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RESEARCH BRIEFSRole Demonstrated for Rare Motor Protein in Hair CellsMechanically sensitive cells--fly bristles, the touch receptors of C. elegans, hair cells in the inner ear--are rare, and each houses a tiny clockwork of molecular springs and moving parts to translate pressure into electrical messages. Identification of the individual components is challenging because of their low numbers and exotic functions.
Movement is sensed by the hair bundle. Extending from the hair cell into the vestibule of the inner ear, individual hairs of the hair bundle (A) are interconnected by elastic tip links (faint gray, B). Displacement of the tip link relative to the actin cytoskeleton produces tension on the channel (C). A myosin "motor" moves along the actin core to reestablish resting conditions (C and D, below). Figure above courtesy of David Corey. Illustration below by Jeff Cleary
Now HMS researchers in the lab of David Corey, HMS professor of neurobiology, in collaboration with Peter Gillespie from Oregon Health and Science University, have devised a method to identify a scarce isozyme in hair cells and demonstrate its role in the machinery of transduction. Hair cells respond to sustained stimuli by modulating the tension on a transmembrane calcium channel. In this process, called slow adaptation, open time depends on the position of hair fibers relative to cytoskeletal structures (see figure). To adjust tension, a putative myosin "motor" cycles through a power stroke of attachment, movement, and release, and climbs, micron-by-micron, along an actin filament running the length of the fiber. As the myosin head ratchets along, it splits ATP, and it is the resulting dissociation of ADP that allows detachment from the actin. Reasoning that a myosin with abnormally high affinity for a modified ADP analogue would bind fast to actin, induce rigor, and eliminate slow adaptation, Jeffrey Holt of the Corey lab created a transgenic mouse that expressed such a mutant. Whole-cell, tight-seal recordings of transduction currents revealed that in the presence of ATP, the transgenic hair cell responded to mechanical stimuli normally. However, adaptation was blocked when the ADP analogue was added, demonstrating that the rare myosin isozyme was the motor. Introducing a "silent" mutation that performs normally during development and thereafter but can be activated on command provides a refined approach for studying esoteric systems. And acute inhibition of the mutant myosin reduces complicating factors. The authors suggest their strategy, published in the Feb. 8 Cell, may have a broader application.
Pollen Production--and Allergies--May Rise Over Next 50 YearsRising carbon dioxide levels associated with global warming could lead to an increase in the incidence of allergies to ragweed and other plants by mid-century, according to a report appearing in the March Annals of Allergy, Asthma, and Immunology by Harvard University researchers. Susannah Foster, a student working with Harvard College scientists, HMS's Paul Epstein, and colleagues found that ragweed grown in an atmosphere with double the current carbon dioxide levels produced 61 percent more pollen than normal. Such a doubling is expected between 2050 and 2100. "The side effects of carbon dioxide, as well as its impact on heat budget and the water cycle, have to be taken very seriously," said Epstein, HMS instructor in medicine and associate director of the Center for Health and the Global Environment at HMS. "This study can help us understand the true costs of burning fossil fuels." The researchers grew ragweed plants from seeds in two different enclosed environments. One was maintained at 350 parts carbon dioxide to a million parts air, which is roughly the current level. The other module was maintained at 700 parts carbon dioxide to a million parts air. The indoor ragweed pollen results--61 percent more in the second module--echo the findings of a recent study conducted outdoors in North Carolina, said Epstein. In that study, excess carbon dioxide was pumped into a pine forest, tripling the number of pine cones and seeds. Taken together, the studies suggest that under carbon dioxide-enriched conditions, plants may boost production of their propagative elements to enhance their reproductive success. --Misia Landau
Dual Role Found for Protein in Blood Clotting and ImmunityA study led by HMS researchers shows a molecule important in the immune system also holds blood clots together. In the absence of the protein CD40L, a member of the tumor necrosis factor family, clots form but are fragile, and experimental thrombi induced in mice lacking CD40L take longer to block vessels. The researchers suggest that the findings, reported in the March Nature Medicine, may improve drug design for heart therapy and organ transplantation. Patrick André and coworkers in the lab of Denisa Wagner, HMS professor of pathology, used intravital microscopy to observe blood clots as they formed. "Thrombi in mice lacking the CD40L gene were profoundly defective," said Wagner. Though clots grew at a rate comparable to that in wild-type mice, fragments peeled off from the mass of platelets forming the clot, delaying and sometimes preventing blockage of the vessel. Recombinant CD40L injected prior to vessel injury fortified the clots, returning the occlusion dynamics to normal (see video). Further experiments performed in collaboration with David Phillips of COR Therapeutics (now part of Millennium) in San Francisco showed that the CD40L molecule interacted with the platelet beta-3-integrin rather than CD40, its usual receptor. Medical interventions to minimize clots are important for patients with cardiovascular disease--the leading cause of death in the U.S.--since platelet deposition on atherosclerotic lesions can be fatal. The findings indicate that since blood clotting and inflammation involve distinct CD40L-receptor interactions, specific strategies might be developed to reduce clotting but not suppress immunity, and vice versa. For example, in clinical trials following kidney transplantation, inhibition of the CD40L-CD40 interaction prolongs allograft survival. Today drugs used for this type of intervention are nonspecific inhibitors and interfere with normal platelet plug formation. "Now we can design inhibitors specific for one or the other, to interfere with plug formation or avoid interfering with it," said Wagner. --Anne Mahon
Clot-busting Drugs May Increase Mortality In OctogenariansA new study led by HMS researchers adds to the growing evidence that thrombolytic drugs may increase the risk of death for some patients, particularly the oldest and those with certain medical conditions. The results suggest that national guidelines on the use of these clot-busting drugs--such as streptokinase and tissue plasminogen activator (t-PA)--should be applied more selectively, and possibly revised, to maximize benefit and minimize risk of death from bleeding or stroke, said lead author Stephen Soumerai, HMS professor of ambulatory care and prevention at Harvard Pilgrim Health Care. Co-authors of the article in the March 11 Archives of Internal Medicine include two of Soumerai's colleagues in the Department of Ambulatory Care and Prevention, assistant professor Thomas McLaughlin and associate professor Dennis Ross-Degnan. The researchers examined records of 2,659 patients with acute myocardial infarction admitted to community hospitals from 1992 to 1996. Of 719 patients eligible for thrombolytic therapy, about 63 percent received the drugs. Thrombolytic therapy was associated with reduced mortality in eligible patients younger than 80, but for eligible patients aged 80 to 90, those who got the drugs had an estimated 40 percent greater risk of death in the hospital. For ineligible patients, use of the drugs increased the risk of death regardless of age. "Many doctors have been hesitant to prescribe thrombolytic therapy for the oldest patients with myocardial infarction, despite guidelines that promote the therapy for patients of all ages," Soumerai said. "Our findings, along with those of an earlier study, really seem to justify their concerns." --Tom Reynolds |
