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Alterations in Blood-Based miRNA Detected in Veterans Affected with Combat-Related PTSD

Individuals affected with PTSD (post-traumatic stress disorder) demonstrate changes in microRNA (miRNA) molecules associated with gene regulation. A controlled study, involving military personnel on deployment to a combat zone in Afghanistan, provided evidence for the role of blood-based miRNAs as candidate biomarkers for symptoms of PTSD. This may offer an approach towards screening for symptoms of PTSD, and holds promise for understanding other trauma-related psychiatric disorders. Limitations of the study are that it was a small pilot study, and the findings need to be validated, extended, and confirmed. First results were to be presented at the 30th Annual ECNP Conference in Paris (September 2-5). ECNP is the European College of Neuropsychopharmacology. PTSD is a psychiatric disorder that can manifest following exposure to a traumatic event, such as combat, assault, or natural disaster. Among individuals exposed to traumatic events, only a minority of individuals will develop PTSD, while others will show resiliency. Little is known of the mechanisms behind these different responses. The last few years have seen much attention given to whether the modification and expression of genes - epigenetic modifications - might be involved. But there are several practical and ethical challenges in designing a research study on humans undergoing such experiences, meaning that designing relevant study approaches is difficult. The research group from the Netherlands, worked with just over 1,000 Dutch soldiers and the Dutch Ministry of Defense to study changes in biology in relation to changes in presentations of symptoms of PTSD in soldiers who were deployed to combat zone in Afghanistan. In a longitudinal study, the researchers collected blood samples before deployment, as well as 6 months after deployment.

CNPY2 Is Key Initiator of a Pathway of Unfolded Protein Response (UPR); May Be Potential Therapeutic Target in UPR-Related Diseases Such As Metabolic Disorders, Inflammation, and Cancer

The cell's response to unfolded or misfolded proteins could be a cause, rather than a consequence, of metabolic disorders, report researchers at the Medical University of South Carolina (MUSC) in an article published online on September 4, 2017 in Nature Structural & Molecular Biology. The researchers identified a little-known molecule as the trigger for this response. The article is titled “CNPY2 Is a Key Initiator of the PERK–CHOP Pathway of the Unfolded Protein Response.” There are links between protein-folding problems at the cellular level and a range of metabolic disorders, though it is unclear if those problems are causes or manifestations of such disorders. This study provides evidence that problems with protein folding contribute to certain metabolic disorders, according to Zihai Li, MD, PhD, Chair of the Department of Microbiology and Immunology at the MUSC Hollings Cancer Center and principal investigator on the project. Feng Hong, MD, PhD, in the Department of Microbiology and Immunology, is lead author on the paper. "The unfolded protein response in the cell plays important roles in aging and in many diseases, such as cancer, diabetes, and neurodegenerative disease," says Dr. Li. "Our study has uncovered a novel mechanism that triggers this response." When improperly folded molecules are encountered in cells, the unfolded protein response (UPR) is activated within the endoplasmic reticulum (ER). The ER is in charge of molecular quality control, making sure proteins, lipids, and other molecules are folded properly before the cell attempts to use them for metabolic processes. Here, a master protein called grp78 is in contact with three main signaling hubs that make up the control center of the UPR.

New Study in Mice Reveals Biological Origins of a Core Symptom (Memory Deficits) of Schizophrenia

A team of Columbia scientists has found that disruptions to the brain's center for spatial navigation -- its internal GPS -- result in some of the severe memory deficits seen in schizophrenia. The new study in mouse models of the disorder marks the first time that schizophrenia's effects have been observed in the behavior of living animals -- and at the level of individual brain cells -- with such high-resolution, precision and clarity. The findings offer a promising entry point for attacking a near-universal and debilitating symptom of schizophrenia, memory deficits, which has thus far withstood all forms of treatment. The results of this study were published online on September 4, 2017 in Nature Neuroscience. The article is titled “Impaired Hippocampal Place Cell Dynamics in a Mouse Model of 22q11.2 Deletion.” "An almost intractably complex disorder, schizophrenia is nearly impossible to fully treat -- in large part because it acts as two disorders in one," said Joseph Gogos, MD, PhD, a principal investigator at Columbia's Mortimer B. Zuckerman Mind Brain Behavior Institute and the paper's co-senior author. "On one hand, you have paranoia, hallucinations, and delusions; while on the other, you have severe memory deficits. Antipsychotic drugs, which treat the first class of symptoms, are entirely ineffective when dealing with the second. The reasons for this are simple: we do not yet understand what happens in the brains of schizophrenia patients.” Cracking schizophrenia's code must therefore start with deciphering its biological origins, says Dr. Gogos, who is also Professor of Physiology, Cellular Biophysics and Neuroscience at Columbia University Medical Center (CUMC). This has led to a recent focus on the memory impairments that are so common among schizophrenia patients.

Scientists Engineer Mutant Ants That Shed Light on Evolution of Social Behavior

Ants run a tight ship. They organize themselves into groups with very specific tasks: foraging for food, defending against predators, building tunnels, etc. An enormous amount of coordination and communication is required to accomplish this. To explore the evolutionary roots of the remarkable system, researchers at The Rockefeller University have created the first genetically altered ants, modifying a gene essential for sensing the pheromones that ants use to communicate. The result, severe deficiencies in the ants’ social behaviors and their ability to survive within a colony, both sheds light on a key facet of social evolution and demonstrates the feasibility and utility of genome editing in ants. “It was well known that ant language is produced through pheromones, but now we understand a lot more about how pheromones are perceived,” says Dr. Daniel Kronauer, Head of the Laboratory of Social Evolution and Behavior. “The way ants interact is fundamentally different from how solitary organisms interact, and with these findings we know a bit more about the genetic evolution that enabled ants to create structured societies.” The most important class of pheromones in ant communication is that of hydrocarbons, which can communicate species, colony, and caste identity, as well as reproductive status. These pheromone signals are detected by porous sensory hairs on the ants’ antennae that contain what are called odorant receptors—proteins that recognize specific chemicals and pass the signal up to the brain. Work in the Kronauer lab, led by graduate student Sean McKenzie and published in PNAS in late 2016, has shown that a group of odorant receptor genes, known as 9-exon-alpha ORs, are responsible for sensing hydrocarbons in the clonal raider ant species Ooceraea biroi.

Study Establishes Fish As Experimental Platform for Studying How Ancient Genetic Information Controls Development and Dysfunction of Human Intestine

Scientists have discovered a network of genes and genetic regulatory elements in the lining of the intestines that has stayed remarkably the same from fishes to humans. Many of these genes are linked to human illnesses, such as inflammatory bowel diseases, diabetes, and obesity. The findings, which were published online on August 29, 2017 in PLOS Biology, establish the fish as an experimental platform for studying how this ancient genetic information -- distilled over 420 million years of evolution -- controls the development and dysfunction of the intestine. "Our research has uncovered aspects of intestinal biology that have been well-conserved during vertebrate evolution, suggesting they are of central importance to intestinal health," said John F. Rawls, PhD, senior author of the study and Associate Professor of Molecular Genetics and Microbiology at Duke University School of Medicine. "By doing so, we have built a foundation for mechanistic studies of intestinal biology in non-human model systems like fish and mice that would be impossible to perform in humans alone." The open-access PLOS Biology article is titled “"Genomic Dissection of Conserved Transcriptional Regulation in Intestinal Epithelial Cells." The intestine serves a variety of important functions that are common to all vertebrates. It takes up nutrients, stimulates the immune system, processes toxins and drugs, and provides a critical barrier to microorganisms. Defects in the intestinal epithelial cells lining the intestine have been implicated in a growing number of ailments, including inflammatory bowel diseases, colorectal cancer, food allergy, diabetes, obesity, malnutrition, and infectious diarrheas.

Asthma Drug Targeting Beta2-Adrenoreceptor May Be Effective in Reducing Parkinson’s Disease by Turning Down Production of Alpha-Synclein

Lewy bodies - abnormal clumps of alpha-synuclein protein that accumulate in the brain - are a hallmark of Parkinson's disease (PD). Traditional drug development approaches for PD have focused on clearing alpha-synuclein from the brain or on preventing its downstream effects. But researchers from Brigham and Women's Hospital (BWH) in Boston want to prevent alpha-synuclein from accumulating in the first place. To do so, the team searched for drugs that turn down alpha-synuclein production. They then tested the drugs in mice and stem cells and studied the health records of millions of people living in Norway. The results of their efforts, which point to a new drug development path for PD, were published in the September 1, 2017 issue of Science. The article is titled “Beta2-Adrenoreceptor Is a Regulator of the alpha-Synuclein Gene Driving Risk of Parkinson's.” "Our study suggests a potential new pathway to target PD," said corresponding author Clemens Scherzer, MD, a neurologist and principal investigator at the Ann Romney Center for Neurologic Diseases at BWH and Harvard Medical School. The research team screened more 1,100 drugs already approved for treating diseases other than PD, looking for compounds that could be repurposed for lowering alpha-synuclein production in neuronal cells. They narrowed in on promising candidates, members of a class of drugs known as beta2-adrenergic agonists. The team studied the effects of this class of drugs in mice, finding that it could significantly reduce alpha-synuclein levels. Working with collaborators from the University of Bergen in Norway, the team combed through data from the health records of more than 4 million Norwegians, pulling out information on patients who had been taking salbutamol, a beta2-adrenergic agonist commonly used to treat of asthma.

Nischarin Protein Plays Key Role in Energy Metabolism; Inhibition May Prove Useful in Treatment or Prevention of Obesity & Diabetes, According to JBC Article

Research led by Suresh Alahari, PhD, Fred Brazda Professor of Biochemistry and Molecular Biology at LSU Health New Orleans School of Medicine, has demonstrated the potential of a particular protein to treat or prevent metabolic diseases including obesity and diabetes. The findings were published online on August 24, 2017 in the Journal of Biological Chemistry. The open-access article is titled “Nischarin Inhibition Alters Energy Metabolism by Activating AMP-Activated Protein Kinase.” Nischarin is a novel protein discovered by the Alahari lab. The research team demonstrated that it functions as a molecular scaffold that holds and interacts with several protein partners in a number of biological processes. The lab's earlier research found that Nischarin acts as a tumor suppressor that may inhibit the metastasis of breast and other cancers. The current research project, conducted in a knockout mouse model, found that Nischarin interacts with and controls the activity of a gene called AMPK. AMPK regulates metabolic stability. The research team discovered that Nischarin binds to AMPK and inhibits its activity. In Nischarin-deleted mice, the researchers found decreased activation of genes that make glucose. The study showed that Nischarin also interacts with a gene regulating glucose uptake. Blood glucose levels were lower in the knockout mice, with improved glucose and insulin tolerance. As well, the researchers showed that Nischarin mutation inhibits several genes involved in fat metabolism and the accumulation of fat in the liver. The knockout mice displayed increased energy expenditure despite their smaller growth and appetite suppression leading to decreased food intake and weight reduction.

Pathogenic Tick-Borne Virus Uses Host Neurons’ Transportation System to Move Its RNA

Flaviviruses are a significant threat to public health worldwide, and some infected patients develop severe, potentially fatal, neurological diseases. Tick-borne encephalitis virus (TBEV), a member of the genus Flavivirus, causes encephalic diseases resulting in photophobia, irritability, and sleep disorders. However, little is known about the pathogenic mechanisms and no effective treatment is available at present. A research team at Hokkaido University in Japan has previously showed that, in mouse neurons, genomic RNAs of TBEV are transported from the cell body to dendrites, the neuron's wire-like protrusions. Viral RNAs then reproduce viruses locally in dendrites disturbing normal neuronal activities. In the new study published online on August 28, 2017 in PNAS, the team looked into the transportation mechanism of viral RNAs in neurons, and discovered these RNAs make use of the cell's transportation system, which is normally used to move neuronal RNAs in dendrites. A specific non-coding sequence near the terminus of viral RNAs was found pivotal in interacting with the transportation system. When the sequence was mutated, the infected mouse showed reduced neurological symptoms. In the researchers’ biochemical experiments, viral RNAs could bind to a protein that forms a neuronal granule, which is part of the neuron's transportation system. Furthermore, their data shows that normal transportation of neuronal RNAs becomes affected by viral RNAs as a result of competition to use the transportation network. Associate Professor Kentaro Yoshii, who led the research team, commented "It is unprecedented for a neuropathogenic virus to hijack the neuronal granule system to transport their genomic RNA, which results in severe neurological diseases.

Gut Bacteria That “Talk” to Human Cells May Lead to New Treatments

We have a symbiotic relationship with the trillions of bacteria that live in our bodies—they help us and we help them. It turns out that they may even speak the same language as we do. And new research from The Rockefeller University and the Icahn School of Medicine at Mount Sinai suggests these newly discovered commonalities may open the door to “engineered” gut flora that can have therapeutically beneficial effects on disease. “We call it mimicry,” says Dr. Sean Brady, Director of Rockefeller University’s Laboratory of Genetically Encoded Small Molecules, where the research was conducted. The breakthrough is described in a paper published online on August 30, 2017 in Nature. The article is titled “Commensal bacteria Make GPCR Ligands That Mimic Human Signalling Molecules.” In a double-barreled discovery, Dr. Brady and co-investigator Dr. Louis Cohen found that gut bacteria and human cells, though different in many ways, speak what is basically the same chemical language, based on molecules called ligands. Building on that, they developed a method to genetically engineer the bacteria to produce molecules that have the potential to treat certain disorders by altering human metabolism. In a test of their system on mice, the introduction of modified gut bacteria led to reduced blood glucose levels and other metabolic changes in the animals. The method involves the lock-and-key relationship of ligands, which bind to receptors on the membranes of human cells to produce specific biological effects. In this case, the bacteria-derived molecules are mimicking human ligands that bind to a class of receptors known as GPCRs, for G-protein-coupled receptors. Many of the GPCRs are implicated in metabolic diseases, Dr. Brady says, and are the most common targets of drug therapy.

Variants in Fetal Genome Associated with Risk of Preeclampsia in Mother

For the first time, a relationship has been found between fetal genes and the risk of preeclampsia in the mother. Norwegian researchers, including a team from the Norwegian University of Science and Technology (NTNU), figure prominently in the international group that presented the discovery in Nature Genetics, first published online earlier this summer, on June 19, 2017. The article is titled “Variants in the Fetal Genome Near FLT1 Are Associated with Risk Of Preeclampsia.” Preeclampsia affects approximately 3 per cent of births in Norway; worldwide, that number is estimated to be about 5 per cent. In the vast majority of cases, the mother has mild symptoms, typically high blood pressure. Nevertheless, preeclampsia is one of the leading causes of death in both mothers and babies around the time of birth, and sometimes the only way to treat it is to deliver the baby, even prematurely. "For the first time ever, we have discovered a fetal gene that increases the risk of preeclampsia," says Dr. Ann-Charlotte Iversen at the Department of Clinical and Molecular Medicine at NTNU. She says there has not been much research on the role of fetal genes in triggering the illness. Preeclampsia usually begins with a problem in the placenta, which is mainly composed of fetal cells. For that reason, it makes sense that fetal cells might have a hand in causing the illness, Dr. Iversen said, even though it is the mother's symptoms during the last part of the pregnancy that lead to the diagnosis. Dr. Iversen is head of a research group at NTNU's Centre of Molecular Inflammation Research (CEMIR).

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