Proceedings of the National Academy of Sciences of the United States of America
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Proc. Natl. Acad. Sci. U.S.A. · Aug 2009
NOD2 contributes to cutaneous defense against Staphylococcus aureus through alpha-toxin-dependent innate immune activation.
Staphylococcus aureus is a major cause of community-acquired and nosocomial infections including the life-threatening conditions endocarditis, necrotizing pneumonia, necrotizing fasciitis, and septicemia. Toll-like receptor (TLR)-2, a membrane-bound microbial sensor, detects staphylococcal components, but macrophages lacking TLR2 or both TLR2 and TLR4 remain S. aureus responsive, suggesting that an alternative microbial recognition receptor might be involved. The cytoplasmic sensor nucleotide-binding oligomerization domain containing (NOD) 2/caspase recruitment domain (CARD) 15 detects muramyl dipeptide from bacterial peptidoglycans and mediates cytokine responses to S. aureus in vitro, but the physiological significance of these observations is not well defined. ⋯ NOD2-dependent recognition of S. aureus and muramyl dipeptide is facilitated by alpha-toxin (alpha-hemolysin), a pore-forming toxin and virulence factor of the pathogen. The action of NOD2 is dependent on IL-1beta-amplified production of IL-6, which promotes rapid bacterial killing by neutrophils. These results significantly broaden the physiological importance of NOD2 in innate immunity from the recognition of bacteria that primarily enter the cytoplasm to the detection of bacteria that typically reside extracellularly and demonstrate that this microbial sensor contributes to the discrimination between commensal bacteria and bacterial pathogens that elaborate pore-forming toxins.
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Proc. Natl. Acad. Sci. U.S.A. · Aug 2009
Leptin derived from adipocytes in injured peripheral nerves facilitates development of neuropathic pain via macrophage stimulation.
Nerve injury may result in neuropathic pain, characterized by allodynia and hyperalgesia. Accumulating evidence suggests the existence of a molecular substrate for neuropathic pain produced by neurons, glia, and immune cells. Here, we show that leptin, an adipokine exclusively produced by adipocytes, is critical for the development of tactile allodynia through macrophage activation in mice with partial sciatic nerve ligation (PSL). ⋯ Administration of peritoneal macrophages treated with leptin to the injured SCN reversed the failure of ob/ob mice to develop PSL-induced tactile allodynia. We suggest that leptin induces recruited macrophages to produce pronociceptive mediators for the development of tactile allodynia. This report shows that adipocytes associated with primary afferent neurons may be involved in the development of neuropathic pain through adipokine secretion.
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Proc. Natl. Acad. Sci. U.S.A. · Jul 2009
Parental stress increases the effect of traffic-related air pollution on childhood asthma incidence.
Exposure to traffic-related pollution (TRP) and tobacco smoke have been associated with new onset asthma in children. Psychosocial stress-related susceptibility has been proposed to explain social disparities in asthma. We investigated whether low socioeconomic status (SES) or high parental stress modified the effect of TRP and in utero tobacco smoke exposure on new onset asthma. ⋯ Stress also was associated with larger effects of in utero tobacco smoke. A similar pattern of increased risk of asthma was observed among children from low SES families who also were exposed to either TRP or in utero tobacco smoke. These results suggest that children from stressful households are more susceptible to the effects of TRP and in utero tobacco smoke on the development of asthma.
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Proc. Natl. Acad. Sci. U.S.A. · Jul 2009
Decoupling of the brain's default mode network during deep sleep.
The recent discovery of a circuit of brain regions that is highly active in the absence of overt behavior has led to a quest for revealing the possible function of this so-called default-mode network (DMN). A very recent study, finding similarities in awake humans and anesthetized primates, has suggested that DMN activity might not simply reflect ongoing conscious mentation but rather a more general form of network dynamics typical of complex systems. Here, by performing functional MRI in humans, it is shown that a natural, sleep-induced reduction of consciousness is reflected in altered correlation between DMN network components, most notably a reduced involvement of frontal cortex. This suggests that DMN may play an important role in the sustenance of conscious awareness.
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Proc. Natl. Acad. Sci. U.S.A. · Jun 2009
Mouse model of OPRM1 (A118G) polymorphism has sex-specific effects on drug-mediated behavior.
A single nucleotide polymorphism (SNP) in the human mu-opioid receptor gene (OPRM1 A118G) has been widely studied for its association in a variety of drug addiction and pain sensitivity phenotypes; however, the extent of these adaptations and the mechanisms underlying these associations remain elusive. To clarify the functional mechanisms linking the OPRM1 A118G SNP to addiction and analgesia phenotypes, we derived a mouse model possessing the equivalent nucleotide/amino acid substitution in the Oprm1 gene. ⋯ In addition, we found sex-specific reductions in the rewarding properties of morphine and the aversive components of naloxone-precipitated morphine withdrawal. Further cross-species analysis will allow us to investigate mechanisms and adaptations present in humans carrying this SNP.