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Archive - Mar 2014

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March 7th

Europe’s Largest Badger Study Finds Rare Long-Distance Movements of Animals That Often Carry Bovine Tuberculosis

European badgers can make journeys of more than 20 kilometers – distances longer than previously thought – researchers have found. The study, published online on March 6, 2014 in the British Ecological Society's Journal of Animal Ecology, could help scientists design more effective interventions to reduce the spread of bovine tuberculosis (bTB) between badger populations, something that is essential if transmission to cattle is to be controlled. Animal movement is a key part of population ecology, helping us to understand how species use their environment and maintain viable populations. In many territorial species, most movements occur within a home range. Occasionally, however, individuals make long-distance movements. Long-distance movements are important: they ensure that populations mix and do not inbreed, but they can also spread infection between populations. They are also rare, so long-distance movements are difficult to study and require large, long-term studies. Because of their importance as a reservoir for bTB, badgers are a well-studied species. While we know a great deal about how badgers move in and around their home territories, very little is known about rare long-distance movements and nothing about how often badgers travel these long distances. To answer these questions, scientists from Ireland and Canada studied badger movements for four years across a 755 square kilometer area of County Kilkenny in the Republic of Ireland – the largest spatial-scale badger study of its type ever conducted in Europe. Dr. Andrew Byrne of University College Dublin, who led the research while at University College Cork, said: “To study these longer-distance movements, a correspondingly large study area is required.

Researchers Identify RBP4 As a Critical Link between Obesity and Diabetes

It's by now well established that obesity is a major risk factor for diabetes. But what exactly is it about extra body fat that leads to insulin resistance and blood glucose elevation, the hallmarks of diabetes? Over the past several years, Beth Israel Deaconess Medical Center (BIDMC) endocrinologist Barbara Kahn, M.D., has developed a large body of research suggesting that a molecule called retinol binding protein 4 (RBP4) (image) plays a key role in the process. Dr. Kahn's lab was the first to show that elevated levels of RBP4 – previously known only for its role as a transport protein for Vitamin A – led to the development of insulin resistance in animal models. Additional work revealed parallel results in human blood samples: obese, insulin-resistant individuals had high RBP4 levels and lean, insulin-sensitive people had low RBP4 levels. Furthermore, people with genetic changes in RBP4 that resulted in high blood levels of the protein had an elevated risk of developing diabetes. Now, Dr. Kahn and her colleagues explain the mechanism by which RBP4 contributes to increased risk of diabetes. In a study that appears online in the March 4, 2014 issue of the journal Cell Metabolism, the investigators describe how the protein sets in motion a complex interplay between two branches of the body's immune system, leading to chronic fat tissue inflammation and, ultimately, insulin resistance. "Although the inflammatory response is a key part of our immune system and an important means of protection and tissue repair in response to infection or injury, under certain conditions of metabolic dysfunction, this response is activated even in the absence of foreign pathogens," explains Dr.

Chemists Discover New Class of Antibiotics to Fight Drug-Resistant Bacteria

A team of University of Notre Dame researchers led by Drs. Mayland Chang and Shahriar Mobashery has discovered a new class of antibiotics to fight bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and other drug-resistant bacteria that threaten public health. The new research is published in the Journal of the American Chemical Society in an article titled "Discovery of a New Class of Non-Beta-Lactam Inhibitors of Penicillin-Binding Proteins with Gram-Positive Antibacterial Activity." The new class, called oxadiazoles, was discovered by in silico (by computer) screening and has shown promise in the treatment of MRSA in mouse models of infection. Researchers who screened 1.2 million compounds found that the oxadiazole inhibits a penicillin-binding protein, PBP2a, and the biosynthesis of the cell wall that enables MRSA to resist other drugs. The oxadiazoles are also effective when taken orally. This is an important feature as there is only one marketed antibiotic for MRSA that can be taken orally. MRSA has become a global public-health problem since the 1960s because of its resistance to antibiotics. In the United States alone, 278,000 people are hospitalized and 19,000 die each year from infections caused by MRSA. Only three drugs currently are effective treatments, and resistance to each of those drugs already exists. The researchers have been seeking a solution to MRSA for years. "Professor Mobashery has been working on the mechanisms of resistance in MRSA for a very long time," Dr. Chang said. "As we understand what the mechanisms are, we can devise strategies to develop compounds against MRSA." "Mayland Chang and Shahriar Mobashery's discovery of a class of compounds that combat drug resistant bacteria such as MRSA could save thousands of lives around the world.

March 6th

Sangamo Presents Additional Data in Support of Enzyme-Based Functional Cure of HIV/AIDS

Sangamo BioSciences, Inc. (Nasdaq: SGMO), announced on March 6, 2014 the presentation of data from its SB-728-T program to develop a “functional cure” for HIV/AIDS at the Conference on Retroviruses and Opportunistic Infections (CROI 2014). The conference was held in Boston from March 3 to 6, 2014. Data from an earlier Phase 1 clinical study in this program were also published in the March 6, 2014 issue of the New England Journal of Medicine(NEJM) (see BioQuick story below). "The achievement of over 7 months of ongoing functional control of viral load without antiretroviral therapy and the progress that we are making in understanding how to best deploy this novel therapy are very exciting," commented Gary Blick, M.D., AAHIVS, Medical & Research Director, CIRCLE CARE Center, who presented the data at CROI and is an investigator on both studies that were reported at the meeting. "The data that have been generated over the course of the clinical investigation of SB-728-T demonstrate immune reconstitution, enhanced survival of the zinc finger nuclease-modified T-cells in the presence of the virus, and associated reductions in viral load and the levels of viral reservoir, all of which are necessary to provide functional control of the virus." At CROI, data were reported from a Phase 1 /2 clinical trial, SB-728-1101, designed to evaluate the effect of increasing doses of Cytoxan preconditioning as a method to increase the numbers of circulating T-cells, including cells that were zinc finger nuclease (ZFN) modified at the CCR5 gene (SB-728-T). The data demonstrate that increasing doses of Cytoxan preconditioning prior to a single infusion of SB-728-T led to a dose-dependent increase in both engraftment of CCR5-modified cells and notable increases in total CD4 cells above the baseline.

Treatment with Sangamo's ZFN-Modified T-Cells Provides Functional Control of HIV without Antiretroviral Drugs

Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced on March 5, 2014 the publication in the March 6, 2014 issue of the New England Journal of Medicine of the first clinical study of Sangamo's proprietary zinc finger nuclease (ZFN)-based genome editing technology in humans. Data from the study, carried out in HIV-positive subjects, demonstrate that the T-cell genome can be safely engineered to mimic a naturally occurring mutation that provides resistance to HIV infection. ZFN-modified T-cells are well tolerated when reinfused and treatment is associated with decreased viral loads (VLs) in several subjects who were taken off their antiretroviral therapy (ART), including one whose viral load became undetectable. The study demonstrates the feasibility of this novel genome editing approach to achieve functional control of HIV. Additional data on the ongoing SB-728-T ongoing clinical trials in HIV will be presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2014), which is taking place in Boston, March 3-6, 2014. "We have used Sangamo's ZFN technology to safely genetically engineer an HIV-infected individual's own T-cells and to make those cells resistant to infection by the virus," said Carl June, M.D., Richard W. Vague Professor in Immunotherapy in the department of Pathology and Laboratory Medicine at the Perelman School of Medicine at the University of Pennsylvania, and a senior author of the paper. "This study demonstrates that ZFN-modified cells can be safely administered back to the individual; are able to persist and circulate throughout the body to key reservoirs of HIV infection; and show preferential survival over unmodified cells when antiviral drugs are withdrawn, potentially keeping the virus under control without the use of drugs.

March 5th

Mutation Underlying Much of Lou Gehrig’s Disease Causes 3-D Changes in DNA

New findings reveal how a mutation that causes neurodegeneration alters the shape of DNA, making cells more vulnerable to stress and more likely to die. The particular mutation, in the C9orf72 gene, is the most common cause for amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease), and frontotemporal degeneration (FTD), the second most common type of dementia in people under 65. This new research by Jiou Wang, Ph.D., and his colleagues at Johns Hopkins University (JHU) was published online on March 5, 2014 in Natureand was partially funded by the National Institutes of Health's National Institute of Neurological Disorders and Stroke (NINDS). In ALS, the muscle-activating neurons in the spinal cord die, eventually causing paralysis. In FTD, neurons in particular brain areas die leading to progressive loss of cognitive abilities. The mutation may also be associated with Alzheimer's and Huntington's diseases. The normal C9orf72 gene contains a section of repeating bases; in most people, this sequence is repeated two to 25 times. In contrast, the mutation associated with ALS and FTD can result in up to tens of thousands of repeats of this section. Using sophisticated molecular techniques, Dr. Wang and his team showed that the C9orf72 mutation causes changes in the three-dimensional shape of DNA. DNA is normally shaped like a twisted ladder. However, the repeating sequences can fold into so-called G-quadruplexes, stacks of square-shaped molecules known as G-quartets. "This structure has been described as a square building with each floor representing one G-quartet, normally two to four stories high," said Dr. Wang, senior author of the Nature article. The team’s results also showed that C9orf72 mutated DNA has profound effects on how the genetic message is processed in the cell.

March 4th

Loss-of-Function Mutations in Key Gene Protect Against Type 2 Diabetes

An international team led by researchers at the Broad Institute and Massachusetts General Hospital (MGH) has identified mutations in a gene that can reduce the risk of developing type 2 diabetes, even in people who have risk factors such as obesity and old age. The results focus the search for developing novel therapeutic strategies for type 2 diabetes; if a drug can be developed that mimics the protective effect of these mutations, it could open up new ways of preventing this devastating disease. Type 2 diabetes affects over 300 million people worldwide and is rising rapidly in prevalence. Lifestyle changes and existing medicines slow the progression of the disease, but many patients are inadequately served by current treatments. The first step to developing a new therapy is discovering and validating a “drug target” — a human protein that, if activated or inhibited, results in prevention and treatment of the disease. The current study breaks new ground in type 2 diabetes research and guides future therapeutic development in this disease. In the new study, researchers describe the genetic analysis of 150,000 patients showing that rare mutations in a gene called SLC30A8 reduce the risk of type 2 diabetes by 65 percent. The results were seen in patients from multiple ethnic groups, suggesting that a drug that mimics the effect of these mutations might have broad utility around the globe. The protein encoded by SLC30A8 had previously been shown to play an important role in the insulin-secreting beta cells of the pancreas, and a common variant in that gene was known to slightly influence the risk of type 2 diabetes. However, it was previously unclear whether inhibiting or activating the protein would be the best strategy for reducing disease risk — and how large an effect could be expected.

March 4th

30,000-Year-Old Giant Virus Found in Siberia

A new type of giant virus called "Pithovirus" has been discovered in the frozen ground of extreme north-eastern Siberia by researchers from the Information Génomique et Structurale laboratory (CNRS/AMU), in association with teams from the Biologie à Grande Echelle laboratory (CEA/INSERM/Université Joseph Fourier), Génoscope (CEA/CNRS), and the Russian Academy of Sciences. Buried underground, this giant virus, which is harmless to humans and animals, has survived being frozen for more than 30,000 years. Although its size and amphora shape are reminiscent of Pandoravirus, analysis of its genome and replication mechanism proves that Pithovirus is very different. This work brings to three the number of distinct families of giant viruses. The discovery was reported online on March 3, 2014 in PNAS. In the families Megaviridae (represented in particular by Mimivirus, discovered in 2003) and Pandoraviridae, researchers thought they had classified the diversity of giant viruses (the only viruses visible under optical microscopy, because their diameter exceeds 0.5 microns). These viruses, which infect amoeba such as Acanthamoeba, contain a very large number of genes compared to common viruses (like influenza or AIDS, which only contain about ten genes). Their genome is about the same size or even larger than that of many bacteria. By studying a sample from the frozen ground of extreme north-eastern Siberia, in the Chukotka autonomous region, researchers were surprised to discover a new giant virus more than 30,000 years old (contemporaneous with the extinction of Neanderthal man), which they have named "Pithovirus sibericum." Because of its amphora shape, similar to Pandoravirus, the scientists initially thought that this was a new member - albeit certainly ancient - of this family.