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 2014
Noble gases identify the mechanisms of fugitive gas contamination in drinking-water wells overlying the Marcellus and Barnett Shales.
Horizontal drilling and hydraulic fracturing have enhanced energy production but raised concerns about drinking-water contamination and other environmental impacts. Identifying the sources and mechanisms of contamination can help improve the environmental and economic sustainability of shale-gas extraction. We analyzed 113 and 20 samples from drinking-water wells overlying the Marcellus and Barnett Shales, respectively, examining hydrocarbon abundance and isotopic compositions (e.g., C2H6/CH4, δ(13)C-CH4) and providing, to our knowledge, the first comprehensive analyses of noble gases and their isotopes (e.g., (4)He, (20)Ne, (36)Ar) in groundwater near shale-gas wells. ⋯ Where fugitive gas contamination occurred, the relative proportions of thermogenic hydrocarbon gas (e.g., CH4, (4)He) were significantly higher (P < 0.01) and the proportions of atmospheric gases (air-saturated water; e.g., N2, (36)Ar) were significantly lower (P < 0.01) relative to background groundwater. Noble gas isotope and hydrocarbon data link four contamination clusters to gas leakage from intermediate-depth strata through failures of annulus cement, three to target production gases that seem to implicate faulty production casings, and one to an underground gas well failure. Noble gas data appear to rule out gas contamination by upward migration from depth through overlying geological strata triggered by horizontal drilling or hydraulic fracturing.
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Proc. Natl. Acad. Sci. U.S.A. · Sep 2014
Hemolysis-induced lethality involves inflammasome activation by heme.
The increase of extracellular heme is a hallmark of hemolysis or extensive cell damage. Heme has prooxidant, cytotoxic, and inflammatory effects, playing a central role in the pathogenesis of malaria, sepsis, and sickle cell disease. However, the mechanisms by which heme is sensed by innate immune cells contributing to these diseases are not fully characterized. ⋯ The activation of NLRP3 by heme required spleen tyrosine kinase, NADPH oxidase-2, mitochondrial reactive oxygen species, and K(+) efflux, whereas it was independent of heme internalization, lysosomal damage, ATP release, the purinergic receptor P2X7, and cell death. Importantly, our results indicated the participation of macrophages, NLRP3 inflammasome components, and IL-1R in the lethality caused by sterile hemolysis. Thus, understanding the molecular pathways affected by heme in innate immune cells might prove useful to identify new therapeutic targets for diseases that have heme release.
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Proc. Natl. Acad. Sci. U.S.A. · Sep 2014
Ubiquitin-conjugating enzyme Ubc13 controls breast cancer metastasis through a TAK1-p38 MAP kinase cascade.
Metastatic spread is the leading cause of cancer mortality. Breast cancer (BCa) metastatic recurrence can happen years after removal of the primary tumor. ⋯ Loss of Ubc13 inhibited BCa growth and survival only at metastatic sites. Ubc13 was dispensable for transforming growth factor β (TGFβ)-induced SMAD activation but was required for activation of non-SMAD signaling via TGFβ-activating kinase 1 (TAK1) and p38, whose activity controls expression of numerous metastasis promoting genes. p38 activation restored metastatic activity to Ubc13-deficient cells, and its pharmacological inhibition attenuated BCa metastasis in mice, suggesting it is a therapeutic option for metastatic BCa.
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Proc. Natl. Acad. Sci. U.S.A. · Sep 2014
Voltage-sensitive dye imaging of transcranial magnetic stimulation-induced intracortical dynamics.
Transcranial magnetic stimulation (TMS) is widely used in clinical interventions and basic neuroscience. Additionally, it has become a powerful tool to drive plastic changes in neuronal networks. However, highly resolved recordings of the immediate TMS effects have remained scarce, because existing recording techniques are limited in spatial or temporal resolution or are interfered with by the strong TMS-induced electric field. ⋯ Furthermore, loss of the "deceleration-acceleration" notch during the rising phase of the response, as a signature of fast intracortical inhibition detectable with VSD imaging, indicated weakened inhibition as an important driving force of increasing cortical excitability. In summary, our data show that high-frequency TMS changes the balance between excitation and inhibition in favor of an excitatory cortical state. VSD imaging may thus be a promising technique to trace TMS-induced changes in excitability and resulting plastic processes across cortical maps with high spatial and temporal resolutions.
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Proc. Natl. Acad. Sci. U.S.A. · Sep 2014
Phospholipase D2 specifically regulates TREK potassium channels via direct interaction and local production of phosphatidic acid.
Membrane lipids serve as second messengers and docking sites for proteins and play central roles in cell signaling. A major question about lipid signaling is whether diffusible lipids can selectively target specific proteins. One family of lipid-regulated membrane proteins is the TWIK-related K channel (TREK) subfamily of K2P channels: TREK1, TREK2, and TWIK-related arachdonic acid stimulated K(+) channel (TRAAK). ⋯ We found that PLD2, but not PLD1, directly binds to the C terminus of TREK1 and TREK2, but not to TRAAK. The results have led to a model for selective lipid regulation by localization of phospholipid enzymes to specific effector proteins. Finally, we show that regulation of TREK channels by PLD2 occurs natively in hippocampal neurons.