555 research outputs found

    Role of orexin A signaling in dietary palmitic acid-activated microglial cells

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    AbstractExcess dietary saturated fatty acids such as palmitic acid (PA) induce peripheral and hypothalamic inflammation. Hypothalamic inflammation, mediated in part by microglial activation, contributes to metabolic dysregulation. In rodents, high fat diet-induced microglial activation results in nuclear translocation of nuclear factor-kappa B (NFκB), and increased central pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6). The hypothalamic neuropeptide orexin A (OXA, hypocretin 1) is neuroprotective in brain. In cortex, OXA can also reduce inflammation and neurodegeneration through a microglial-mediated pathway. Whether hypothalamic orexin neuroprotection mechanisms depend upon microglia is unknown. To address this issue, we evaluated effects of OXA and PA on inflammatory response in immortalized murine microglial and hypothalamic neuronal cell lines. We demonstrate for the first time in microglial cells that exposure to PA increases gene expression of orexin-1 receptor but not orexin-2 receptor. Pro-inflammatory markers IL-6, TNF-α, and inducible nitric oxide synthase in microglial cells are increased following PA exposure, but are reduced by pretreatment with OXA. The anti-inflammatory marker arginase-1 is increased by OXA. Finally, we show hypothalamic neurons exposed to conditioned media from PA-challenged microglia have increased cell survival only when microglia were pretreated with OXA. These data support the concept that OXA may act as an immunomodulatory regulator of microglia, reducing pro-inflammatory cytokines and increasing anti-inflammatory factors to promote a favorable neuronal microenvironment

    Magnetic Domains and Stripes in the Spin-Fermion Model for Cuprates

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    Monte Carlo simulations applied to the Spin-Fermion model for cuprates show the existence of antiferromagnetic spin domains and charge stripes upon doping. The stripes are partially filled, with a filling of approximately 1/2 hole per site, and they separate spin domains with a π\pi phase shift among them. The stripes observed run either along the x or y axes and they are separated by a large energy barrier. No special boundary conditions or external fields are needed to stabilize these structures at low temperatures. When magnetic incommensurate peaks are observed at momentum π(1,1δ)\pi(1,1-\delta) and symmetrical points, charge incommensurate peaks appear at (0,2δ)(0,2 \delta) and symmetrical points, as experimentally observed. The strong charge fluctuations responsible for the formation of the stripes also induce a pseudogap in the density of states.Comment: Four pages with four figures embedded in tex

    Pairing, Charge, and Spin Correlations in the Three-Band Hubbard Model

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    Using the Constrained Path Monte Carlo (CPMC) method, we simulated the two-dimensional, three-band Hubbard model to study pairing, charge, and spin correlations as a function of electron and hole doping and the Coulomb repulsion VpdV_{pd} between charges on neighboring Cu and O lattice sites. As a function of distance, both the dx2y2d_{x^2 - y^2}-wave and extended s-wave pairing correlations decayed quickly. In the charge-transfer regime, increasing VpdV_{pd} decreased the long-range part of the correlation functions in both channels, while in the mixed-valent regime, it increased the long-range part of the s-wave behavior but decreased that of the d-wave behavior. Still the d-wave behavior dominated. At a given doping, increasing VpdV_{pd} increased the spin-spin correlations in the charge-transfer regime but decreased them in the mixed-valent regime. Also increasing VpdV_{pd} suppressed the charge-charge correlations between neighboring Cu and O sites. Electron and hole doping away from half-filling was accompanied by a rapid suppression of anti-ferromagnetic correlations.Comment: Revtex, 8 pages with 15 figure

    Starting the conversation: land issues and critical conservation studies in post-colonial Africa

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    This thematic issue brings together the scholarly fields of critical conservation studies and African land issues, a relationship largely unexplored to date. The alienation of land for conservation purposes, introduced to Africa under colonial rule and still taking place today, has fundamental impacts on the politics of land and land use, and is contested in contemporary nation-states - including those that are attempting to implement land restitution and reform. The contributors explore these issues in a range of African contexts. Three key themes are identified: the problematic constructions of ‘community’ by outside agencies; spatial exclusion and the silencing of local voices; and the neoliberalisation of conservation spaces. In contributing to new perspectives on these themes, this thematic issue shows how discourses and practices of conservation, increasingly shaped by neoliberalism, currently impact on land ownership, access and use. It further highlights some important historical continuities. These trends can be observed in transfrontier conservation areas, on state-owned land used for conservation and ‘green’ initiatives, but also on private land where conservation is increasingly turned to commercial purposes.International Bibliography of Social Science

    Amplitude Reduction and Phase Shifts of Melatonin, Cortisol and Other Circadian Rhythms after a Gradual Advance of Sleep and Light Exposure in Humans

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    Background: The phase and amplitude of rhythms in physiology and behavior are generated by circadian oscillators and entrained to the 24-h day by exposure to the light-dark cycle and feedback from the sleep-wake cycle. The extent to which the phase and amplitude of multiple rhythms are similarly affected during altered timing of light exposure and the sleepwake cycle has not been fully characterized. Methodology/Principal Findings: We assessed the phase and amplitude of the rhythms of melatonin, core body temperature, cortisol, alertness, performance and sleep after a perturbation of entrainment by a gradual advance of the sleep-wake schedule (10 h in 5 days) and associated light-dark cycle in 14 healthy men. The light-dark cycle consisted either of moderate intensity ‘room ’ light (,90–150 lux) or moderate light supplemented with bright light (,10,000 lux) for 5 to 8 hours following sleep. After the advance of the sleep-wake schedule in moderate light, no significant advance of the melatonin rhythm was observed whereas, after bright light supplementation the phase advance was 8.1 h (SEM 0.7 h). Individual differences in phase shifts correlated across variables. The amplitude of the melatonin rhythm assessed under constant conditions was reduced after moderate light by 54 % (17–94%) and after bright light by 52 % (range 12–84%), as compared to the amplitude at baseline in the presence of a sleep-wake cycle. Individual differences in amplitude reduction of the melatonin rhythm correlated with the amplitude of body temperature, cortisol and alertness

    State-building, war and violence : evidence from Latin America

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    In European history, war has played a major role in state‐building and the state monopoly on violence. But war is a very specific form of organized political violence, and it is decreasing on a global scale. Other patterns of armed violence now dominate, ones that seem to undermine state‐building, thus preventing the replication of European experiences. As a consequence, the main focus of the current state‐building debate is on fragility and a lack of violence control inside these states. Evidence from Latin American history shows that the specific patterns of the termination of both war and violence are more important than the specific patterns of their organization. Hence these patterns can be conceptualized as a critical juncture for state‐building. While military victories in war, the subordination of competing armed actors and the prosecution of perpetrators are conducive for state‐building, negotiated settlements, coexistence, and impunity produce instability due to competing patterns of authority, legitimacy, and social cohesion

    Neutrophil/lymphocyte ratio predicts chemotherapy outcomes in patients with advanced colorectal cancer

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    BACKGROUND: Advances in the treatment of metastatic colorectal cancer (mCRC) in the last decade have significantly improved survival; however, simple biomarkers to predict response or toxicity have not been identified, which are applicable to all community oncology settings worldwide. The use of inflammatory markers based on differential white-cell counts, such as the neutrophil/ lymphocyte ratio (NLR), may be simple and readily available biomarkers. METHODS: Clinical information and baseline laboratory parameters were available for 349 patients, from two independent cohorts, with unresectable mCRC receiving first-line palliative chemotherapy. Associations between baseline prognostic variables, including inflammatory markers such as the NLR and tumour response, progression and survival were investigated. RESULTS: In the training cohort, combination-agent chemotherapy (P ¼ 0.001) and NLRp5 (P ¼ 0.003) were associated with improved clinical benefit. The ECOG performance status X1 (P ¼ 0.002), NLR45 (P ¼ 0.01), hypoalbuminaemia (P ¼ 0.03) and single-agent chemotherapy (Po0.0001) were associated with increased risk of progression. The ECOG performance status X1 (P ¼ 0.004) and NLR45 (P ¼ 0.002) predicted worse overall survival (OS). The NLR was confirmed to independently predict OS in the validation cohort (Po0.0001). Normalisation of the NLR after one cycle of chemotherapy in a subset of patients resulted in improved progression-free survival (P ¼ 0.012). CONCLUSION: These results have highlighted NLR as a potentially useful clinical biomarker of systemic inflammatory response in predicting clinically meaningful outcomes in two independent cohorts. Results of this study have also confirmed the importance of a chronic systemic inflammatory response influencing clinical outcomes in patients with mCRC
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