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 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.
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Proc. Natl. Acad. Sci. U.S.A. · Aug 2015
Molecular and preclinical basis to inhibit PGE2 receptors EP2 and EP4 as a novel nonsteroidal therapy for endometriosis.
Endometriosis is a debilitating, estrogen-dependent, progesterone-resistant, inflammatory gynecological disease of reproductive age women. Two major clinical symptoms of endometriosis are chronic intolerable pelvic pain and subfertility or infertility, which profoundly affect the quality of life in women. Current hormonal therapies to induce a hypoestrogenic state are unsuccessful because of undesirable side effects, reproductive health concerns, and failure to prevent recurrence of disease. ⋯ The objective of the present study was to determine the effects of pharmacological inhibition of PGE2 receptors, EP2 and EP4, on molecular and cellular aspects of the pathogenesis of endometriosis and associated clinical symptoms. Using human fluorescent endometriotic cell lines and chimeric mouse model as preclinical testing platform, our results, to our knowledge for the first time, indicate that selective inhibition of EP2/EP4: (i) decreases growth and survival of endometriosis lesions; (ii) decreases angiogenesis and innervation of endometriosis lesions; (iii) suppresses proinflammatory state of dorsal root ganglia neurons to decrease pelvic pain; (iv) decreases proinflammatory, estrogen-dominant, and progesterone-resistant molecular environment of the endometrium and endometriosis lesions; and (v) restores endometrial functional receptivity through multiple mechanisms. Our novel findings provide a molecular and preclinical basis to formulate long-term nonestrogen or nonsteroidal therapy for endometriosis.