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Study Suggests New Strategy Against Vascular Disease in Diabetes--Insulin-Mimicking Peptide Not Only Lowers Blood Sugars, But Also Slows Progression of Atherosclerosis In Mouse Model

Recent findings suggest a novel approach for protecting people with diabetes from their higher risk of advanced blood vessel disease, which sets the stage for early heart attacks and strokes. Cardiovascular problems from atherosclerosis - plaque-like lesions forming in artery walls - are the major cause of death in people with type 2 diabetes and metabolic syndrome. People with metabolic syndrome exceed the normal range for several clinical measurements: blood pressure, blood sugar levels, harmful lipids, body mass index, and belly fat. The researchers studied mice with metabolic syndrome. The mice were obese and had impaired glucose tolerance, a sign of pre-diabetes. In the study, an insulin-mimicking synthetic peptide called S597 was shown to both reduce blood sugar levels and slow the progression of atherosclerotic lesions. Insulin, even when it controls diabetes, does not prevent atherosclerosis. The findings were published in the February 26, 2018 issue of Diabetes. The article is titled “A Novel Strategy to Prevent Advanced Atherosclerosis and Lower Blood Glucose in a Mouse Model of Metabolic Syndrome.” The senior author is Karin E. Bornfeldt, University of Washington (UW) School of Medicine Professor of Medicine, Division of Metabolism, Endocrinology and Nutrition. Jenny Kanter, UW Research Assistant Professor of Medicine, was the lead author. They are scientists at the UW Medicine Diabetes Institute. The study was conducted as a research collaboration with Novo Nordisk A/S. Although S597 is composed of a single chain of amino acids and looks nothing like insulin, S597 can still activate insulin receptors. But, unlike insulin, it's more selective in what it turns on inside the cells.

Study Unravels Novel Pathway That Regulates Innate and Adaptive Immunity Via Mast Cells, Exclusively, and Underscores Therapeutic Potential of NAD+ in Myriad Diseases

Researchers at Brigham and Women's Hospital (BWH) in Boston have discovered a new cellular and molecular pathway that regulates CD4+ T cell response--a finding that may lead to new ways to treat diseases that result from alterations in these cells. The discovery, published online on February 19, 2018 in the Journal of Allergy and Clinical Immunology, shows that administering oxidized nicotinamide adenine dinucleotide (NAD+), a natural molecule found in all living cells, shuts off the capacity of dendritic cells and macrophages to dictate CD4+ T fate. Researchers found that NAD+ administration regulated CD4+ T cells via mast cells (MCs), cells that have been mainly described in the context of allergy, exclusively. "This is a novel cellular and molecular pathway that is distinct from the two major pathways that were previously known. Because it is distinct and because it has the ability to regulate the immune system systemically, we can use it as an alternative to bypass the current pathways," said Abdallah ElKhal, PhD, BWH Department of Surgery, senior study author. The open-access article is titled “Mast Cells Regulate CD4+ T Cell Differentiation in Absence of Antigen Presentation.” CD4+ T helper cells and dendritic cells play a central role in immunity. Alterations or aberrant dendritic cells and T cell responses can lead to many health conditions including autoimmune diseases, infections, allergy, primary immunodeficiencies, and cancer. As of today, two major pathways have been described to regulate CD4+ T cell response. The first pathway was described by Peter C. Doherty and Rolf M. Zinkernagel (1996 Nobel prize winners) showing the requirement of MHC-TCR signaling machinery.

Better Diet May Ease Depression

People who eat vegetables, fruit, and whole grains may have lower rates of depression over time, according to a preliminary study released on February 25, 2018 and that will be presented at the American Academy of Neurology's 70th Annual Meeting in Los Angeles, April 21 to 27, 2018 (https://www.aan.com/conferences-community/annual-meeting/registration-an...). The study found that people whose diets adhered more closely to the Dietary Approaches to Stop Hypertension (DASH) diet were less likely to develop depression than people who did not closely follow the diet. In addition to fruit and vegetables, the DASH diet recommends fat-free or low-fat dairy products and limits foods that are high in saturated fats and sugar. Studies have shown health benefits such as lowering high blood pressure and bad cholesterol (LDL), along with lowering body weight. "Depression is common in older adults and more frequent in people with memory problems, vascular risk factors such as high blood pressure or high cholesterol, or people who have had a stroke," said study author Laurel Cherian, MD, of the Rush University Medical Center in Chicago and a member of the American Academy of Neurology. "Making a lifestyle change such as changing your diet is often preferred over taking medications, so we wanted to see if diet could be an effective way to reduce the risk of depression." For the study, 964 participants with an average age of 81 were evaluated yearly for an average of six-and-a-half years. They were monitored for symptoms of depression such as being bothered by things that usually didn't affect them and feeling hopeless about the future.

Lizard Genome Sequencing Reveals Molecular Genetic Evidence for Rapid Evolution

Lizards have special superpowers. While birds can regrow feathers and mammals can regrow skin, lizards can regenerate entire structures such as their tails. Despite these differences, all have evolved from the same ancestor as lizards. Spreading through the Americas, one lizard group, the anoles, evolved like Darwin's finches, adapting to different islands and different habitats on the mainland. Today there are more than 400 species. Constructing a family tree for three lizard species collected in Panama at the Smithsonian Tropical Research Institute (STRI) and a fourth from the southeastern U.S., scientists at Arizona State University (ASU) compared lizard genomes--their entire DNA code--to those of other animals. The researchers discovered that changes in genes involved in the interbrain (the site of the pineal gland and other endocrine glands), for color vision, hormones, and the colorful dewlap that males bob to attract females, may contribute to the formation of boundaries between species. Genes regulating limb development also evolved especially quickly. "While some reptiles, such as tortoises, changed remarkably little over millions of years, anole lizards evolved quickly, generating a diversity of shapes and behaviors," said Dr. Kenro Kusumi, corresponding author and Professor at the ASU School of Life Sciences. "Now that sequencing entire genomes is cheaper and easier, we discovered molecular genetic evidence for rapid evolution that may account for striking differences between bodies of animals living in different environments." The study's findings were published in the February 1, 2018 issue of Genome Biology and Evolution. The open-access article is titled "Comparative Genomics Reveals Accelerated Evolution in Conserved Pathways during the Diversification of Anole Lizards." Dr.

Cutting-Edge Technology Enables Identification of Novel Nanoparticles (Exomeres) Released by Cancer Cells and Similar to Exosomes, But Smaller and with Different Functions

A new cellular messenger discovered by Weill Cornell Medicine scientists may help reveal how cancer cells co-opt the body’s intercellular delivery service to spread to new locations in the body. In a paper published online on February 19, 2018 in Nature Cell Biology, the scientists show that a cutting-edge technique called asymmetric flow field-flow fractionation (AF4) can efficiently sort nano-sized particles, called exosomes, that are secreted by cancer cells and contain DNA, RNA, fats, and proteins. This technology allowed the investigators to separate two distinct exosome subtypes and discover a new nanoparticle, which they named an “exomere.” The article is titled "Identification of Distinct Nanoparticles and Subsets of Extracellular Vesicles by Asymmetric Flow Field-Flow Fractionation." Also published online on February 19, 2018 was a description of the protocol used to identify the nanoparticles. “We found that exomeres are the most predominant particle secreted by cancer cells,” said senior author Dr. David Lyden, the Stavros S. Niarchos Professor in Pediatric Cardiology, and a scientist in the Sandra and Edward Meyer Cancer Center and the Gale and Ira Drukier Institute for Children’s Health at Weill Cornell Medicine. “They are smaller and structurally and functionally distinct from exosomes. Exomeres largely fuse with cells in the bone marrow and liver, where they can alter immune function and metabolism of drugs.

Mutation in Gene Controlling RNA Lariat Metabolism Implicated in Susceptibility to Lethal Brain Stem Infections by Common Viruses

For previously healthy children, brain infections are rare. But about one out of every 10,000 people who are exposed to common viruses like herpes simplex or influenza will develop a potentially deadly disease, encephalitis. Rockefeller's Dr. Jean-Laurent Casanova has identified mutations in a single gene that may explain what goes wrong in cases of encephalitis of the brain stem, the part of the brain that controls many basic functions including heart rate and breathing. Shen-Ying Zhang, Assistant Professor of Clinical Investigation in the Casanova lab, evaluated seven children from unrelated families who had been exposed to a common virus (herpes simplex virus 1, influenza virus, or norovirus) and developed a life-threatening or lethal infection of the brain stem. The scientists discovered mutations in a gene called DBR1, which is responsible for producing a protein (image) that helps process the loops formed in RNA during a step called mRNA splicing. Without it, immunity to viruses is selectively impaired in the brain stem. Dr. Casanova's experiments, published in the February 22, 2018 issue of Cell, point to an almost complete loss of DBR1 (debranching RNA lariats 1) as the culprit, enabling brain stem virus invasion in all seven patients. The findings also reveal an unexpected connection between an RNA processing mechanism and protective immunity in a specific region of the brain. The Cell article is titled “Inborn Errors of RNA Lariat Metabolism in Humans with Brainstem Viral Infection.” The study is a new example of the Casanova lab's ongoing work to identify mutations that underlie infectious diseases in otherwise healthy individuals. Previous work has found genetic factors that cause increased vulnerability to staph infections, the flu, and fungal infections, among others.

Genome of Asexually Reproducing Amazon Molly Fish Sequenced

No species is immune from the suffering of unrequited love, but scientists expect to learn volumes about the biological basis of sex from the newly sequenced genome of an all-female, asexual Texas native - the Amazon molly - that has thrived over millennia. The fresh waters along the Texas-Mexico border serve as home to this evolutionary anomaly - a fish that has flourished by defying nature's odds to reproduce asexually through a natural form known as parthenogenesis in which growth and development of embryos occurs without fertilization, resulting only in daughters that are true clones of their mothers. Texas A&M University Hagler Institute for Advanced Study (HIAS) Faculty Fellow Dr. Manfred Schartl led the international team that recently sequenced the first Amazon molly genome and the genomes of the original parental species that created this unique fish in an effort to better understand how its reproduction deviates from the male-female sexual norm and why the Amazon molly as a species has fared so well in the process. The findings from their National Institutes of Health-funded research were published online on February 12, 2018 in Nature Ecology & Evolution. The open-access article is titled” Clonal Polymorphism and High Heterozygosity in the Celibate Genome of the Amazon Molly.” "The existence of two sexes, male and female, is one of the oldest and most widespread phenomena in biology," says Dr. Schartl, a world leader in cellular and molecular biology of Xiphophorus model systems, including platyfish and swordtails. "Studies on the exceptional case of asexuality helps us to better understand the biological meaning and evolution of sex." Animals that reproduce asexually are rare, compared to the overwhelming majority of species that exist as males and females and reproduce sexually.

Ancient Fused Gene Offers Insight into How Mosses Build Cell Walls

Researchers have identified a fused gene in moss that provides insight into how moss cells build their external walls. The same discovery raises questions about the one-of-a-kind gene that codes for two distinct proteins that participate in two distinct functions. The research team identified the novel gene, known as For1F, while studying exocytosis. Exocytosis is the process by which cells secrete packets of protein and carbohydrates outside their membranes to support extracellular processes like the construction of cell walls. The gene discovered in the research couples the exocytosis-regulating protein Sec10 with formin, a protein that regulates the remodeling of the actin cytoskeleton critical to forming cell shapes. The new study also shows that the gene fusion occurred early in moss evolution and has been retained for more than 170 million years. "We were surprised to find this fused gene in the moss genome," said Magdalena Bezanilla, PhD, the Ernest Everett Just 1907 Professor of Biology at Dartmouth College. "Through our research, we know that the analysis is correct; now it will be interesting to explore the advantage of this coupling of proteins." Dr. Bezanilla led a team at Dartmouth and the University of Massachusetts-Amherst to conduct the study. The research was published online on January 26, 2018 in the Journal of Cell Biology. The article is titled “An Ancient Sec10–Formin Fusion Provides Insights into Actin-Mediated Regulation of Exocytosis.” Once For1F was observed, Dr. Bezanilla and her team set out to determine how unique this particular conjoined arrangement is. By consulting the database of the 1000 Genomes Project, the researchers found that the fused gene was evident in many diverse species of mosses, but not in other plants.

Progress Reported in Using CRISPR/Cas9 Editing to Correct Sickle Cell Mutation

Scientists have successfully used gene editing to repair 20 to 40 percent of stem and progenitor cells taken from the peripheral blood of patients with sickle cell disease, according to Rice University bioengineer Gang Bao., PhD. Dr. Bao, in collaboration with colleagues at the Baylor College of Medicine, Texas Children's Hospital, and Stanford University, is working to find a cure for the hereditary disease. A single DNA mutation causes the body to make sticky, crescent-shaped red blood cells that contain abnormal hemoglobin and can block blood flow in limbs and organs. In his talk on February 16, 2018 at the annual American Association for the Advancement of Science (AAAS) meeting (http://meetings.aaas.org/) in Austin, Texas, Dr. Bao revealed results from a series of tests to see whether CRISPR/Cas9-based editing can fix the mutation. His presentation was part of a scientific session titled "Gene Editing and Human Identity: Promising Advances and Ethical Challenges." (https://aaas.confex.com/aaas/2018/meetingapp.cgi/Session/17907) "Sickle cell disease is caused by a single mutation in the beta-globin gene (in the stem cell's DNA)," Dr. Bao said. "The idea is to correct that particular mutation, and then stem cells that have the correction would differentiate into normal blood cells, including red blood cells. Those will then be healthy blood cells." Dr. Bao's lab collaborated with Dr. Vivien Sheehan, an Assistant Professor of Pediatrics and Hematology at Baylor and a member of the Sickle Cell Program at Texas Children's, to collect stem and progenitor cells (CD34-positive cells) from patients with the disease. These cells were then edited in the Bao lab with CRISPR/Cas9 together with a custom template, a piece of DNA designed to correct the mutation.

Dynamic Ligand Discrimination Shown in Notch Signaling Pathway

Multicellular organisms like ourselves depend on a constant flow of information between cells, coordinating their activities in order to proliferate and differentiate. Deciphering the language of intercellular communication has long been a central challenge in biology. Now, Caltech scientists have discovered that cells have evolved a way to transmit more messages through a single pathway, or communication channel, than previously thought, by encoding the messages rhythmically over time. The work, conducted in the laboratory of Michael Elowitz (photo), PhD, Professor of Biology and Bioengineering, Howard Hughes Medical Institute Investigator, and Executive Officer for Biological Engineering, is described in a paper in the February 8, 2018 issue of Cell. The open-access paper is titled "Dynamic Ligand Discrimination in the Notch Signaling Pathway." In particular, the scientists studied a key communication system called "Notch," which is used in nearly every tissue in animals. Malfunctions in the Notch pathway contribute to a variety of cancers and developmental diseases, making it a desirable target to study for drug development. Cells carry out their conversations using specialized communication molecules called ligands, which interact with corresponding molecular antennae called receptors. When a cell uses the Notch pathway to communicate instructions to its neighbors--telling them to divide, for example, or to differentiate into a different kind of cell--the cell sending the message will produce certain Notch ligands on its surface. These ligands then bind to Notch receptors embedded in the surface of nearby cells, triggering the receptors to release gene-modifying molecules called transcription factors into the interior of their cell.

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