Notebook

Contents AIDS pioneer Jonathan Mann dies in crash Genetics and mental retardation Stress and memory Morning After' to market No pain, no gain, but a pill? Nitric oxide gets renewed attention A scientist's way of winemaking AIDS PIONEER DIES IN CRASH Epidemiologist Jonathan Mann and his wife, Mary Lou, were among the 229 people killed Sept. 3 when a Swissair flight traveling from New York to Geneva crashed off Nova Scotia. Mann was founding director of the World Health Organization's Global Program on AIDS from 1986 to 1990 and was appointed professor at the Harvard School of Public Health in 1990. He founded the François-Xavier Bagnoud Center for Health and Human Rights at the Harvard School of Public Health in 1992 and subsequently launched Health and Human Rights: An International Journal . In 1993 he was named the school's first François-Xavier Bagnoud Professor of Health and Human Rights. Mann left the school this January to become dean of the School of Public Health at Allegheny University of the Health Sciences in Philadelphia. He co-edited AIDS in the World, published in 1992 by Harvard University Press and AIDS in the World II, published in 1996 by Oxford University Press. Mann also was a member of the Institute of Medicine, a fellow of the American College of Epidemiology, president of Doctors of the World, and chairman of the Global AIDS Policy Coalition. Harvey Fineburg , Harvard provost and former dean of faculty, called Mann a "visionary" in AIDS prevention, "His leadership will be sorely missed," Fineburg adds. Illustration: Steve Moskowitz, Advanced Medical Graphics DECREASED EFFICIENCY: The ability of neurons to convey messages efficiently by expanding the necks of their dendritic spines (illustrated above) may be impaired in people with MRX. GOOD THINKING From a research point of view, the problem with most genetic causes of mental retardation is that a number of genes are involved, affecting several organs, and therefore providing little new insight into how the brain works. But recent discoveries concerning mutations that cause nonsyndromic X-linked mental retardation (MRX), show promise of helping to explain normal cognitive functions. MRX affects 1 in 600 males, whose brain development generally seems otherwise normal, and who exhibit few or no other signs of retardation. However, MRX syndromes are genetically diverse, comprising more than 60 pedigrees. Genes for several pedigrees have been located on the X chromosome, the latest identified by a multi-institution research group that found a defect in the PAK3 (p21-activated kinase) gene for the MRX30 pedigree (K.M. Allen et al., Nature Genetics, 20:25-30, Sept. 1998). "Because the protein is brain-specific and clearly has a brain phenotype, we can isolate its functions," explains lead author Kristina M. Allen , a Harvard Medical School researcher at Beth Israel Deaconess Medical Center. PAK3 appears to be involved in both signal transduction and in regulating neuronal cell shape. In particular, it may affect axonal and dendritic development. Although the group has been working with cell lines, the amino acid sequence of PAK proteins is highly conserved. "Our next step is to look at the effects [of PAK3] on neuronal growth and development in cells," Allen says, after which the mutation can be introduced into mice, to see what role it plays in relation to other known mental retardation genes. SOUND FAMILIAR? A looming meeting, an overdue manuscript, an upcoming lecture; hopefully you'll catch your kid's late afternoon soccer game. Life is one big spreadsheet. And now you can't remember where you put that manuscript, which was in your hand just five minutes ago. Despite repeated backtracking and choice epithets, it's gone. But don't be too hard on yourself. A team from the University of California, Irvine thinks your lousy memory is steeped in stress-induced corticosteroids (D.J.-F. de Quervain et al., Nature, 394:787-90, Aug. 20, 1998). Learning something and remembering it are complex processes in which new information is consolidated before it's retrieved. Elevated glucocorticoids affect memory, and although researchers often focused on the consolidation phase, the new results confirm suspicions that memory retrieval can suffer, too. The group trained rats to find a submerged platform in a water maze, then tested their memory 24 hours later. Rats subjected to foot-shock stress 30 minutes before testing did not remember as well as nonstressed controls, an effect correlated with elevated blood corticosterone. Stress applied earlier or later gave lower corticosterone levels at testing and did not disrupt memory. Metyrapone, an inhibitor of glucocorticoid synthesis, offset stress, and injected corticosterone-impaired memory retrieval in unstressed animals. While the rats were subjected to acute stress, Irvine Research Associate Benno Roozendaal believes that "it's possible and even likely that chronic effects on memory are [also] due to retrieval and not just consolidation." Research on the relationship in humans is under way in Switzerland, according to Roozendaal. The goal is a treatment in which people "will feel stress but memory will be intact," something that any college student panicking over a big exam would relish. 'MORNING AFTER' GOES TO MARKET The Food and Drug Administration Sept. 2 gave Gynétics Inc. of Somerville, N.J., permission to market a "morning after" kit that would prevent pregnancy up to three days after unprotected sex. Each kit--available as of late September under the name PREVEN--will include a pregnancy test and four pills that can prevent pregnancy for up to 72 hours after unprotected sex. The FDA issued a broad statement last year saying the method was safe and effective, then accepted Gynétics Inc.'s application for the emergency oral contraceptive Feb. 25. Calls to company chair and founder Roderick Mackenzie, yielded only a recorded message directing media inquiries to an outside public relations firm. "There are no spokesmen in the office at this time," Mackenzie's voice mail message concludes. The pills, which contain progestin and estrogen, work primarily by delaying or preventing ovulation, a spokesperson hired by the company, who asked not to be identified, told The Scientist. "It may also prevent fertilization and implantation," the spokesperson continues, adding that the drug acts before pregnancy technically begins, unlike the RU-486 pills, which end pregnancy several weeks after it has begun. NEXT, THE MUSCLE PILL? If scientists could discover how exercise builds muscle, could muscle be built without exercise? Researchers at University of Texas Southwestern Medical Center think there might be something in it. They have delineated a transcriptional pathway that appears to tell cells what type of skeletal muscle fiber to build-either fast-twitch, rapidly fatigueable myofibers, or slow-twitch fibers associated with endurance (E.R. Chin et al., Genes & Development, 12:2499-2509, Aug. 1998). The slow fiber type maintains higher levels of intracellular calcium, which is known to be essential to muscle contraction. Slow-twitch fibers lower the risk of atherosclerosis and are more sensitive to insulin, making them important to those with cardiovascular disease and some forms of diabetes. "We've been interested in this [muscle fiber activity] for more than 20 years," says chief of cardiology R. Sanders Williams, "but the mechanism that drives it has been elusive." Working with cultured muscle cells and mice, Williams's group has shown that the calcineurin protein reacts to rising levels of calcium during physical exercise, by triggering a signaling sequence that selectively up-regulates slow-fiber-specific gene promoters. Drugs already are in use to inactivate calcineurin prior to kidney and heart transplants, and Williams is hopeful that a medication might similarly be developed to promote regeneration of endurance muscle for people unable to exercise. "We don't propose that you'd ever create an exercise pill," he warns. But a patent has been filed on the signaling pathway, and pharmaceutical companies have shown interest in the potential for a muscle-building pill. IT'S A GAS For years, plants had the market on gaseous hormones cornered with ethylene, which mediates processes such as leaf fall and fruit ripening. Focus on gaseous regulators shifted to animals when researchers discovered nitric oxide (NO), which helps defend against pathogens and relaxes arterial smooth muscle leading to enhanced blood flow. But, what goes around comes around. Two recent studies show that plants also produce NO in response to pathogens. A team led by Chris Lamb of the Salk Institute for Biological Studies in La Jolla, Calif., and Richard Dixon of The Noble Foundation, Ardmore, Okla. (M. Delledonne et al., Nature, 394:585-8, Aug. 6, 1998), and another headed by Daniel Klessig of Rutgers University, Piscataway, N.J. (J. Durner et al., Proceedings of the National Academy of Sciences. 95:10328-33, Aug. 18, 1998) found that NO helps soybean, arabidopsis, and tobacco fend off infection by bacterial and viral pathogens. NO acts together with or through additional signalling agents (salicylic acid, reactive oxygen species including hydrogen peroxide) to elicit the hypersensitive (cell death) response and the activation of PR-1 defense genes. Other responses are controlled separately, however. For example, NO turns on genes for the phenlypropanoid pathway that produces phenolic antibiotics, while peroxide stimulates synthesis of the protectant enzyme glutathione S-transferase. The responses still intersect because the phenylpropanoid pathway also produces salicylic acid, which helps elevate reactive oxygen. Both groups uncovered NO synthase activity similar to that in mammals (it's inhibited by the same agents). Klessig believes that NO is part of an evolutionary related "common innate immune system [that] provides the first active line of defense against microbial pathogens," a hypothesis supported by findings that cyclic GMP and cyclic ADP ribose act downstream in the plant NO response chain, as in animals. MAKING MEAD: Robert Kime dumps honey into a mixing tank prior to making honey wine. Inset, four varieties of raspberry wine. GRAPE ESCAPE For those who eschew the cloying flavors of nongrape fruit wines and mead, Cornell University food scientist Robert Kime has news. He has developed wine-making techniques at the university's New York State Agricultural Experiment Station in Ithaca that result in high-quality fruit wines and honey wine. Experimenting with plum and banana wines, Kime discovered that the usual practice of fermenting to 11 percent or 12 percent alcohol causes flavor compounds in nongrape wines to either vaporize or become sickly sweet. Halting fermentation by refrigeration at about 10.5 percent alcohol, he created strawberry, raspberry, and cherry wines that won gold medals in competition sponsored by the New York state chapter of the American Wine Society. This year, his entries include a peach wine. He has had similar success with mead, which has been made from honey for thousands of years(R.M. Kime et al., American Bee Journal, 138[2]:121-3, Feb. 1998). It traditionally is boiled to eliminate a small percentage of astringent protein, then fermented for nine months and aged for three years. Kime deleted the protein by running the honey at room temperature through an ultrafiltration machine he uses to make apple juice. His mead takes 10 days to ferment and needs no aging. "It comes out crystal clear," Kime says. "You actually run the product into the glass and drink it." In the past two years, 13 honey wineries using the new method have started up across the country. Kime is confident of the eventual outcome: "It will revolutionize mead-making worldwide."

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