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November 12th, 2015

Single-Molecule, Real-Time (SMRT) Sequencing Using PacBio RS II Sequencing System Enables Genome Sequencing of Drought-Tolerant “Resurrection Plant” The Effort Is Part of PacBio’s “Most Interesting Genome in the World" Grant Program

A new paper published online on November 11, 2015 in an open-access article in Nature reports the virtually complete draft genome sequence of Oropetium thomaeum, a grass species that can re-grow after exposed to extreme drought when water again becomes available. The plant's 245-Mb genome was analyzed with 72X coverage on the PacBio® RS II Sequencing System by researchers at the Donald Danforth Plant Science Center (DDPSC) in St. Louis, Missouri. The resulting assembly has an accuracy of 99.99995% and includes telomere and centromere sequences, long terminal repeat retrotransposons, tandem duplicated genes, and other difficult-to-assemble genomic elements. This plant was sequenced through the Pacific Biosciences "Most Interesting Genome in the World" grant program designed to help scientists determine the biological mechanisms behind its extreme drought tolerance for potential application in crop improvement. The Nature article is titled “Single-Molecule Sequencing of the Desiccation Tolerant Grass Oropetium thomaeum.” The senior author of the Nature article is is Todd Mockler, Ph.D., Associate Member, DDPSC, Geraldine and Robert Virgil Distinguished Investigator, DDPSC; and the lead authors are Post-Doctoral Associate Robert VanBuren, Ph.D., DDPSC; and Doug Bryant, Ph.D., DDPSC. Scientists from numerous other institutions (see below) also contributed to this effort. "We submitted the idea to sequence the resurrection grass Oropetium thomaeum to PacBio because it has the smallest known genome among the grasses. Having the genomic data of a highly drought-tolerant species is really powerful in facilitating crop improvement, and providing a valuable resource for the plant comparative genomics community.

Longer Reproductive Period, Contraceptive Use, IUD Use All Associated with Better Cognitive Function in Elderly Women; Shorter Reproductive Period, More Full-Term Pregnancies, & No Incomplete Pregnancies All Linked to Worse Cognitive Function

Researchers led by Professor Jun-Fen Lin at the Zhejiang Provincial Center for Disease Control and Prevention in China have found that reproductive history, an important modifier of estrogen exposure across women's lifetimes, is associated with risk of cognitive impairment in post-menopausal women. These findings are published online on September 28, 2015 in the Journal of Alzheimer's Disease. In particular, the scientists found a longer reproductive period (menarche to menopause) was associated with significantly better cognitive function in elderly women. On the other hand, shorter reproductive period, higher number of full-term pregnancies, and no incomplete pregnancies are all significantly associated with increased risk of cognitive impairment. Further, the use of contraceptives and/or IUDs was associated with decreased risk of cognitive impairment. The article is titled “Reproductive History and Risk of Cognitive Impairment in Elderly Women: A Cross-Sectional Study in Eastern China.” Professor Lin notes that post-menopausal women carry an increased risk of developing Alzheimer's disease (AD) than age-matched men, probably due to the marked reduction of estrogen level that occurs following menopause. Animal and in vitro studies have identified that estrogen has several possible neuroprotective effects on cognitive function. There has been substantial research on the association between reproductive history, as an important modifer of estrogen exposure, and risk of cognitive impairment. However, there are still inconsistencies in some epidemiological and clinical studies. Only a few studies have been conducted in Chinese populations. The Zhejiang Major Public Health Surveillance Program (ZPHS) is a community-based cohort study focusing on aging and health among elderly in Zhejiang, China.

Mayo Clinic Researchers ID Completely Novel Mechanism for Predisposition to Type 2 Diabetes; Understanding Glucagon-Suppressing Effect of TCF7L2 Gene Variant May Lead to Novel Therapies

Researchers at the Mayo Clinic in Rochester, Minnesota, together with colleagues from the Universita’ di Padova in Italy, have discovered an unexpected effect from a gene already known to increase diabetes risk. The scientists had assumed that the specific allele in the gene TCF7L2 that increases the risk of type 2 diabetes, impairs insulin production in response to increased insulin resistance. Some slight evidence of that was found in the current Mayo Clinic study, but more significantly, the researchers discovered that this variant impaired a person’s ability to balance blood sugar (glucose) by suppressing glucagon – the hormone that raises the level of glucose in the bloodstream. The findings were published online on November 2, 2015, in the journal Diabetes. The article is titled “TCF7L2 Genotype and α-Cell Function in Nondiabetic Humans.” “This was surprising. It demonstrates a completely novel mechanism of predisposition to diabetes that could lead to novel therapies,” says Adrian Vella, M.D., Mayo Clinic endocrinologist and senior author of the study. “Ultimately, this sheds new light on how this gene actually predisposes to diabetes.” Dr. Vella notes that more-detailed clinical studies need to be done to confirm the finding, as well as to better understand how this affects diabetes in more heterogeneous populations over the long term.

[Mayo Clinic press release] [Diabetes abstract]

November 11th

Exosome-Based Approach to Diagnose Lupus in Patients with Renal Impairment; High Levels of miRNA-146a in Urine-Derived Exosomes from Patients May Be Diagnostic for This Pathology

Researchers at the INCLIVA Biomedical Research Institute in Valencia, Spain, together with collaborators, have demonstrated the presence of extracellular vesicles (EVs) in the urine of patients diagnosed with lupus and renal impairment (lupus nephritis) and shown that exosomes (a subset of EVs) in this urine contain unusually high levels of microRNA-146a (miR-146a) that may be diagnostic for this pathology. The work was originally published online on September 21, 2015 in the open-access journal PLOS ONE. This article was titled “Increased Urinary Exosomal MicroRNAs in Patients with Systemic Lupus Erythematosus." A related review article titled “Extracellular Vesicles as Biomarkers of Systemic Lupus Erythematosus,” was published online at about the same time in the open-access journal Disease Markers. Lupus (systemic lupus erythematosus or SLE) is a chronic autoimmune disease that can affect almost every organ of the body, joints, kidneys, heart, skin, blood vessels, lungs, etc., whose cause is unknown. It is a very heterogeneous disease, with symptoms that come and go in outbreaks, hence the complexity of diagnosis. To date, lupus has no single diagnostic technique that has become final. The diagnosis is mainly based on symptoms, clinical findings, and complementary laboratory tests. It is a disease that most often affects women, at a time of life in which they are fertile, between 20 and 40 years. According to the Spanish Society of Rheumatology, lupus currently affects about 40,000 people in Spain. Coordinated by the Scientific Director of the INCLIVA Research Institute, Josep Redon, M.D., Ph.D., the project has focused on lupus patients with renal impairment (lupus nephritis), as, in the kidney, microRNAs play an indispensable role in regulating the mechanisms of development and maintenance renal function.

Chimpanzees Separated from Mothers in First Two Years of Life Show Impaired Social Behavior As Adults; Separated Chimps Who Have Since Lived in Social Groups for 40 Years Still Show Impaired Behavior

Wild-caught chimpanzees, who were orphaned and imported from Africa in their early infancy, exhibit impaired social behavior, even as adults, and even when living in social groups for many years. So far, long-term effects of early traumatic experiences on social behavior were known only for humans and socially isolated chimpanzees. An Austrian-Dutch research team, led by Elfriede Kalcher-Sommersguter, Ph.D., of the University of Graz and Jorg Massen. Ph.D., of both the University of Vienna and Utrecht University, published these results online on November 10, 2015 in Scientific Reports. The article is titled “Early Maternal Loss Affects Social Integration of Chimpanzees Throughout Their Lifetime.” Between 1950 and 1980, thousands of chimpanzee infants were wild-caught in West Africa and exported to Europe, Japan, and the USA, where these chimpanzees have been used in biomedical research. But also many zoos have wild-caught chimpanzees: the so-called founder populations. The new study shows that chimpanzees, who were maternally deprived within their first two years of life, were restricted in their social grooming behavior, even decades later. Social grooming is highly important for the establishment and maintenance of social relationships within groups of chimpanzees. "The orphaned chimpanzees had a lower number of partners they groomed and were less active than were chimpanzees reared by their mothers," says Dr. Kalcher-Sommersguter. These deficits in social grooming are found, not only in chimpanzees that were kept singly caged for decades in a biomedical laboratory, before being re-socialized, but also in individuals, who, after being orphaned, grew up in social groups in a zoo.

Are You Listening, Vincent? DNA-Based Living Replica of van Gogh’s Ear on Exhibit in New York

Vincent van Gogh's ear is nearly as famous as his jaw-dropping painting Starry Night. Though its final resting place may never be found (as the legend goes, van Gogh severed off part of his ear and then gave it to a prostitute), museum-goers in New York can now get a look at the next best thing. ArtNet's Sarah Cascone reports that a living replica of van Gogh's ear, created using the artist's DNA, is now on display at Ronald Feldman Fine Arts in New York City. The ear is the gruesome brainchild of Diemut Strebe, a conceptual artist who partnered with scientists from MIT and other universities to create a copy of van Gogh's ear. Using DNA extracted from a stamp licked by the artist, as well as cell samples collected from van Gogh's great-great-grandnephew, Strebe and team created "Sugababe," an artificially grown ear suspended in a clear gel. Visitors don't have to merely look at the ear—they can talk into it, too. On her website, Strebe writes that "the input sound is connected to a computer processor, using a software program to generate simulated nerve impulses from the sound signal in real time. They mimic sounds recorded from an electrode inserted into the auditory nerve, when firing." Noam Chomsky was the first person to speak into the ear after it debuted in Germany last year. In a 2014 story about the bizarre art project, Cascone wrote that the ear is "just one of a limited edition." Neither van Gogh's relatives nor the Dutch museum that bears his name want copies of their own. If "Sugababe" is a slightly macabre commentary on fame and art, it is also a tribute to a world-famous artistic body part.

Sangamo BioSciences & USC Collaborate to Improve Zinc Finger Nuclease-Based Gene Editing for Hematopoietic Stem and Progenitor Cells (HPSCs)

Genome editing techniques for blood stem cells just got better, thanks to a collaborating team of researchers at the University of Southern California and Sangamo BioSciences. In a study published online on November 9, 2015 in Nature Biotechnology, co-first authors Colin M. Exline, Ph.D., from USC, and Jianbin Wang, Ph.D., from Sangamo BioSciences, describe a new, more efficient way to edit genes in blood-forming or "hematopoietic" stem and progenitor cells (HSPCs). The article is titled “Homology-Driven Genome Editing in Hematopoietic Stem and Progenitor Cells Using ZFN mRNA and AAV6 Donors.” "Gene therapy using HSPCs has enormous potential for treating HIV and other diseases of the blood and immune systems," said co-corresponding author Paula Cannon, Ph.D., Professor of Molecular Microbiology and Immunology, Pediatrics, Biochemistry and Molecular Biology, and Stem Cell Biology and Regenerative Medicine at USC. "And using genome editing techniques now allows us to make very precise changes that could repair genetic mutations -- the gene typos -- that can cause disease." Despite the enormous potential of such targeted gene medicine to cure patients, getting genome editing to work has proven challenging in human HSPCs -- especially in the most primitive, least differentiated cells with the greatest ability to become any blood cell type. Dr. Cannon's group, working with a team at Sangamo, has been using "genetic scissors" called zinc finger nucleases (ZFNs) to cut a cell's DNA at a precise location or sequence. The cell normally uses a copy of the cut DNA sequence as a template to repair the DNA break. During this process, there is the opportunity to introduce new DNA sequences or to repair mutations, effectively fooling the cell into making a genetic edit.

Unprecedented Diversity of Extracellular Vesicles (EVs) & Extracellular Compartments Seen in Human Ejaculates; New Cryo-EM & Tomography Study Published in Journal of Extracellular Vesicles

A new article, published online today (November 11, 2015) in an open-access article in the Journal of Extracellular Vesicles (JEV), reports that studies employing cryo-electron microsopy and tomography show what the authors describe as “an unprecedented diversity of extracellular structures in a single body fluid.” The extracellular environment of human ejaculate was revealed to be quite diverse and multi-faceted, with five major sub-categories of extracellular vesicles (EVs) and six sub-categories of extracellular membrane compartments, including lamellar bodies. Furthermore, three morphological features, including electron density, double-membrane bilayers, and coated surface, were described in all subcategories. The authors identified several novel morphological EV subcategories and suggested that clues to their cellular origin might be found in their morphology. This structural inventory, they added, will be important for developing future experimental approaches, and to interpret previously published data to understand the role of EVs in human male fertility. The new JEV article is titled “Diversity of Extracellular Vesicles in Human Ejaculates Revealed by Cryo-Electron Microscopy,” and was authored by Johanna L. Höög, Ph.D., and Jan Lötvall (photo), M.D., Ph.D., both of the University of Gothenburg in Sweden. Senior author Dr. Lotvall is a Swedish clinical allergist and scientist working on translational research primarily in the field of asthma. He is the Director of the Krefting Research Centre at the University of Gothenburg, and Professor of Allergology at this same institution. Dr.

CHOP-Led Study Suggests Safe Viruses Containing DNA Code for TPP1 Gene Can Be Injected into Brain Ventricles to Slow Childhood Batten Disease, a Rare and Currently Fatal Inherited Lysosomal Storage Disease

In a study of dogs, scientists showed that a new way to deliver replacement genes may be effective at slowing the development of childhood Batten disease, a rare and fatal neurological disease. The key may be to inject viruses that carry the codes for the gene products into the ventricles, which are fluid-filled compartments in the center of the brain that serve as a plumbing system. The study, published online on November 11, 2015 in Science Translational Medicine, was partially funded by the NIH. The article is titled “AAV Gene Transfer Delays Disease Onset in a TPP1-Deficient Canine Model of the Late Infantile Form of Batten Disease.” Batten disease is an inherited, autosomal recessive lysosomal storage disorder, one of a group of diseases that causes problems with a cell's ability to break down specific molecules. Early symptoms may include vision loss, subtle changes in personality and behavior, slow learning, clumsiness, or stumbling. Eventually, the children become blind, bedridden, and demented, and typically die within the first decade of their lives. Currently there are no effective treatments. "Our study opens up the possibility of a one-and-done treatment for this form of Batten disease," said Beverly Davidson (photo), Ph.D., Director of the Raymond G. Perelman Center for Cellular and Molecular Therapeutics at Children's Hospital of Philadelphia (CHOP) and the senior author of the study. Working with scientists at the University of Missouri-Columbia, Dr. Davidson's CHOP team focused on the late infantile form of the disease that starts in children 2 to 4 years of age and is most often caused by mutations in the gene for the soluble lysosomal enzyme tripeptidyl peptidase 1 (TPP1), an enzyme that degrades proteins.

Targeting Systolic Blood Pressure to Under 120 Reduces Rate of CVS Events Such As Heart Attack and Heart Failure, As Well As Stroke, by 25% in Those Over 50 with High BP; Rate of Death Reduced 27% by Lowering from 140 to Under 120

NIH-supported researchers are reporting more details on a landmark study that announced preliminary findings (see link below) in September, showing a lower-than-current-standard blood pressure target can save lives and reduce the risk of cardiovascular disease in a group of non-diabetic adults 50 years and older with high blood pressure. Results of the Systolic Blood Pressure Intervention Trial (SPRINT) appear in an open-access article published on November 9, 2015 in the New England Journal of Medicine and were discussed on at the American Heart Association 2015 Scientific Sessions in Orlando, Florida (November 7-11). The NEJM article is titled “A Randomized Trial of Intensive versus Standard Blood-Pressure Control.” Note that the NEJM article includes a video describing the new results—see link below. The study confirms that, in adults 50 years and older with high blood pressure, targeting a systolic blood pressure of less than 120 millimeters of mercury (mm Hg) reduced rates of cardiovascular events, such as heart attack and heart failure, as well as stroke, by 25 percent. Additionally, this target reduced the risk of death by 27 percent—as compared to a target systolic pressure of 140 mm Hg. The NEJM article is accompanied by an editorial titled “Redefining Blood-Pressure Targets — SPRINT Starts the Marathon” (see link below). “SPRINT is part of a proud legacy of NIH-funded clinical trials that will change clinical practice and save lives for decades to come. These results reinforce the compelling public health importance of enhancing the awareness, treatment, and control of hypertension in this country and around the world,” said Gary H. Gibbons, M.D., Director of the National Heart, Lung, and Blood Institute (NHLBI), the primary sponsor of SPRINT.