Racial Profiling is Bad Medicine, Too

Researchers from Mount Sinai School of Medicine suggested that using racial labels to guide treatment decisions is problematic at best – because in members of minority groups there is what they termed "a continuum in ancestral genetic heritage," meaning that most African Americans and Hispanics in fact have some amount of European ancestry, and the risk genes to prove it. The team genotyped nearly 1,000 participants of Biobank, a program that collects DNA and plasma samples to aid in genomic and personalized medicine research from consenting patients representing the diverse communities surrounding the Mount Sinai Medical Center. Participants self-identified as Caucasian, African American or Hispanic. Senior author Erwin Bottinger said "Our data indicate that historical population labels may not be helpful in predicting disease risk or guiding how a patient will respond to certain medications. . . . Rather, a spectrum of mixed ancestry is emerging in the largest U.S. minority groups. The findings further validate the importance of considering the unique genotype of the individual patient rather than grouping patients by self-reported ethnicity." The data supporting his conclusions were published in the May 4, 2011, online edition of PLoS ONE.

Dousing Inflammation

You'd think that water douses flames. But researchers from the University of California, San Francisco discovered that the protein aquaporin-4, a water channel, is part of what makes brain cells vulnerable to inflammation. Aquaporin's most prominent role is in the kidney, but the protein is also expressed on support cells of the brain known as astrocytes. The scientists found aquaporin-4 knockouts prevented inflammation after cellular stress, apparently because astrocytes with aquaporin channels swell and release proinflammatory cytokines. The authors said their work suggested "inhibition or down-regulation of aquaporin-4 expression in brain and spinal cord may offer a new therapeutic option in diseases . . . associated with neuroinflammation." The studies appeared in the May 2011 print issue of the FASEB Journal.

Being Fat is in the Head

Researchers from Johns Hopkins University have reported that in rats, they were able to turn calorie-storing regular fat into calorie-burning brown fat by knocking out the brain appetite stimulant neuropeptide Y. Animals lacking neuropeptide Y weighed less after 11 weeks, both on a regular and on a high-fat diet. But to their surprise, the researchers also found out that neuropeptide Y knockouts also developed brown fat cells in their gut, which could explain part of their weight loss as well as other metabolic effects of knocking out the peptide, such as increased activity and better blood sugar control. The authors contended neuropeptide Y may stimulate brown fat stem cells. Their work was published in the May 4, 2011, issue of Cell Metabolism.

What Makes an HIV Vaccine

2009 marked the first successful trial of an HIV vaccine, the RV144 Thai trial. But why exactly the vaccine was able to reduce its recipients risk of becoming infected by roughly 30 percent, when a number of others have failed or even increased risk, is still not clear. Researchers from Harvard Medical School have tested a related vaccine in monkeys, and found both genetic and immune system contributors to how well the vaccine works. Genetically, two copies of the TRIM5 gene, which hinders viral replication, helped monkeys avoid infection. The authors also found that while differences in innate immune responses and killer T cells played no role in the vaccine's effects, antibodies and helper T cells to a specific viral protein, the envelope protein, correlated with protection. The results were reported in the May 5, 2011, issue of Science Translational Medicine.

Rapid Response Team Bags up Bacteria

Interferon-gamma is critical to immune responses, but little is known about most of the 2,000 genes it induces. Now, researchers from Yale University School of Medicine have described how one family of IFN-gamma activated proteins works. One of the protein families that IFN-gamma affects are GTPases, molecular switch enzymes that are active when they are bound to GTP and inactive when they are bound to GDP. The authors focused on a subset of GTPases, guanylate binding proteins, and found that at least four family members conferred immunity to infection with several different bacterial types. The binding proteins killed off bacteria by delivering antimicrobial vesicles in sacs. The immune response began only 20 to 30 minutes after bacterial infection. The authors contended that "such cooperative effects could provide broad host protection against different pathogen classes." Their work was published in the May 6, 2011, issue of Science.

PPAR Gamma Activators Increase Weight Via Fat

Two separate groups of scientists from the University of Cincinnati and the University of California, San Diego, respectively, published evidence that in addition to effects on fat cells and water retention, thiazolidinediones also have effects in the brain that could account for the weight gain that people taking them experience. Either short-term or long-term activation of PPAR-gamma receptors in the hypothalamus led to increased eating and weight gain; this was true whether the activation happened by treatment with Avandia (rosiglitazone, Glaxo-Smith Kline plc) or overexpression of the receptor. Conversely, brain PPAR-gamma knockouts were protected from the effects of Avandia on eating and weight. The papers appeared back to back in the May 1, 2011, issue of Nature Medicine.

. . . And Water

PPAR-gamma activators thiazolidinediones are treatments for Type II diabetes that sensitize fat cells to the effects of insulin by activating a nuclear receptor and inducing gene expression. Ironically, possible side effects include weight gain. Part of that is due to fluid retention, which can be serious enough to cause cardiovascular problems. Researchers from the University of Tokyo have described one mechanism for that water retention that does not depend on PPAR-gamma's ability to initiate gene transcription. Instead, the thiazolidinediones bind directly to ion channels in the kidney, which leads to sodium influx and fluid retention. Because this activity occurs regardless of whether thiazolidinediones stimulate transcription, the authors suggested it may be able to develop PPAR-gamma activators that do not lead to fluid retention. The work was published in the May 4, 2011, issue of Cell Metabolism.

Amyloid Affects Cell's Division Highways

One of the problems cells develop in Alzheimer's disease is that they can no longer separate out chromosomes during cell division. Researchers from the University of South Florida discovered that amyloid-beta interferes with the motor proteins that are responsible for pulling chromosomes apart during cell division. They found amyloid beta prevented motor proteins from interacting with the mitotic spindle, the key structure for chromosome separation. The authors said "the resulting defect in neurogenesis can account for the more than 30 percent aneuploid/hyperploid, degeneration-prone neurons observed in Alzheimer disease brain." Also, they found motor proteins in nondividing neurons, suggesting amyloid-beta's effect on them may interfere with neuronal function whether cells are dividing or not. The work was published in the May 1, 2011, issue of Cell Cycle.

Vaulting Past Delivery Problems

A team from the University of California, Los Angeles has found that so-called vault nanocapsules were able to deliver the antitumor chemokine CCL21 to inhibit tumor growth. In earlier work, the same team had shown that engineering dendritic cells to overexpress the same chemokine increased the immune response to lung tumors. But the engineered cells needed to be injected directly into the lung, and the method was overall, the authors wrote, "cumbersome, expensive and time consuming." In their follow-up work, they showed that vaults, which the authors described as made of a naturally occurring nanocapsule that is present in all cells, could also deliver CCL21 to lung tumors, increasing the T-cell response to tumor cells. This approach, the authors wrote, is more efficient and could "serve as an 'off-the-shelf' approach to deliver antitumor cytokines to treat a broad range of malignancies." The study was published in the May 3, 2011, issue of PLoS ONE.

Buenos Notches

Researchers from Washington University in St. Louis have reported that the developmental protein Notch also helps prevent the learning problems that are induced by sleep deprivation. The authors became interested in Notch's role when they found that sleep deprivation decreases the expression of Notch. Preventing this decrease in Notch expression also prevented the learning problems that usually come with sleep deprivation. In another paper in the same journal, a different group of authors from Brown University linked Notch to sleep in worms. Their findings appeared online May 5, 2011, in Current Biology.

Separating Phantom Pain from the Real Thing

Pain, for all its unpleasantness – or rather, because of its unpleasantness – is a critical feeling. Those who cannot feel pain have a drastically shortened life span because they lack a major mechanism for telling when they are physically damaged. Sometimes, however, acute pain can turn chronic in the absence of external stimuli. Treating such pain is fraught with pitfalls, because ideally, treatment should affect the phantom pain but leave the ability to feel real pain intact. Researchers from Cornell University have described synthesizing a series of compounds that appear to meet this goal. The compounds target the TRPV1 receptor, which senses pain and noxious heat, but it specifically blocks the activity of hyperactive TRPV1 receptors. Though the work to date has been done purely in cell culture, the authors said their work "highlights the possibility to further engineer existing TRPV1 ligands into ideal analgesics that can reduce pain arising from electrical activity without impairing signaling critical for other TRPV1 functions." Their experiments appeared in the May 2, 2011, online edition of the Proceedings of the National Academy of Sciences.

– Anette Breindl, Science Editor