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Archive - Sep 23, 2015

Physiologists Discover New Code That Impacts All Biology; Choice Among Synonymous “Fast” Preferred Codons and “Slow” Non-Preferred Codons Regulates Speed of Protein Elongation, Which Influences Protein Folding, Which Determines Function

University of Texas (UT) Southwestern physiologists, trying to understand the genetic code, have discovered a previously unknown code that helps explain which protein should be created to form a particular type of cell. The human body is made up of tens of trillions of cells. Each cell contains thousands of proteins, which determine how the cell should form and what functions it needs to perform. Proteins, in turn, are made up of hundreds of amino acids. The blueprint for each protein is specified by genetic codons, which are triplets of nucleotides that can code for 20 different types of amino acids. The way in which amino acids are linked together then determines which proteins are eventually produced, and in turn, what functions the cell will have. What researchers found was that, not only does the sequence of the amino acids matter, but so does the speed of the process in which the amino acids are put together into a functional protein. “Our results uncovered a new ‘code’ within the genetic code. We feel this is quite important, as the finding uncovers an important regulatory process that impacts all biology,” said Dr. Yi Liu, Professor of Physiology. It was long known that almost every amino acid can be encoded by multiple synonymous codons and that every organism, from humans to fungi, has a preference for certain codons. The researchers found that more frequently used codons − the “preferred codons” − speed up the process of producing an amino acid chain, while less frequently produced codons slow the process. The use of either preferred or non-preferred codons is like having speed signs on the protein production highway: some segments need to be made quickly and others slowly. “The genetic code of nucleic acids is central to life, as it specifies the amino acid sequences of proteins,” said Dr. Liu, the Louise W.

Master Pancreas Endocrine Development Gene NGN3 Surprisingly Found Normally Expressed in Adult Human Pancreas; May Possibly Be Manipulated to Produce New, Insulin-Producing Beta Cells for Diabetes Treatment

Cells that express neurogenin 3 (NGN3) may one day be harnessed to create a plentiful supply of insulin-producing beta cells for the treatment of diabetes, a study led by researchers at the University of South Florida (USF) suggests. NGN3 is the master gene driving development of the human endocrine pancreas, including the beta cells that make and secrete the hormone insulin, which helps control blood sugar levels. In type 1, or juvenile, diabetes, insulin-producing beta cells are generally destroyed by the person's immune system, and patients need insulin injections to survive. Patients with the more common type 2 diabetes, referred to as adult-onset diabetes, typically produce at least some insulin but their bodies cannot use it properly, and they often require extra insulin. In a study published on August 19, 2015 in the open-access journal PLOS ONE, researchers from the Children's Research Institute, USF Health Morsani College of Medicine; Johns Hopkins University School of Medicine; and the University of Illinois at Chicago, detected the NGN3 protein in histologically normal pancreatic biopsies from two sources -- cadavers and patients requiring biopsy for diagnostic purposes. The PLOS ONE article is titled “Neurogenin 3 Expressing Cells in the Human Exocrine Pancreas Have the Capacity for Endocrine Cell Fate.” "NGN3 expression in the adult pancreas was unexpected, because it cannot be detected in the adult rodent pancreas - only during fetal development," said the study's principal investigator Michael Shamblott, Ph.D., an Endowed Chair of Pediatrics at the Children's Research Institute, USF Health Morsani College of Medicine, whose research focuses on regenerative cell therapies to replenish the insulin-producing cells destroyed or damaged by diabetes.

Infectious Prions Detected Very Early and in Potentially Treatable Area of Brain in NIH Mouse Study

Prion diseases--incurable, ultimately fatal, transmissible neurodegenerative disorders of mammals--are believed to develop undetected in the brain over several years from infectious prion proteins. In a new study, National Institutes of Health (NIH) scientists report they can detect infectious prion protein in mouse brains within a week of inoculation. Equally surprising, the protein was generated outside blood vessels in a place in the brain where scientists believe drug treatment could be targeted to prevent disease. The study, from NIH's National Institute of Allergy and Infectious Diseases (NIAID), was published online in the September 22, 2015 issue of mBio. The article is titled “Early Generation of New PrPSc on Blood Vessels after Brain Microinjection of Scrapie in Mice.” The first author of the study is Bruce Chesebro, M.D., Chief of the NIAID Laboratory of Persistent Viral Diseases. Scientists believe prion diseases could potentially be treated if therapy stwere to start early in the disease cycle. However, identifying who needs treatment and pinpointing the optimal time frame for treatment are open questions for researchers. Human prion diseases include variant, familial, and sporadic Creutzfeldt-Jakob disease (CJD). The most common form, sporadic CJD, affects an estimated one in one million people annually worldwide. Other prion diseases include scrapie in sheep; chronic wasting disease in deer, elk, and moose; and bovine spongiform encephalopathy (mad cow disease) in cattle. In their study, the NIAID scientists injected infectious scrapie prion protein into the brains of mice. After 30 minutes, they began observing whether the injected material generated new infectious protein at the injection site.

Exosomes from Repurposed Macrophages Deliver GDNF Directly to Brain in Novel Approach to Possible Treatment of Parkinson’s Disease

As a potential treatment for Parkinson’s disease, scientists at the University of North Carolina (UNC) at Chapel Hill have created smarter immune cells that produce and deliver a neuron-healing protein to the brain, while also teaching nerve cells to begin making the protein for themselves. Associate Professor Elena Batrakova, Ph.D., and her team at the UNC Eshelman School of Pharmacy’s Center for Nanotechnology in Drug Delivery genetically modified white blood cells called macrophages to produce glial cell–derived neurotrophic factor (GDNF), and deliver it to the brain. Glial cells provide support and protection for nerve cells throughout the brain and body, and GDNF can heal and stimulate the growth of damaged neurons. “Currently, there are no treatments that can halt or reverse the course of Parkinson’s disease. There are only therapies to address quality of life, such as dopamine replacement,” Dr. Batrakova said. “However, studies have shown that delivering neurotrophic factor to the brain not only promotes the survival of neurons, but also reverses the progression of Parkinson’s disease.” In addition to delivering GDNF, the engineered macrophages can “teach” neurons to make the protein for themselves by delivering both the tools and the instructions needed: DNA, messenger RNA, and transcription factor. Successfully delivering the treatment to the brain is the key to the success of GDNF therapy, Dr. Batrakova said. Using immune cells avoids the body’s natural defenses. The repurposed macrophages are also able to penetrate the blood-brain barrier, something most medicines cannot do. The reprogrammed cells travel to the brain and produce tiny vesicles called exosomes that contain GDNF. The cells release the exosomes, which are then able to deliver the GDNF proteins to neurons in the brain.

New Technique May Enable More Effective Targeting & Stimulation of Cholinergic Neurons Affected by Parkinson’s Disease; Technique Reverses Motor Deficits in Rat Model

Researchers from Imperial College London and Newcastle University believe they have found a potential new way to target cells of the brain affected by Parkinson's disease. The new technique is relatively non-invasive and has worked to improve symptoms of the disease in a rat model. Parkinson's disease causes progressive problems with movement, posture, and balance. It is currently treated with drugs, but these have severe side-effects and can become ineffective after approximately five years. The only treatment subsequently available to patients is deep-brain stimulation, a surgical technique where an electrical current is used to stimulate nerve cells in the brain. In addition to being an invasive treatment, this approach has mixed results - some patients benefit, while others experience no improvement or even deteriorate. Researchers believe this is because the treatment is imprecise, stimulating all types of nerve cells, not just the intended target. The new study, published online on September 23, 2015 in an open-access article in the journal Molecular Neurodegeneration, examined a less invasive and more precise alternative, designed to target and stimulate a particular type of nerve cell called cholinergic neurons. These cells are found within a part of the brain called the pedunculopontine nucleus, or PPN. The article is titled “Pharmacogenetic Stimulation of Cholinergic Pedunculopontine Neurons Reverses Motor Deficits in a Rat Model of Parkinson’s Disease.” "If you were to peer inside the PPN, it is like a jungle with a massive variety of nerve cells that behave differently and have different jobs to do," said Dr. Ilse Pienaar, Honorary Lecturer in Neuroscience at Imperial College London. Scientists already suspect that cholinergic neuron cells are involved in Parkinson's disease.

Particular Genotype for Serotonin Transporter Gene Magnifies Psychological Impact of Life Events, for Better and Worse, New Study Shows

People with a certain geneotype for a particular serotonin transporter gene are more deeply affected by their life experiences, a new study has revealed. The findings challenge traditional thinking about depression, showing that what might be considered a risk gene for depression in one context, may actually be beneficial in another. Researchers at the University of Melbourne in Australia were interested in why some, but not all, adults who have experienced sexual or physical abuse as children go on to develop long-term depression. The research, published in an open-access article in the September 2015 issue of the British Journal of Psychiatry Open focused on a particular gene, known as the sodium-dependent serotonin transporter (SLC6A4) gene, that codes for a protein that transports the mood-regulating chemical serotonin. Due to length polymorphisms (short and long) in the 5′-flanking promoter region (5-HTT gene-linked polymorphic region, 5HTTLPR) of the SLC6A4 gene, every person has one of three possible SLC6A4 genotypes for his or her two alleles for the SLC6A4 gene: either the long-long (l/l) genotype, the short-long (s/l) genotype, or the short-short (s/s) genotype. The new research article is titled “Serotonin Transporter Polymorphism (5HTTLPR), Severe Childhood Abuse and Depressive Symptom Trajectories in Adulthood.” The team tested the DNA of 333 middle-aged Victorians of Northern and Western European ancestry. [It is important to note that the participants in this study were of Northern and Western European descent, as there are substantial differences in prevalence of the s/s genotype in different populations.] The scientists also recorded these subjects’ depressive symptoms each year over a five-year period.