"The Rockefeller University Scientist"

Family planning for mosquitoes. Smart females the world over try to avoid giving birth in places where predators lurk. From an evolutionary perspective, such logic would be likely rewarded within a species. Surprisingly, however, few studies have sought to test for such behavior in a natural habitat.

Rockefeller’s Joel Cohen, in collaboration with scientists at the University of Haifa, Israel, and the University of California, Santa Cruz, designed an experiment in which mosquitoes and tiny flies called midges were released into artificial pools containing the predator Notonecta maculata, an insect commonly known as a backswimmer. They found that mosquitoes, which are Notonecta prey, avoided laying eggs in the pools, while midges, which are not Notonecta prey, did not. A second experiment in natural rock pools confirmed the results.

The researchers went on to demonstrate that the mosquitoes’ cue came from a chemical released by Notonecta — mosquitoes refused to lay eggs in infested pools for eight days after the predators had been removed. The research could lead to new chemicals that repel mosquitoes.

The dendritic blame game. People with chronic hepatitis C virus (HCV) infections typically lack the CD8 T lymphocyte immune cells that fight off the virus. For this reason, many scientists who study HCV have concluded that immune system dendritic cells, which “train” CD8 T lymphocytes, must be defective in people unable to clear HCV.

Not so, say Charles Rice, the university’s Maurice R. and Corinne P. Greenberg Professor and head of the Laboratory of Virology and Infectious Disease, and his colleagues, who point out that it’s difficult to reconcile this theory with the fact that patients with chronic HCV have otherwise healthy immune systems. Rice, along with graduate fellow Randy Longman, former postdoc Matthew Albert, and Ira Jacobson and Andy Talal at Weill-Cornell, looked at several measures of dendritic function in 13 volunteers with chronic HCV infections. All 13 had fully functional dendritic cells.

“Our findings are consistent with clinical and immunologic data that show the deficit in the patient’s immune repertoire is HCV-specific and suggests that refined models are required for understanding the role of dendritic cells in HCV pathogenesis,” the authors say.

The shape of cell death. Scientists in Milton Werner’s Laboratory of Molecular Biophysics have identified and described the surface at the heart of the death-inducing signaling complex (DISC) that initiates one type of programmed cell death. When cell death is triggered, several components come together to form the DISC at the cell’s cytoplasmic membrane.

While several of the structures involved in this process have been studied, the mechanism by which the proteins recognize one another had not, until now, been defined. Detailed analysis of the “death domain” interaction now shows it consists of an expansive surface that is common to many other, unrelated proteins, and a secondary surface that may be responsible for stabilizing the other components of the DISC.

Accounting for misclassified genes. Studies that seek to associate genes with specific traits rely on scientists correctly identifying which organisms display the trait being studied. But when misclassifications occur there is often no way to correct them. Derek Gordon, a research assistant professor in Jürg Ott’s Laboratory of Statistical Genetics, has now figured out, statistically, how much damage such genotyping errors cause.

His findings: even relatively small error rates in some parameters can require large increases in sample size in order to maintain statistical significance. Gordon’s research will help scientists better evaluate the accuracy of their results when genotyping errors are unavoidable. And it complements Gordon’s previous work, which resulted in a method (and available computer program) to allow for errors in genetic association analyses, thereby avoiding inflated false positive results that

occur when errors are ignored.

New schizophrenia gene ID’d. A new cellular pathway, identified by Maria Karayiorgou, head of the Laboratory of Human Neurogenetics, may help explain how schizophrenia develops. Karayiorgou, working with colleagues at Columbia University and the University of Pennsylvania, found decreased levels of the protein Akt1 in the brains of deceased schizophrenia patients as well as in the blood of living individuals with schizophrenia — and they identified a particular form of the Akt1 gene that increases an individual’s risk of developing the illness. The researchers also found an increase in the activation of a protein called GSK3beta, which forms a molecular pathway with Akt1.

Abnormalities in the Akt1-GSK3beta pathway have been linked with diabetes, stroke and Alzheimer’s disease, and the pathway is also a target of lithium, one of the most established treatments for mood disorders.

Karayiorgou’s new findings suggest that changes in the signaling of the Akt1-GSK3beta pathway may contribute to the development of schizophrenia and that the antipsychotic drug haloperidol (Haldol), which increases activity of Akt1 in mice, may compensate for the pathway’s impaired functioning.

Controlling fat. Leptin, a hormone secreted by fat cells, has been highly successful in treating diabetes, insulin resistance and fatty liver degeneration associated with lipodystrophy in lab mice and humans. Lipodys-trophy is a condition characterized by a disruption in the way the body produces, uses and distributes fat.

Now Jeffrey Friedman’s lab has identified the central nervous system as the primary site where leptin’s effects on the disease occur. Leptin is known to act on a variety of tissues including the brain, skeletal muscles, heart and pancreatic beta cells. Using a congenital mouse model of lipodystrophy, Friedman, who is head of the Laboratory of Molecular Genetics, graduate fellow Esra Asilmaz, and colleagues observed that subcutaneous administration of leptin was not as potent as a much lower dose administered directly to the central nervous system, which was able to correct the metabolic abnormalities associated with lipodystrophy.

Furthermore, using microarray (“gene chip”) technology, the researchers identified repression of the enzyme SCD-1 as a mechanism of leptin action to improve fatty liver degeneration. The findings may have profound effects on the use of leptin treatment for metabolic diseases.