Macrophage pro-inflammatory cytokine secretion is enhanced following interaction with autologous platelets

<p>Abstract</p> <p>Background</p> <p>Macrophages are the dominant phagocyte at sites of wound healing and inflammation, and the cellular and acellular debris encountered by macrophages can have profound effects on their inflammatory profile. Following interaction with apoptotic cells, macrophages are known to switch to an anti-inflammatory phenotype. Activated platelets, however, are also a major component of inflammatory lesions and have been proposed to be pro-inflammatory mediators. In the present study, we tested the hypothesis that macrophage interaction with activated platelets results in an inflammatory response that differs from the response following phagocytosis of apoptotic cells.</p> <p>Methods</p> <p>Human monocyte-derived macrophages (hMDMs) were co-incubated with autologous activated platelets (AAPs) and the platelet-macrophage interaction was examined by electron microscopy and flow cytometry. The cytokines TNF-α, IL-6, and IL-23 were also measured during LPS-activated hMDM co-incubation with AAPs, which was compared to co-incubation with apoptotic lymphocytes. Cytokine secretion was also compared to platelets pre-treated with the gluococorticoid dexamethasone.</p> <p>Results</p> <p>Macrophages trapped and phagocytized AAPs utilizing a mechanism that was significantly inhibited by the scavenger receptor ligand fucoidan. LPS-induced macrophage secretion of TNF-α, IL-6, and IL-23 was inhibited by co-incubation with apoptotic cells, but enhanced by co-incubation with AAPs. The platelet-dependent enhancement of LPS-induced cytokines could be reversed by pre-loading the platelets with the glucocorticoid dexamethasone.</p> <p>Conclusions</p> <p>The interaction of human macrophages with autologous platelets results in scavenger-receptor-mediated platelet uptake and enhancement of LPS-induced cytokines. Therefore, the presence of activated platelets at sites of inflammation may exacerbate pro-inflammatory macrophage activation. The possibility of reversing macrophage activation with dexamethasone-loaded platelets is a promising therapeutic approach to treating unresolved inflammation.</p

Mutations to the caveolin scaffolding domain reduces Caveolin-1 targeting of glycolytic enzymes to lymphocyte membranes [abstract]

Abstract only availablePreviously, we found caveolin (CAV-1) expressed by transfection in cultured lymphocytes induced caveolae formation and targeted the glycolytic enzyme phosphofructokinase (PFK) to the membrane. We also found CAV-1 targets other glycolytic enzymes such as aldolase (ALD)and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) to the plasma membrane in the CAV-1 transfected lymphocytes. Here we hypothesized that if a mutant CAV-1 (which has essential aromatic residues in the caveolin scaffolding domain (CSD) mutated) is expressed in the lymphocyte then colocalization of the glycolytic enzyme PFK with CAV-1 will be reduced. We tested this hypothesis by comparing the colocalization of CAV-1 with the glycolytic enzymes PFK, ALD and GAPDH in lymphocytes which expressed either a wild type CAV-1 (WT) or a mutant CAV-1 which had either one mutation (SM) or two mutations (DM) in the CSD. Colocalization analysis by confocal microscopy of cells immunoassayed for CAV-1 and ALD was 76.59% in lymphocytes transfected with CAV-1 WT, 23.96% in lymphocytes transfected with CAV-1 SM, and 58.74% in the lymphocytes transfected with CAV-1 DM. Analysis of colocalization of the enzymes PFK, GAPDH, and ALD with CAV-1 averaged 65.17% for the CAV-1 WT cells, 49.29% for the CAV-1 SM cells and 50.81% for the CAV-1 DM cells. The shift in distribution of glycolytic enzymes and CAV-1 in the CAV-1 WT, the CAV-1 SM or DM CAV-1 types indicates that a single mutation to the CSD reduces membrane targeting of glycolytic enzymes, and two mutations in the CSD produces retention of CAV-1 in the cytosol. These results suggest that an intact CSD domain is essential to the CAV-1 targeting of glycolytic enzymes to the membrane

Radiative absorption enhancements by black carbon controlled by particle-to-particle heterogeneity in composition.

Black carbon (BC) absorbs solar radiation, leading to a strong but uncertain warming effect on climate. A key challenge in modeling and quantifying BC's radiative effect on climate is predicting enhancements in light absorption that result from internal mixing between BC and other aerosol components. Modeling and laboratory studies show that BC, when mixed with other aerosol components, absorbs more strongly than pure, uncoated BC; however, some ambient observations suggest more variable and weaker absorption enhancement. We show that the lower-than-expected enhancements in ambient measurements result from a combination of two factors. First, the often used spherical, concentric core-shell approximation generally overestimates the absorption by BC. Second, and more importantly, inadequate consideration of heterogeneity in particle-to-particle composition engenders substantial overestimation in absorption by the total particle population, with greater heterogeneity associated with larger model-measurement differences. We show that accounting for these two effects-variability in per-particle composition and deviations from the core-shell approximation-reconciles absorption enhancement predictions with laboratory and field observations and resolves the apparent discrepancy. Furthermore, our consistent model framework provides a path forward for improving predictions of BC's radiative effect on climate

Inside-out sustainability: the neglect of inner worlds

In the context of continuing ecosystem degradation and deepening socio-economic inequality, sustainability scientists must question the adequacy of current scholarship and practice. We argue that pre-occupation with external phenomena and collective social structures has led to the neglect of people’s ‘inner worlds’—their emotions, thoughts, identities and beliefs. These lie at the heart of actions for sustainability, and have powerful transformative capacity for system change. The condition of people’s inner worlds ought to also be considered a dimension of sustainability itself. Compassion, empathy and generosity, for example, are personal characteristics that mark individual expressions of sustainability. Sustainability science must take inner life more seriously by considering how language shapes and is shaped by paradigms about the world, prioritising enquiry into how spirituality, contemplation and sustainability transformation relate, and encouraging scholars and practitioners to intentionally cultivate their inner worlds to strengthen inner resources necessary for addressing sustainability challenges

The political economy of management knowledge : management texts in English healthcare organizations

Have generic management texts and associated knowledges now extensively diffused into public services organizations? If so, why? Our empirical study of English healthcare organizations detects an extensive presence of such texts. We argue that their ready diffusion relates to two macro-level forces: (i) the influence of the underlying political economy of public services reform and (ii) a strongly developed business school/management consulting knowledge nexus. This macro perspective theoretically complements existing explanations from the meso or middle level of analysis which examine diffusion processes within the public services field, and also more micro literature which focuses on agency from individual knowledge leaders

Citizen Science Provides Valuable Data for Monitoring Global Night Sky Luminance

The skyglow produced by artificial lights at night is one of the most dramatic anthropogenic modifications of Earth’s biosphere. The GLOBE at Night citizen science project allows individual observers to quantify skyglow using star maps showing different levels of light pollution. We show that aggregated GLOBE at Night data depend strongly on artificial skyglow, and could be used to track lighting changes worldwide. Naked eye time series can be expected to be very stable, due to the slow pace of human eye evolution. The standard deviation of an individual GLOBE at Night observation is found to be 1.2 stellar magnitudes. Zenith skyglow estimates from the ‘‘First World Atlas of Artificial Night Sky Brightness’’ are tested using a subset of the GLOBE at Night data. Although we find the World Atlas overestimates sky brightness in the very center of large cities, its predictions for Milky Way visibility are accurate

Co-crystal structure of the Fusobacterium ulcerans ZTP riboswitch using an X-ray free-electron laser.

Riboswitches are conformationally dynamic RNAs that regulate gene expression by binding specific small molecules. ZTP riboswitches bind the purine-biosynthetic intermediate 5-aminoimidazole-4-carboxamide riboside 5\u27-monophosphate (ZMP) and its triphosphorylated form (ZTP). Ligand binding to this riboswitch ultimately upregulates genes involved in folate and purine metabolism. Using an X-ray free-electron laser (XFEL), the room-temperature structure of the Fusobacterium ulcerans ZTP riboswitch bound to ZMP has now been determined at 4.1 Å resolution. This model, which was refined against a data set from ∼750 diffraction images (each from a single crystal), was found to be consistent with that previously obtained from data collected at 100 K using conventional synchrotron X-radiation. These experiments demonstrate the feasibility of time-resolved XFEL experiments to understand how the ZTP riboswitch accommodates cognate ligand binding

Excited OH+, H2O+, and H3O+ in NGC 4418 and Arp 220

We report on Herschel/PACS observations of absorption lines of OH+, H2O+ and H3O+ in NGC 4418 and Arp 220. Excited lines of OH+ and H2O+ with E_lower of at least 285 and \sim200 K, respectively, are detected in both sources, indicating radiative pumping and location in the high radiation density environment of the nuclear regions. Abundance ratios OH+/H2O+ of 1-2.5 are estimated in the nuclei of both sources. The inferred OH+ column and abundance relative to H nuclei are (0.5-1)x10^{16} cm-2 and \sim2x10^{-8}, respectively. Additionally, in Arp 220, an extended low excitation component around the nuclear region is found to have OH+/H2O+\sim5-10. H3O+ is detected in both sources with N(H3O+)\sim(0.5-2)x10^{16} cm-2, and in Arp 220 the pure inversion, metastable lines indicate a high rotational temperature of ~500 K, indicative of formation pumping and/or hot gas. Simple chemical models favor an ionization sequence dominated by H+ - O+ - OH+ - H2O+ - H3O+, and we also argue that the H+ production is most likely dominated by X-ray/cosmic ray ionization. The full set of observations and models leads us to propose that the molecular ions arise in a relatively low density (\gtrsim10^4 cm-3) interclump medium, in which case the ionization rate per H nucleus (including secondary ionizations) is zeta>10^{-13} s-1, a lower limit that is severalx10^2 times the highest rate estimates for Galactic regions. In Arp 220, our lower limit for zeta is compatible with estimates for the cosmic ray energy density inferred previously from the supernova rate and synchrotron radio emission, and also with the expected ionization rate produced by X-rays. In NGC 4418, we argue that X-ray ionization due to an AGN is responsible for the molecular ion production.Comment: 24 pages, 13 figures. Accepted for publication in Astronomy & Astrophysic

Autonomic Dysregulation in Adolescent Concussion Is Sex- and Posture-Dependent

Objective: To study autonomic responses to postural changes in concussed adolescents. The influence of sex was also studied. Design: Longitudinal cohort observational study. Participants: Concussed adolescents (CONC; n = 65; 26 male adolescents; age 15 ± 1 years, range = 12-18 years) and a control (CTRL) group of nonconcussed adolescents of similar age and sport (CTRL; n = 54; 29 male adolescents; age 14 ± 1 years, range = 12-18 years). Interventions: Concussed participants were monitored through 6 weekly visits throughout usual physician care. Control participants underwent 2 visits separated by at least 1 week to account for intrapersonal variation in testing measures. Main Outcome Measures: Heart rate variability as the root mean square of successive differences in R–R intervals (RMSSD), heart rate (HR), and blood pressure [mean arterial pressure (MAP) and diastolic blood pressure (DBP)] were measured in supine, sitting, and standing postures. Results: A mixed analysis of variance revealed a group 3 sex 3 posture interaction (P = 0.04) where seated values of RMSSD were less in concussed female participants versus control female participants (42 ± 4 vs 61 ± 7 ms; P = 0.01; Mann–Whitney rank test). Compared with CTRL, CONC exhibited increased pretesting seated DBP (69 ± 1 vs 74 ± 1 mm Hg; P\u3c 0.01), MAP (83 ± 1 vs 86 ± 1 mm Hg; P = 0.02), and baseline seated HR (72 ± 1 vs 77 ± 2 bpm; P = 0.03). Values of DBP (P = 0.03) and MAP (P, 0.01) improved at clinical discharge, whereas the RMSSD in female participants did not (P \u3e 0.5). Data are mean ± SEM. Conclusions: A modest reduction in female cardiac autonomic regulation was observed during seated postures. Alterations in seated concussed DBP and MAP, but not RMSSD, resolved at clinical discharge (median = 37 days). The results indicate that, in adolescents, concussion may impair cardiovagal function in a sex- and posture-dependent manner. The findings also suggest that BP metrics, but not RMSSD, are associated with clinical concussion recovery