomyopathies. This points the way toward future personalized care for ischemic cardiomyopathy. The study used heart tissue samples collected at UAB during surgeries to implant small mechanical pumps alongside the hearts of patients with end-stage heart failure that assist in the pumping of blood. As a routine part of this procedure, a small piece of heart tissue is excised and ultimately discarded as medical waste. The current study acquired these samples from the left ventricles of five ischemic cardiomyopathy patients and six non-ischemic cardiomyopathy patients, all men between ages 49 and 70. The research team, led by Adam Wende, PhD, Assistant Professor in the UAB Department of Pathology, found that epigenetic changes in ischemic cardiomyopathy hearts likely reprogram the heart's metabolism and alter cellular remodeling in the heart. Epigenetics is a field that describes molecular modifications known to alter the activity of genes without changing their DNA sequence. One well-established epigenetic change is the addition or removal of methyl groups to the cytosine bases of DNA.

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