This week in PNAS Early Edition

"The fetal liver is a niche for maturation of primitive erythroid cells"
by Joan Isern, Stuart T. Fraser, Zhiyong He, and Margaret H. Baron
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Within days of fertilization, primitive blood cells begin to circulate through the mammalian embryo and rapidly differentiate, but there is a lag in the time it takes to achieve the final step to a functioning cell. To complete their maturation, these erythrocytes must first expel their nucleus—a process that Joan Isern et al. investigated by tracking the developing cells. Previous research had found that primitive erythrocytes express adhesion molecules play a role in the migration of circulating cells into the fetal liver. Because the fetal liver does not develop until midgestation, its hosting of the final differentiation step could explain the time lag to maturation. Using transgenic mouse embryos with fluorescently tagged erythrocyte nuclei, the authors found that large numbers of extruded nuclei are present in the fetal liver around the time that mature cells are released into the bloodstream. Macrophages in the fetal liver appear to digest the discarded nuclei. The importance of the fetal liver in the maturation of erythrocytes may help to explain the lag between the first appearance of primitive erythrocytes and their differentiation to functional form, the authors say. — T.H.D.

Immunology

Inactivating a human protein blocks HIV

Inactivating a human protein can block many steps of the HIV replication cycle, suggesting a new target for antiretroviral drugs. Julie Readinger et al. found that interfering with the ITK protein had multiple protective effects against HIV. Inactivation of ITK by RNA interference or chemical inhibition made it more difficult for HIV to enter a cell, spread throughout a tissue culture, transcribe its genes, and assemble into a functional viral particle, according to the authors. ITK is normally involved in activating the immune system's T cells so they can attack foreign organisms; HIV similarly infects and commandeers T cells in order to replicate, compromising the entire immune system. Readinger et al. show that without an active ITK protein, many of the pathways that HIV exploits were less functional, and viral replication was inhibited or slowed. Because HIV is also notoriously quick to develop drug resistance through gene mutation, the authors suggest that targeting ITK—a human gene that is potentially less sensitive to drug resistance—could provide a new pathway for HIV treatment. — P.D.

"Selective targeting of ITK blocks multiple steps of HIV replication"
by Julie A. Readinger, Gillian M. Schiralli, Jian-Kang Jiang, Craig Thomas, Avery August, Andrew J. Henderson, and Pamela L. Schwartzberg
[Full Text] OPEN ACCESS ARTICLE

Psychology

Training "fluid intelligence"

General intelligence, some psychologists maintain, is separable into "fluid" and "crystalline" components. An individual solving a variety of problems brings the same amount of fluid intelligence to bear on all problems, whereas crystalline intelligence is task-specific. Researchers have generally thought it impossible to increase fluid intelligence by training, except by practicing the tests themselves. Susanne Jaeggi et al. now report that a regimen of exercises designed to improve working memory also improves fluid intelligence. In four parallel experiments, subjects were first given a standard test of fluid intelligence in which they were asked to find and correctly match patterns in sets of images. They were then given a series of training exercises designed to improve working memory. The training was repeated for 8, 12, 17, or 19 days, after which the authors administered a second test of fluid intelligence. Although the performance of untrained controls improved slightly, the trained subjects showed significant improvement. Furthermore, the improvement appeared to increase linearly with training time. The authors say that the training exercises strengthen multiple "executive processes" that function in problem-solving. — K.M.

"Improving fluid intelligence with training on working memory"
by Susanne M. Jaeggi, Martin Buschkuehl, John Jonides, and Walter J. Perrig
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Physiology

Erythrocyte suicide

Eryptosis, the programmed cell death of nucleus-free erythrocytes, shares a signaling pathway with apoptosis, Michael Föller et al. report. During eryptosis, a rise in intracellular calcium triggers exposure of phosphatidylserine to the external cell membrane, after which macrophages digest the erythrocytes. In nucleated cells, apoptosis is inhibited by NO via a pathway involving cyclic GMP and cGMP-dependent protein kinase type I (cGKI). Erythrocytes also possess a NO/cGMP pathway. To explore the influence of this pathway and cGKI on erythrocyte survival, the authors generated and characterized a cGKI knockout mouse model. These mice rapidly developed anemia and enlarged spleens, but the health of the strain was poor because cGKI expression appears to be crucial in smooth muscle. Conventional knockouts suffer from gastrointestinal dysfunction. The authors, therefore, generated a second knockout line in which cGKI expression was enabled only in smooth muscle. These mice also developed anemia and enlarged spleens, which contained large numbers of erythrocytes that displayed the molecular markers of eryptosis. In vitro experiments on erythrocytes from knockout and wild-type mice indicated that cGKI was active in erythrocytes. The authors suggest that cGKI reduces intracellular calcium and thus inhibits the exposure of phosphatidylserine. — K.M.

Spleens of control (upper) and cGKI-
deficient (lower) mice.

"Anemia and splenomegaly in cGKI-deficient mice"
by Michael Föller, Susanne Feil, Kamran Ghoreschi, Saisudha Koka, Andrea Gerling, Martin Thunemann, Franz Hofmann, Beat Schuler, Johannes Vogel, Bernd Pichler, Ravi S. Kasinathan, Jan P. Nicolay, Stephan M. Huber, Florian Lang, and Robert Feil
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The articles in the Proceedings of the National Academy of Sciences report original research by independent authors and do not necessarily represent the view of the National Academies.