256 research outputs found

    Sources, variability and fate of freshwater in the Bellingshausen Sea, AntarcticaSources, variability and fate of freshwater in the Bellingshausen Sea, Antarctica

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    During the second half of the twentieth century, the Antarctic Peninsula was subjected to a rapid increase in air temperatures. This was accompanied by a reduction in sea ice extent, increased precipitation and a dramatic retreat of glaciers associated with an increase in heat flux from deep ocean water masses. Isotopic tracers have been used previously to investigate the relative importance of the different freshwater sources to the adjacent Bellingshausen Sea (BS), but the data coverage is strongly biased toward summer. Here we use a regional model to investigate the ocean's response to the observed changes in its different freshwater inputs (sea ice melt/freeze, precipitation, evaporation, iceberg/glacier melt, and ice shelf melt). The model successfully recreates BS water masses and performs well against available freshwater data. By tracing the sources and pathways of the individual components of the freshwater budget, we find that sea ice dominates seasonal changes in the total freshwater content and flux, but all sources make a comparable contribution to the annual-mean. Interannual variability is dominated by sea ice and precipitation. Decadal trends in the salinity and stratification of the ocean are investigated, and a 20-year surface freshening from 1992-2011 is found to be predominantly driven by decreasing autumn sea ice growth. These findings will help to elucidate the role of freshwater in driving circulation and water column structure changes in this climatically-sensitive region

    Steroid Hormone Signaling Is Essential to Regulate Innate Immune Cells and Fight Bacterial Infection in Drosophila

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    Coupling immunity and development is essential to ensure survival despite changing internal conditions in the organism. Drosophila metamorphosis represents a striking example of drastic and systemic physiological changes that need to be integrated with the innate immune system. However, nothing is known about the mechanisms that coordinate development and immune cell activity in the transition from larva to adult. Here, we reveal that regulation of macrophage-like cells (hemocytes) by the steroid hormone ecdysone is essential for an effective innate immune response over metamorphosis. Although it is generally accepted that steroid hormones impact immunity in mammals, their action on monocytes (e.g. macrophages and neutrophils) is still not well understood. Here in a simpler model system, we used an approach that allows in vivo, cell autonomous analysis of hormonal regulation of innate immune cells, by combining genetic manipulation with flow cytometry, high-resolution time-lapse imaging and tissue-specific transcriptomic analysis. We show that in response to ecdysone, hemocytes rapidly upregulate actin dynamics, motility and phagocytosis of apoptotic corpses, and acquire the ability to chemotax to damaged epithelia. Most importantly, individuals lacking ecdysone-activated hemocytes are defective in bacterial phagocytosis and are fatally susceptible to infection by bacteria ingested at larval stages, despite the normal systemic and local production of antimicrobial peptides. This decrease in survival is comparable to the one observed in pupae lacking immune cells altogether, indicating that ecdysone-regulation is essential for hemocyte immune functions and survival after infection. Microarray analysis of hemocytes revealed a large set of genes regulated at metamorphosis by EcR signaling, among which many are known to function in cell motility, cell shape or phagocytosis. This study demonstrates an important role for steroid hormone regulation of immunity in vivo in Drosophila, and paves the way for genetic dissection of the mechanisms at work behind steroid regulation of innate immune cells.FCT fellowships: (SFRH/BPD/44613/2008, SFRH/BD/51175/2010), EMBO: (ALTF 178-2009), Gulbenkian Institute PhD Program

    Long-lasting geroprotection from brief rapamycin treatment in early adulthood by persistently increased intestinal autophagy

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    The licensed drug rapamycin has potential to be repurposed for geroprotection. A key challenge is to avoid adverse side effects from continuous dosing. Here we show that geroprotective effects of chronic rapamycin treatment can be obtained with a brief pulse of the drug in early adulthood in female Drosophila and mice. In Drosophila, a brief, early rapamycin treatment of adults extended lifespan and attenuated age-related decline in the intestine to the same degree as lifelong dosing. Lasting memory of earlier treatment was mediated by elevated autophagy in intestinal enterocytes, accompanied by increased levels of intestinal LManV and lysozyme. Brief elevation of autophagy in early adulthood itself induced a long-term increase in autophagy. In mice, a 3-month, early treatment also induced a memory effect, with maintenance similar to chronic treatment, of lysozyme distribution, Man2B1 level in intestinal crypts, Paneth cell architecture and gut barrier function, even 6 months after rapamycin was withdrawn

    Phase I Study of Cetuximab, Irinotecan, and Vandetanib (ZD6474) as Therapy for Patients with Previously Treated Metastastic Colorectal Cancer

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    BACKGROUND: To determine the maximum tolerated dose (MTD) and safety, and explore efficacy and biomarkers of vandetanib with cetuximab and irinotecan in second-line metastatic colorectal cancer. METHODS: Vandetanib (an orally bioavailable VEGFR-2 and EGFR tyrosine kinases inhibitor) was combined at 100 mg, 200 mg, or 300 mg daily with standard dosed cetuximab and irinotecan (3+3 dose-escalation design). Ten patients were treated at the MTD and plasma angiogenesis biomarkers (VEGF, PlGF, bFGF, sVEGFR1, sVEGFR2, IL-1ÎČ, IL-6, IL-8, TNF-α, SDF1α) were measured before and after treatment. RESULTS: Twenty-seven patients were enrolled at 4 dose levels and the MTD. Two dose-limiting toxicities (grade 3 QTc prolongation and diarrhea) were detected at 300 mg of vandetanib with cetuximab and irinotecan resulting in 200 mg being the MTD. Seven percent of patients had a partial response, 59% stable disease and 34% progressed. Median progression-free survival was 3.6 months (95% CI, 3.2-5.6) and median overall survival was 10.5 months (95% CI, 5.1-20.7). Toxicities were fairly manageable with grade 3 or 4 diarrhea being most prominent (30%). Vandetanib and cetuximab treatment induced a sustained increase in plasma PlGF and a transient decrease in plasma sVEGFR1, but no changes in plasma VEGF and sVEGFR2. CONCLUSIONS: Vandetanib can be safely combined with cetuximab and irinotecan for metastatic colorectal cancer. Exploratory biomarker analyses suggest differential effects on certain plasma biomarkers for VEGFR inhibition when combined with EGFR blockade and a potential correlation between baseline sVEGFR1 and response. However, while the primary endpoint was safety, the observed efficacy raises concern for moving forward with this combination. TRIAL REGISTRATION: Clinicaltrials.gov NCT00436072
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