Proceedings of the National Academy of Sciences of the United States of America
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Proc. Natl. Acad. Sci. U.S.A. · Sep 2006
A Drosophila model for age-associated changes in sleep:wake cycles.
One of the most consistent behavioral changes that occurs with age in humans is the loss of sleep consolidation. This can be quite disruptive and yet little is known about its underlying basis. To better understand the effects of aging on sleep:wake cycles, we sought to study this problem in Drosophila melanogaster, a powerful system for research on aging and behavior. ⋯ The effect of temperature on lifespan was not mediated by changes in overall activity level or sleep amount. Flies treated with the oxidative stress-producing reagent paraquat showed a breakdown of sleep:wake cycles similar to that seen with aging, leading us to propose that the accumulation of oxidative damage with age contributes to the changes in rhythm and sleep. Together, these findings establish Drosophila as a valuable model for studying age-associated sleep fragmentation and breakdown of rhythm strength, and indicate that these changes in sleep:wake cycles are an integral part of the physiological aging process.
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Proc. Natl. Acad. Sci. U.S.A. · Jul 2006
CD4+ T cells and CXC chemokines modulate the pathogenesis of Staphylococcus aureus wound infections.
T cells are critical for the formation of intraabdominal abscesses by Staphylococcus aureus. We hypothesized that T cells modulate the development of experimental staphylococcal infections by controlling polymorphonuclear leukocyte (PMN) trafficking. In models of staphylococcal s.c. abscess formation, hindpaw infection, and surgical wound infection, S. aureus multiplied in the tissues of WT C57BL/6J mice and elicited a marked inflammatory response. ⋯ The severity of the wound infection was enhanced by administration of a CXC chemokine and abrogated by antibodies that blocked the CXC receptor. An acapsular mutant was less virulent than the parental S. aureus strain in both the s.c. abscess and the surgical wound infection models in WT mice. These data reveal an important and underappreciated role for CD4(+) alphabeta T cells in S. aureus infections in controlling local CXC chemokine production, neutrophil recruitment to the site of infection, and subsequent bacterial replication.
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Proc. Natl. Acad. Sci. U.S.A. · Jun 2006
Involvement of human left dorsolateral prefrontal cortex in perceptual decision making is independent of response modality.
Perceptual decision making typically entails the processing of sensory signals, the formation of a decision, and the planning and execution of a motor response. Although recent studies in monkeys and humans have revealed possible neural mechanisms for perceptual decision making, much less is known about how the decision is subsequently transformed into a motor action and whether or not the decision is represented at an abstract level, i.e., independently of the specific motor response. To address this issue, we used functional MRI to monitor changes in brain activity while human subjects discriminated the direction of motion in random-dot visual stimuli that varied in coherence and responded with either button presses or saccadic eye movements. ⋯ We previously found that, when subjects made categorical decisions about degraded face and house stimuli, left posterior DLPFC showed a greater response to high- relative to low-coherence stimuli. Furthermore, the left posterior DLPFC appears to perform a comparison of signals from sensory processing areas during perceptual decision making. These data suggest that the involvement of left posterior DLPFC in perceptual decision making transcends both task and response specificity, thereby enabling a flexible link among sensory evidence, decision, and action.
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Proc. Natl. Acad. Sci. U.S.A. · Jun 2006
Phosphatidylinositol 3-kinase mediates activation of ATM by high NaCl and by ionizing radiation: Role in osmoprotective transcriptional regulation.
High NaCl causes DNA double-strand breaks and activates the transcription factor, TonEBP/OREBP, resulting in increased transcription of several protective genes, including those involved in accumulation of compatible organic osmolytes. Several kinases are known to contribute to signaling activation of TonEBP/OREBP, including ATM, which is a member of the phosphatidylinositol 3-kinase (PI3K)-like kinase family and is activated by DNA double-strand breaks. The purpose of the present studies was to investigate a possible role of PI3K Class IA (PI3K-IA). ⋯ Further, suppression of PI3K-IA inhibits the activation of ATM that is caused by either ionizing radiation or high NaCl. High NaCl-induced increase in TonEBP/OREBP activity is reduced equally by inhibition of ATM or PI3K-IA, and the effects are not additive. The conclusions are as follows: (i) PI3K-IA activity is necessary for both high NaCl- and ionizing radiation-induced activation of ATM and (ii) high NaCl activates PI3K-IA, which, in turn, contributes to full activation of TonEBP/OREBP via ATM.