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Intrinsically Disordered Proteins (IDPs) Can Allosterically Control Function Using Principle of “Energetic Frustration” to Simultaneously Tune Transcriptional Activation and Repression;

Proteins carry out almost all processes in living organisms, including moving other molecules from one place to another, replicating DNA, conveying genetic information from genes to cells, controlling immune response, driving metabolism, and building muscle. Not all protein molecules are created equal, however, and some are better understood than others. Now, a team of scientists led by a Johns Hopkins University biologist has cracked a key part of the mystery surrounding a particular group of proteins that emerged as a distinct type less than 30 years ago. The finding, reported on October 12, 2017 in the online journal eLife, could eventually lead to treatments for diseases that range from cancer to neurological disorders. The title of the article is “Genetically Tunable Frustration Controls Allostery in an Intrinsically Disordered Transcription Factor.” Dr. Vincent Hilser, Professor and Chair of the Johns Hopkins Department of Biology, said it's not possible to say when this new research will translate into improved treatments, "but what is clear is understanding how these things work is a critical step toward that." These so-called "intrinsically disordered proteins" (IDPs) do not look like the more familiar type, but they make up about 40 percent of all proteins. Perhaps more importantly, they constitute the majority of proteins involved in the process called "transcription." That's how the instructions in the DNA genetic code are converted to messenger RNA that codes for the production of proteins in the ribosomes. It is not clear exactly how errors in transcription affect human health, but it is known that these errors are involved in most cancers, Dr. Hilser said.

New Species of Butterfly Found Flying Over Northern Slopes of Caucasus Mountains; Identification of Unusual Butterfly with 46 Chromosomes Culminates 20 Years of Study

What looked like a population of a common butterfly species turned out to be an entirely new species, and, moreover - one with a very peculiar genome organization. Discovered by Dr. Vladimir Lukhtanov, entomologist and evolutionary biologist at the Zoological Institute in St. Petersburg, Russia, and Dr. Alexander Dantchenko, entomologist and chemist at the Moscow State University, the discovery was named South-Russian blue (Polyommatus australorossicus). It was found flying over the northern slopes of the Caucasus mountains in southern Russia. The study was published online on November 24, 2017 in the open-access journal Comparative Cytogenetics. The article is titled “A New Butterfly Species from South Russia Revealed Through Chromosomal and Molecular Analysis of the Polyommatus (Agrodiaetus) damonides Complex (Lepidoptera, Lycaenidae). (Editor's note: The image here shows a common blue butterfly from norther Norway, not the newly identified species.) "This publication is the long-awaited completion of a twenty-year history," says Dr. Lukhtanov. In the mid-nineties, Dr. Lukhtanov, together with his students and collaborators, started an exhaustive study of Russian butterflies using an array of modern and traditional research techniques. In 1997, Dr. Dantchenko, who was mostly focused on butterfly ecology, sampled a few blue butterfly specimens from northern slopes of the Caucasus mountains. These blues looked typical at first glance and were identified as Azerbaijani blue (Polyommatus aserbeidschanus). However, when the scientists looked at the cells of these butterflies under a microscope, it became clear that they had 46 chromosomes - a very unusual number for this group of the blue butterflies and exactly the same count as in humans.

Medical Professionals Hold Free Clinic for the “Hardest-Working Feet in Madison, Wisconsin”

On a snowy Saturday morning just before Thanksgiving, almost 40 of Madison, Wisconsin’s homeless and disadvantaged were welcomed to a free bimonthly foot-care clinic hosted by the First United Methodist Church and organized by the Madison Street Medicine Initiative, which is operated under the Madison Area Care for the Homeless OneHealth (MACH OneHealth) organization (http://machonehealth.org/). This clinic has been underway for almost two years and has become increasingly successful, popular, and efficient with each successive session. At the November 18 event (see ten photos at end), running from 9 am to 12 noon, the number of participating health professionals (MDs, nurses, wound specialists, and volunteer helpers) was approximately the same as the number of homeless (38) seeking help with their feet. As Meg Collins, an RN and certified wound care nurse from Madison and Dane County Public Health said, this clinic is a great opportunity to care for the “hardest-working feet in Madison.” One of the medical professionals who is key to this wonderful effort is Ann Catlett, MD, who is a trained internist specializing in palliative care at University of Wisconsin (UW) Health. Dr. Catlett is also Medical Director of the Madison Street Medicine Initiative. This recently founded Initiative is funded by a two-year $100,000 UW Ira and Ineva Baldwin Grant intended to leverage University expertise to do good for the greater Wisconsin community. Dr. Catlett said that before the foot-care clinic was started, MACH OneHealth had heard from those experiencing homelessness, as well as from outreach workers, that foot care was a major health need for the homeless. After the clinic had been launched, the Madison Street Medicine Initiative undertook a survey that confirmed this need. Dr.

Schizophrenia Drug Development May Be Aided by Use of Image-Based Biomarkers for Glutamate-Targeted Drug Development

Researchers at Columbia University Medical Center (CUMC) and the New York State Psychiatric Institute (NYSPI) have identified biomarkers that can aid in the development of better treatments for schizophrenia. The findings were published online on November 22, 2017 in JAMA Psychiatry. The open-access article is titled "Utility of Image-Based Biomarkers for Glutamate-Targeted Drug Development in Psychotic Disorders: A Randomized Clinical Trial." In the past two decades, the pharmaceutical industry has spent over $2.5 billion to develop new schizophrenia drugs. But while many appear to be effective in animal models, most fail when tested in late-stage human clinical trials. "While a great deal of money has been invested in developing schizophrenia drugs, a similar investment hasn't been made to develop biomarkers that could improve the reliability and consistency of test results," said Daniel Javitt, MD, PhD, Professor of Psychiatry and Director of the Division of Experimental Therapeutics at CUMC, Director of Schizophrenia Research at the Nathan Kline Institute for Psychiatric Research, and Co-Principal Investigator of the study. The National Institute of Mental Health's FAST Initiative, which was established to validate the use of biomarkers to facilitate drug development, aligns with the 21st Century Cures Act passed last year by Congress. The legislation authorized the U.S. Food and Drug Administration to approve treatments based on biomarker data alone, and created a formal Biomarker Qualification Program. In this context, FAST-Psychosis researchers identified biomarkers using MRI applications to support the development of drugs that target the glutamate system. Previous studies have shown that drugs such as phencyclidine (PCP or "angel dust") and ketamine, which block glutamate receptors, cause schizophrenia-like symptoms in healthy volunteers.

Exosome Diagnostics and MD Anderson Cancer Center Demonstrate Superior Liquid Biopsy Performance of Exosome Diagnostics’ ExoLution® Plus Platform That Simultaneously Analyzes Exosomal Nucleic Acids and Cell-Free DNA

In a November 13, 2017 press release, it was announced that Exosome Diagnostics, Inc., and MD Anderson Cancer Center had a unique study published online on October 19, 2017 in Clinical Cancer Research, a peer-reviewed publication of the American Association of Clinical Cancer Research. The analysis directly compared Exosome Diagnostics’ ExoLution® Plus platform with two different platforms, BEAMing and ddPCR, that analyze cell-free (cf) DNA alone. The article is titled “Liquid Biopsies Using Plasma Exosomal Nucleic Acids and Plasma Cell-Free DNA compared with Clinical Outcomes of Patients with Advanced Cancers.” Teams at MD Anderson Cancer Center and Exosome Diagnostics showed that the ExoLution Plus platform, which simultaneously analyses exosome nucleic acids (exoNA) and cfDNA correlated better to clinical outcome than cfDNA analysis alone in a cohort of 43 patients with progressive advanced cancer. The teams studied overall survival among the patients and linked low amounts of mutated exoNA with longer survival times and high amounts of mutated exoNA with shorter survival times. "Our study reports two novel observations. First, our data suggest that next-generation sequencing of plasma-derived exosomal nucleic acids from patients with advanced cancers has high sensitivity compared to molecular testing of plasma cell-free DNA or archival tumor samples. Second, we demonstrated that the amount of mutated exosomal nucleic acids is an independent prognostic factor for survival" said Dr. Filip Janku, MD Anderson Cancer Center senior author on the study.

Antibodies As a Potential Fix to HIV/AIDS—Interview with Adrian McDermott, Acting Chief of the Immunology Core in the NIH’s Vaccine Research Center

by Sara Malmanger, University of Wisconsin-Madison, Science Writing Intern with BioQuick News

HIV researchers have found that giving the human body’s immune system a boost of specific antibodies may be a potential fix to HIV/AIDS as we seek a cure or vaccine. Our world could be free of this deadly virus sooner than we ever thought possible. Researchers are hopeful that they have found a way to turn our own immune systems against the disease. In an interview, Adrian McDermott (photo), PhD, from the NIH’s Vaccine Research Center, said, “We are hoping to use HIV-specific antibodies that target vulnerable parts of the HIV envelope to prevent and treat HIV.” The Vaccine Research Center is within the NIH’s National Institute of Allergy and Infectious Diseases, and Dr. McDermott is presently Acting Chief, Immunology Core, within the Vaccine Research Center. He is a former Director of Immunobiology and Vaccine Design at the International AIDS Vaccine Initiative (IAVI) in New York. The antibody studies are important because more than 35 million people have HIV worldwide, and around one million people have HIV in the United States. Despite the common feeling that AIDS (acquired immunodeficiency syndrome) is a disease of the past, it is still harming and destroying many lives. HIV (human immunodeficiency virus) essentially erodes and ultimately destroys the immune system over time. HIV, without appropriate health care and treatment, can develop into AIDS. Once a person reaches the AIDS stage of the infection, the immune system can’t fight off pathogens that cause common illnesses, where a healthy immune system could knock these bugs out with ease.

Autoimmune Disease Discovery Could Spark New Treatments; Scientists Synthesize Small Molecule Inhibitor of Toll-Like Receptor 8 (TLR8)

University of Colorado (UC) Boulder researchers have discovered a potent, drug-like compound that could someday revolutionize treatment of rheumatoid arthritis and other autoimmune diseases by inhibiting a protein instrumental in prompting the body to start attacking its own tissue. "We have discovered a key to lock this protein in a resting state," said Dr. Hang Hubert Yin, a biochemistry professor at the BioFrontiers Institute and lead author of a paper, published on November 20, 2017 in Nature Chemical Biology, describing the discovery. "This could be paradigm shifting." The article is titled “Small-Molecule Inhibition of TLR8 Through Stabilization of Its Resting State.” More than 23.5 million Americans suffer from autoimmune diseases like rheumatoid arthritis, scleroderma, and lupus, in which an excessive immune response leads to pain, inflammation, skin disorders, and other chronic health problems. Three of the top five selling drugs in the United States aim to ease autoimmune disease symptoms. But no cure exists, and treatments are expensive and come with side effects. "Given the prevalence of these diseases, there is a big push for alternatives," Dr. Yin said. For years, scientists have suspected that a protein called Toll-like receptor 8 (TLR8) plays a key role in the innate immune response. When TLR8 senses the presence of a virus or bacterium, it goes through a series of steps to transform from its passive to active state, triggering a cascade of inflammatory signals to fight off the foreign invader. But, as Dr. Yin explained, "it can be a double-edged sword" leading to disease when that response is excessive.

Dog Ownership Linked to Lower Mortality, Especially in Persons Living Alone

A team of Swedish scientists have used national registries of more than 3.4 million Swedes aged 40 to 80 to study the association between dog ownership and cardiovascular health. Their study shows that dog owners had a lower risk of death due to cardiovascular disease or to other causes during the 12-year follow-up. A total of more than 3.4 million individuals without any prior cardiovascular disease in 2001 were included in the researchers' study linking together seven different national data sources, including two dog ownership registers. The results were published for the first time on November 17, 2017 in Scientific Reports. The goal was to determine whether dog owners had a different risk of cardiovascular disease and death than non-dog owners. The open-access Scientific Reports article is titled “Dog Ownership and the Risk of Cardiovascular Disease and Death – A Nationwide Cohort Study.” "A very interesting finding in our study was that dog ownership was especially prominent as a protective factor in persons living alone, which is a group reported previously to be at higher risk of cardiovascular disease and death than those living in a multi-person household. Perhaps a dog may stand in as an important family member in the single households. The results showed that single dog owners had a 33% reduction in risk of death and 11% reduction in risk of myocardial infarction during follow-up compared to single non-owners. Another interesting finding was that owners of dogs from breed groups originally bred for hunting were most protected," says Mwenya Mubanga, lead junior author of the study and a PhD student at the Department of Medical Sciences and the Science for Life Laboratory, Uppsala University. In Sweden, every person carries a unique personal identity number.

Ancient RNA-Detecting Enzyme (TGIRT) Could Boost Power of Liquid Biopsies to Detect and Profile Cancers

Scientists are developing a set of medical tests called liquid biopsies that can rapidly detect the presence of cancers, infectious diseases, and other conditions from only a small blood sample. Researchers at The University of Texas at Austin are developing a new tool for liquid biopsy that could soon provide doctors with a more complete picture of an individual's disease, improving their chances of finding the best treatment, while also sparing patients the pain, inconvenience, and long wait times associated with surgical biopsies. Dr. Alan Lambowitz, a Professor in the Institute for Cellular and Molecular Biology and the Department of Molecular Biosciences, and his team are studying an ancient enzyme in bacteria that can be used to detect bits of genetic material shed by cancer or other diseased cells into a patient's bloodstream. Many current liquid biopsies can detect DNA in blood; others can detect RNA, although they tend to miss many key RNA biomarkers and misinterpret others. But this ancient enzyme, described in a paper published online on November 16, 2017 in Molecular Cell, detects the full range of RNAs with much higher accuracy, which is helpful for understanding both the general profile of a disease such as cancer and specific information about its activity in a particular patient. This improved method could provide a key tool for doctors pursuing the dream of precision medicine, or treatments tailored to individuals based on their genetics and life histories, as well as the unique aspects of their diseases. In this new study, postdoctoral researcher Dr. Jennifer Stamos uncovered for the first time the molecular structure of this RNA-detecting enzyme in action, offering clues about how it works and how it can be improved for use in medical tests.

How Bacteria in the Gut May Influence Neurodegenerative Disorders

Humans have roughly as many bacterial cells in their bodies as human cells, and most of those bacteria live in the gut. New research released on November 13, 2017 reveals links between the gut microbiome -- the population of microorganisms living in the gastrointestinal tract -- and brain diseases such as Parkinson's and Alzheimer's, including potential new ways to track and treat these diseases. The studies were presented at Neuroscience 2017, the annual meeting of the Society for Neuroscience and the world's largest source of emerging news about brain science and health. Neuroscience 2017 took place in Washington, DC, November 11-15. Almost 100 trillion microbes -- some beneficial and some harmful -- live in the human gastrointestinal tract at any time, helping to regulate immune function and inflammation, two factors hypothesized to play a role in neurodegenerative diseases like Parkinson's and Alzheimer's. As brain-focused cures for such diseases remain elusive, scientists are looking to the microbiome for new insight and novel strategies. New findings presented at the meeting include the following: Metabolites derived from the microbiome block protein misfolding in test tubes and prevent neurodegeneration in a fly model of a disease related to Parkinson's, hinting that gut-derived metabolites may hold therapeutic promise (Lap Ho, abstract 573.23). A rat model of Parkinson's disease displays increased levels of an inflammatory protein in the colon, identifying a possible new biomarker for the disease (Doris J. M. Doudet, abstract 133.13). Nonhuman primates that received stomach injections of a protein associated with Parkinson's disease show signs of the disease in their brains, revealing that pathology can spread from the gut to the brain (Erwan Bezard, abstract 131.02).

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