Stable isotope record, carbonate and organic carbon content of the Miocene section of IODP Site 321-U1337

The Miocene Climatic Optimum (~17-14.7 Ma) represents one of several major interruptions in the long-term cooling trend of the past 50 million years. To date, the processes driving high-amplitude climate variability and sustaining global warmth during this remarkable interval remain highly enigmatic. We present high-resolution benthic foraminiferal and bulk carbonate stable isotope records in an exceptional, continuous, carbonate-rich sedimentary archive (Integrated Ocean Drilling Program Site U1337, eastern equatorial Pacific Ocean), which offer a new view of climate evolution over the onset of the Climatic Optimum. A sharp decline in d18O and d13C at ~16.9 Ma, contemporaneous with a massive increase in carbonate dissolution, demonstrates that abrupt warming was coupled to an intense perturbation of the carbon cycle. The rapid recovery in d13C at ~16.7 Ma, ~200 k.y. after the beginning of the MCO, marks the onset of the first carbon isotope maximum within the long-lasting "Monterey Excursion". These results lend support to the notion that atmospheric pCO2 variations drove profound changes in the global carbon reservoir through the Climatic Optimum, implying a delicate balance between changing CO2 fluxes, rates of silicate weathering and global carbon sequestration. Comparison with a high-resolution d13C record spanning the onset of the Cretaceous Oceanic Anoxic Event 1a (~120 Ma ago) reveals common forcing factors and climatic responses, providing a long-term perspective to understand climate-carbon cycle feedbacks during warmer periods of Earth's climate with markedly different atmospheric CO2 concentrations.

Miocene stable isotope record of IODP Site 320-U1335 and revised stable isotope record of IODP Site 321-U1337

The Miocene Climatic Optimum (MCO; ~16.9 to 14.7 Ma) provides an outstanding opportunity to investigate climate-carbon cycle dynamics during a geologically recent interval of global warmth. We present benthic stable oxygen (d18O) and carbon (d13C) isotope records (5-12 kyr time resolution) spanning the late early to middle Miocene interval (18 to 13 Ma) at Integrated Ocean Drilling Program (IODP) Site U1335 (eastern equatorial Pacific Ocean). The U1335 stable isotope series track the onset and development of the MCO as well as the transitional climatic phase culminating with global cooling and expansion of the East Antarctic ice-sheet at ~13.8 Ma. We integrate these new data with published stable isotope, geomagnetic polarity and X-ray fluorescence (XRF) scanner-derived carbonate records from IODP Sites U1335, U1336, U1337 and U1338 on a consistent, astronomically-tuned timescale. Benthic isotope and XRF scanner-derived CaCO3 records depict prominent 100 kyr variability with 400 kyr cyclicity additionally imprinted on d13C and CaCO3 records, pointing to a tight coupling between the marine carbon cycle and climate variations. Our inter-site comparison further indicates that the lysocline behaved in highly dynamic manner throughout the MCO, with >75% carbonate loss occurring at paleo-depths ranging from ~3.4 to ~4 km in the eastern equatorial Pacific Ocean. Carbonate dissolution maxima coincide with warm phases (d18O minima) and d13C decreases, implying that climate-carbon cycle feedbacks fundamentally differed from the late Pleistocene glacial-interglacial pattern, where dissolution maxima correspond to d13C maxima and d18O minima. Carbonate dissolution cycles during the MCO were, thus, more similar to Paleogene hyperthermal patterns.

Decreased Expression Of Stem Cell Markers By Simvastatin In 7,12-dimethylbenz(a)anthracene (dmba)-induced Breast Cancer.

Simvastatin, a competitive inhibitor of HMG-CoA reductase widely used in the treatment and prevention of hyperlipidemia-related diseases, has recently been associated to in vitro anticancer stem cell (CSC) actions. However, these effects have not been confirmed in vivo. To assess in vivo anti-CSC effects of simvastatin, female Sprague-Dawley rats with 7,12-dimethyl-benz(a)anthracene (DMBA)-induced mammary cancer and control animals were treated for 14 days with either simvastatin (20 or 40 mg/kg/day) or soybean oil (N = 60). Tumors and normal breast tissues were removed for pathologic examination and immunodetection of CSC markers. At 40 mg/kg/day, simvastatin significantly reduced tumor growth and the expression of most CSC markers. The reduction in tumor growth (80%) could not be explained solely by the decrease in CSCs, since the latter accounted for less than 10% of the neoplasia (differentiated cancer cells were also affected). Stem cells in normal, nonneoplastic breast tissues were not affected by simvastatin. Simvastatin was also associated with a significant decrease in proliferative activity but no increase in cell death. In conclusion, this is the first study to confirm simvastatin anti-CSC actions in vivo, further demonstrating that this effect is specific for neoplastic cells, but not restricted to CSCs, and most likely due to inhibition of cell proliferation.

Long-term Efficacy And Safety Of Tenofovir Disoproxil Fumarate In Hiv-1-infected Adolescents Failing Antiretroviral Therapy: The Final Results Of Study Gs-us-104-0321.

Reports of long-term tenofovir disoproxil fumarate (TDF) treatment in HIV-infected adolescents are limited. We present final results from the open-label (OL) TDF extension following the randomized, placebo (PBO)-controlled, double-blind phase of GS-US-104-0321 (Study 321). HIV-infected 12- to 17-year-olds treated with TDF 300 mg or PBO with an optimized background regimen (OBR) for 24-48 weeks subsequently received OL TDF plus OBR in a single arm study extension. HIV-1 RNA and safety, including bone mineral density (BMD), was assessed in all TDF recipients. Eighty-one subjects received TDF (median duration 96 weeks). No subject died or discontinued OL TDF for safety/tolerability. At week 144, proportions with HIV-1 RNA <50 copies/mL were 30.4% (7 of 23 subjects with baseline HIV-1 RNA >1000 c/mL initially randomized to TDF), 41.7% (5 of 12 subjects with HIV-1 RNA <1000 c/mL who switched PBO to TDF) and 0% (0 of 2 subjects failed randomized PBO plus OBR with HIV-1 RNA >1000 c/mL and switched PBO to TDF). Viral resistance to TDF occurred in 1 subject. At week 144, median decrease in estimated glomerular filtration rate was 38.1 mL/min/1.73 m (n = 25). Increases in median spine (+12.70%, n = 26) and total body less head BMD (+4.32%, n = 26) and height-age adjusted Z-scores (n = 21; +0.457 for spine, +0.152 for total body less head) were observed at week 144. Five of 81 subjects (6%) had persistent >4% BMD decreases from baseline. Some subjects had virologic responses to TDF plus OBR, and TDF resistance was rare. TDF was well tolerated and can be considered for treatment of HIV-infected adolescents.

Oropouche Virus Infection And Pathogenesis Is Restricted By Mavs, Irf-3, Irf-7, And Type I Ifn Signaling Pathways In Non-myeloid Cells.

Oropouche virus (OROV) is a member of the Orthobunyavirus genus in the Bunyaviridae family and a prominent cause of insect-transmitted viral disease in Central and South America. Despite its clinical relevance, little is known about OROV pathogenesis. To define the host defense pathways that control OROV infection and disease, we evaluated OROV pathogenesis and immune responses in primary cells and mice that were deficient in the RIG-I-like receptor signaling pathway (MDA5, RIG-I, or MAVS), downstream regulatory transcription factors (IRF-3 or IRF-7), IFN-β, or the receptor for type I IFN signaling (IFNAR). OROV replicated to higher levels in primary fibroblasts and dendritic cells lacking MAVS signaling, the transcription factors IRF-3 and IRF-7, or IFNAR. In mice, deletion of IFNAR, MAVS, or IRF-3 and IRF-7 resulted in uncontrolled OROV replication, hypercytokinemia, extensive liver damage, and death whereas wild-type (WT) congenic animals failed to develop disease. Unexpectedly, mice with a selective deletion of IFNAR on myeloid cells (CD11c Cre(+) Ifnar(f/f) or LysM Cre(+) Ifnar(f/f)) did not sustain enhanced disease with OROV or La Crosse virus, a closely related encephalitic orthobunyavirus. In bone marrow chimera studies, recipient irradiated Ifnar(-/-) mice reconstituted with WT hematopoietic cells sustained high levels of OROV replication and liver damage, whereas WT mice reconstituted with Ifnar(-/-) bone marrow were resistant to disease. Collectively, these results establish a dominant protective role for MAVS, IRF-3 and IRF-7, and IFNAR in restricting OROV virus infection and tissue injury, and suggest that IFN signaling in non-myeloid cells contributes to the host defense against orthobunyaviruses. Oropouche virus (OROV) is an emerging arthropod-transmitted orthobunyavirus that causes episodic outbreaks of a debilitating febrile illness in humans in countries of South and Central America. The continued expansion of the range and number of its arthropod vectors increases the likelihood that OROV will spread into new regions. At present, the pathogenesis of OROV in humans or other vertebrate animals remains poorly understood. To define cellular mechanisms of control of OROV infection, we performed infection studies in a series of primary cells and mice that were deficient in key innate immune genes involved in pathogen recognition and control. Our results establish that a MAVS-dependent type I IFN signaling pathway has a dominant role in restricting OROV infection and pathogenesis in vivo.

Crescimento, composição corporal e performance motora em crianças e adolescentes de 7 a 14 anos provenientes de familias de baixo nivel socio-economico e participantes do projeto esporte solidario, São Luis - MA

Universidade Estadual de Campinas . Faculdade de Educação Física