The Jak2 Pathway Is Activated In Idiopathic Pulmonary Fibrosis

Background: Idiopathic pulmonary fibrosis (IPF) is the most rapidly progressive and fatal fibrotic disorder, with no curative therapies. The signal transducer and activator of transcription 3 (STAT3) protein is activated in lung fibroblasts and alveolar type II cells (ATII), thereby contributing to lung fibrosis in IPF. Although activation of Janus kinase 2 (JAK2) has been implicated in proliferative disorders, its role in IPF is unknown. The aim of this study was to analyze JAK2 activation in IPF, and to determine whether JAK2/STAT3 inhibition is a potential therapeutic strategy for this disease. Methods and results: JAK2/p-JAK2 and STAT3/pSTAT3 expression was evaluated using quantitative real time-PCR, western blotting, and immunohistochemistry. Compared to human healthy lung tissue (n = 10) both proteins were upregulated in the lung tissue of IPF patients (n = 12). Stimulating primary ATII and lung fibroblasts with transforming growth factor beta 1 or interleukin (IL)-6/IL-13 activated JAK2 and STAT3, inducing epithelial to mesenchymal and fibroblast to myofibroblast transitions. Dual p-JAK2/p-STAT3 inhibition with JSI-124 or silencing of JAK2 and STAT3 genes suppressed ATII and the fibroblast to myofibroblast transition, with greater effects than the sum of those obtained using JAK2 or STAT3 inhibitors individually. Dual rather than single inhibition was also more effective for inhibiting fibroblast migration, preventing increases in fibroblast senescence and Bcl-2 expression, and ameliorating impaired autophagy. In rats administered JSI-124, a dual inhibitor of p-JAK2/p-STAT3, at a dose of 1 mg/kg/day, bleomycin-induced lung fibrosis was reduced and collagen deposition in the lung was inhibited, as were JAK2 and STAT3 activation and several markers of fibrosis, autophagy, senescence, and anti-apoptosis. Conclusions: JAK2 and STAT3 are activated in IPF, and their dual inhibition may be an attractive strategy for treating this disease

Using present-day observations to detect when anthropogenic change forces surface ocean carbonate chemistry outside preindustrial bounds

© The Author(s), 2016. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Biogeosciences 13 (2016): 5065-5083, doi:10.5194/bg-13-5065-2016.One of the major challenges to assessing the impact of ocean acidification on marine life is detecting and interpreting long-term change in the context of natural variability. This study addresses this need through a global synthesis of monthly pH and aragonite saturation state (Ωarag) climatologies for 12 open ocean, coastal, and coral reef locations using 3-hourly moored observations of surface seawater partial pressure of CO2 and pH collected together since as early as 2010. Mooring observations suggest open ocean subtropical and subarctic sites experience present-day surface pH and Ωarag conditions outside the bounds of preindustrial variability throughout most, if not all, of the year. In general, coastal mooring sites experience more natural variability and thus, more overlap with preindustrial conditions; however, present-day Ωarag conditions surpass biologically relevant thresholds associated with ocean acidification impacts on Mytilus californianus (Ωarag < 1.8) and Crassostrea gigas (Ωarag < 2.0) larvae in the California Current Ecosystem (CCE) and Mya arenaria larvae in the Gulf of Maine (Ωarag < 1.6). At the most variable mooring locations in coastal systems of the CCE, subseasonal conditions approached Ωarag =  1. Global and regional models and data syntheses of ship-based observations tended to underestimate seasonal variability compared to mooring observations. Efforts such as this to characterize all patterns of pH and Ωarag variability and change at key locations are fundamental to assessing present-day biological impacts of ocean acidification, further improving experimental design to interrogate organism response under real-world conditions, and improving predictive models and vulnerability assessments seeking to quantify the broader impacts of ocean acidification.The CO2 and ocean acidification observations were funded by NOAA’s Climate Observation Division (COD) in the Climate Program Office and NOAA’s Ocean Acidification Program. The maintenance of the Stratus and WHOTS Ocean Reference Stations were also supported by NOAA COD (NA09OAR4320129). Additional support for buoy equipment, maintenance, and/or ancillary measurements was provided by NOAA through the US Integrated Ocean Observing System office: for the La Parguera buoy under a Cooperative Agreement (NA11NOS0120035) with the Caribbean Coastal Ocean Observing System, for the Chá b˘a buoy under a Cooperative Agreement (NA11NOS0120036) with the Northwest Association of Networked Ocean Observing System, for the Gray’s Reef buoy under a Cooperative Agreement (NA11NOS0120033) with the Southeast Coastal Ocean Observing Regional Association, and for the Gulf of Main buoy under a Cooperative Agreement (NA11NOS0120034) with the Northeastern Regional Association of Coastal and Ocean Observing Systems

Autonomous and Lagrangian ocean observations for Atlantic tropical cyclone studies and forecasts

Author Posting. © The Oceanography Society, 2017. This article is posted here by permission of The Oceanography Society for personal use, not for redistribution. The definitive version was published in Oceanography 30, no. 2 (2017): 92–103, doi:10.5670/oceanog.2017.227.The tropical Atlantic basin is one of seven global regions where tropical cyclones (TCs) commonly originate, intensify, and affect highly populated coastal areas. Under appropriate atmospheric conditions, TC intensification can be linked to upper-ocean properties. Errors in Atlantic TC intensification forecasts have not been significantly reduced during the last 25 years. The combined use of in situ and satellite observations, particularly of temperature and salinity ahead of TCs, has the potential to improve the representation of the ocean, more accurately initialize hurricane intensity forecast models, and identify areas where TCs may intensify. However, a sustained in situ ocean observing system in the tropical North Atlantic Ocean and Caribbean Sea dedicated to measuring subsurface temperature, salinity, and density fields in support of TC intensity studies and forecasts has yet to be designed and implemented. Autonomous and Lagrangian platforms and sensors offer cost-effective opportunities to accomplish this objective. Here, we highlight recent efforts to use autonomous platforms and sensors, including surface drifters, profiling floats, underwater gliders, and dropsondes, to better understand air-sea processes during high-wind events, particularly those geared toward improving hurricane intensity forecasts. Real-time data availability is key for assimilation into numerical weather forecast models.The NOAA/AOML component of this work was originally funded by the Disaster Relief Appropriations Act of 2013, also known as the Sandy Supplemental, and is currently funded through NOAA research grant NA14OAR4830103 by AOML and CARICOOS, as well as NOAA’s Integrated Ocean Observing System (IOOS). The TEMPESTS component of this work is supported by NOAA through the Cooperative Institute for the North Atlantic Region (NA13OAR4830233) with additional analysis support from the WHOI Summer Student Fellowship Program, Nortek Student Equipment Grant, and the Rutgers University Teledyne Webb Graduate Student Fellowship Program. The drifter component of this work is funded through NOAA grant NA15OAR4320071(11.432) in support of the Global Drifter Program

IL-6 serum levels predict severity and response to tocilizumab in COVID-19: An observational study

Background: Patients with coronavirus disaese 2019 (COVID-19) can develop a cytokine release syndrome that eventually leads to acute respiratory distress syndrome requiring invasive mechanical ventilation (IMV). Because IL-6 is a relevant cytokine in acute respiratory distress syndrome, the blockade of its receptor with tocilizumab (TCZ) could reduce mortality and/or morbidity in severe COVID-19. Objective: We sought to determine whether baseline IL-6 serum levels can predict the need for IMV and the response to TCZ. Methods: A retrospective observational study was performed in hospitalized patients diagnosed with COVID-19. Clinical information and laboratory findings, including IL-6 levels, were collected approximately 3 and 9 days after admission to be matched with preadministration and postadministration of TCZ. Multivariable logistic and linear regressions and survival analysis were performed depending on outcomes: need for IMV, evolution of arterial oxygen tension/fraction of inspired oxygen ratio, or mortality. Results: One hundred forty-six patients were studied, predominantly males (66%); median age was 63 years. Forty-four patients (30%) required IMV, and 58 patients (40%) received treatment with TCZ. IL-6 levels greater than 30 pg/mL was the best predictor for IMV (odds ratio, 7.1; P < .001). Early administration of TCZ was associated with improvement in oxygenation (arterial oxygen tension/fraction of inspired oxygen ratio) in patients with high IL-6 (P = .048). Patients with high IL-6 not treated with TCZ showed high mortality (hazard ratio, 4.6; P = .003), as well as those with low IL-6 treated with TCZ (hazard ratio, 3.6; P = .016). No relevant serious adverse events were observed in TCZ-treated patients. Conclusions: Baseline IL-6 greater than 30 pg/mL predicts IMV requirement in patients with COVID-19 and contributes to establish an adequate indication for TCZ administrationThis study was funded by Spanish Ministry of Economy, Industry and Competitiveness (MINECO) and Instituto de Salud Carlos III (grant nos. RD16/0011/0012 and PI18/ 0371 to I.G.A., grant no. PI19/00549 to A.A., and grant no. SAF2017-82886-R to F.S.-M.) and co-funded by the European Regional Development Fund. The study was also funded by ‘‘La Caixa Banking Foundation’’ (grant no. HR17-00016 to F.S.-M.) and ‘‘Fondos Supera COVID19’’ by Banco de Santander and CRUE. None of these sponsors have had any role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publicatio

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Nitrogenase activity of Microcoleus lyngbyaceus mat communities in a eutrophic, tropical marine environment

Floating and attached cyanobacterial mats consisting primarily of Microcoleus lyngbyaceus, a nonheterocystous, filamentous cyanobacterium, are a permanent feature of the nearshore marine environment at La Parguera, Puerto Rico. Nitrogenase activity in these mat communities, as determined by acetylene reduction, exhibited a diel cycle with daytime inhibition and enhanced nocturnal activity. Contrary to reports regarding benthic cyanobacterial mats adapted to oligotrophic conditions, nitrogenase activity in M. lyngbyaceus mats is closely regulated by concentrations of NH4+ and NO3− within the range of values common to their environment. The opportunistic strategy of N utilization used by M. lyngbyaceus, whereby molecular N is primarily consumed only in the absence of significant concentrations of alternate inorganic N sources, assures the success of these cyanobacterial mat communities

Seasonal Net Ecosystem Metabolism of the Near-Shore Reef System in La Parguera, Puerto Rico

Changes in ocean chemistry as a direct response to rising atmospheric carbon dioxide (CO 2 ) concentrations is causing a reduction of pH in the surface ocean. While the dynamics and trends in carbonate chemistry are reasonably constrained for open ocean waters, the ways in which ocean acidification (OA) manifests within the shallow near-shore waters, where coral reefs reside, is less understood. Constraining near-reef variability in carbonate chemistry and net ecosystem metabolic processes across diel, seasonal, and annual scales is important in evaluating potential biogeochemical thresholds of OA that could result in ecological community changes. The OA Test-Bed at La Parguera Marine Reserve in Puerto Rico provides long-term carbonate chemistry observations at high-temporal resolution within a Caribbean near-shore coral reef ecosystem. A 1-D model was developed using the carbon mass balance approach to yield information about net ecosystem production and calcification processes occurring in the water column adjacent to the reef. We present results of nine years of sustained monitoring at the Enrique mid-shelf forereef, which provides for the characterization of temporal dynamics in carbonate chemistry and net ecosystem metabolic processes encompassing near-shore and upstream locations. Results indicate that net heterotrophy and net dissolution dominate over most of the year, while net autotrophic conditions coupled with calcification dominated from only January to mid-April. The average carbonate dissolution rate observed during summer is estimated at −2.19 g CaCO 3  m −2  day −1 and net community dissolution persists 76 % of the seasonal year despite the water column remaining super-saturated with respect to aragonite. This corresponds to −0.62 kg CaCO 3  m −2  year −1 , classifying the Enrique fore-reef and off-reef areas in a net dissolutional state. The combination of thermodynamically-driven depressed aragonite saturation state and high rates of respiration during the summer cause conditions that jeopardize the most soluble carbonate minerals and the free energy in the system for calcification. These data suggest that the reef area and associated ecosystems upstream of the sampling location are experiencing a net loss of CaCO 3 , possibly compromising coral ecosystem health and reef accretion processes necessary for maintenance as sea level increases. Resiliency from other climate-scale stressors including rising sea surface temperatures and coral bleaching is likely to be compromised in a system exhibiting net carbonate loss. Status: This preprint has been withdrawn by the authors

The Jak2 Pathway Is Activated In Idiopathic Pulmonary Fibrosis

Background: Idiopathic pulmonary fibrosis (IPF) is the most rapidly progressive and fatal fibrotic disorder, with no curative therapies. The signal transducer and activator of transcription 3 (STAT3) protein is activated in lung fibroblasts and alveolar type II cells (ATII), thereby contributing to lung fibrosis in IPF. Although activation of Janus kinase 2 (JAK2) has been implicated in proliferative disorders, its role in IPF is unknown. The aim of this study was to analyze JAK2 activation in IPF, and to determine whether JAK2/STAT3 inhibition is a potential therapeutic strategy for this disease. Methods and results: JAK2/p-JAK2 and STAT3/pSTAT3 expression was evaluated using quantitative real time-PCR, western blotting, and immunohistochemistry. Compared to human healthy lung tissue (n = 10) both proteins were upregulated in the lung tissue of IPF patients (n = 12). Stimulating primary ATII and lung fibroblasts with transforming growth factor beta 1 or interleukin (IL)-6/IL-13 activated JAK2 and STAT3, inducing epithelial to mesenchymal and fibroblast to myofibroblast transitions. Dual p-JAK2/p-STAT3 inhibition with JSI-124 or silencing of JAK2 and STAT3 genes suppressed ATII and the fibroblast to myofibroblast transition, with greater effects than the sum of those obtained using JAK2 or STAT3 inhibitors individually. Dual rather than single inhibition was also more effective for inhibiting fibroblast migration, preventing increases in fibroblast senescence and Bcl-2 expression, and ameliorating impaired autophagy. In rats administered JSI-124, a dual inhibitor of p-JAK2/p-STAT3, at a dose of 1 mg/kg/day, bleomycin-induced lung fibrosis was reduced and collagen deposition in the lung was inhibited, as were JAK2 and STAT3 activation and several markers of fibrosis, autophagy, senescence, and anti-apoptosis. Conclusions: JAK2 and STAT3 are activated in IPF, and their dual inhibition may be an attractive strategy for treating this disease