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Archive - 2016

December 16th

Balance Between Enhancer Activation and Repression a Key to Gene Expression

The complex process regulating gene expression is often compared to following a recipe. Miss a genetic ingredient, or add it in the wrong order, and you could have a disaster on your hands. New research from the Stowers Institute for Medical Research in Kansas City suggests the process may be more like a battle between two opposing genetic forces rather than a step-wise assembly of ingredients. In their report, published online on November 14, 2016 in Genome Research, Stowers researchers examined regions of fruit fly DNA, called enhancers, which increase the likelihood of gene expression. The open-access article is titled “Drosophila Poised Enhancers Are Generated During Tissue Patterning with the Help of Repression.” Gene expression is the process of turning genes on or off, and is crucial for creating specific cells in the body such as nerve cells or cells that make up skin and bone. But a duel comes first. Stowers Associate Investigator Julia Zeitlinger, Ph.D., and Postdoctoral Research Associate Nina Koenecke, Ph.D., discovered that DNA enhancers engage in an ongoing contest between activation and repression, which results in a different epigenetic state of the histone proteins around which DNA is wrapped. Activation sparks the addition of acetyl groups to histones, which in turn loosen their grip on DNA enhancers, allowing them to be switched on. Repression, on the other hand, removes this acetylation mark and prevents the switch from ever being flipped. "Through this balance between forces you can shift an enhancer more easily from inactivity to activity," Dr. Zeitlinger says. Enhancer activation and repression are known to occur both in the fruit fly Drosophila melanogaster and in mammals. But repression is much less studied in mammals.

December 15th

Domestic Horses Signal Humans When Faced with an Insoluble Task

Research Fellow Monamie Ringhofer and Associate Professor Shinya Yamamoto (Kobe University Graduate School of Intercultural Studies) have proved that when horses face unsolvable problems they use visual and tactile signals to get human attention and ask for help. The study also suggests that horses alter their communicative behavior based on humans' knowledge of the situation. These findings were published in the online version of Animal Cognition on November 24, 2016. The article is titled “Domestic Horses Send Signals to Humans When They Face an Unsolvable Task.” Communicating with other individuals in order to get information about foraging sites and predators is a valuable survival skill. Chimpanzees, who are evolutionarily close to humans, are especially skilled at understanding others. Studies suggest that chimpanzees distinguish the attentional states of other individuals (seeing or not seeing), and they are also able to understand others' knowledge states (knowing or not knowing). Some domestic animals are also very good at communicating with humans - recent studies of dogs have revealed that they are excellent at understanding various human gestures and expressions. It is thought that these abilities were influenced by the domestication process. Because they were domesticated 6000 years ago, horses have contributed to human society in various shapes and forms, from transport to companionship. Horse-riding has recently drawn attention for its positive effects on our physical and mental health. The high social cognitive skills of horses towards humans might partially explain why humans and horses have a collaborative relationship today. However, the scientific evidence for this ability is still scarce.

December 13th

Exosome Diagnostics Announces First Instrument for Point-of-Care Liquid Biopsy

On December 8, 2016, Exosome Diagnostics, Inc., announced today that it has developed the first instrument for exosomal protein (exoProtein) capture and analysis directly from any biofluid. The capabilities of this system will revolutionize drug development and point-of-care diagnostics using liquid biopsy. The specifications of the instrument are as follows: no up-front sample prep is required; ten microliters of biofluid input; label-free detection; four-minute run time; high sensitivity and specificity (100x more sensitive than ELISA); and small desktop footprint (12” x 16” x 18”) - optimal for clinical laboratories System placement and consumables will drive significant incremental revenues in 2017. In addition, the system will drive additional CDx partnerships and novel target identification. Analysis of low-abundant proteins in plasma is complicated and often drowned out by the background. “Exosomes carry membrane-associated proteins that are not normally released in blood. This new platform uniquely enables detection of low-abundant membrane proteins, even in the background of complex plasma proteins. exoProteins are important biomarkers for drug development, disease monitoring, and the rapidly expanding field of immuno-oncology” stated Dr. Johan Skog, Chief Scientific Officer at Exosome Diagnostics. Signatures in ovarian cancer and other disease states have been published in peer-reviewed journals using this instrument. “Given the current unmet need in point-of-care diagnostics, this instrument has been designed with a simple workflow for clinicians. Development of this instrument was led by our engineering and regulatory teams, providing a clear regulatory path forward.

Researchers Identify Biochemical Mechanism Behind a Rare, Painful Genetic Disease

A team of researchers at NIH has uncovered a possible biochemical mechanism behind a rare, painful genetic disorder called ACDC disease, which causes calcium buildup in the arteries. The finding could lead to the first effective treatment for the potentially debilitating condition and might provide insight into other vascular diseases, including atherosclerosis, the researchers say. The study was published in the December 13, 2016 issue of Science Signaling. ACDC is short for arterial calcification due to deficiency of CD73 (image). (CD73 is an enzyme that reduces calcium buildup in the arteries). The disease targets the hands and feet and can limit a person's ability to walk and exercise. The Science Signaling article is titled “Increased Activity Of TNAP Compensates for Reduced Adenosine Production and Promotes Ectopic Calcification in the Genetic Disease ACDC.” In the current study, researchers discovered how a deficiency of CD73 triggers a cascade of adverse biochemical events that leads to increased calcium buildup. That discovery quickly fueled progress on a possible treatment. Scientists generated stem cells from the skin of patients with ACDC disease and injected them into mouse models. They found that tissue formed in the mice by the patient-derived cells calcified over time. The researchers showed that treating these mice with several drugs including etidronate, which is used to strengthen bone in certain diseases involving bone loss, helped reduce calcification of the human tissue. The findings suggest that a similar strategy might help treat people with ACDC disease. Senior author of the article was Manfred Boehm, M.D., Senior Investigator, Laboratory of Cardiovascular Regenerative Medicine, NHLBI.

Research ID’s Molecular Basis for Common Congenital Defect

Scientists at Sanford Burnham Prebys Medical Discovery Institute (SBP) have discovered a molecular cause of hydrocephalus, a common, potentially life-threatening birth defect in which the head is enlarged due to excess fluid surrounding the brain. Because the same molecule is also implicated in Down's syndrome, the finding, published on December 13, 2016 in the Journal of Neuroscience, may explain the ten-fold increased risk of hydrocephalus in infants born with Down's. "We found that deleting the gene for sorting nexin 27, or SNX27, which plays a major role in the development of Down's syndrome, causes hydrocephalus," said Huaxi Xu, Ph.D., the Jeanne and Gary Herberger Leadership Chair of SBP's Neuroscience and Aging Research Center. "The mechanism we uncovered likely only accounts for a fraction of hydrocephalus cases, but we identified potential non-surgical treatments for these cases that deserve further study." Hydrocephalus affects one or two of every 1,000 births. Some causes of hydrocephalus are known, including several well-characterized brain and skull malformations that block fluid outflow, but it can also arise in the absence of other obvious abnormalities. The condition is treated by surgically inserting a shunt to divert the fluid to another part of the body where it can be absorbed. However, these tubes can become infected, and about half the time, they fail, causing headaches, vomiting, fever, and irritability until the shunt is replaced. The new study followed up on prior results from Dr. Xu's lab showing that SNX27, a protein that regulates traffic of other proteins within cells, is found at lower than normal levels in the brains of individuals with Down's syndrome. They also found that inactivating the gene for SNX27 in mice causes learning and memory problems similar to those in Down's. Here, Dr.

Kelp Beats the Heat--Using Long-Term Ecological Data, Marine Scientists Evaluate Sentinel Status of Giant Kelp During Recent Marine Heat Wave

In early 2014, when a large-scale marine heat wave in the Pacific Ocean produced temperature anomalies greater than anything seen since recordkeeping began in the early 1900s, marine scientists saw something else, too: opportunity. Ocean researchers at UC Santa Barbara quickly seized the chance to evaluate the sentinel status of giant kelp forests along the Southern California coastline as an indicator of climate change. They expected forests of giant kelp (Macrocystis pyrifera), known to be sensitive to such increases, as well as to the resulting low-nutrient conditions, to respond quite rapidly to a rise in water temperature. However, to the scientists' surprise, that was not the case. The kelp, they discovered, was all right. Their findings appear in the journal Nature Communications. The article is titled “Extreme Warming Challenges Sentinel Status of Kelp Forests As Indicators of Climate Change.” "The response that we saw in kelp was really no different than what we'd seen in our temporal record," explained lead author Daniel Reed, Ph.D., Deputy Director of UCSB's Marine Science Institute (MSI). "The values were low, but not necessarily lower than what we'd seen during cool-water years." Giant kelp does not have the capacity to store nutrients for very long (only about three weeks), and in the absence of new nutrients, the kelp cannot support its rapid growth of about 2 percent per day. The standing biomass -- the amount of living kelp present at a given time -- is relatively transitory and turns over about seven times a year. "Each frond only lives about three to four months," Dr. Reed said.

Scientists Discover New Bone-Forming Growth Factor That Reverses Osteoporosis in Mice

A team of scientists at the Children’s Medical Center Research Institute at the University of Texas (UT) Southwestern (CRI) discovered a new bone-forming growth factor, Osteolectin (Clec11a), which reverses osteoporosis in mice and has implications for regenerative medicine. Although Osteolectin is known to be made by certain bone marrow and bone cells, CRI researchers are the first to show Osteolectin promotes the formation of new bone from skeletal stem cells in the bone marrow. The study, published online on December 13, 2016 in eLife, also found that deletion of Osteolectin in mice causes accelerated bone loss during adulthood and symptoms of osteoporosis, such as reduced bone strength and delayed fracture healing. The article is titled “Clec11a/osteolectin Is an Osteogenic Growth Factor That Promotes the Maintenance of the Adult Skeleton.” “These results demonstrate the important role Osteolectin plays in new bone formation and maintaining adult bone mass. This study opens up the possibility of using this growth factor to treat diseases like osteoporosis,” said Dr. Sean Morrison, who led the team that made the discovery. Dr. Morrison, CRI Director, holds the Mary McDermott Cook Chair in Pediatric Genetics at UT Southwestern Medical Center, and the Kathryne and Gene Bishop Distinguished Chair in Pediatric Research at Children’s Research Institute at UT Southwestern. Osteoporosis, a progressive bone disease characterized by decreased bone mass and an increase in fractures, affects over 200 million people worldwide. Most existing therapies such as bisphosphonate drugs reduce the rate of bone loss, but they do not promote new bone growth. Teriparatide (PTH) is the only agent currently approved for the formation of new bone, but its use is limited to two years due to a potential risk of osteosarcoma.

December 12th

Researchers Find Enzyme Deficiency in Stem Cell-Derived Nerve Cells of Those With Prader-Willi Syndrome, Genetic Condition of Extreme Hunger and Severe Obesity

Columbia University Medical Center (CUMC) researchers have discovered that a deficiency of the enzyme prohormone covertase (PC1) in the brain is linked to most of the neuro-hormonal abnormalities in Prader-Willi syndrome, a genetic condition that causes extreme hunger and severe obesity beginning in childhood. The discovery provides insight into the molecular mechanisms underlying the syndrome and highlights a novel target for drug therapy. The findings were published online on December 12, 2016 in the Journal of Clinical Investigation. The study is titled, "Deficiency in Prohormone Convertase PC1 Impairs Prohormone Processing in Prader-Willi Syndrome." "While we've known for some time which genes are implicated in Prader-Willi syndrome, it has not been clear how those mutations actually trigger the disease," said lead author Lisa C. Burnett, Ph.D., a post-doctoral research scientist in pediatrics at CUMC. "Now that we have found a key link between these mutations and the syndrome's major hormonal features, we can begin to search for new, more precisely targeted therapies." An estimated one in 15,000 people have Prader-Willi syndrome (PWS). The syndrome is caused by abnormalities in a small region of chromosome 15, which leads to dysfunction in the hypothalamus--which contains cells that regulate hunger and satiety--and other regions of the brain. A defining characteristic of PWS is insatiable hunger. People with PWS typically have extreme obesity, reduced growth hormone and insulin levels, excessive levels of ghrelin (a hormone that triggers hunger), and developmental disabilities. There is no cure and few effective treatments for PWS. Dr.

Smallpox, Once Thought an Ancient Disease, May Have Emerged in More Recent Times

New genetic research from an international team including scientists from McMaster University, University of Helsinki, Vilnius University, and the University of Sydney, suggests that smallpox, a pathogen that caused millions of deaths worldwide, may not be an ancient disease but a much more modern killer that went on to become the first human disease eradicated by vaccination. The findings, published in the journal Current Biology, raise new questions about the role smallpox may have played in human history and fuel a longstanding debate over when the virus that causes smallpox, variola, first emerged and later evolved in response to inoculation and vaccination. The article is titled “17th Century Variola Virus Reveals the Recent History of Smallpox.” "Scientists don't yet fully comprehend where smallpox came from and when it jumped into humans," says evolutionary geneticist Hendrik Poinar, senior author of the study, Director of the McMaster Ancient DNA Centre and a researcher with Michael G. DeGroote Institute of Infectious Disease Research. "This research raises some interesting possibilities about our perception and age of the disease." Smallpox, one of the most devastating viral diseases ever to strike humankind, had long been thought to have appeared in human populations thousands of years ago in ancient Egypt, India, and China, with some historical accounts suggesting that the pharaoh Ramses V -who died in 1145 BC--suffered from smallpox.

Study Shows Fasting Kills Cancer Cells of Common Childhood Leukemia

University of Texas (UT) Southwestern Medical Center researchers have found that intermittent fasting inhibits the development and progression of the most common type of childhood leukemia. This strategy was not effective, however, in another type of blood cancer that commonly strikes adults. "This study using mouse models indicates that the effects of fasting on blood cancers are type-dependent and provides a platform for identifying new targets for leukemia treatments," said Dr. Chengcheng "Alec" Zhang, Associate Professor of Physiology at UT Southwestern and senior author of the study, published online on December 12, 2016 in Nature Medicine. The article is titled “Fasting Selectively Blocks Development of Acute Lymphoblastic Leukemia via Leptin-Receptor Upregulation.” "We also identified a mechanism responsible for the differing response to the fasting treatment," he added. The researchers found that fasting both inhibits the initiation and reverses the progression of two subtypes of acute lymphoblastic leukemia, or ALL - B-cell ALL and T-cell ALL. The same method did not work with acute myeloid leukemia (AML), the type that is more common in adults. ALL, the most common type of leukemia found in children, can occur at any age. Current ALL treatments are effective about 90 percent of the time in children, but far less often in adults, said Dr. Zhang, who also holds the Hortense L. and Morton H. Sanger Professorship in Oncology and is a Michael L. Rosenberg Scholar in Medical Research. The two types of leukemia arise from different bone marrow-derived blood cells, he explained. ALL affects B cells and T cells, two types of the immune system's disease-fighting white blood cells. AML targets other types of white blood cells such as macrophages and granulocytes, among other cells.