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September 2nd, 2017

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.

September 1st

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.

September 1st

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.

August 31st

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).

FDA Approval of Novartis’ Kymriah Brings First Gene Therapy to United States; CAR T-Cell Therapy Approved to Treat Certain Children and Young Adults with B-Cell Acute Lymphoblastic Leukemia (ALL)

On August 30, 2017, the U.S. Food and Drug Administration issued a historic action making the first gene therapy available in the United States, ushering in a new approach to the treatment of cancer and other serious and life-threatening diseases. The FDA approved Kymriah (tisagenlecleucel) for certain pediatric and young adult patients with a form of acute lymphoblastic leukemia (ALL). “We’re entering a new frontier in medical innovation with the ability to reprogram a patient’s own cells to attack a deadly cancer,” said FDA Commissioner Scott Gottlieb, MD. “New technologies such as gene and cell therapies hold out the potential to transform medicine and create an inflection point in our ability to treat and even cure many intractable illnesses. At the FDA, we’re committed to helping expedite the development and review of groundbreaking treatments that have the potential to be life-saving.” Kymriah, a cell-based gene therapy, is approved in the United States for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse. Kymriah is a genetically-modified autologous T-cell immunotherapy. Each dose of Kymriah is a customized treatment created using an individual patient’s own T-cells, a type of white blood cell known as a lymphocyte. The patient’s T-cells are collected and sent to a manufacturing center where they are genetically modified to include a new gene that contains a specific protein (a chimeric antigen receptor or CAR) that directs the T-cells to target and kill leukemia cells that have a specific antigen (CD19) on the surface. Once the cells are modified, they are infused back into the patient to kill the cancer cells.

August 30th

Rare Genetic Variant in CX3CR1 Gene for Microglia Receptor May Contribute to Risk of Schizophrenia and Autism

Huntington's disease, cystic fibrosis, and muscular dystrophy are each diseases that can be traced to a single mutation. Diagnosis in asymptomatic patient for these diseases is relatively easy – if you have the mutation, then you are at risk. Complex diseases, on the other hand, do not have a clear mutational footprint. A new multi-institutional study by Japanese researchers shows a potential rare gene mutation that could act as a predictor for two neurodevelopmental disorders, schizophrenia and autism. "Aberrant synapse formation is important in the pathogenesis of schizophrenia and autism," says Osaka University Professor Toshihide Yamashita, one of the authors of the study. "Microglia contribute to the structure and function of synapse connectivities." Microglia are the only cells in the brain that express the receptor CX3CR1. Mutations in this receptor are known to affect synapse connectivity and cause abnormal social behavior in mice. Such mutations have also been associated with neuroinflammatory diseases such as multiple sclerosis, but no study has shown a role in neurodevelopment disorders. Working with this hypothesis, the researchers conducted a statistical analysis of the CX3CR1 gene in over 7,000 schizophrenia and autism patients and healthy subjects, finding one mutant candidate, a single amino acid switch from alanine to threonine, as a candidate marker for prediction. "Rare variants alter gene function, but occur at low frequency in a population. They are of high interest for the study of complex diseases that have no clear mutational cause," said Dr. Yamashita, who added the alanine-to-threonine substitution was a rare variant. The structure of CX3CR1 includes a domain known as Helix 8, which is important for initiating a signaling cascade. Computer models showed that one amino acid change is enough to compromise the signaling.

University of Buffalo Pharmacy Professor Awarded $1.5 Million to Silence Exosome-Mediated Chatter Among Cancer Cells

With the support of a new $1.58 million grant from the National Institutes of Health (NIH), University at Buffalo researchers aim to develop a targeted treatment to prevent communication between cancer cells. By developing biomaterials that target exosomes – lipid vesicles secreted by many cells that act as a courier between them – the researchers will deliver anti-cancer drugs to alter the pathogenic messages being delivered. Exosomes, once thought of as the cell’s garbage disposal, have the ability to transport genetic information, allowing them to reprogram cells and alter their function. When secreted by a cancer cell into the circulatory system, exosomes may carry genetic material that enhances the spread of cancer to surrounding tissue and other parts of the body. “Reprograming these exosomes may disarm the dangerous package that they carry, potentially preventing tumor growth and spread to distant sites or organs,” says Juliane Nguyen (photo), PharmD, PhD, Principal Investigator and Assistant Professor in the Department of Pharmaceutical Sciences in the School of Pharmacy and Pharmaceutical Sciences. The announcement was made in a UB press release dated August 28, 2017 and authored by Marcene Robinson. “This will lay the foundation for the development of novel drug carriers for treating diseases in which exosomes are pathological. More specifically, these new carriers have the potential to prevent metastasis in cancer patients.” Currently, there are no therapeutic strategies capable of disrupting the pathogenic communication facilitated by exosomes. The four-year grant is provided through the NIH’s National Institute of Biomedical Imaging and Bioengineering.