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Archive - Oct 2015

October 3rd

Glucose Starvation in Cardiomyocytes Enhances Exosome Secretion and Promotes Angiogenesis in Endothelial Cells

New work by researchers in Spain indicates that exosome-mediated communication between cardiomyocytes (CMs) and endothelial cells (ECs) establishes a functional relationship that could have potential implications for the induction of local neovascularization during acute situations such as cardiac injury. The researchers noted that it has been well known that CMs and ECs have an intimate anatomical relationship that is essential for maintaining normal development and function in the heart. However, the scientists said that little had been known about about the mechanisms that regulate cardiac and endothelial crosstalk, particularly in situations of acute stress when local active processes are required to regulate endothelial function. Consequently, the research team examined whether CM-derived exosomes could modulate endothelial function. Under conditions of glucose deprivation, immortalized H9C2 CMs increase their secretion of exosomes. CM-derived exosomes are loaded with a broad repertoire of miRNAs and proteins in a glucose-availability-dependent manner. Gene Ontology (GO) analysis of exosome cargo molecules identified an enrichment of biological process that could alter EC activity. The researchers observed experimentally that addition of CM-derived exosomes to ECs induced changes in the transcriptional activity of pro-angiogenic genes. In addition, the scientists demonstrated that incubation of H9C2-derived exosomes with ECs induced proliferation and angiogenesis in the ECs. Thus, they concluded that exosome-mediated communication between CMs and ECs establishes a functional relationship that could have potential implications for the induction of local neovascularization during acute situations such as cardiac injury.

Urine miRNAs Found Mainly in Exosomes in Patients with Systemic Lupus Erythematosus (SLE); One Exosomal miRNA Distinguishes Acute Lupus Nephritis

Researchers from the INCLIVA Biomedical Research Institute in Valencia, Spain, together with collaborators, have shown that microRNAs (miRNAs) in the urine of patients with systemic lupus erythematosus (SLE) are found mainly in exosomes, and the most significant SLE-associate increase in a specific miRNA associated with SLE was found in miR-146a (100-fold increase) and this increase was specifically in patients with active lupus nephritis. Among the exosomal miRNAs tested, only the miR-146a discriminated the presence of active lupus nephritis. The research was published online on September 21, 2015 in PLOS ONE. The article was titled “Increased Urinary Exosomal MicroRNAs in Patients with Systemic Lupus Erythematosus.” In their work, the research team quantified specific miRNAs in the urine of patients with SLE (n = 38) and healthy controls (n = 12) by quantitative reverse-transcription PCR in cell-free urine, exosome-depleted supernatant, and exosome pellet obtained by ultracentrifugation. In the ontrol group, miR-335* and miR-302d were consistently higher in exosomes than in exosome-depleted supernatant, and miR-200c and miR-146a were higher in the cell-free fraction. In SLE patients, all urinary miRNAs tested were mainly in exosomes, with lower levels outside them (p<0.05 and p<0.01, respectively). The researchers noted that this pattern was especially relevant in patients with active lupus nephritis compared to the control group or to SLE patients in absence of lupus nephritis, with miR-146a being the most augmented (100-fold change, p<0.001). Among the exosomal miRNAs tested, only the miR-146a discriminated the presence of active lupus nephritis. The researchers concluded that urinary miRNAs are contained primarily in exosomes in SLE, and the main increment was found in the presence of active lupus nephritis.

Computational Geneticist at University of Chicago Named 2015 MacArthur Fellow: Awarded $625,000 Stipend

John Novembre, Ph.D., a computational geneticist at the University of Chicago, who studies the evolutionary history and genetic diversity of human populations, has been named a 2015 MacArthur Fellow. Awarded by the John D. and Catherine T. MacArthur Foundation to individuals for their exceptional creativity, significant accomplishments, and potential for important future achievements, MacArthur Fellowships are among the most prestigious honors in academia and the creative arts. The fellowship comes with an unrestricted stipend of $625,000 over the next five years that provides recipients the freedom to pursue creative endeavors. Dr. Novembre, Associate Professor in Human Genetics, is one of 24 new MacArthur Fellows drawn from diverse fields ranging from stem cell biology to puppetry. He is the 34th current or former University of Chicago faculty member to receive the award. “It is a profound honor to be named a MacArthur Fellow, and I look forward to living up to the foundation’s call to fulfill our creative potential,” Dr. Novembre said. “I’m still processing it all, but I hope to use the fellowship to fuel my creativity and explore exciting new projects, such as collecting and analyzing ancient DNA data.” Dr. Novembre’s research focuses on the development of powerful mathematical and statistical algorithms that shed light on the evolutionary history of populations, particularly on the processes that shaped human genetic diversity and disease.

October 3rd

Surprisingly, Generalist Caterpillar Sequesters More of One Toxic Chemical from Vismia Poisonous Plants Than Does Specialist Caterpillar That Feeds Exclusively on These Toxic Plants

Scientists at the Smithsonian Tropical Research Institute (STRI) in Panama compared the diets of two caterpillar species, expecting that the caterpillar that exclusively consumed plants containing toxic chemicals would more easily incorporate toxins into its body than the one with a broad diet. They found just the opposite. The new finding, published online on August 20, 2015 in the Journal of Chemical Ecology, flies in the face of a long-held theory that specialist insects are better adapted to use toxic plant chemicals than non-specialists. The discovery opens new avenues for understanding plant-insect co-evolution--an ongoing arms race of plants producing new defense chemicals and insects finding ways around them. Toxic plant chemicals also have potential medical applications against microbes and cancer cells. The Journal of Chemical Ecology article is titled “Differential Sequestration of a Cytotoxic Vismione from the Host Plant Vismia baccifera by Periphoba arcaei and Pyrrhopyge thericles.” The tropical plant Vismia baccifera protects itself by producing a number of repellent chemicals, including three compounds that are toxic to living cells. Few plant-eating insects can stomach such a cocktail, but for those that can, the advantages are clear--less competition for a meal, and a chemical toolkit they can use in their own defense. Skipper butterfly, Pyrrhopyge thericles, caterpillars only eat plants in the genus Vismia. The caterpillars of a large moth, Periphoba arcaei, have a much broader diet, including Vismia plants and many others. Both are brightly colored caterpillars, one with flamboyant stripes, and the other blue-green with bristles, and they teach predators to associate their striking looks with toxicity--a defensive warning system known as aposematism.

Pacific Biosciences Launches New Nucleic Acid Sequencing Platform Based on Its Single Molecule, Real-Time (SMRT) Technology; Sequel™ System Said to Offer Significantly Higher Throughput, Reducing Project Costs and Timelines

On September 30, 2015, Pacific Biosciences of California, Inc., (NASDAQ:PACB), a pioneer and leader in long-read sequencing using its Single Molecule, Real-Time (SMRT®) Technology, announced that it has launched a new nucleic acid sequencing platform. The Sequel™ System (photo) provides higher throughput, more scalability, a reduced footprint and lower sequencing project costs compared to the PacBio® RS II System, while maintaining the existing benefits of the company’s SMRT Technology, the company said. Pacific Biosciences will showcase the new product at the American Society of Human Genetics (ASHG) 2015 annual meeting taking place in Baltimore, Maryland from October 6 through October 10. The core of the Sequel System is the capacity of its re-designed SMRT Cells, which contain one million zero-mode waveguides (ZMWs) at the product’s launch, compared to 150,000 ZMWs in the earlier SMRT Technology instrument, the PacBio RS II. Active individual polymerases are immobilized within the ZMWs, providing windows to observe and record DNA sequencing in real time. With approximately seven times as many reads per SMRT Cell as the PacBio RS II, customers should be able to realize lower costs and shorter timelines for sequencing projects, with approximately half the up-front capital investment compared to previous technology. The Sequel System also occupies a smaller footprint — less than one-third the size and weight — compared to the PacBio RS II. Because the new system is built on the Pacific Biosciences established SMRT Technology, most aspects of the sequencing workflow are unchanged.

Researchers Achieve 26-Hour Rapid Whole-Genome Sequencing In Critically Ill Infants; Fastest Turnaround Time in World; STAT-Seq Test IDs Mutations for 5,300 Genetic Diseases; Edico Data Analysis & Illumina Sequencer Among Keys to Record Speed

A study published on September 30, 2015 in an open-access article in Genome Medicine describes how researchers at Children's Mercy Kansas City, and colleagues, have cut in half the time needed for rapid whole-genome sequencing and genetic diagnosis in critically-ill infants, using a test that is called STAT-Seq. Through a variety of enhancements, the Center for Pediatric Genomic Medicine at Children's Mercy completed the STAT-Seq test in 26 hours compared to 50 hours, improving on a turnaround time that was already the fastest available in the world. The STAT-Seq test can identify mutations across the genome associated with approximately 5,300 known genetic diseases, and in some cases even identify previously unknown genetic diseases. In contrast, standard clinical practice calls for an array of genetic tests to be performed, which are time-consuming, costly and can only test for a limited set of disorders. The Genome Medicine article is titled “A 26-Hour System of Highly Sensitive Whole genome sequencing for emergency management of genetic diseases.” Lead authors of the study were Neil Millerand Emily Farrow, Ph.D., C.G.C., of Children's Mercy Kansas City, and senior author was Stephen Kingsmore, D.Sc., who was previously also at Children’s Mercy, but recently became the inaugural CEO of the Genomics Institute at Rady Children’s Hospital San Diego. "We believe rapid genome sequencing of critically-ill infants with suspected genetic diseases is a breakthrough application for genomic medicine," said Dr. Farrow, Director of Laboratory Operations and a genetic research scientist at the Center for Pediatric Genomic Medicine at Children's Mercy.

20 miRNAs in Exosome-Enriched Plasma Identified As Potential Biomarkers for Alzheimer’s Disease

Researchers at the University of Illinois at Chicago (UIC), and collaborators, have identified 20 potentially useful microRNA biomarkers for Alzheimer’s disease (AD) in their analysis of plasma fractions, enriched in exosomes by differential centrifugation, from 35 AD patients and 35 controls. Seven of these miRNAs were highly informative in a machine learning model for predicting AD status of individual samples with 83–89% accuracy. The researchers noted that perhaps the most interesting single miRNA was miR-342-3p, which was (a) expressed in the AD group at about 60% of control levels, (b) highly correlated with several of the other miRNAs that were significantly down-regulated in AD, and (c) also reported to be down-regulated in AD in two previous studies. The miRNAs were analyzed by expression measurement using Illumina deep sequencing technology. The scientists said that their findings warrant replication and follow-up with a larger cohort of patients and controls who have been carefully characterized in terms of cognitive and imaging data, other biomarkers (e.g., CSF amyloid and tau levels) and risk factors (e.g., apoE4 status), and who are sampled repeatedly over time. They further noted their belief that integrating miRNA expression data with other data is likely to provide informative and robust biomarkers in Alzheimer disease. This work was published on October 1, 2015 in the open-access journal PLOS ONE. The article is titled “Plasma Exosomal miRNAs in Persons with and without Alzheimer Disease: Altered Expression and Prospects for Biomarkers.” This BioQuick summary was written by Editor & Publisher Michael D. O’Nell. This research has also been reported by Genome Web (see link below). The image shows exsomes released by a cell.

International Team Seeks to Revolutionize Understanding of How Gene Variants Affect Organ Transplant Outcomes

Nearly 30,000 organ transplants are performed in the United States every year. These operations routinely extend lives, but the success of these procedures continues to be limited by problems that arise when the recipient's immune system rejects the new organ and by other complications. Now, a large international team of transplant surgeons and scientists, co-led by researchers from the Perelman School of Medicine at the University of Pennsylvania (Penn), has come together to investigate the genetic factors behind transplant successes and failures. The project, involving more than three dozen research institutions around the world, is called the International Genetics & Translational Research in Transplantation Network (iGeneTRAiN). Their efforts are detailed in a pair of papers published in Genome Medicine (open-access article) on October 1, 2015 and in Transplantation (in press). The Genome Medicine article is titled “Concept and Design of a Genome-Wide Association Genotyping Array Tailored for Transplantation-Specific Studies.” The Transplantation article is titled “Design and Implementation of the International Genetics & Translational Research in Transplantation Network (iGeneTRAiN). "The genetic datasets we've put together in this project are by far the largest ever assembled in transplant genomics," said Brendan J. Keating, D.Phil., an Assistant Professor of Transplant Surgery at Penn Medicine. "We want to revolutionize our understanding of how genetic variants affect transplant outcomes, and use those findings to improve these outcomes in the future." Dr. Keating is senior author of the Genome Medicine publication and first author of the Transplantation publication.

October 2nd

Drug in Class of Anti-Cancer Compounds (HDAC Inhibitors) Appears to Sharpen Memory

Can you imagine a drug that would make it easier to learn a language, sharpen your memory, and help those with dementia and Alzheimer's disease by rewiring the brain and keeping neurons alive? New Rutgers University research published in the September 23, 2015 issue of the Journal of Neuroscience found that a drug (RGFP966)administered to rats, made them more attuned to what they were hearing, able to retain and remember more information, and able to develop new connections that allowed these memories to be transmitted between brain cells. The Journal of Neuroscience article is titled “Histone Deacetylase Inhibition via RGFP966 Releases the Brakes on Sensory Cortical Plasticity and the Specificity of Memory Formation.” "Memory-making in neurological conditions like Alzheimer's disease is often poor or absent altogether, once a person is in the advanced stages of the disease," said Dr. Kasia M. Bieszczad, the lead author and Assistant Professor in Behavioral and Systems Neuroscience in the Department of Psychology at Rutgers. "This drug could rescue the ability to make new memories that are rich in detail and content, even in the worst-case scenarios." What happens with dementias such as Alzheimer's is that brain cells shrink and die because the synapses that transfer information from one neuron to another are no longer strong and stable. There is currently no therapeutic treatment available that reverses this situation. The drug being tested in this animal study is among a class known as histone deacetylase (HDAC) inhibitors, now being used in cancer therapies to stop the activation of genes that turn normal cells into cancerous ones. HDAC inhibitors, in general, act to transcriptionally activate certain genes and to inactivate certain other genes.

Two New Mutations Found in Dogs with Achromatopsia Support Gene Therapy Approach to Curing This Genetic Vision Disorder in Humans and Dogs; Supercomputer Analysis Reveals the Mutations Destabilize CNG Ion Channel Essential to Light Signal Transduction

Cyclic-nucleotide-gated (CNG) ion channels are key mediators underlying signal transduction in retinal and olfactory receptors. Genetic defects in the CNGA3 and CNGB3 genes, encoding two structurally related subunits of cone CNG channels, lead to achromatopsia. This is a congenital, autosomal recessive retinal disorder that manifests by cone photoreceptor dysfunction, severely reduced visual acuity, impaired or complete color blindness, and photophobia. The disorder often strikes people early in life, and currently there is no cure for the condition. In human achromatopsia, nearly 100 different mutations have already been identified in the CNGA3 gene alone. Famously, achromatopsia was the subject of a book titled “The Island of the Colorblind,” by neurologist/author Oliver Sacks, M.D. (see image of book jacket). In this work, Dr. Sacks described the surprising prevalence of a particular rare form of the disease (complete achromatopsia) on the remote Pacific atoll of Pingelap. It is believed that the disease on Pingelap can be traced back to a so-called “founder mutation” passed down from an early ruler, who was one of just approximately 20 Pingelap survivors of a 1775 typhoon that hit the atoll. Signifcant inbreeding amongst the Pingelapese is believed to be the reason that much of the island’s small population now suffers from the autosomal recessive disorder, which, in more outbred populations, is relatively rare. One of the most promising avenues for developing a cure for achromatopsi is believed to be gene therapy, but to develop such therapies it is necessary to create animal models of disease that closely replicate the human condition. In a new study, a collaboration between University of Pennsylvania (Penn) and Temple University scientists has identified two naturally occurring genetic mutations in dogs that result in achromatopsia.