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Archive - Jun 2017

Date

June 21st

Study Answers Why Ketamine Helps Depression, Suggests Target For Safer Therapy

University of Texas (UT) Southwestern Medical Center scientists have identified a key protein that helps trigger ketamine’s rapid antidepressant effects in the brain, a crucial step to developing alternative treatments to the controversial drug being dispensed in a growing number of clinics across the country. Ketamine is drawing intense interest in the psychiatric field after multiple studies have demonstrated it can quickly stabilize severely depressed patients. But ketamine – sometimes illicitly used for its psychedelic properties – could also impede memory and other brain functions, spurring scientists to identify new drugs that would safely replicate ketamine’s antidepressant response without the unwanted side effects. A new study from the Peter O’Donnell Jr. Brain Institute at UT Southwestern has jump-started this effort in earnest by answering a question vital to guiding future research: what proteins in the brain does ketamine target to achieve its effects? “Now that we have a target in place, we can study the pathway and develop drugs that safely induce the antidepressant effect,” said Dr. Lisa Monteggia (photo), Professor of Neuroscience at UT Southwestern’s O’Donnell Brain Institute. The study, published online on June 21, 2017 in Nature, shows that ketamine blocks a protein responsible for a range of normal brain functions. The blocking of the N-methyl-D-aspartate (NMDA) receptor creates the initial antidepressant reaction, and a metabolite of ketamine is responsible for extending the duration of the effect. The Nature article is titled “Effects of a Ketamine Metabolite on Synaptic NMDAR Function.” The blocking of the NMDA receptor also induces many of ketamine’s hallucinogenic responses. The drug – used for decades as an anesthetic – can distort the senses and impair coordination.

June 20th

Thousands of Genes Influence Most Complex Diseases, Stanford Researchers Report in Cell; “Compelling Paper” Presents “Plausible and Fascinating Model”

A core assumption in the study of complex-disease-causing genes has been that they are clustered in molecular pathways directly connected to the disease. But work by a group of researchers at the Stanford University School of Medicine suggests otherwise. The gene activity of cells is so broadly networked that virtually any gene can influence disease, the researchers found. As a result, most of the heritability of complex diseases is due not to a handful of core genes, but to tiny contributions from vast numbers of peripheral genes that function outside disease pathways. Any given trait, it seems, is not controlled by a small set of genes. Instead, nearly every gene in the genome influences everything about us. The effects may be tiny, but they add up. The work is described in a Perspective piece published in the June 15, 2017 issue of Cell. Jonathan Pritchard (photo), PhD, Professor of Genetics and of Biology, is the senior author. Graduate student Evan Boyle and postdoctoral scholar Yang Li, PhD, share lead authorship. The article is titled “An Expanded View of Complex Traits: From Polygenic to Omnigenic.” The researchers call their provocative new understanding of complex disease genes an "omnigenic model" to indicate that almost any gene can influence complex diseases and other complex traits. In any cell, there might be 50 to 100 core genes with direct effects on a given complex trait, as well as easily another 10,000 peripheral genes that are expressed in the same cell with indirect effects on that complex trait, said Dr. Pritchard, who is also a Howard Hughes Medical Institute investigator. Each of the peripheral genes has a small effect on the complex trait.

June 20th

Penn Study Details Impact of Antibiotics, Antiseptics on Skin Microbiomes; Results Show Antibiotic Effects Can Linger, Antiseptic Impact Not As Strong As Expected

The use of topical antibiotics can dramatically alter communities of bacteria that live on the skin, while the use of antiseptics has a much smaller, less durable impact, according to results of a new study. The study, conducted in mice in the laboratory of Elizabeth Grice, PhD, an Assistant Professor of Dermatology in the Perelman School of Medicine at the University of Pennsylvania, is the first to show the long-term effects of antimicrobial drugs on the skin microbiome. Researchers published their findings online on June 20, 2017 in Antimicrobial Agents and Chemotherapy. The article is titled “Topical Antimicrobial Treatments Can Elicit Shifts to Resident Skin Bacterial Communities and Reduce Colonization by Staphylococcus aureus Competitors.” The skin, much like the gut, is colonized by a diverse multitude of microorganisms which generally coexist as a stable ecosystem -- many of which are harmless or even beneficial to the host. However, when that ecosystem is disturbed or destabilized, colonization and/or infection by more dangerous microbes can occur. Antiseptics, such as ethanol or iodine, are commonly used to disinfect the skin prior to surgical procedures or following exposure to contaminated surfaces or objects. Topical antibiotics may be used to decolonize skin of specific types of bacteria or for rashes, wounds, or other common conditions. In the gut, research shows medication that alters microbial communities can lead to complications like Clostridium difficile, or C. diff -- which causes diarrhea and is the most common hospital-acquired infection. But when it comes to the skin, the impact of these medications on bacteria strains like Staphylococcus aureus, or S. aureus -- the most common cause of skin infections -- is still largely unstudied.

Research into Octopus Sight Leads to Screening Device for Age-Related Macular Degeneration in Humans; Work Recognized with BBSRC Innovator of the Year 2017 Award

In a June 20, 2017 press release, it was announced that Dr. Shelby Temple, from the University of Bristol’s School of Biological Sciences, has been named Innovator of the Year 2017 for his ground-breaking work into polarization and macular degeneration. The Biotechnology and Biological Sciences Research Council (BBSRC) award recognizes Dr Temple’s work in developing a device that can rapidly screen people at increased risk of age-related macular degeneration (AMD), the worldwide leading cause of incurable blindness in people over 55. The innovation arose from BBSRC-funded research carried out at the University of Bristol, which looked at the ability of octopuses, cuttlefish, and coral reef fish to see polarized light - an aspect of light that humans aren’t typically aware they can see. Dr. Temple invented a series of unique devices to display polarized light to animals, and in doing so, realized he could see a pattern as well. “What I was seeing was an effect known as Haidinger’s brushes, which happens within the eye when people perceive polarized light. The ability to see this phenomenon is linked to an aspect of eye health and can be an early indicator of disease. “It became clear that the tools I had developed for octopuses and cuttlefish could be the foundation for a novel ophthalmic device that could rapidly screen people for susceptibility to AMD,” said Dr. Temple. This award acknowledges the important impact this device could have in preventing sight loss worldwide. In the UK alone, AMD affects more than 600,000 people and is estimated to cost the healthcare system £1.6 billion (~$2 billion) annually.

June 19th

Scientists Demonstrate Adaptation of Animal Vision in Extreme Cold Environments; Rhodopsin Evolves to Increase Reaction Rates

Cell biologists at the University of Toronto (U of T) have discovered animals can adapt their ability to see even with extreme changes in temperature. The researchers looked deeply into the eyes of catfish living in cold-water streams at altitudes of up to nearly three kilometers (1.6 miles) in the Andes Mountains to find out how. Their findings were published online on June 19, 2017 in PNAS. The article is titled “Evolution of Non-Spectral Rhodopsin Function at High Altitudes.” Vision is initiated when several chemical proteins in the retina are activated. It is a key sensory system that enables organisms to adapt to their environment, as how killer whales did to improve their ability to see underwater in predominantly blue-tinted light. Examining the impact of cold temperatures on the habitats of Andean catfishes, the team of researchers led by U of T evolutionary biologist Belinda Chang, PhD, studied the role of a protein known as rhodopsin that enables vision in dim light. The scientists found that rhodopsin serves another function as well: it accelerates the speed at which vision occurs among the fish living at the highest - and therefore coldest - elevations. "When we think about adaptations to the visual system, light and color are usually the first variables that come to mind," said Dr. Chang, Professor in the Departments of Ecology & Evolutionary Biology and Cell & Systems Biology at U of T. "These results add a new dimension to the question of how complex biological processes can adapt to extreme environments." Vision is critical for these nocturnal animals' survival. In the high-altitude fishes, the rates at which the chemical reactions involving the protein occurred, changed. The kinetic rates sped up in order to compensate for decreases in ambient temperature.

New Three-In-One Blood Test (Liquid Biopsy) Opens Door to Precision Medicine for Prostate Cancer; Test Picks Out Men for Treatment, Detects Early Signs of Resistance, and Monitors Cancer's Evolution Over Time

Scientists have developed a three-in-one blood test that could transform treatment of advanced prostate cancer through use of precision drugs designed to target mutations in the BRCA genes. By testing cancer DNA in the bloodstream, researchers found they could pick out which men with advanced prostate cancer were likely to benefit from treatment with exciting new drugs called PARP inhibitors. The scientists also used the test to analyze DNA in the blood after treatment had started, so people who were not responding could be identified and switched to alternative therapy in as little as four to eight weeks. And finally, they used the test to monitor a patient's blood throughout treatment, quickly picking up signs that the cancer was evolving genetically and might be becoming resistant to the drugs. The researchers, at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, say their test is the first developed for a precision prostate cancer therapy targeted at specific genetic faults within tumors. It could, in the future, allow the PARP inhibitor olaparib to become a standard treatment for advanced prostate cancer, by targeting the drug at the men most likely to benefit, picking up early signs that it might not be working, and monitoring for the later development of resistance. The study was published online on June 19, 2017 in Cancer Discovery.

Scientists Identify Single-Gene (CARD11) Mutations That Lead to Atopic Dermatitis; Mutations Lead to Defective T-Cell Signaling; Study Points to Possible Therapeutic Effect of Supplemental Glutamine

Researchers have identified mutations in a gene called CARD11 that lead to atopic dermatitis, or eczema, an allergic skin disease. Scientists from the National Institute of Allergy and Infectious Diseases (NIAID) and other institutions discovered the mutations in four unrelated families with severe atopic dermatitis and studied the resulting cell-signaling defects that contribute to allergic disease. Their findings, reported online on June 19, 2017 in Nature Genetics, also suggest that some of these defects potentially could be corrected by supplementation with the amino acid glutamine. The article is titled “Germline Hypomorphic CARD11 Mutations in Severe Atopic Disease.” The scientists analyzed the genetic sequences of patients with severe atopic dermatitis and identified eight individuals from four families with mutations in the CARD11 gene, which provides instructions for production of a cell-signaling protein of the same name. While some people with these mutations had other health issues, such as infections, others did not, implying that mutations in CARD11 could cause atopic dermatitis without leading to other medical issues often found in severe immune system syndromes. The scientists next set out to understand how the newly discovered CARD11 mutations contribute to atopic dermatitis. Each of the four families had a distinct mutation that affected a different region of the CARD11 protein, but all the mutations had similar effects on T-cell signaling. With cell culture and other laboratory experiments, the researchers determined that the mutations led to defective activation of two cell-signaling pathways, one of which typically is activated in part by glutamine.

June 16th

Meditation & Yoga Can Reverse Gene Expression Changes That Cause Stress, New Study Suggests

Mind-body interventions (MBIs) such as meditation, yoga, and Tai Chi don't simply relax us; they can 'reverse' the molecular reactions in our DNA which cause ill-health and depression, according to a study by the Universities of Coventry and Radboud. The research, published online on June 16, 2017 in Frontiers in Immunology, reviews over a decade of studies analyzing how the behavior of our genes is affected by different MBIs including mindfulness and yoga. The open-access review article is titled “What Is the Molecular Signature of Mind–Body Interventions? A Systematic Review of Gene Expression Changes Induced by Meditation and Related Practices.” Experts from the universities conclude that, when examined together, the 18 studies -- featuring 846 participants over 11 years -- reveal a pattern in the molecular changes that happen to the body as a result of MBIs, and how those changes benefit our mental and physical health. The researchers focus on how gene expression is affected; in other words, the way that genes activate to produce proteins which influence the biological make-up of the body, the brain, and the immune system. When a person is exposed to a stressful event, their sympathetic nervous system (SNS) -- the system responsible for the “fight-or-flight” response -- is triggered, in turn increasing production of a molecule called nuclear factor kappa B (NF-kB) which regulates how our genes are expressed. NF-kB translates stress by activating genes to produce proteins called cytokines that cause inflammation at cellular level -- a reaction that is useful as a short-lived fight-or-flight reaction, but if persistent leads to a higher risk of cancer, accelerated aging, and psychiatric disorders like depression.

Japan Research Collaboration Reveals Father-Daughter Inheritance of Mosaic Skin Disease As Sperm Cell Mutation Causing Whole-Body Skin Disorder; Relevance to Genetic Counseling

Birthmarks can be caused by an overgrowth of cells in the top layer of skin, as in the case of epidermolytic nevus (EN), which is visible as patches of thickened skin over small areas of the body. Mutations in genes encoding the skin proteins keratin 1 or keratin 10 are responsible for EN, but these mutations only occur in some cell populations of the body so they are known as mosaic. Birthmarks are not usually inherited because the genes of sperm and cells are rarely mutated. However, when inheritance does occur, the children develop skin symptoms identical to their affected parent but covering their entire body. Research at Nagoya University in collaboration with Juntendo University Urayasu Hospital, both in Japan, has led to the identification of one such case of EN in a father that was transmitted to his daughter as a sperm cell (germline) mutation, resulting in the more widespread skin disorder epidermolytic ichthyosis (EI), which affects the whole body. The study was reported online on May 19, 2017 in the Journal of Investigative Dermatology. The article is titled “A Child with Epidermolytic Ichthyosis from a Parent with Epidermolytic Nevus: Risk Evaluation of Transmission from Mosaic to Germline." EI symptoms are obvious from birth as skin redness and blistering that completely covers the body. This worsens over time, with the skin becoming scaly and thickened. Nagoya University researchers clinically diagnosed EI in a 2-year-old Japanese girl, and confirmed her diagnosis with the detection of a mutation in the gene encoding keratin 10. The girl's father had small patches of thickened skin on his hand, abdomen, and groin, affecting just 0.5% of his body surface. "We took a skin sample from one of these areas and identified the identical keratin 10 mutation that we detected in his daughter," co-author Dr. Yasushi Suga says.

Why Those with Autism Often Avoid Direct Eye Contact; MGH Findings Suggest Slow Habituation to Eye Contact May Help Overcome Excitatory Overreaction and Cascading Effects That This Eye-Avoidance May Have on Development of the Social Brain

Individuals with autism spectrum disorder (ASD) often find it difficult to look others in the eyes. This avoidance has typically been interpreted as a sign of social and personal indifference, but reports from people with autism suggest otherwise. Many say that looking others in the eye is uncomfortable or stressful for them - some will even say that "it burns" - all of which points to a neurological cause. Now, a team of investigators based at the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital has shed light on the brain mechanisms involved in this behavior. They reported their findings in a Scientific Reports paper published online on June 9, 2017. The open-access article is titled “Look Me in the Eyes: Constraining Gaze in the Eye-Region Provokes Abnormally High Subcortical Activation in Autism.” "The findings demonstrate that, contrary to what has been thought, the apparent lack of interpersonal interest among people with autism is not due to a lack of concern," says Nouchine Hadjikhani, MD, PhD, Director of Neurolimbic Research in the Martinos Center and corresponding author of the new study. "Rather, our results show that this behavior is a way to decrease an unpleasant excessive arousal stemming from overactivation in a particular part of the brain." The key to this research lies in the brain's subcortical system, which is responsible for the natural orientation toward faces seen in newborns and is important later for emotion perception. The subcortical system can be specifically activated by eye contact, and previous work by Dr. Hadjikhani and colleagues revealed that, among those with autism, it was oversensitive to effects elicited by direct gaze and emotional expression.