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Archive - May 2017

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May 12th

Cryo-EM Study Reveals Structural Advantage for Use of C-Type Adenovirus in Gene Therapy

In their quest to replicate themselves, viruses have become awfully good at tricking human cells into pumping out viral proteins. That's why scientists have been working to use viruses as forces for good: to deliver useful genes to human cells and help patients who lack important proteins or enzymes. A team of researchers led by Associate Professor Vijay Reddy at The Scripps Research Institute (TSRI) has now uncovered the structural details that make one virus a better tool for future therapies than its closely related "cousin." As Dr. Reddy and his colleagues reported in the May 10, 2017 issue of Science Advances, the structure of a less prevalent species D adenovirus may work well as a gene-delivery vector because its structure doesn't let it get spirited away to the liver, minimizing liver toxicity. The Reddy lab's study is the first to show the structural details on species D's surface that set it apart from another common subtype of adenovirus, called species C, which does travel to the liver. "Greater understanding of the structures of adenoviruses from different species will help generate better gene therapies and/or vaccine vectors," said Reddy. The Science article is titled “Cryo-EM Structure of Human Adenovirus D26 Reveals the Conservation of Structural Organization Among Human Adenoviruses.” Using an imaging technique called cryo-electron microscopy, the researchers discovered that while these two species of adenoviruses share the same shell-like core, they have different surface structures, which Dr. Reddy called "decorations" or "loops." These loops are key to a virus's behavior. They determine which receptors on human cells the virus can bind to. For species C adenoviruses, specific loops help the virus attach to blood coagulation factors (adaptor proteins) and get targeted to the human liver.

Researchers Find Key Molecule for Iron Transport That Could Lead to New Therapies for Anemia; Molecule Found Naturally in Japanese Cypress Tree Leaves

Scientists have identified a key molecule that could lead to new therapies for anemia and other iron disorders "Without iron, life itself wouldn't be feasible," says Barry Paw, MD, PhD, a co-senior author of a new report in Science and Associate Professor at Harvard Medical School, Dana Farber Cancer Institute, Brigham and Women’s Hospital, and Boston Children’s Hospital . "Iron transport is very important because of the role it plays in oxygen transport in blood, key metabolic processes and DNA replication." New findings reported in the May 12, 2017 issue of Science by a multi-institutional team, including researchers from University of Illinois, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Brigham and Women's Hospital and Northeastern University, could impact a wide range of iron disorders, ranging from iron-deficiency anemia to iron-overload liver disease. The team has discovered that a small molecule found naturally in Japanese cypress tree leaves, hinokitiol, can bypass iron disorders in animals. Dr. Paw, co-senior author on the new Science paper and physician at Dana-Farber/Boston Children's, and members of his lab demonstrated that hinokitiol can successfully reverse iron deficiency and iron overload in zebrafish disease models. As a result, hinokitiol is believed to have significant therapeutic potential. The Science article is titled “Restored Iron Transport by a Small Molecule Promotes Absorption and Hemoglobinization in Animals." Although iron is crucial to many aspects of health, it cannot transport itself without the help of the body's iron-transporting proteins.

May 11th

Scientists ID Human Protein Essential for Human Cytomegalovirus Replication

Scientists have demonstrated that a human protein known as valosin containing protein (VCP) is essential for replication of human cytomegalovirus (HCMV). The findings, published in the open-access journal PLOS Pathogens, identify VCP as a potential new treatment target. The article is titled “The Host Ubiquitin-Dependent Segregase VCP/p97 Is Required for the Onset of Human Cytomegalovirus Replication.” HCMV infects 30 to 100 percent of people worldwide, depending on socioeconomic status. While most remain symptom-free, HCMV can be dangerous or deadly for people with weakened immune systems or for babies infected before birth. Some HCMV treatments exist, but their benefits are limited, and scientists are investigating new ways to treat and prevent infection. To better understand how HCMV replicates during active infection, Dr. Yao-Tang Lin and colleagues at the University of Edinburgh, U.K., performed a search for human genes needed by the virus for replication. They found that reducing the expression of the VCP gene in HCMV-infected human cells significantly reduced viral replication in the cells. Additional experiments showed that, without VCP, HCMV is unable to express a critical gene known as IE2. This viral gene is known to be essential for replication and is thought to play a major role when the virus switches from symptom-free, dormant infection to active infection. Given the critical importance of VCP for HCMV replication, the scientists tested the effects of a chemical known to inhibit the activity of VCP. They found that the inhibitor, known as NMS-873, reduced HCMV replication and IE2 expression in infected cells. NMS-873 appeared to be ten times more potent than Ganciclovir, the most commonly used antiviral treatment for HCMV.

Study Shows Age-Associated B Cells (ABCs) Drive Autoimmune Disease

Researchers at National Jewish Health have identified a trigger for autoimmune diseases such as lupus, Crohn's disease and multiple sclerosis. The findings, published in the April 2017 issue of the Journal of Clinical Investigation, help explain why women suffer autoimmune disease more frequently than men, and suggest a therapeutic target to prevent autoimmune disease in humans. The open-access article is titled “B cells Expressing the Transcription Factor T-Bet Drive Lupus-Like Autoimmunity.” "Our findings confirm that age-associated B cells (ABCs) drive autoimmune disease," said Kira Rubtsova, PhD, an instructor in biomedical science at National Jewish Health. "We demonstrated that the transcription factor T-bet inside B cells causes ABCs to develop. When we deleted T-bet inside B cells, mice prone to develop autoimmune disease remained healthy. We believe the same process occurs in humans with autoimmune disease, more often in elderly women." Autoimmune diseases occur when the immune system attacks and destroys the organs and tissue of its own host. Dozens of autoimmune diseases afflict millions of people in the United States. Several autoimmune diseases, including lupus, rheumatoid arthritis and multiple sclerosis strike women 2 times to 10 times as often as men. Overall, about 80 percent of autoimmune patients are women. There is no cure for autoimmune disease. B cells are important players in autoimmune disease. The National Jewish Health research team, led by Chair of Biomedical Science Philippa Marrack, PhD, previously identified a subset of B cells that accumulate in autoimmune patients, and in autoimmune and elderly female mice.

Gene Sequencing Study Reveals Unusual Mutations in Endometriosis

Using gene sequencing tools, scientists from Johns Hopkins Medicine and the University of British Columbia have found a set of genetic mutations in samples from 24 women with benign endometriosis, a painful disorder marked by the growth of uterine tissue outside of the womb. The findings, described in the May 11, 2017 issue of the New England Journal of Medicine, may eventually help scientists develop molecular tests to distinguish between aggressive and clinically "indolent," or non-aggressive, types of endometriosis. The NEJM article is titled “Cancer-Associated Mutations in Endometriosis without Cancer.” "Our discovery of these mutations is a first step in developing a genetics-based system for classifying endometriosis so that clinicians can sort out which forms of the disorder may need more aggressive treatment and which may not," says Ie-Ming Shih, MD, PhD, the Richard W. TeLinde Distinguished Professor in the Department of Gynecology & Obstetrics at the Johns Hopkins University School of Medicine and Co-Director of the Breast and Ovarian Cancer Program at the Johns Hopkins Kimmel Cancer Center. Endometriosis occurs when tissue lining the uterus forms and grows outside of the organ, most often into the abdomen. The disease occurs in up to 10 percent of women before menopause and half of those with abdominal pain and infertility problems. In the 1920s, Johns Hopkins graduate and trained gynecologist John Sampson first coined the term "endometriosis" and proposed the idea that endometriosis resulted when normal endometrial tissue spilled out through the fallopian tubes into the abdominal cavity during menstruation. The new study, Dr. Shih says, challenges that view.

May 10th

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.

Study of 80 Birch Genomes Across Europe

Forests of silver birch stretch across Europe, and they are a wonder to behold: stands of slender, white-barked trees sheltering vast swathes of earth.But these woodlands also have value beyond their beauty: they are an economic asset, generating raw material for papermaking, construction, furniture-building, and more. A new study illuminates the evolutionary history of birch, a tree that has not been studied much by scientists despite its commercial value. "Birch is one of the major trees for forest products in the Northern Hemisphere. Others, like spruce, pine, and poplar, all have genome sequences, but birch did not -- until now," says University at Buffalo biologist Victor Albert, PhD, who co-led the Finnish-funded project with Dr. Jaakko Kangasjärvi, Dr. Ykä Helariutta, Dr. Petri Auvinen, and Dr. Jarkko Salojärvi of the University of Helsinki in Finland. Dr. Helariutta is also a professor at the University of Cambridge. "We sequenced about 80 individuals of one species, Betula pendula, the silver birch," says Dr. Kangasjärvi. "We sampled populations of this species throughout its range, so up and down Finland, down to Germany, over to Norway and Ireland, and all the way up to Siberia." By analyzing the 80 genomes sequenced, the team was able to identify genetic mutations that may be of interest to industry, including mutations that may affect how well birch trees grow and respond to light at different latitudes and longitudes and under different environmental conditions. The research could be a starting point for breeding trees that better meet the needs of various industries. "What makes a birch tree hardy in different environments? A tree in Finland may die if you plant it in Siberia because plants have local adaptations -- specific genetic mutations -- that help them survive where they are found," Dr. Helariutta says.

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.”