Proceedings of the National Academy of Sciences of the United States of America
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Proc. Natl. Acad. Sci. U.S.A. · Nov 2018
Humanized cereblon mice revealed two distinct therapeutic pathways of immunomodulatory drugs.
Immunomodulatory drugs (IMiDs), including thalidomide derivatives such as lenalidomide and pomalidomide, offer therapeutic benefit in several hematopoietic malignancies and autoimmune/inflammatory diseases. However, it is difficult to study the IMiD mechanism of action in murine disease models because murine cereblon (CRBN), the substrate receptor for IMiD action, is resistant to some of IMiDs therapeutic effects. To overcome this difficulty, we generated humanized cereblon (CRBNI391V) mice thereby providing an animal model to unravel complex mechanisms of action in a murine physiological setup. ⋯ Additionally, we assessed the potential therapeutic effects of IMiDs in dextran sodium sulfate (DSS)-induced colitis. In both WT and humanized mice, lenalidomide showed a significant therapeutic effect in the DSS model of colitis, while the effect of pomalidomide was less pronounced. Thus, while IMiDs' degradative effect on IKZF1 and CK-1α, and up-regulation of IL-2, is dependent on CRBN, the therapeutic benefit of IMiDs in a mouse model of inflammatory bowel disease occurs through a CRBN-IMiD binding region independent pathway.
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Proc. Natl. Acad. Sci. U.S.A. · Nov 2018
The demise of caterpillar fungus in the Himalayan region due to climate change and overharvesting.
Demand for traditional medicine ingredients is causing species declines globally. Due to this trade, Himalayan caterpillar fungus (Ophiocordyceps sinensis) has become one of the world's most valuable biological commodities, providing a crucial source of income for hundreds of thousands of collectors. However, the resulting harvesting boom has generated widespread concern over the sustainability of its collection. ⋯ They indicate that caterpillar fungus is more productive under colder conditions, growing in close proximity to areas likely to have permafrost. With significant warming already underway throughout much of its range, we conclude that caterpillar fungus populations have been negatively affected by a combination of overexploitation and climate change. Our results underscore that harvesting is not the sole threat to economically valuable species, and that a collapse of the caterpillar fungus system under ongoing warming and high collection pressure would have serious implications throughout the Himalayan region.
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Proc. Natl. Acad. Sci. U.S.A. · Nov 2018
Median nerve stimulation induces analgesia via orexin-initiated endocannabinoid disinhibition in the periaqueductal gray.
Adequate pain management remains an unmet medical need. We previously revealed an opioid-independent analgesic mechanism mediated by orexin 1 receptor (OX1R)-initiated 2-arachidonoylglycerol (2-AG) signaling in the ventrolateral periaqueductal gray (vlPAG). Here, we found that low-frequency median nerve stimulation (MNS) through acupuncture needles at the PC6 (Neiguan) acupoint (MNS-PC6) induced an antinociceptive effect that engaged this mechanism. ⋯ A cannabinoid (2-AG)-dependent mechanism was also implicated by the observations that MNS-PC6-IA was prevented by intravlPAG inhibition of 2-AG synthesis and was attenuated in Cnr1-/- mice. These findings suggest that PC6-targeting low-frequency MNS activates hypothalamic orexin neurons, releasing orexins to induce analgesia through a CB1R-dependent cascade mediated by OX1R-initiated 2-AG retrograde disinhibition in the vlPAG. The opioid-independent characteristic of MNS-PC6-induced analgesia may provide a strategy for pain management in opioid-tolerant patients.
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Proc. Natl. Acad. Sci. U.S.A. · Oct 2018
Distinct facial expressions represent pain and pleasure across cultures.
Real-world studies show that the facial expressions produced during pain and orgasm-two different and intense affective experiences-are virtually indistinguishable. However, this finding is counterintuitive, because facial expressions are widely considered to be a powerful tool for social interaction. Consequently, debate continues as to whether the facial expressions of these extreme positive and negative affective states serve a communicative function. ⋯ Together, our data show that mental representations of the facial expressions of pain and orgasm are distinct, which questions their nondiagnosticity and instead suggests they could be used for communicative purposes. Our results also highlight the potential role of cultural and perceptual factors in shaping the mental representation of these facial expressions. We discuss new research directions to further explore their relationship to the production of facial expressions.
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Proc. Natl. Acad. Sci. U.S.A. · Oct 2018
p38α MAPK signaling drives pharmacologically reversible brain and gastrointestinal phenotypes in the SERT Ala56 mouse.
Autism spectrum disorder (ASD) is a common neurobehavioral disorder with limited treatment options. Activation of p38 MAPK signaling networks has been identified in ASD, and p38 MAPK signaling elevates serotonin (5-HT) transporter (SERT) activity, effects mimicked by multiple, hyperfunctional SERT coding variants identified in ASD subjects. Mice expressing the most common of these variants (SERT Ala56) exhibit hyperserotonemia, a biomarker observed in ASD subjects, as well as p38 MAPK-dependent SERT hyperphosphorylation, elevated hippocampal 5-HT clearance, hypersensitivity of CNS 5-HT1A and 5-HT2A/2C receptors, and behavioral and gastrointestinal perturbations reminiscent of ASD. ⋯ Strikingly, 1-week treatment of adult SERT Ala56 mice with MW150, a selective p38α MAPK inhibitor, normalized hippocampal 5-HT clearance, CNS 5-HT1A and 5-HT2A/2C receptor sensitivities, social interactions, and colonic motility. Conditional elimination of p38α MAPK in 5-HT neurons of SERT Ala56 mice restored 5-HT1A and 5-HT2A/2C receptor sensitivities as well as social interactions, mirroring effects of MW150. Our findings support ongoing p38α MAPK activity as an important determinant of the physiological and behavioral perturbations of SERT Ala56 mice and, more broadly, supports consideration of p38α MAPK inhibition as a potential treatment for core and comorbid phenotypes present in ASD subjects.