830 research outputs found

    Ca2+/Calmodulin-Dependent Kinase Kinase α Is Expressed by Monocytic Cells and Regulates the Activation Profile

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    Macrophages are capable of assuming numerous phenotypes in order to adapt to endogenous and exogenous challenges but many of the factors that regulate this process are still unknown. We report that Ca2+/calmodulin-dependent kinase kinase α (CaMKKα) is expressed in human monocytic cells and demonstrate that its inhibition blocks type-II monocytic cell activation and promotes classical activation. Affinity chromatography with paramagnetic beads isolated an approximately 50 kDa protein from nuclear lysates of U937 human monocytic cells activated with phorbol-12-myristate-13-acetate (PMA). This protein was identified as CaMKKα by mass spectrometry and Western analysis. The function of CaMKKα in monocyte activation was examined using the CaMKKα inhibitors (STO-609 and forskolin) and siRNA knockdown. Inhibition of CaMKKα, enhanced PMA-dependent CD86 expression and reduced CD11b expression. In addition, inhibition was associated with decreased translocation of CaMKKα to the nucleus. Finally, to further examine monocyte activation profiles, TNFα and IL-10 secretion were studied. CaMKKα inhibition attenuated PMA-dependent IL-10 production and enhanced TNFα production indicating a shift from type-II to classical monocyte activation. Taken together, these findings indicate an important new role for CaMKKα in the differentiation of monocytic cells

    Fatty acid nitroalkenes ameliorate glucose intolerance and pulmonary hypertension in high-fat diet-induced obesity

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    Aims Obesity is a risk factor for diabetes and cardiovascular diseases, with the incidence of these disorders becoming epidemic. Pathogenic responses to obesity have been ascribed to adipose tissue (AT) dysfunction that promotes bioactive mediator secretion from visceral AT and the initiation of pro-inflammatory events that induce oxidative stress and tissue dysfunction. Current understanding supports that suppressing pro-inflammatory and oxidative events promotes improved metabolic and cardiovascular function. In this regard, electrophilic nitro-fatty acids display pleiotropic anti-inflammatory signalling actions. Methods and results It was hypothesized that high-fat diet (HFD)-induced inflammatory and metabolic responses, manifested by loss of glucose tolerance and vascular dysfunction, would be attenuated by systemic administration of nitrooctadecenoic acid (OA-NO2). Male C57BL/6j mice subjected to a HFD for 20 weeks displayed increased adiposity, fasting glucose, and insulin levels, which led to glucose intolerance and pulmonary hypertension, characterized by increased right ventricular (RV) end-systolic pressure (RVESP) and pulmonary vascular resistance (PVR). This was associated with increased lung xanthine oxidoreductase (XO) activity, macrophage infiltration, and enhanced expression of pro-inflammatory cytokines. Left ventricular (LV) end-diastolic pressure remained unaltered, indicating that the HFD produces pulmonary vascular remodelling, rather than LV dysfunction and pulmonary venous hypertension. Administration of OA-NO2 for the final 6.5 weeks of HFD improved glucose tolerance and significantly attenuated HFD-induced RVESP, PVR, RV hypertrophy, lung XO activity, oxidative stress, and pro-inflammatory pulmonary cytokine levels. Conclusions These observations support that the pleiotropic signalling actions of electrophilic fatty acids represent a therapeutic strategy for limiting the complex pathogenic responses instigated by obesity.Fil: Kelley, Eric E.. University of Pittsburgh; Estados UnidosFil: Baust, Jeff. University of Pittsburgh; Estados UnidosFil: Bonacci, Gustavo Roberto. University of Pittsburgh; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Golin Bisello, Franca. University of Pittsburgh; Estados UnidosFil: Devlin, Jason E.. University of Pittsburgh; Estados UnidosFil: Croix, Claudette M. St.. University of Pittsburgh; Estados UnidosFil: Watkins, Simon C.. University of Pittsburgh; Estados UnidosFil: Gor, Sonia. University of Pittsburgh; Estados UnidosFil: Cantu Medellin, Nadiezhda. University of Pittsburgh; Estados UnidosFil: Weidert, Eric R.. University of Pittsburgh; Estados UnidosFil: Frisbee,Jefferson C.. University of Virginia; Estados UnidosFil: Gladwin, Mark T.. University of Pittsburgh; Estados UnidosFil: Champion, Hunter C.. University of Pittsburgh; Estados UnidosFil: Freeman, Bruce A.. University of Pittsburgh; Estados UnidosFil: Khoo, Nicholas K.H.. University of Pittsburgh; Estados Unido

    The quest to model chronic traumatic encephalopathy: a multiple model and injury paradigm experience

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    Chronic neurodegeneration following a history of neurotrauma is frequently associated with neuropsychiatric and cognitive symptoms. In order to enhance understanding about the underlying pathophysiology linking neurotrauma to neurodegeneration, a multi-model preclinical approach must be established to account for the different injury paradigms and pathophysiologic mechanisms. We investigated the development of tau pathology and behavioral changes using a multi-model and multi-institutional approach, comparing the preclinical results to tauopathy patterns seen in post-mortem human samples from athletes diagnosed with chronic traumatic encephalopathy (CTE). We utilized a scaled and validated blast-induced traumatic brain injury model in rats and a modified pneumatic closed-head impact model in mice. Tau hyperphosphorylation was evaluated by western blot and immunohistochemistry. Elevated-plus maze and Morris water maze were employed to measure impulsive-like behavior and cognitive deficits respectively. Animals exposed to single blast (~50 PSI reflected peak overpressure) exhibited elevated AT8 immunoreactivity in the contralateral hippocampus at 1 month compared to controls (q = 3.96, p \u3c 0.05). Animals exposed to repeat blast (six blasts over 2 weeks) had increased AT8 (q = 8.12, p \u3c 0.001) and AT270 (q = 4.03, p \u3c 0.05) in the contralateral hippocampus at 1 month post-injury compared to controls. In the modified controlled closed-head impact mouse model, no significant difference in AT8 was seen at 7 days, however a significant elevation was detected at 1 month following injury in the ipsilateral hippocampus compared to control (q = 4.34, p \u3c 0.05). Elevated-plus maze data revealed that rats exposed to single blast (q = 3.53, p \u3c 0.05) and repeat blast (q = 4.21, p \u3c 0.05) spent more time in seconds exploring the open arms compared to controls. Morris water maze testing revealed a significant difference between groups in acquisition times on days 22–27. During the probe trial, single blast (t = 6.44, p \u3c 0.05) and repeat blast (t = 8.00, p \u3c 0.05) rats spent less time in seconds exploring where the platform had been located compared to controls. This study provides a multi-model example of replicating tau and behavioral changes in animals and provides a foundation for future investigation of CTE disease pathophysiology and therapeutic development

    Disentangling the Regional Climate Impacts of Competing Vegetation Responses to Elevated Atmospheric CO<sub>2</sub>

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    Biophysical vegetation responses to elevated atmospheric carbon dioxide (CO(2)) affect regional hydroclimate through two competing mechanisms. Higher CO(2) increases leaf area (LAI), thereby increasing transpiration and water losses. Simultaneously, elevated CO(2) reduces stomatal conductance and transpiration, thereby increasing rootzone soil moisture. Which mechanism dominates in the future is highly uncertain, partly because these two processes are difficult to explicitly separate within dynamic vegetation models. We address this challenge by using the GISS ModelE global climate model to conduct a novel set of idealized 2×CO(2) sensitivity experiments to: evaluate the total vegetation biophysical contribution to regional climate change under high CO(2); and quantify the separate contributions of enhanced LAI and reduced stomatal conductance to regional hydroclimate responses. We find that increased LAI exacerbates soil moisture deficits across the sub‐tropics and more water‐limited regions, but also attenuates warming by ∼0.5–1°C in the US Southwest, Central Asia, Southeast Asia, and northern South America. Reduced stomatal conductance effects contribute ∼1°C of summertime warming. For some regions, enhanced LAI and reduced stomatal conductance produce nonlinear and either competing or mutually amplifying hydroclimate responses. In northeastern Australia, these effects combine to exacerbate radiation‐forced warming and contribute to year‐round water limitation. Conversely, at higher latitudes these combined effects result in less warming than would otherwise be predicted due to nonlinear responses. These results highlight substantial regional variation in CO(2)‐driven vegetation responses and the importance of improving model representations of these processes to better quantify regional hydroclimate impacts

    Quantifying methane emissions from the global scale down to point sources using satellite observations of atmospheric methane

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    [EN] We review the capability of current and scheduled satellite observations of atmospheric methane in the shortwave infrared (SWIR) to quantify methane emissions from the global scale down to point sources. We cover retrieval methods, precision and accuracy requirements, inverse and mass balance methods for inferring emissions, source detection thresholds, and observing system completeness. We classify satellite instruments as area flux mappers and point source imagers, with complementary attributes. Area flux mappers are high-precision (< 1 %) instruments with 0.1-10 km pixel size designed to quantify total methane emissions on regional to global scales. Point source imagers are fine-pixel (< 60 m) instruments designed to quantify individual point sources by imaging of the plumes. Current area flux mappers include GOSAT (2009-present), which provides a high-quality record for interpretation of long-term methane trends, and TROPOMI (2018-present), which provides global continuous daily mapping to quantify emissions on regional scales. These instruments already provide a powerful resource to quantify national methane emissions in support of the Paris Agreement. Current point source imagers include the GHGSat constellation and several hyperspectral and multispectral land imaging sensors (PRISMA, Sentinel-2, Landsat-8/9, WorldView-3), with detection thresholds in the 100-10 000 kg h(-1) range that enable monitoring of large point sources. Future area flux mappers, including MethaneSAT, GOSAT-GW, Sentinel-5, GeoCarb, and CO2M, will increase the capability to quantify emissions at high resolution, and the MERLIN lidar will improve observation of the Arctic. The averaging times required by area flux mappers to quantify regional emissions depend on pixel size, retrieval precision, observation density, fraction of successful retrievals, and return times in a way that varies with the spatial resolution desired. A similar interplay applies to point source imagers between detection threshold, spatial coverage, and return time, defining an observing system completeness. Expanding constellations of point source imagers including GHGSat and Carbon Mapper over the coming years will greatly improve observing system completeness for point sources through dense spatial coverage and frequent return times.This research has been supported by the Collaboratory to Advance Methane Science (CAMS) and the National Aeronautics and Space Administration, Earth Sciences Division (grant no. NNH20ZDA001N-CMS).Jacob, DJ.; Varon, DJ.; Cusworth, DH.; Dennision, PE.; Frankenberg, C.; Gautam, R.; Guanter-Palomar, LM.... (2022). Quantifying methane emissions from the global scale down to point sources using satellite observations of atmospheric methane. ATMOSPHERIC CHEMISTRY AND PHYSICS. 14:9617-9646. https://doi.org/10.5194/acp-22-9617-2022961796461

    Radiative Flux and Forcing Parameterization Error in Aerosol-Free Clear Skies

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    This article reports on the accuracy in aerosol- and cloud-free conditions of the radiation parameterizations used in climate models. Accuracy is assessed relative to observationally validated reference models for fluxes under present-day conditions and forcing (flux changes) from quadrupled concentrations of carbon dioxide. Agreement among reference models is typically within 1 W/m2, while parameterized calculations are roughly half as accurate in the longwave and even less accurate, and more variable, in the shortwave. Absorption of shortwave radiation is underestimated by most parameterizations in the present day and has relatively large errors in forcing. Error in present-day conditions is essentially unrelated to error in forcing calculations. Recent revisions to parameterizations have reduced error in most cases. A dependence on atmospheric conditions, including integrated water vapor, means that global estimates of parameterization error relevant for the radiative forcing of climate change will require much more ambitious calculations
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