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Archive - Mar 18, 2015

Rare African MRI Instrument Reveals Massive Brain Swelling As Cause of Death in Children with Cerebral Malaria; Finding May Lead to Effective Treatments

Malaria kills one child every minute. While medical researchers have successfully developed effective drugs to kill the malaria parasite, efforts to treat the effects of the disease have not been as successful. But that soon may change. In a groundbreaking study published in the March 19, 2015 issue of the New England Journal of Medicine, Michigan State University's (MSU’s) Dr. Terrie Taylor (photo) and her team discovered what causes death in children with cerebral malaria, the deadliest form of the disease. "We discovered that some children with cerebral malaria develop massively swollen brains and those are the children who die," Dr. Taylor said. Dr. Taylor and her research team found that the brain becomes so swollen it is forced out through the bottom of the skull and compresses the brain stem. This pressure causes the children to stop breathing and die. "Because we know now that the brain swelling is what causes death, we can work to find new treatments," Dr. Taylor said. "The next step is to identify what's causing the swelling and then develop treatments targeting those causes. It's also possible that using ventilators to keep the children breathing until the swelling subsides might save lives, but ventilators are few and far between in Africa at the moment." While increased efforts targeting malaria elimination and eradication have had some effect on malaria infection and illness, death rates from malaria are still too high, Dr. Taylor said. "It's gut-wrenching when children die, but what keeps us going is that we are making progress against this Voldemort [an arch villain in the Harry Potter series] of parasites," Dr. Taylor said. "It's been an elusive quarry, but I think we have it cornered." In 2008, GE Healthcare provided a $1-million MRI to the Queen Elizabeth Hospital in Blantyre, Malawi, where Dr.

Insect Wings May Serve Gyroscopic Function

Gyroscopes measure rotation in everyday technologies, from unmanned aerial vehicles to cell phone screen stabilizers. Though many animals can move with more precision and accuracy than our best-engineered aircraft and technologies, gyroscopes are rarely found in nature. Scientists know of just one group of insects, the group including flies, that has something that behaves like a gyroscope -- sensors called halteres, clublike structures that evolved from wings. Halteres provide information about the rotation of the body during flight, which helps flies perform aerial acrobatics and maintain stability and direction. But how do other insects without these sensors regulate flight dynamics, biologists have wondered? University of Washington (UW) research suggests that insects' wings may also serve a gyroscopic function -- a discovery that sheds new insight on natural flight and could help with developing new sensory systems in engineering. Published online on January 28, 2015 in an open-access article in Interface, the research was supported by the Air Force Office of Scientific Research. It was a key part of the successful proposal for an Air Force Center of Excellence on Nature-Inspired Flight Technologies and Ideas, a new UW center focused on understanding how elements in nature can inform the development of remotely controlled small aircraft. "I was surprised at the results," said Brad Dickerson, a graduate student in biology and co-author of the study. "This idea of wings being gyroscopes has existed for a long time, but this paper is the first to really address how that would be possible." Dickerson and another UW graduate student, Annika Eberle, conducted the research seeking to determine whether insects could use the bending of their wings to sense rotations of their bodies during flight.

Interplay of Two Insulin Receptors Underlies Crucial Switch Between Short Wings and Long Wings in Leaf Hopper Pests

Each year, rice in Asia faces a big threat from a sesame-seed-sized insect called the brown plant hopper. Now, a study reveals the molecular switch that enables some plant hoppers to develop short wings and others long -- a major factor in their ability to invade new rice fields. The findings were published online on March 18, 2015 in Nature. Lodged in the stalks of rice plants, plant hoppers use their sucking mouthparts to siphon sap. Eventually the plants turn yellow and dry up, a condition called "hopper burn." Each year, plant hopper outbreaks destroy hundreds of thousands of acres of rice, the staple crop for roughly half the world's population. The insects have a developmental strategy that makes them particularly effective pests. When conditions in a rice field are good, young plant hoppers develop into adults with stubby wings that barely reach their middles. These short-winged adults cannot fly, but they are prolific breeders. A single short-winged female can lay more than 700 eggs in her lifetime. "The short-winged ones have great big fat abdomens. They're basically designed to stay put and reproduce," said biologist Dr. Fred Nijhout of Duke University, who co-authored the study with colleagues at Zhejiang University in China. But in the fall, as days get shorter and temperatures begin to drop -- signs that the rice plants they're munching on will soon disappear -- more plant hopper nymphs develop into slender adults with long wings. These long-winged plant hoppers lay fewer eggs, but are built for travel, eventually flying away to invade new rice fields. Until now, scientists did not know exactly how the shorter days and cooler temperatures triggered the shift between short and long wings, or which hormones were involved.

Possibly Helpful Therapeutic for Myotonic Muscular Dystrophy; Drug Is Targeted to Inhibit TWEAK Pathway

A doctor who was one of the discoverers of the gene responsible for myotonic muscular dystrophy has now identified a therapeutic that could modify progression of muscle damage and muscle dysfunction associated with the disease - issues that cause patients significant disability and deterioration in quality of life. The potential treatment is an experimental drug currently being evaluated for treating other conditions, such as rheumatoid arthritis. In lab tests, mice with myotonic dystrophy that were given the treatment had better muscle function in tests such as running on a treadmill and had improved grip strength. In addition, their muscles became healthier and, notably, many even lived longer. While more testing needs to be done, Mani S. Mahadevan, M.D., of the University of Virginia (UVA) School of Medicine, is hopeful about the drug's potential in humans as well. "The nice thing about this therapy is that we know that it's already been shown to be safe, because clinical trials have already been done with it for other conditions. That's a big, big hurdle that's been overcome," Dr. Mahadevan said. "With a lot of drugs, the problem is that once you do these proof-of-concept studies, the drugs need to be developed a lot further, refined, and tested for safety and efficacy. But a lot of that work has been done, so therefore we can leapfrog the development of this therapy so that it can be moved into clinical trials sooner." Dr. Mahadevan, of UVA's Department of Pathology, has been conducting pioneering research into the causes of myotonic dystrophy, the most common form of muscular dystrophy, for more than two decades. His work revealed that the condition is caused by an expanding piece of DNA - a mutation that grows worse with each generation.

Toxoplasmosis Infection Causes Rodents to Fatally Lose Fear of Cats; Parasite Also Infects 1 in 4 Humans with Unknown Effects; Organism Appears Able to Alter Acetylation of Multiple Proteins in Cortical Astrocytes

Rodents infected with a common parasite lose their fear of cats, resulting in easy meals for the felines. Now Indiana University (IU) School of Medicine researchers have identified a new way the parasite may modify brain cells, possibly helping explain changes in the behavior of mice -- and humans. The parasite is Toxoplasma gondii, which has infected an estimated one in four Americans and even larger numbers worldwide. Not long after infecting a human, Toxoplasma parasites encounter the body's immune response and retreat to a latent state, enveloped in hardy cysts that the body cannot remove. Before entering that inactive state, however, the parasites appear to make significant changes in some of the brain's most common, and critical cells, the researchers said. The team, led by William Sullivan, Ph.D., Professor of Pharmacology and Toxicology and of Microbiology and Immunology, reported two sets of related findings about those cells, called astrocytes, on March 18, 2015, in the journal PLOS ONE. The article is titled “Proteome-Wide Lysine Acetylation in Cortical Astrocytes and Alterations That Occur during Infection with Brain Parasitr Toxoplasma gondii.” Astrocytes are found throughout the brain and are involved in a variety of important brain structures and activities. Dr. Sullivan and his team evaluated the proteins in astrocyte cells and found 529 sites on 324 proteins where compounds called acetyl groups are added to proteins, creating a map called an "acetylome," much as a map of all the genes in a particular species is known as its "genome." In addition, 277 sites on 186 of the proteins had not been reported in previous studies of other types of cells.

Sangamo Presents Dramatic Data Indicating Their ZFP Enzymatic Approach Can Prevent and Reverse Pathogenic Accumulation of Mutant Protein in Huntington’s Disease in Animal Models; Wexler Terms Results a “Significant Step Forward”

On November 19, 2014, Sangamo BioSciences, Inc., announced its presentation of positive preclinical data from its joint program with Shire plc, to develop a novel ZFP (zinc-finger protein) Therapeutic® approach to Huntington's disease (HD), at the 2014 Annual Meeting of the Society for Neuroscience. Note that zinc fingers are proteins that normally bind at different bases in DNA in order to regulate gene activity. The dramatically exciting data were generated by Sangamo scientists and the CHDI Foundation, which is dedicated to accelerating therapeutic developments for HD. "These data are very exciting and represent a significant step forward in the quest for a therapeutic for Huntington's disease," said Nancy Wexler, Ph.D., Higgins Professor of Neuropsychology in the Departments of Neurology and Psychiatry of the College of Physicians and Surgeons at Columbia University, and the President of the Hereditary Disease Foundation. "They provide the first demonstration of a therapeutic approach that can not only prevent, but reverse the accumulation of mutant Huntingtin protein aggregates in the brains of animal models of the disease. Furthermore, the treatment does not affect the expression of the normal form of the protein, which is believed to be essential." The mutant form of the Huntingtin protein (Htt) accumulates in cells and forms protein aggregates which are associated with disease symptoms. Pioneering basic research in transgenic animal models has shown that the levels of the defective Htt protein correlate with disease progression, stimulating the search for strategies to reduce mutant Htt levels as a therapeutic intervention. However, most "Htt-lowering" methods decrease the levels of both disease-causing and normal forms of Htt.

Ras Protein Regulates Circadian Rhythms and Responds to External Time Cues

Biochemists at the Ruhr-Universität Bochum in Germany have gained new insights into the generation and maintenance of circadian rhythms. They have demonstrated that the Ras protein (image) is important for setting the phase of such a circadian clock, as its activity determines the period length of the rhythm. Ras is also contributing to induce phase-shifts in circadian rhythms in response to external time cues such as light. The team headed by Professor Dr. Rolf Heumann published its results online on March 12, 2015 in Molecular Neurobiology. The circadian clock “ticks” in every cell of the body; a central master clock, however, is located in the brain, more specifically in the suprachiasmatic nucleus (SCN) of the hypothalamus, which is old in evolutionary terms. Its activity determines the cycle’s period length, which is close to, but not exactly, 24 hours; it has to be continuously adjusted by external signals such as light, motor activity, or food intake to an exact 24-hour rhythm. Such regulation is the result of many proteins acting and interacting in various signal cascades. A central switch for such signal cascades is the Ras protein, which is present either in its active or in its inactive form. The group from Bochum demonstrated in mice that Ras activity in the SCN is high during the day and low during the night. Moreover, Ras activity was increased after brief exposure to light during the night. In collaboration with a Frankfurt-based team, headed by Professor Dr. Jörg Stehle, the researchers from Bochum also studied the phenomenon in genetically modified mice, whose Ras activity is increased exclusively in neurons of the brain. They found that the activity in the SCN oscillated with a significant shorter period than 24 hours – additional evidence for the relevance of Ras for the circadian rhythm.

Major Neurobiology Question Answered: SCN Neurons Expressing NMS Neuropeptide Are the Cells Controlling Circadian Rhythms

University of Texas (UT) Southwestern Medical Center neuroscientists have identified key cells within the brain that are critical for determining circadian rhythms, the 24-hour processes that control sleep and wake cycles, as well as other important body functions such as hormone production, metabolism, and blood pressure. Circadian rhythms are generated by the suprachiasmatic nucleus (SCN) located within the hypothalamus of the brain, but researchers had previously been unable to pinpoint which of the many thousands of neurons in the region were involved in controlling the body's timekeeping mechanisms. "We have found that a group of SCN neurons that express a neuropeptide called neuromedin S (NMS) is both necessary and sufficient for the control of circadian rhythms," said Dr. Joseph Takahashi (photo), Chairman of Neuroscience and Howard Hughes Medical Institute (HHMI) Investigator at UT Southwestern, who holds the Loyd B. Sands Distinguished Chair in Neuroscience. The findings, published in the March 4, 2015 issue of Neuron, may offer important targets for future treatments of diseases and problems related to circadian dysfunction, which range from jet lag and sleep disorders to neurological problems such as Alzheimer's disease, as well as metabolism issues and psychiatric disorders such as depression. Key studies in the 1970s revealed that the SCN communicates and coordinates cells throughout the body to control circadian rhythms, but the SCN contains many neurons with different expression patterns of neuropeptides and neurotransmitters. "Which of these neurons are responsible for producing circadian rhythms was a major unanswered question in neurobiology. This study marks a significant advancement in our understanding of the body clock" said senior author Dr.