Syndicate content

Experiment of Nature: Regeneration of Beta Cells in Human Insulinomas Offers Clues to Molecular Pathways in Beta Cell Regeneration

Rare benign tumors known as insulinomas contain a complicated wiring diagram for regeneration of insulin-producing human beta cells, which may hold the key to diabetes drug development, researchers at the Icahn School of Medicine at Mount Sinai in New York report. The study, titled "Insights into Beta Cell Regeneration for Diabetes via Integration of Molecular Landscapes in Human Insulinomas," was published as an open-access article on October 3, 2017 in Nature Communications. With the help of an international group of investigators, the Mount Sinai team collected 38 human insulinomas -- rare pancreatic tumors that secrete too much insulin -- and analyzed their genomics and expression patterns. "For the first time, we have a genomic recipe -- an actual wiring diagram in molecular terms that demonstrates how beta cells replicate," said Andrew Stewart, MD, Director of the Diabetes, Obesity, and Metabolism Institute at the Icahn School of Medicine and lead author of the study. Approximately 30 million people living in the United States have diabetes and nearly 50 to 80 million are living with prediabetes. Diabetes occurs when there are not enough beta cells in the pancreas, or when those beta cells secrete too little insulin, the hormone required to keep blood sugar levels in the normal range. Diabetes can lead to major medical complications: heart attack, stroke, kidney failure, blindness, and limb amputation. Loss of insulin-producing beta cells has long been recognized as a cause of type 1 diabetes, in which the immune system mistakenly attacks and destroys beta cells. In recent years, researchers have concluded that a deficiency of functioning beta cells also contributes importantly to type 2 diabetes--the primary type that occurs in adults.

CRISPR-Gold Delivery Vehicle for CRISPR-Cas9 Fixes Duchenne Muscular Dystrophy Mutation in Mouse Model

Scientists at the University of California, Berkeley, have engineered a new way to deliver CRISPR-Cas9 gene-editing technology inside cells and have demonstrated in a mouse model that the technology can repair the mutation that causes Duchenne muscular dystrophy, a severe muscle-wasting disease. A new study shows that a single injection of CRISPR-Gold, as the new delivery system is called, into mice with Duchenne muscular dystrophy led to an 18-times-higher correction rate and a two-fold increase in a strength and agility test compared to control groups. Since 2012, when study co-author Dr. Jennifer Doudna, a Professor of Molecular and Cell Biology and of Chemistry at UC Berkeley, and colleague Emmanuelle Charpentier, of the Max Planck Institute for Infection Biology, repurposed the Cas9 protein to create a cheap, precise, and easy-to-use gene editor, researchers have hoped that therapies based on CRISPR-Cas9 would one day revolutionize the treatment of genetic diseases. Yet developing treatments for genetic diseases remains a big challenge in medicine. This is because most genetic diseases can be cured only if the disease-causing gene mutation is corrected back to the normal sequence, and this is impossible to do with conventional therapeutics. CRISPR/Cas9, however, can correct gene mutations by cutting the mutated DNA and triggering homology-directed DNA repair. However, strategies for safely delivering the necessary components (Cas9, guide RNA that directs Cas9 to a specific gene, and donor DNA) into cells need to be developed before the potential of CRISPR-Cas9-based therapeutics can be realized. A common technique to deliver CRISPR-Cas9 into cells employs viruses, but that technique has a number of complications. CRISPR-Gold does not need viruses.

Genetic Targets for Potential Reduction of the Development of Chemo-Resistance in Triple-Negative Breast Cancer Identified

Research led by Dr. Carlos Arteaga, Director of the Harold C. Simmons Comprehensive Cancer Center, has identified potential targets for treatment of triple negative breast cancer, the most aggressive form of breast cancer. Increased activity of two genes, MCL1 and MYC, is associated with the development of chemotherapy resistance. The increased action of these two genes boosts mitochondrial oxidative phosphorylation, which promotes the growth of chemotherapy-resistant cancer stem cells, the research showed. "Alterations in these two genes are easily detectable with tumor gene tests in current use. Combinations of drugs that inhibit MCL1 or MYC, or both, have the potential to reduce the development of chemotherapy resistance and should be studied in clinical trials," said Dr. Arteaga, Professor of Internal Medicine at UT Southwestern Medical Center. Dr. Arteaga holds The Lisa K. Simmons Distinguished Chair in Comprehensive Oncology. Most breast cancers can be treated with hormone therapy, but about 15 percent of cases are triple-negative breast cancer, meaning the cancer cells are not influenced by hormones like estrogen or progesterone. These triple-negative breast cancers must, therefore, be treated with chemotherapy, which is toxic to healthy cells as well as cancer cells. Furthermore, most triple negative breast cancers eventually become resistant to chemotherapy and the cancer then spreads unchecked. Drugs that inhibit activity of the MCL1 or MYC genes are in development, Dr. Arteaga said. These drugs, given in conjunction with standard chemotherapies, could potentially slow or even prevent the development of chemotherapy resistance, improving the outlook for this aggressive form of breast cancer.

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.

Syndicate content