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Archive - May 10, 2017


Novel Tissue-Engineered Islet Transplant Achieves Insulin Independence in Type 1 Diabetes

Scientists from the Diabetes Research Institute (DRI) at the University of Miami Miller School of Medicine have produced the first clinical results demonstrating that pancreatic islet cells transplanted within a tissue-engineered platform can successfully engraft and achieve insulin independence in type 1 diabetes. The findings, published in the May 11, 2017 issue of the New England Journal of Medicine, are part of an ongoing clinical study to test this novel strategy as an important step toward offering this life-changing cell replacement therapy to millions living with the disease. The NEJM letter is titled “Bioengineering of an Intraabdominal Endocrine Pancreas.” Islet transplantation has demonstrated the ability to restore natural insulin production and eliminate severe hypoglycemia in people with type 1 diabetes. The insulin-producing cells have traditionally been implanted within the liver, but this transplant site poses some limitations for emerging applications, leading researchers to investigate other options. DRI scientists have focused on the omentum, an apron-like tissue covering abdominal organs, which is easily accessed with minimally invasive surgery and has the same blood supply and physiological drainage characteristics as the pancreas.

Ongoing Natural Selection Against Damaging Genetic Mutations in Humans

The survival of the human species in the face of high rates of genetic mutations has remained an important problem in evolutionary biology. While mutations provide a source of novelty for the species, a large fraction of these genetic changes can also be damaging. A newborn human is estimated to have ~70 new mutations that the parents did not have. In a project conducted by Brigham and Women's Hospital research geneticist Shamil Sunyaev (photo), PhD, and University of Michigan professor Alexey Kondrashov, PhD, scientists studied natural selection in humans. Their findings were published in the May 5, 2017 issue of Science, where the scientists report that, as a species, humans are able to keep the accumulation of damaging mutations in check because each additional mutation that's added to a genome causes larger, and larger consequences, decreasing an individual's ability to pass on genetic material. The article is titled “Negative Selection in Humans and Fruit Flies Involves Synergistic Epistasis.” A damaging mutation is one that likely interferes with the biological function that a gene has for the organism. The researchers studied population samples from Europe, Asia, and Africa and found a significant depletion of individuals carrying a large number of highly damaging mutations overall. They inferred that if a new mutation occurs in a genome that already contains many damaging mutations, it has a stronger effect than if it occurred in a genome with just a few other damaging mutations. Thus, the more damaging mutations a genome carries, the less likely that individual will be able to contribute progeny to the next generation.

A Natural Defense Mechanism That Can Trap and Kill TB Bacteria

A natural mechanism by which our cells kill the bacterium responsible for tuberculosis (TB) has been discovered by scientists at the Francis Crick Institute, which could help in the battle against antibiotic-resistant bacteria. The findings, published in the May 10, 2017 issue of Cell Host & Microbe, could enable scientists to develop treatments for TB - one of the world's biggest health challenges - without the use of antibiotics, meaning that even antibiotic-resistant strains could be eliminated. The open-access article is titled “A Rab20-Dependent Membrane Trafficking Pathway Controls M. tuberculosis Replication by Regulating Phagosome Spaciousness and Integrity.” The research was done in collaboration with scientists at the University of Oslo, the Max Planck Institute for Infection Biology in Germany, and the Radboud Institute for Molecular Life Sciences in the Netherlands. "We are trying to better understand how our cells kill the bacteria with the idea of boosting people's natural defenses in conjunction with conventional therapies to overcome TB," says Maximiliano Gutierrez, PhD, Group Leader at the Francis Crick Institute, who led the study. Immune cells called macrophages recognize and engulf Mycobacterium tuberculosis - the bacterium responsible for TB - securing it within tight-fitting internal compartments known as phagosomes. But before enzymes and toxic products can enter the phagosome to kill the bacterium, M. tuberculosis often escapes by puncturing holes in the phagosome membrane and leaking into the cell. In doing so, M. tuberculosis kills the cell and then feeds on its nutrients. By imaging the infection of cells with TB bacteria in real time, the team uncovered an innate mechanism that prevents M.

Four Risk Genes for Tourette Syndrome Identified by Analysis of De Novo Mutations

Tourette disorder (also known as Tourette syndrome) afflicts as many as one person in a hundred worldwide with potentially disabling symptoms including involuntary motor and vocal tics. However, researchers have so far failed to determine the cause of the disorder, and treatments have only limited effectiveness, in part because the genetics underlying the disorder have remained largely a mystery. Now, as reported in the May 3, 2017 issue of Neuron, a consortium of top researchers -- led by scientists at UC San Francisco, Rutgers University, Massachusetts General Hospital, the University of Florida, and Yale School of Medicine -- has made a significant advance, identifying the first "high-confidence" risk gene for Tourette disorder as well as three other probable risk genes. These findings are a step forward in understanding the biology of the disorder, the authors said, which will aid in the search for better treatments. "In the clinic, I have seen, again and again, the frustration that patients and families experience because of our lack of understanding and the limitations of our current treatments. But we have now taken a major initial step forward in changing this reality, thanks to new genomic technologies and a very successful long-term collaboration between clinicians and geneticists," said Matthew State, MD, PhD, Oberndorf Family Distinguished Professor and Chair of the Department of Psychiatry at UCSF and a co-senior author on the new paper. The open-access article is titled “De Novo Coding Variants Are Strongly Associated with Tourette Disorder.”

Potential Biomarker for Glaucoma Damage Identified

Glaucoma, a leading cause of blindness worldwide, is most often diagnosed during a routine eye exam. Over time, elevated pressure inside the eye damages the optic nerve, leading to vision loss. Unfortunately, there's no way to accurately predict which patients might lose vision most rapidly. Now, studying mice, rats, and fluid removed from the eyes of patients with glaucoma, researchers at the Washington University School of Medicine in St. Louis have identified a marker of damage to cells in the eye that potentially could be used to monitor progression of the disease and the effectiveness of treatment. The findings were published online on May 4, 2017 in the journal JCI Insight. The open-access article is titled “GDF15 Is Elevated in Mice Following Retinal Ganglion Cell Death and in Glaucoma Patients.” "There hasn't been a reliable way to predict which patients with glaucoma have a high risk of rapid vision loss," said principal investigator Rajendra S. Apte, MD, PhD, the Paul A. Cibis Distinguished Professor of Ophthalmology and Visual Sciences. "But we've identified a biomarker that seems to correlate with disease severity in patients, and what that marker is measuring is stress to the cells rather than cell death. Other glaucoma tests are measuring cell death, which is not reversible, but if we can identify when cells are under stress, then there's the potential to save those cells to preserve vision." Glaucoma is the second-leading cause of blindness in the world, affecting more than 60 million people. The disease often begins silently, with peripheral vision loss that occurs so gradually that it can go unnoticed. Over time, central vision becomes affected, which can mean substantial damage already has occurred before any aggressive therapy begins.

New Evidence Indicates Traffic Jams in Nuclear Pores Cause Brain Cell Death in Huntington’s Disease

Working with mouse, fly, and human cells and tissue, Johns Hopkins researchers and collaborators report new evidence that disruptions in the movement of cellular materials in and out of a cell's control center -- the nucleus -- appear to be a direct cause of brain cell death in Huntington's disease, an inherited adult neurodegenerative disorder. Moreover, they suggest, laboratory experiments with drugs designed to clear up these cellular "traffic jams" restored normal transport in and out of the nucleus and saved the cells. In the featured article published in the April 5, 2017 issue of Neuron, the researchers also conclude that potential treatments targeting the transport disruptions they identified in Huntington's disease neurons may also work for other neurodegenerative diseases, such as ALS and forms of dementia. The Neuron article is titled “Mutant Huntingtin Disrupts the Nuclear Pore Complex.” Huntington's disease is a relatively rare fatal inherited condition that gradually kills off healthy nerve cells in the brain, leading to loss of language, thinking and reasoning abilities, memory, coordination, and movement. Its course and effects are often described as Alzheimer's disease, Parkinson's disease, and ALS rolled into one, making Huntington's disease a rich focus of scientific investigation. "We're trying to get at the heart of the mechanism behind neurodegenerative diseases and with this research believe we've found one that seems to be commonly disrupted in many of them, suggesting that similar drugs may work for some or all of these disorders," says Jeffrey Rothstein, M.D., Ph.D., a Professor of Neurology and Neuroscience, and Director of the Brain Science Institute and the Robert Packard Center for ALS Research at the Johns Hopkins University School of Medicine.

Genetic Findings in “Type 1.5” Diabetes May Shed Light on Better Diagnosis, Treatment

Researchers investigating a form of adult-onset diabetes that shares features with the two better-known types of diabetes have discovered genetic influences that may offer clues to more accurate diagnosis and treatment. Latent autoimmune diabetes in adults (LADA) is informally called "type 1.5 diabetes" because like type 1 diabetes (T1D), LADA is marked by circulating autoantibodies, an indicator that an overactive immune system is damaging the body's insulin-producing beta cells. But LADA also shares clinical features with type 2 diabetes (T2D), which tends to appear in adulthood. Also, as in T2D, LADA patients do not require insulin treatments when first diagnosed. A study published on April 25, 2017 in BMC Medicine used genetic analysis to show that LADA is closer to T1D than to T2D. The open-access article is titled “Relative Contribution of Type 1 And Type 2 Diabetes Loci to the Genetic Etiology of Adult-Onset, Non-Insulin-Requiring Autoimmune Diabetes.” "Correctly diagnosing subtypes of diabetes is important, because it affects how physicians manage a patient's disease," said co-study leader Struan F.A. Grant, PhD, a genomics researcher at Children's Hospital of Philadelphia (CHOP). "If patients are misdiagnosed with the wrong type of diabetes, they may not receive the most effective medication." Dr. Grant collaborated with European scientists, led by Richard David Leslie of the University of London, U.K.; and Bernhard O. Boehm, of Ulm University Medical Center, Germany and the Lee Kong Chian School of Medicine, a joint medical school of Imperial College London and Nanyang Technological University, Singapore. Occurring when patients cannot produce their own insulin or are unable to properly process the insulin they do produce, diabetes is usually classified into two major types.

Scientists Assess Impact of Cytosine Methylation on Binding Specificities of Human Transcription Factors

A new study published online on May 4, 2017 in Science from Karolinska Institutet and collaborating institutions maps out how different DNA-binding proteins in human cells react to certain biochemical modifications of the DNA molecule. The article is titled “'Impact of Cytosine Methylation on DNA Binding Specificities of Human Transcription Factors.” The scientists report that some “master”' regulatory proteins can activate regions of the genome that are normally inactive due to epigenetic changes. Their findings contribute to a better understanding of gene regulation, embryonic development, and the processes leading to diseases such as cancer. The DNA molecule carries information in the form of a sequence of four nucleotide bases, adenine (A), cytosine (C), guanine (G) and thymine (T), which can be thought of as the letters of the genomic language. Short sequences of the letters form “DNA words” that determine when and where proteins are made in the body. Almost all of the cells in the human body contain the letters in precisely the same order. Different genes are however active (expressed) in different cell types, allowing the cells to function in their specialized roles, for example as a brain cell or a muscle cell. The key to this gene regulation lies in specialized DNA-binding proteins -- transcription factors -- that bind to the sequences and activate or repress gene activity. The DNA letter C exists in two forms, cytosine and methylcytosine, which can be thought of as the same letter with and without an accent (C and Ç). Methylation of DNA bases is a type of epigenetic modification, a biochemical change in the genome that does not alter the DNA sequence. The two variants of C have no effect on the kind of proteins that can be made, but they can have a major influence on when and where the proteins are produced.

Scientists Gain Insights into How Fragile X Syndrome Disrupts Perception

A collaboration among scientists in Belgium, the United States, Norway, France, and the UK has resulted in a study that sheds light on the neural mechanisms of fragile X syndrome. This genetic disorder, which affects males twice as often as females due to males’ single X chromosome, causes disruptions in the way neurons transmit information to each other. Led by one current and two former VIB scientists during their tenure at VIB, the multidisciplinary team used fruit fly models to demonstrate that the Fragile X mutation causes signals between neurons to be more widely spread, possibly leading to confusion in the perception and discrimination of information from the environment. The work was published online on March 30, 2017 in Current Biology. The open-access article is titled “Reduced Lateral Inhibition Impairs Olfactory Computations and Behaviors in a Drosophila Model of Fragile X Syndrome.” In normal brains, 20% of neurons are inhibitory, meaning that they send signals that limit communication between other neurons to make sure that signals exchanged within the brain are finely tuned and confined to specific areas, depending on what the person or animal is doing or perceiving. Fragile X syndrome, which is caused by a fault on the X chromosome, leads to defects in how brain neurons communicate with each other. In this study, scientists observed that fruit flies that lack the fragile X protein have much less inhibition among their brain neurons, possibly leading to “noise” during information processing. Even though the research was performed on fruit flies, there are many analogues between flies and humans that lead to insights into human brain diseases.

Cell Factory Claims Milestone in Development of EV-Based Treatment of Drug-Resistant Epilepsy in Children; Full Results Will Be Presented at ISEV 2017 Meeting in Toronto May 18-21

Esperite`s biotech subsidiary The Cell Factory develops the extracellular vesicles (EVs) biologic drug (CF-MEV-117) for treatment of drug-resistant epilepsy in children. In a May 5, 2017 press release, Espertite announced that a consortium sponsored by The Cell Factory has achieved an important milestone in the CF-MEV-117 drug development, confirming an anti-inflammatory and immunosuppressive activity of the CF-MEV-117 in a dose response manner. Full results will be presented during the International Society for Extracellular Vesicles (ISEV) meeting in Toronto, Canada fromMay 18-21, 2017. The Cell Factory, a company subsiadiery of the Esperite Group, in collaboration with Bambino Gesù Children`s Hospital in Rome, Mario Negri Institute for Pharmacological Research in Milan, and Women`s and Children`s Health Department of the University of Padua is developing the EV drug candidate (CF-MEV-117) for treatment of drug-resistant epilepsy in children. The consortium is investigating the immunomodulatory properties of EVs derived from mesenchymal stem cells (MSCs) in several in vitro and in vivo models. It has been previously demonstrated by independent research groups that inhibitory effects of MSCs on human leukocytes are mediated by secreted EVs. Subsequently, it was demonstrated by Cell Factory partners that MSC-derived EVs were responsible for inhibition of B-cell proliferation and differentiation and for activation of T-cell apoptosis (Budoni et al., 2013; Del Fattore et al., 2015). These results have been recently confirmed with the CF-MEV-117 drug candidate manufactured by The Cell Factory. Preclinical and clinical study demonstrate that brain inflammation could be responsible for severe epileptic seizures. Pro-inflammatory molecules secreted by the stimulated glial cells are responsible for a status epilepticus.