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Archive - Aug 29, 2014

How Ebola Virus Blocks the Immune System

The Ebola virus, in the midst of its biggest outbreak on record, is a master at evading the body’s immune system. But researchers at the Washington University School of Medicine in St. Louis and elsewhere have learned one way the virus dodges the body’s antiviral defenses, providing important insight that could lead to new therapies. The virus has infected approximately 1,800 people since March 2014 in four West African nations and killed more than half of them, according to the World Health Organization. The researchers developed a detailed map of how an Ebola protein, VP24, binds to a host protein that takes signaling molecules in and out of the cell nucleus. Their map revealed that the viral protein takes away the host protein’s ability to carry an important immune signal into the nucleus. This signal helps activate the immune system’s antiviral defenses, and blocking it is believed to contribute significantly to the virus’s deadliness. “We’ve known for a long time that infection with Ebola obstructs an important arm in our immune system that is activated by molecules called interferons,” said senior author Gaya Amarasinghe, Ph.D., assistant professor of pathology and immunology at the Washington University School of Medicine. “Now that our map of the combined structure of these two proteins has revealed one critical way Ebola does this, the information it provides will guide the development of new treatments.” The results appeared online on August 13, 2014 in Cell Host & Microbe. A National Institutes of Health (NIH) grant of up to $15 million, awarded March 1, 2014, is helping Dr. Amarasinghe and other researchers look for drugs to block VP24 and another Ebola protein, VP35.

How Wild Rabbits Were Genetically Transformed into Domesticated Rabbits

Until recently, little has been known about what genetic changes transform wild animals into domesticated ones. An international team of scientists, one of whom is a University of Montana (UM) assistant professor, has made a breakthrough by showing that genes controlling the development of the brain and the nervous system were particularly important for rabbit domestication. The study was published in the August 29, 2014 issue of Science and gives answers to many genetic questions. The domestication of animals and plants, a prerequisite for the development of agriculture, is one of the most important technological revolutions during human history. Domestication of animals started as early as 9,000 to 15,000 years ago and initially involved dogs, cattle, sheep, goats, and pigs. The rabbit was domesticated much later, about 1,400 years ago, at monasteries in southern France. It has been claimed that rabbits were domesticated because the Catholic Church had declared that young rabbits were not considered meat, but fish, and could therefore be eaten during Lent. When domestication occurred, the wild ancestor, the European rabbit, was confined to the Iberian Peninsula and southern France. “The domestication of rabbits depended upon small genetic changes in many genes rather than more radical mutations in a few genes,” explained Dr. Jeffrey Good, UM assistant professor and a co-author on the study. “This pattern contrasts with the large-effect genetic changes that are typically associated with striking differences in the size or appearance of diverse domestic dog breeds, for example.

Good to Bad and Bad to Good--“Tour de Force” by Nobel Prize Winner and MIT Team Reverses Emotional Associations of Memories--Possible Applications in Mental Illness

Most memories have some kind of emotion associated with them: recalling the week you just spent at the beach probably makes you feel happy, while reflecting on being bullied provokes more negative feelings. A new study by MIT neuroscientists reveals the brain circuit that controls how memories become linked with positive or negative emotions. Furthermore, the researchers found that they could reverse the emotional association of specific memories by manipulating brain cells with optogenetics — a technique that uses light to control neuron activity. The findings, described online on August 27, 2014 in Nature, demonstrated that a neuronal circuit connecting the hippocampus and the amygdala plays a critical role in associating emotion with memory. This circuit could offer a target for new drugs to help treat conditions such as post-traumatic stress disorder, the researchers say. “In the future, one may be able to develop methods that help people to remember positive memories more strongly than negative ones,” says Dr. Susumu Tonegawa (image), the Picower Professor of Biology and Neuroscience, director of the RIKEN-MIT Center for Neural Circuit Genetics at MIT’s Picower Institute for Learning and Memory, and senior author of the paper. Dr. Tonegawa won the Nobel Prize for Physiology or Medicine in 1987 for his discovery of the genetic mechanism that produces antibody diversity. The paper’s lead authors are Dr. Roger Redondo, a Howard Hughes Medical Institute postdoc at MIT, and Joshua Kim, a graduate student in MIT’s Department of Biology. Memories are made of many elements, which are stored in different parts of the brain.

Small Molecule Is On-Off Switch for Antibiotic Production by Streptomyces

AScientists have identified the developmental on-off switch for Streptomyces, a group of soil microbes that produce more than two-thirds of the world's naturally derived antibiotic medicines. Their hope now would be to see whether it is possible to manipulate this switch to make nature's antibiotic factory more efficient. The study, appearing in an open-access article in the August 28, 2014 issue of Cell, found that a unique interaction between a small molecule called cyclic-di-GMP and a larger protein called BldD ultimately controls whether a bacterium spends its time in a vegetative state or gets busy making antibiotics. Researchers found that the small molecule assembles into a sort of molecular glue, connecting two copies of BldD as a cohesive unit that can regulate development in the Gram-positive bacteria Streptomyces. "For decades, scientists have been wondering what flips the developmental switch in Streptomyces to turn off normal growth and to begin the unusual process of multicellular differentiation in which it generates antibiotics," said Maria A. Schumacher, Ph.D., an associate professor of biochemistry at the Duke University School of Medicine. "Now we not only know that cyclic-di-GMP is responsible, but we also know exactly how it interacts with the protein BldD to activate its function." Streptomyces has a complex life cycle with two distinct phases: the dividing, vegetative phase and a distinct phase in which the bacteria form a network of thread-like filaments to chew up organic debris and churn out antibiotics and other metabolites. At the end of this second phase, the bacteria form filamentous branches that extend into the air to create spiraling towers of spores. In 1998, researchers discovered a gene that kept cultured Streptomyces bacteria from creating these spiraling towers of fuzz on their surface.

Scientists Synthesize Recently Discovered Antibiotic

A fortuitous collaboration at Rice University has led to the total synthesis of a recently discovered natural antibiotic. The laboratory recreation of a fungus-derived antibiotic, viridicatumtoxin B, may someday help bolster the fight against bacteria that evolve resistance to treatments in hospitals and clinics around the world. As part of the process, Rice organic chemist Dr. K.C. Nicolaou and structural biologist Dr. Yousif Shamoo and their colleagues created and tested a number of variants of viridicatumtoxin B that could lead to the simplified synthesis of a new generation of more effective antibiotics. The work, reported online on August 15, 2014 in the Journal of the American Chemical Society (JACS), focused on a tetracycline discovered in 2008 by scientists who isolated small amounts from penicillium fungi. The yield wasn’t nearly enough for extensive testing, but it provided a basis for the discoverers to analyze its structure through magnetic resonance imaging, Dr. Nicolaou said. “We’re inspired by molecules that are biologically active and have the potential to become medicines one day,” he said. The new discovery belongs to a class of antibiotics known as tetracyclines for their distinctive molecular structure. They proved potent in initial tests on Gram-positive bacteria, so named for a staining technique to mark bacteria that are more susceptible to antibiotics than their Gram-negative counterparts. The first tetracyclines, discovered in the late 1940s, ushered in a new class of powerful antibacterial agents to treat high-mortality diseases, among them anthrax and plague, as well as such bacterial infections as chlamydia, syphilis, and Lyme disease.