Data report of oblique reflection-refraction radio-sonobuoy profiles on the African Atlantic continental margin : (R/V Atlantis II cruises 67 and 75)

Two hundred sixty-four unreversed oblique reflection-refraction profiles using expendable radio-sonobuoys were obtained during two geophysical cruises to the Atlantic continental margin of Africa. This data report gives the profile locations, a summary of the data collection and analysis, and 780 interval reflection and refraction velocities and thicknesses that were determined.Prepared for the International Decade of Ocean Exploration, National Science Foundation Grant GX-28193 for the Eastern Atlantic Continental Margin program

Basic Apoptotic Mechanisms of Lead Toxicity in Human Leukemia (Hl-60) Cells

Lead exposure represents a medical and public health emergency, especially in children consuming high amounts of lead-contaminated flake paints. It may also cause hematological effects to people of all ages. Recent studies in our laboratory have indicated that apoptosis may be associated with the lead-induced oxidative stress and DNA damage. However, the mechanisms underlying its effect on lymphocytes are still largely unknown. Therefore, the aim of the present study was to investigate the apoptotic mechanisms of lead nitrate [Pb(NO3)2] using HL-60 cells as a test model. HL-60 cells were treated with different concentrations of Pb(NO3)2 for 24 h prior to cell viability assay and flow cytometry assessment. The results obtained from the trypan blue exclusion test indicated that at very low concentration, Pb(NO3)2 has no effect on the viability of HL-60 cells. A significant (p < 0.05) decrease in cell viability was observed when exposed to high level of Pb(NO3)2. Data generated from the flow cytometric assessment indicated that Pb(NO3)2 exposure significantly (p < 0.05) increased the proportion of annexin V positive cells (apoptotic cells) compared to the control. Pb(NO3)2 induced apoptosis of HL-60 cells was associated with the activation of caspase-3. In summary, these studies demonstrated that Pb(NO3)2 represents an apoptosis-inducing agent in HL-60 promyelocytic leukemia cells and its apoptotic mechanism functions, at least in part via, induction of phosphatidylserine externalization and caspase-3 activation

Measurement of H₂O₂ within living drosophila during aging using a ratiometric mass spectrometry probe targeted to the mitochondrial matrix

Hydrogen peroxide (H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt;) is central to mitochondrial oxidative damage and redox signaling, but its roles are poorly understood due to the difficulty of measuring mitochondrial H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; in vivo. Here we report a ratiometric mass spectrometry probe approach to assess mitochondrial matrix H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; levels in vivo. The probe, MitoB, comprises a triphenylphosphonium (TPP) cation driving its accumulation within mitochondria, conjugated to an arylboronic acid that reacts with H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; to form a phenol, MitoP. Quantifying the MitoP/MitoB ratio by liquid chromatography-tandem mass spectrometry enabled measurement of a weighted average of mitochondrial H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; that predominantly reports on thoracic muscle mitochondria within living flies. There was an increase in mitochondrial H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; with age in flies, which was not coordinately altered by interventions that modulated life span. Our findings provide approaches to investigate mitochondrial ROS in vivo and suggest that while an increase in overall mitochondrial H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; correlates with aging, it may not be causative

Design and implementation of the START (STem cells for ARDS Treatment) trial, a phase 1/2 trial of human mesenchymal stem/stromal cells for the treatment of moderate-severe acute respiratory distress syndrome

Background: Despite advances in supportive care, moderate-severe acute respiratory distress syndrome (ARDS) is associated with high mortality rates, and novel therapies to treat this condition are needed. Compelling pre-clinical data from mouse, rat, sheep and ex vivo perfused human lung models support the use of human mesenchymal stem (stromal) cells (MSCs) as a novel intravenous therapy for the early treatment of ARDS. Methods: This article describes the study design and challenges encountered during the implementation and phase 1 component of the START (STem cells for ARDS Treatment) trial, a phase 1/2 trial of bone marrow-derived human MSCs for moderate-severe ARDS. A trial enrolling 69 subjects is planned (9 subjects in phase 1, 60 subjects in phase 2 treated with MSCs or placebo in a 2:1 ratio). Results: This report describes study design features that are unique to a phase 1 trial in critically ill subjects and the specific challenges of implementation of a cell-based therapy trial in the ICU. Conclusions: Experience gained during the design and implementation of the START study will be useful to investigators planning future phase 1 clinical trials based in the ICU, as well as trials of cell-based therapy for other acute illnesses. Trial registration Clinical Trials Registration: NCT01775774 and NCT02097641

Secondary Prevention of Cervical Cancer : ASCO Resource–Stratified Guideline Update

Q2Q2PURPOSE: To update resource-stratified, evidence-based recommendations on secondary prevention of cervical cancer globally. METHODS: American Society of Clinical Oncology convened a multidisciplinary, multinational Expert Panel to produce recommendations reflecting four resource-tiered settings. A review of existing guidelines, formal consensus-based process, and modified ADAPTE process to adapt existing guidelines was conducted. Other experts participated in formal consensus. RESULTS: This guideline update reflects changes in evidence since the previous update. Five existing guidelines were identified and reviewed, and adapted recommendations form the evidence base. Cost-effectiveness analyses provided indirect evidence to inform consensus, which resulted in ≥ 75% agreement. RECOMMENDATIONS: Human papillomavirus (HPV) DNA testing is recommended in all resource settings; visual inspection with acetic acid may be used in basic settings. Recommended age ranges and frequencies vary by the following setting: maximal: age 25-65 years, every 5 years; enhanced: age 30-65 years, if two consecutive negative tests at 5-year intervals, then every 10 years; limited: age 30-49 years, every 10 years; basic: age 30-49 years, one to three times per lifetime. For basic settings, visual assessment is used to determine treatment eligibility; in other settings, genotyping with cytology or cytology alone is used to determine treatment. For basic settings, treatment is recommended if abnormal triage results are obtained; in other settings, abnormal triage results followed by colposcopy is recommended. For basic settings, treatment options are thermal ablation or loop electrosurgical excision procedure; for other settings, loop electrosurgical excision procedure or ablation is recommended; with a 12-month follow-up in all settings. Women who are HIV-positive should be screened with HPV testing after diagnosis, twice as many times per lifetime as the general population. Screening is recommended at 6 weeks postpartum in basic settings; in other settings, screening is recommended at 6 months. In basic settings without mass screening, infrastructure for HPV testing, diagnosis, and treatment should be developed.https://orcid.org/0000-0001-7187-9946Revista Internacional - IndexadaCN

Examining the predictability of the Stratospheric Sudden Warming of January 2013 using multiple NWP systems

The first multi-model study to estimate the predictability of a boreal Sudden Stratospheric Warming (SSW) is performed using five NWP systems. During the 2012-2013 boreal winter, anomalous upward propagating planetary wave activity was observed towards the end of December, which followed by a rapid deceleration of the westerly circulation around 2 January 2013, and on 7 January 2013 the zonal mean zonal wind at 60°N and 10 hPa reversed to easterly. This stratospheric dynamical activity was followed by an equatorward shift of the tropospheric jet stream and by a high pressure anomaly over the North Atlantic, which resulted in severe cold conditions in the UK and Northern Europe. In most of the five models, the SSW event was predicted 10 days in advance. However, only some ensemble members in most of the models predicted weakening of westerly wind when the models were initialized 15 days in advance of the SSW. Further dynamical analysis of the SSW shows that this event was characterized by the anomalous planetary wave-1 amplification followed by the anomalous wave-2 amplification in the stratosphere, which resulted in a split vortex occurring between 6 January 2013 and 8 January 2013. The models have some success in reproducing wave-1 activity when initialized 15 days in advance, they but generally failed to produce the wave-2 activity during the final days of the event. Detailed analysis shows that models have reasonably good skill in forecasting tropospheric blocking features that stimulate wave-2 amplification in the troposphere, but they have limited skill in reproducing wave-2 amplification in the stratosphere

p90RSK Targets the ERK5-CHIP Ubiquitin E3 Ligase Activity in Diabetic Hearts and Promotes Cardiac Apoptosis and Dysfunction

RATIONALE: Cardiomyocyte apoptosis is one of the key events in the development and progression of heart failure, and a crucial role for ICER (inducible cAMP early repressor) in this process has been previously reported. ERK5 is known to inhibit cardiac apoptosis after myocardial infarction (MI), especially in hyperglycemic states, via association with CHIP ubiquitin (Ub) ligase and subsequent up-regulation of CHIP ligase activity, which induces ICER ubiquitination and subsequent protein degradation. The regulatory mechanism governing ERK5/CHIP interaction is unknown. OBJECTIVE: We previously demonstrated increased p90RSK activation in the diabetic heart. As a logical extension of this work, we now investigate whether p90RSK activation inhibits ERK5-mediated CHIP activation, and subsequently increases ICER levels and apoptosis. METHODS AND RESULTS: p90RSK activation inhibits ERK5/CHIP association and CHIP Ub ligase activity. p90RSK and CHIP share a common binding site in the ERK5 C-terminal domain (aa571-807). Overexpression of either p90RSK or an ERK5 fragment (aa571-807) inhibits ERK5/CHIP association, suggesting that p90RSK and CHIP competes for ERK5 binding and that p90RSK activation is critical for inhibiting ERK5/CHIP interaction. We also identified ERK5-S496 as being directly phosphorylated by p90RSK, and demonstrated that an ERK5-S496A mutant significantly impairs Angiotensin II-mediated inhibition of CHIP activity and subsequent increase in ICER levels. In vivo, either cardiac specific depletion of ERK5 or overexpression of p90RSK inhibits CHIP activity and accelerates cardiac apoptosis after MI--a phenomenon fully reversible by activating ERK5. CONCLUSION: These data suggest a role for p90RSK in inhibiting CHIP activity and promoting cardiac apoptosis through binding to and phosphorylation of ERK5-S496

A Conserved Mechanism for Sulfonucleotide Reduction

Sulfonucleotide reductases are a diverse family of enzymes that catalyze the first committed step of reductive sulfur assimilation. In this reaction, activated sulfate in the context of adenosine-5′-phosphosulfate (APS) or 3′-phosphoadenosine 5′-phosphosulfate (PAPS) is converted to sulfite with reducing equivalents from thioredoxin. The sulfite generated in this reaction is utilized in bacteria and plants for the eventual production of essential biomolecules such as cysteine and coenzyme A. Humans do not possess a homologous metabolic pathway, and thus, these enzymes represent attractive targets for therapeutic intervention. Here we studied the mechanism of sulfonucleotide reduction by APS reductase from the human pathogen Mycobacterium tuberculosis, using a combination of mass spectrometry and biochemical approaches. The results support the hypothesis of a two-step mechanism in which the sulfonucleotide first undergoes rapid nucleophilic attack to form an enzyme-thiosulfonate (E-Cys-S-SO(3) (−)) intermediate. Sulfite is then released in a thioredoxin-dependent manner. Other sulfonucleotide reductases from structurally divergent subclasses appear to use the same mechanism, suggesting that this family of enzymes has evolved from a common ancestor

Limitations in representation of physical processes preven successful simulation of PM2.5 during KORUS-AQ

High levels of fine particulate matter (PM2.5) pollution in East Asia often exceed local air quality standards. Observations from the Korea United States-Air Quality (KORUS-AQ) field campaign in May and June 2016 showed that development of extreme pollution (haze) occurred through a combination of long-range transport and favorable meteorological conditions that enhanced local production of PM2.5. Atmospheric models often have difficulty simulating PM2.5 chemical composition during haze, which is of concern for the development of successful control measures. We use observations from KORUS-AQ to examine the ability of the GEOS-Chem chemical transport model to simulate PM2.5 composition throughout the campaign and identify the mechanisms driving the pollution event. In the surface level, the model underestimates campaign average sulfate aerosol by −64 % but overestimates nitrate aerosol by 36 %. The largest underestimate in sulfate occurs during the pollution event in conditions of high relative humidity, where models typically struggle to generate the high concentrations due to missing heterogeneous chemistry in aerosol liquid water in the polluted boundary layer. Hourly surface observations show that the model nitrate bias is driven by an overestimation of the nighttime peak. In the model, nitrate formation is limited by the supply of nitric acid, which is biased by +100 % against aircraft observations. We hypothesize that this is due to a missing sink, which we implement here as a factor of five increase in dry deposition. We show that the resulting increased deposition velocity is consistent with observations of total nitrate as a function of photochemical age. The model does not account for factors such as the urban heat island effect or the heterogeneity of the built-up urban landscape resulting in insufficient model turbulence and surface area over the study area that likely results in insufficient dry deposition. Other species such as NH3 could be similarly affected but were not measured during the campaign. Nighttime production of nitrate is driven by NO2 hydrolysis in the model, while observations show that unexpectedly elevated nighttime ozone (not present in the model) should result in N2O5 hydrolysis as the primary pathway. The model is unable to represent nighttime ozone due to an overly rapid collapse of the afternoon mixed layer and excessive titration by NO. We attribute this to missing nighttime heating driving deeper nocturnal mixing that would be expected to occur in a city like Seoul. This urban heating is not considered in air quality models run at large enough scales to treat both local chemistry and long-range transport. Key model failures in simulating nitrate, mainly overestimated daytime nitric acid, incorrect representation of nighttime chemistry, and an overly shallow and insufficiently turbulent nighttime mixed layer, exacerbate the model’s inability to simulate the buildup of PM2.5 during haze pollution. To address the underestimate in sulfate most evident during the haze event, heterogeneous aerosol uptake of SO2 is added to the model which previously only considered aqueous production of sulfate from SO2 in cloud water. Implementing a simple parameterization of this chemistry improves the model abundance of sulfate but degrades the SO2 simulation implying that emissions are underestimated. We find that improving model simulations of sulfate has direct relevance to determining local vs. transboundary contributions to PM2.5. During the haze pollution event, the inclusion of heterogeneous aerosol uptake of SO2 decreases the fraction of PM2.5 attributable to long-range transport from 66 % to 54 %. Locally-produced sulfate increased from 1 % to 46 % of locally-produced PM2.5, implying that local emissions controls would have a larger effect than previously thought. However, this additional uptake of SO2 is coupled to the model nitrate prediction which affects the aerosol liquid water abundance and chemistry driving sulfate-nitrate-ammonium partitioning. An additional simulation of the haze pollution with heterogeneous uptake of SO2 to aerosol and simple improvements to the model nitrate simulation results in 30 % less sulfate due to 40 % less nitrate and aerosol water, and results in an underestimate of sulfate during the haze event. Future studies need to better consider the impact of model physical processes such as dry deposition and boundary layer mixing on the simulation of nitrate and the effect of improved nitrate simulations on the overall simulation of secondary inorganic aerosol (sulfate+nitrate+ammonium) in East Asia. Foreign emissions are rapidly changing, increasing the need to understand the impact of local emissions on PM2.5 in South Korea to ensure continued air quality improvements