Proceedings of the National Academy of Sciences of the United States of America
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Proc. Natl. Acad. Sci. U.S.A. · Oct 2015
Imaging robust microglial activation after lipopolysaccharide administration in humans with PET.
Neuroinflammation is associated with a broad spectrum of neurodegenerative and psychiatric diseases. The core process in neuroinflammation is activation of microglia, the innate immune cells of the brain. We measured the neuroinflammatory response produced by a systemic administration of the Escherichia coli lipopolysaccharide (LPS; also called endotoxin) in humans with the positron emission tomography (PET) radiotracer [11C]PBR28, which binds to translocator protein, a molecular marker that is up-regulated by microglial activation. ⋯ This increase was accompanied by an increase in blood levels of inflammatory cytokines, vital sign changes, and sickness symptoms, well-established consequences of LPS administration. To our knowledge, this is the first demonstration in humans that a systemic LPS challenge induces robust increases in microglial activation in the brain. This imaging paradigm to measure brain microglial activation with [11C]PBR28 PET provides an approach to test new medications in humans for their putative antiinflammatory effects.
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Proc. Natl. Acad. Sci. U.S.A. · Sep 2015
Inhibition of the oxygen sensor PHD2 in the liver improves survival in lactic acidosis by activating the Cori cycle.
Loss of prolyl hydroxylase 2 (PHD2) activates the hypoxia-inducible factor-dependent hypoxic response, including anaerobic glycolysis, which causes large amounts of lactate to be released from cells into the circulation. We found that Phd2-null mouse embryonic fibroblasts (MEFs) produced more lactate than wild-type MEFs, as expected, whereas systemic inactivation of PHD2 in mice did not cause hyperlacticacidemia. This unexpected observation led us to hypothesize that the hypoxic response activated in the liver enhances the Cori cycle, a lactate-glucose carbon recycling system between muscle and liver, and thereby decreases circulating lactate. ⋯ Phd2-LKO mice were resistant to lactic acidosis induced by injection of a lethal dose of lactate, displaying a significant elongation of survival. Moreover, oral administration of a PHD inhibitor improved survival in an endotoxin shock mice model. These data suggest that PHD2 is a potentially novel drug target for the treatment of lactic acidosis, which is a serious and often fatal complication observed in some critically ill patients.
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Proc. Natl. Acad. Sci. U.S.A. · Sep 2015
RGS9-2-controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states.
The striatal protein Regulator of G-protein signaling 9-2 (RGS9-2) plays a key modulatory role in opioid, monoamine, and other G-protein-coupled receptor responses. Here, we use the murine spared-nerve injury model of neuropathic pain to investigate the mechanism by which RGS9-2 in the nucleus accumbens (NAc), a brain region involved in mood, reward, and motivation, modulates the actions of tricyclic antidepressants (TCAs). ⋯ Furthermore, information from RNA-sequencing analysis reveals that RGS9-2 in the NAc affects the expression of many genes known to be involved in nociception, analgesia, and antidepressant drug actions. Our findings provide novel information on NAc-specific cellular mechanisms that mediate the actions of TCAs in neuropathic pain states.
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Proc. Natl. Acad. Sci. U.S.A. · Aug 2015
ReviewSystematic review of current efforts to quantify the impacts of climate change on undernutrition.
Malnutrition is a challenge to the health and productivity of populations and is viewed as one of the five largest adverse health impacts of climate change. Nonetheless, systematic evidence quantifying these impacts is currently limited. Our aim was to assess the scientific evidence base for the impact of climate change on childhood undernutrition (particularly stunting) in subsistence farmers in low- and middle-income countries. ⋯ Comparable interdisciplinary studies based on primary data at a household level are urgently required to guide effective adaptation, particularly for rural subsistence farmers. Systemization of data collection at the global level is indispensable and urgent. We need to assimilate data from long-term, high-quality agricultural, environmental, socioeconomic, health, and demographic surveillance systems and develop robust statistical methods to establish and validate causal links, quantify impacts, and make reliable predictions that can guide evidence-based health interventions in the future.
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Proc. Natl. Acad. Sci. U.S.A. · Aug 2015
Modulation of the cGAS-STING DNA sensing pathway by gammaherpesviruses.
Infection of cells with DNA viruses triggers innate immune responses mediated by DNA sensors. cGMP-AMP synthase (cGAS) is a key DNA sensor that produces the cyclic dinucleotide cGMP-AMP (cGAMP) upon activation, which binds to and activates stimulator of interferon genes (STING), leading to IFN production and an antiviral response. Kaposi's sarcoma-associated herpesvirus (KSHV) is a DNA virus that is linked to several human malignancies. We report that KSHV infection activates the cGAS-STING pathway, and that cGAS and STING also play an important role in regulating KSHV reactivation from latency. ⋯ Moreover, the depletion of vIRF1 in the context of KSHV infection prevented efficient viral reactivation and replication, and increased the host IFN response to KSHV. The vIRF1-expressing cells also inhibited IFN-β production following infection with DNA pathogens. Collectively, our results demonstrate that gammaherpesviruses encode inhibitors that block cGAS-STING-mediated antiviral immunity, and that modulation of this pathway is important for viral transmission and the lifelong persistence of herpesviruses in the human population.