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Archive - Mar 25, 2017

An Adipocyte-Biiary-Uridine Axis That Regulates Energy Homeostasis; Fat Cells Dominate Uridine Biosynthesis and Blood Levels in the Fasted State

How do mammals keep two biologically crucial metabolites in balance during times when they are feeding, sleeping, and fasting? The answer may require rewriting some textbooks. In a study published online on March 17, 2017 in Science, University of Texas (UT) Southwestern Medical Center researchers report that fat cells “have the liver’s back,” so to speak, to maintain tight regulation of glucose (blood sugar) and uridine, a metabolite the body uses in a range of fundamental processes such as building RNA molecules, properly making proteins, and storing glucose as energy reserves. The article is titled “An Adipo-Biliary-Uridine Axis That Regulates Energy Homeostasis.” The scientists’ study may have implications for several diseases, including diabetes, cancer, and neurological disorders. Metabolites are substances produced by a metabolic process, such as glucose generated in the metabolism of complex sugars and starches, or amino acids used in the biosynthesis of proteins. “Like glucose, every cell in the body needs uridine to stay alive. Glucose is needed for energy, particularly in the brain’s neurons. Uridine is a basic building block for a lot of things inside the cell,” said Dr. Philipp Scherer, senior author of the study and Director of UT Southwestern’s Touchstone Center for Diabetes Research. “Biology textbooks indicate that the liver produces uridine for the circulatory system,” said Dr. Scherer, also Professor of Internal Medicine and Cell Biology. “But what we found is that the liver serves as the primary producer of this metabolite only in the fed state. In the fasted state, the body’s fat cells take over the production of uridine.” Basically, this method of uridine production can be viewed as a division of labor.

Rhythmic Variation in Sleeping Sickness Parasite’s Biologic Clock Make It More Vulnerable to Treatment in the Afternoon

The parasite that causes deadly sleeping sickness has its own biological clock that makes it more vulnerable to medications during the afternoon, according to international research that may help improve treatments for one of Africa’s most lethal diseases. The finding, from the Peter O’Donnell Jr. Brain Institute at the University of Texas Southwestern Medical Center (UTSWMC), could be especially beneficial for patients whose bodies can’t handle side effects of toxic treatments used to eradicate the parasite. By knowing the optimal time to administer these medications – which can be fatal – doctors hope to reduce the duration and dosage of the treatment and save more lives. “This research has opened a door,” said Dr. Filipa Rijo-Ferreira, first author of the study from the O’Donnell Brain Institute. “If the same therapeutic effect can be obtained with a lower dose, then it may be possible to reduce the mortality associated with the treatment.” Establishing that parasites have their own internal clock is a key step in finding new ways to treat a variety of parasitic conditions, from sleeping sickness to malaria. While many of these diseases are often not deadly, sleeping sickness has been among the most lethal. The condition – known formally as African trypanosomiasis – is transmitted through the bite of the tsetse fly and threatens tens of millions of people in sub-Saharan African countries. After entering the body, the parasite causes such symptoms as inverted sleeping cycles, fever, muscle weakness, and itching. It eventually invades the central nervous system and, depending on its type, can kill its host in anywhere from a few months to several years. Control efforts have significantly reduced the number of cases over the last decade.

“Bench to Bedside to Bench—And Back Again”

In the era of genome sequencing, it's time to update the old "bench-to-bedside" shorthand for how basic research discoveries inform clinical practice, researchers from The Jackson Laboratory (JAX), the National Human Genome Research Institute (NHGRI), and institutions across the U.S. declare in a Leading Edge commentary published in the March 23, 2017 issue of Cell. The article is titled “Bedside Back to Bench: Building Bridges between Basic and Clinical Genomic Research.” "Interactions between basic and clinical researchers should be more like a 'virtuous cycle' of bench to bedside and back again," says JAX Professor Carol Bult, Ph.D., senior author of the commentary. "New technologies to determine the function of genetic variants, together with new ways to share data, mean it's now possible for basic and clinical scientists to build upon each other's work. The goal is to accelerate insights into the genetic causes of disease and the development of new treatments." Genome sequencing technologies are generating massive quantities of patient data, revealing many new genetic variants. The challenge, says commentary first author Teri Manolio, M.D., Ph.D., Director of the NHGRI Division of Genomic Medicine, "is in mining all these data for genes and variants of high clinical relevance." In April 2016, NHGRI convened a meeting of leading researchers from 26 institutions to explore ways to build better collaborations between basic scientists and clinical genomicists, in order to link genetic variants with disease causation. The Cell commentary outlines the group's recommendations, which include promoting data sharing and prioritizing clinically relevant genes for functional studies.

Astrocytes Play Role in Workings of Biological Clock

Until recently, work on biological clocks that dictate daily fluctuations in most body functions, including core body temperature and alertness, focused on neurons, those electrically excitable cells that are the divas of the central nervous system. Asked to define the body's master clock, biologists would say it is two small spheres -- the suprachiasmatic nuclei, or SCN -- in the brain that consist of 20,000 neurons. The scientists likely wouldn't even mention the 6,000 astroglia mixed in with the neurons, said Erik Herzog, Ph.D., a neuroscientist in Arts & Sciences at Washington University in St. Louis. In a March 23, 2017 advance online publication from Current Biology (“Astrocytes Regulate Daily Rhythms in the Suprachiasmatic Nucleus and Behavior”), Dr. Herzog and his collaborators show that the astroglia help to set the pace of the SCN to schedule a mouse's day. The astroglia, or astrocytes, were passed over in silence partly because they weren't considered to be important. Often called "support cells," they were supposed to be gap fillers or place holders. Their Latin name, after all, means "starry glue." Then two things happened. Scientists discovered that almost all the cells in the body keep time, with a few exceptions such as stem cells. And they also began to realize that the astrocytes do a lot more than they had thought. Among other things, astrocytes secrete and slurp neurotransmitters and help neurons form strengthened synapses to consolidate what we've learned. In fact, scientists began to speak of the tripartite synapse, emphasizing the role of an astrocyte in the communication between two neurons. So, for a neuroscientist like Dr. Herzog, the obvious question was: What were the astrocytes doing in the SCN? Were they keeping time?

Study Shows Potential of Stem Cell Therapy to Repair Lung Damage

A new study has found that stem cell therapy can reduce lung inflammation in an animal model of chronic obstructive pulmonary disease (COPD) and cystic fibrosis. Although still at a pre-clinical stage, these findings have important potential implications for the future treatment of patients. The findings were presented in Estoril, Portugal on March 25, 2017 at the European Respiratory Society's Lung Science Conference. Lung damage caused by chronic inflammation in conditions such as COPD and cystic fibrosis, leads to reduced lung function and eventually respiratory failure. Mesenchymal stem cell (MSC) therapy is currently being investigated as a promising therapeutic approach for a number of incurable, degenerative lung diseases. However, there is still limited data on the short and long-term effects of administering stem cell therapy in chronic respiratory disease. The new research investigated the effectiveness of MSC therapy in a mouse model of chronic inflammatory lung disease, which reflects some of the essential features of diseases such as COPD and cystic fibrosis. Researchers delivered stem cells intravenously to ?-ENaC overexpressing mice at 4 and 6 weeks of age, before collecting sample tissue and cells from the lungs at 8 weeks. The scientists compared these findings to those of a control group that did not receive the MSC therapy. The results showed that inflammation was significantly reduced in the group receiving MSC therapy. Cells counts for both monocytic cells and neutrophils, both signs of inflammation, were significantly reduced after MSC therapy. Analysis of lung tissue revealed a reduction in the mean linear intercept and other measures of lung destruction in MSC treated mice.