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Genetic Variant Implicated in Bipolar Disorder and Schizophrenia Associated with Larger Amygdala Volume and Altered Prefrontal-Limbic Connectivity

A genetic variant associated with multiple psychiatric disorders drives changes in a brain network that may increase an individual's risk of developing bipolar disorder and schizophrenia, finds a study published in the Journal of Neuroscience. The article is titled “A Multi-Level Functional Study of a SNAP25 At-Risk Variant for Bipolar Disorder and Schizophrenia.” Dr. Stéphane Jamain (Inserm U955, Institut Mondor de Recherches Biomédicales, Psychiatrie Translationnelle, Créteil, France) and colleagues used genetic analysis and neuroimaging in samples of adults with schizophrenia, early-onset bipolar disorder, and healthy controls -- in addition to postmortem analysis of brain tissue from schizophrenia patients -- to demonstrate that a variant of a gene involved in neurotransmission is associated with both disorders. They found that this genetic variation changes the expression of the SNAP25 protein in the brain, which may impact information processing between brain regions involved in regulating emotions. Consistent with this idea, the variant was associated with larger amygdala volume and altered prefrontal-limbic connectivity. The authors replicated these findings in independent samples, minimizing the potential for false positives and increasing confidence in their results. The research confirms a shared genetic component of these disorders and points to a potentially new condition that may arise in patients with varying diagnoses in which this gene is implicated, such as attention-deficit/hyperactivity disorder. (Image credit: Stéphane Jamain [data from diffusion-imaging.com].)

[Press release] [Journal of Neuroscience abstract]

Study of Mutations Causing Rare Blood Disease Reveal Key Domain in Antithrombin Protein

When a person is injured, blood clotting is essential. However, once the danger has passed, it is equally essential to stop the clotting response in order to prevent thrombosis, or the obstruction of blood flow by clots. A protein called antithrombin is responsible for stopping coagulation, but about one in two thousand people have a hereditary deficiency in antithrombin that puts them at much higher risk of life-threatening blood clots. A group of researchers in Spain has analyzed the mutations in the antithrombin proteins of these patients and discovered that a section of the protein plays an unexpected role in its function. This insight into how antithrombin works could lead to treatments not only for patients with antithrombin deficiency, but also to better-designed drugs for other blood disorders. The research, which has been published online, will be published in the October 6, 2017 issue of the Journal of Biological Chemistry. The article is titled “Disease-Causing Mutations in the Serpin Antithrombin Reveal a Key Domain Critical for Inhibiting Protease Activities.” The Centro Regional de Hemodonacion and Hospital Universitario Morales Meseguer of the Universidad de Murcia in Spain is a reference center for the diagnosis of antithrombin deficiency. For over 15 years, researchers at the laboratory have been receiving samples from patients with diverse mutations that affect how their antithrombin works. Antithrombin normally inhibits thrombin by inserting a loop-shaped region, called the reactive center loop, into the active site of the thrombin protein, preventing thrombin from catalyzing clot formation by distorting the shape of the thrombin's active site. Many antithrombin mutations that cause clotting diseases directly or indirectly affect the reactive center loop.

Scientists Fine-Tune Thin Films of DNA with Eye Toward Biomedical Devices

Using DNA from salmon, researchers in South Korea hope to make better biomedical and other photonic devices based on organic thin films. Often used in cancer treatments and health monitoring, thin films have all the capabilities of silicon-based devices with the possible added advantage of being more compatible with living tissue. A thin film is just what it sounds like, a layer of material only nanometers or micrometers thick that can be used to channel light. If the film is a dielectric--that is, an insulator such as glass--it can be used without worrying that it might conduct electricity. "DNA is the most abundant organic material, and it is a transparent dielectric, comparable to silica," said Dr. Kyunghwan "Ken" Oh, of the Photonic Device Physics Laboratory at Yonsei University, Seoul, South Korea. In the November 1, 2017 issue of Optical Materials Express, from The Optical Society (OSA), Dr. Oh and his colleagues lay out their method for fabricating the thin films of DNA in a way that gives them fine control over the material's optical and thermal properties. The open-access article is titled “Cationic Lipid Binding Control in DNA Based Biopolymer and Its Impacts on Optical and Thermo-Optic Properties of Thin Solid Films." As the basis for the silica glass that makes up optical fibers, silicon has long been a dominant material in inorganic photonic devices because it's readily available and easy to work with from the materials perspective. Dr. Oh argues that DNA can play the same role in organic photonic devices because it can be found throughout the living world. It could, for instance, be used to make waveguides similar to silica fibers to carry light within the body. Organic devices should also be easy to manufacture, more flexible than silicon and environmentally friendly.

ASEMV 2017 Annual Meeting (Exosomes & Microvesicles) in Asilomar, California (October 8-12); Program Now Available

The American Society for Exosomes and Microvesicles (ASEMV) is inviting interested scientists to the ASEMV 2017 meeting, to be held October 8-12, 2017 at the Asilomar Conference Center in California. This center is located on the Monterrey peninsula, just south of San Francisco (www.visitasilomar.com). The meeting will cover the full breadth of the exosome field, from basic cell biology to clinical applications, and follow the ASEMV tradition of inclusion and diversity as participants learn about the latest advances in the field. ASEMV 2017 is a forum for learning the latest discoveries in the field of exosomes, microvesicles, and extracellular RNAs. Over the course of four days at the Asilomar Conference Center, ASEMV 2017 will offer presentations from leading scientists and young researchers. Topics will span the breadth of the extracellular vesicle/RNA field, including the basic sciences, disease research, translation efforts, and clinical applications. Talks will be presented in multiple sessions, beginning at 7 pm on Sunday, October 8, 2017, and concluding at 4 pm on Thursday, October 12, 2017. Poster sessions will run throughout the meeting, with ample time to get to know your colleagues in the field and explore the many opportunities in this rapidly expanding field. Please see the links below. The meeting program is now available at http://www.asemv.org/program.html.

Scientists Develop Broad-Spectrum Peptide Inhibitors of Influenza Virus

A team of researchers from The Scripps Research Institute (TSRI) and Janssen Research & Development (Janssen) has devised artificial peptide molecules that neutralize a broad range of influenza virus strains. Peptides are short chains of amino acids - like proteins but with smaller, simpler structures. These designed molecules have the potential to be developed into medicines that target influenza, which causes up to 500,000 deaths worldwide each year and costs Americans billions of dollars in sick days and lost productivity. The developed peptides block the infectivity of most circulating strains of group 1 influenza A viruses, including H5N1, an avian flu strain that has caused hundreds of human infections and deaths in Asia, and the H1N1 swine flu strain that caused a global pandemic in 2009-10. The scientists designed the peptides to mimic the virus-gripping regions of two recently discovered "super-antibodies" that are known to neutralize virtually all influenza A strains. Antibodies are large proteins that are expensive to produce and must be delivered by injection or infusion--whereas, "the peptides developed in the study have the potential to be medicines delivered via pill-based drugs in the future." "Making small molecules that do essentially what these larger, broadly neutralizing antibodies do is a really exciting and promising strategy against influenza, as our new results show," said co-senior investigator Dr. Ian Wilson, Hansen Professor of Structural Biology at TSRI. The report on the new peptides appeared as an online First Release paper in Science on September 27, 2017. The article is titled “"Potent Peptidic Fusion Inhibitors of Influenza Virus." The two anti-flu super-antibodies on which these peptides are based, called FI6v3 and CR9114, were discovered in 2011 and 2012. Since then, Dr.

Genes Possibly Underlying Animal Complexity Identified; They Code for Proteins That Interact with Each Other to Regulate the Dynamic Organization of Chromatin

Genes that determine animal complexity - or what makes humans so much more complex than a fruit fly or a sea urchin - have been identified for the first time. The secret mechanism for how a cell in one animal can be significantly more complex than a similar cell in another animal appears to be due to certain proteins and their ability to control “events” in a cell's nucleus. The research, by biochemist Dr. Colin Sharpe and colleagues at the University of Portsmouth in the UK, was published online on September 25, 2017 in PLoS One. The open-access article is titled “Relating Protein Functional Diversity to Cell Type Number Identifies Genes That Determine Dynamic Aspects of Chromatin Organisation As Potential Contributors to Organismal Complexity.” Dr. Sharpe said: "Most people agree that mammals, and humans in particular, are more complex than a worm or a fruit fly, without really knowing why. The question has been nagging at me and others for a long time. One common measure of complexity is the number of different cell types in an animal, but little is known about how complexity is achieved at the genetic level. The total number of genes in a genome is not a driver; this value varies only slightly in multicellular animals, so we looked for other factors." Dr. Sharpe and MRes student, Daniela Lopes Cardoso interrogated large amounts of data from the genomes of nine animals - from humans and macaque monkeys to nematode worms and the fruit fly, and calculated how diverse each was at the genetic level. The scientists found a small number of proteins that were better at interacting with other proteins and with chromatin, the packaged form of DNA in the cell nucleus. "These proteins appear to be excellent candidates for what lies behind enormously varied degrees of complexity in animals," Dr. Sharpe said.

Yale Freshman Named a 2017 Davidson Fellow for Project Focusing on Possible Role of Exosomes in Alzheimer’s Disease

The Davidson Institute of Talent Development has announced the 2017 Davidson Fellows. Among the honorees is 18-year-old Alexander Kirov of Evans, Georgia. Kirov won a $25,000 Davidson Fellows Scholarship for his project “Exosomes in Amyloid Aggregates Promote Neuronal Damage: A Mechanism of Alzheimer's Pathology.” He is one of only 20 students across the United States to receive this honor. “Being named a Davidson Fellow is the most rewarding culmination of a year’s work for which anyone could ask,” said Kirov. “Just finishing the project and having something significant to submit was gratifying, but progressing this far is really an incredible honor that I had not expected to achieve. I am humbled to be included in this close group of extraordinary young people, and I hope our paths will cross again in the near future.” Affecting more than 5.3 million people in the United States alone, Alzheimer’s disease damages and eventually kills brain cells, specifically neurons that transmit signals essential for memory. Miniscule nanovesicles called exosomes are released by most cells and have been observed to help form clusters of amyloid, a protein that plays a major role in Alzheimer’s disease. However, this process is still unknown. Kirov’s research found a specific molecule in exosomes, ceramide, that binds to amyloid, contributing to its aggregation. His research has shown for the first time that this combination of exosomes and amyloid is extremely toxic to brain cells, and these findings suggest a treatment for Alzheimer’s disease that includes using drugs that reduce ceramide levels, slowing the formation of deadly amyloid aggregates and the accompanying onset of the disease.

Confronted with Bacteria, Infected Cells Die Allowing Others to Live, Penn Study Finds

The immune system is constantly performing surveillance to detect foreign organisms that might do harm. But pathogens, for their part, have evolved a number of strategies to evade this detection, such as secreting proteins that hinder a host's ability to mount an immune response. In a new study, a team of researchers led by Dr. Igor E. Brodsky of the University of Pennsylvania, identified a "back-up alarm" system in host cells that responds to a pathogen's attempt to subvert the immune system. "In the context of an infection, the cells that are dying are talking to the other cells that aren't infected," said Dr. Brodsky, an Assistant Professor in the Department of Pathobiology in Penn's School of Veterinary Medicine and senior author on the study. "I don't think of it as altruistic, exactly, but it's a way for the cells that can't respond any longer to still alert their neighbors that a pathogen is present." The findings address the long-standing question of how a host can generate an immune response to something that is designed to shut off that very response. A potential future application of this new understanding may enable the cell-death pathway triggered by bacteria to be harnessed in order to target tumor cells and encourage their demise. The work was published online on August 30, 2017 in the Journal of Experimental Medicine. The article is titled “RIPK1-Dependent Apoptosis Bypasses Pathogen Blockade of Innate Signaling to Promote Immune Defense.” A major way that the immune system recognizes pathogens is by detecting patterns that are shared among microbes but are distinct from a host's own cells. Pathogens, however, don't make it easy for immune cells to destroy them. Some can inject proteins into host cells that interfere with this detection, allowing an infection to become established.

Novel Class of Lipid Mediators (Elovanoids) May Protect Brain from Stroke, Neurodegenerative Diseases

Research led by Nicolas Bazan (photo), MD, PhD, Boyd Professor and Director of the Neuroscience Center of Excellence at LSU Health New Orleans, has discovered a new class of molecules in the brain that synchronize cell-to-cell communication and neuroinflammation/immune activity in response to injury or diseases. Elovanoids (ELVs) are bioactive chemical messengers made from omega-3 very-long-chain polyunsaturated fatty acids (VLC-PUFAs, n-3). They are released on demand when cells are damaged or stressed. "Although we knew about messengers from omega-3 fatty acids such as neuroprotectin D1 (22 carbons) before, the novelty of the present discovery is that elovanoids are made of 32 to 34 carbon atoms in length," notes Dr. Bazan. "We expect that these structures will profoundly increase our understanding of cellular cross talk to sustain neuronal circuitry and particularly to restore cell equilibrium after pathological insults." Working in neuronal cell cultures from the cerebral cortex and from the hippocampus and a model of ischemic stroke, the researchers found that elovanoids not only protected neuronal cells and promoted their survival, but helped maintain their integrity and stability. The work was published online on September 27, 2017 in Science Advances. The open-access article is titled “Elovanoids Are a Novel Class of Homeostatic Lipid Mediators That Protect Neural Cell Integrity Upon Injury.” "Our findings represent a breakthrough in the understanding of how the complexity and resiliency of the brain are sustained when confronted with adversities such as stroke, Parkinson's, or Alzheimer's and neuroprotection signaling needs to be activated," says Dr. Bazan. "A key factor is how neurons communicate among themselves.

Extracellular Vesicle (EV) ARMMs Carry Receptors That Allow Signaling Without Direct Contact Between Cells; New Research May Have “Tremendous Potential for Therapeutics and Public Health”

A newly discovered cellular messaging mechanism could lead to a new way to deliver therapeutics to tissues affected by disease, according to a new study from the Harvard T.H. Chan School of Public Health. Researchers found that a type of extracellular vesicle (EV) -- a membrane-bounded sac secreted by cells that contains proteins and RNA molecules -- known as ARMMs (ARRDC1-mediated microvesicles) also carries receptors that allow signaling without direct contact between cells. This capability may make ARMMs uniquely suited to be engineered to send therapeutics directly to affected areas of the body. "EVs are like messages in a bottle between cells," said senior author Dr. Quan Lu (photo), Associate Professor of Environmental Genetics and Pathophysiology. "We think that within the next few years, we may be able to swap the endogenous molecules in ARMMs for therapeutic cargos -- such as antibodies -- and to engineer ARMMs to home in on a particular tissue." The new study was published online on September 27, 2017 in Nature Communications. The open-access article is titled “Plasma Membrane-Derived Extracellular Microvesicles Mediate Non-Canonical Intercellular NOTCH Signaling.” There are an estimated 37 trillion cells in the human body -- and 100 times that many EVs. The EVs circulate in the blood and other bodily fluids and are involved in processes such as coagulation and the immune response. They can also be hijacked to spread cancer or viruses like HIV and Ebola. EVs are generating a great deal of interest in the biotechnology field. Researchers believe that the molecules EVs can carry include the fingerprints of disease and harmful environmental exposures. Work is already underway on developing a "liquid biopsy" to test EVs in a drop of blood.

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