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Noninvasive early indicators of treatment response are crucial to the successful delivery of precision medicine in children with cancer. Neuroblastoma is a common solid tumor of young children that arises from anomalies in neural crest development. Therapeutic approaches aiming to destabilize MYCN protein, such as small-molecule inhibitors of Aurora A and mTOR, are currently being evaluated in early phase clinical trials in children with high-risk MYCN-driven disease, with limited ability to evaluate conventional pharmacodynamic biomarkers of response. T1 mapping is an MRI scan that measures the proton spin-lattice relaxation time T1. Using a multiparametric MRI-pathologic cross-correlative approach and computational pathology methodologies including a machine learning–based algorithm for the automatic detection and classification of neuroblasts, we show here that T1 mapping is sensitive to the rich histopathologic heterogeneity of neuroblastoma in the Th-MYCN transgenic model. Regions with high native T1 corresponded to regions dense in proliferative undifferentiated neuroblasts, whereas regions characterized by low T1 were rich in apoptotic or differentiating neuroblasts. Reductions in tumor-native T1 represented a sensitive biomarker of response to treatment-induced apoptosis with two MYCN-targeted small-molecule inhibitors, Aurora A kinase inhibitor alisertib (MLN8237) and mTOR inhibitor vistusertib (AZD2014). Overall, we demonstrate the potential of T1 mapping, a scan readily available on most clinical MRI scanners, to assess response to therapy and guide clinical trials for children with neuroblastoma. The study reinforces the potential role of MRI-based functional imaging in delivering precision medicine to children with neuroblastoma. Significance: This study shows that MRI-based functional imaging can detect apoptotic responses to MYCN-targeted small-molecule inhibitors in a genetically engineered murine model of MYCN-driven neuroblastoma.

BackgroundPhotographic diabetic retinopathy screening requires labour-intensive grading of retinal images by humans. Automated retinal image analysis software (ARIAS) could provide an alternative to human grading. We compare the performance of an ARIAS using true-colour, wide-field confocal scanning images and standard fundus images in the English National Diabetic Eye Screening Programme (NDESP) against human grading.MethodsCross-sectional study with consecutive recruitment of patients attending annual diabetic eye screening. Imaging with mydriasis was performed (two-field protocol) with the EIDON platform (CenterVue, Padua, Italy) and standard NDESP cameras. Human grading was carried out according to NDESP protocol. Images were processed by EyeArt V.2.1.0 (Eyenuk Inc, Woodland Hills, California). The reference standard for analysis was the human grade of standard NDESP images.ResultsWe included 1257 patients. Sensitivity estimates for retinopathy grades were: EIDON images; 92.27% (95% CI: 88.43% to 94.69%) for any retinopathy, 99% (95% CI: 95.35% to 100%) for vision-threatening retinopathy and 100% (95% CI: 61% to 100%) for proliferative retinopathy. For NDESP images: 92.26% (95% CI: 88.37% to 94.69%) for any retinopathy, 100% (95% CI: 99.53% to 100%) for vision-threatening retinopathy and 100% (95% CI: 61% to 100%) for proliferative retinopathy. One case of vision-threatening retinopathy (R1M1) was missed by the EyeArt when analysing the EIDON images, but identified by the human graders. The EyeArt identified all cases of vision-threatening retinopathy in the standard images.ConclusionEyeArt identified diabetic retinopathy in EIDON images with similar sensitivity to standard images in a large-scale screening programme, exceeding the sensitivity threshold recommended for a screening test. Further work to optimise the identification of ‘no retinopathy’ and to understand the differential lesion detection in the two imaging systems would enhance the use of these two innovative technologies in a diabetic retinopathy screening setting.

Background: Chronic kidney disease (CKD) risk is elevated in patients with type 2 diabetes mellitus (T2DM). Disease management in these patients has been generally focused on glycemic control and controlling other renal and cardiac risk factors as, historically, few protective therapies have been available. The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation ­(CREDENCE) trial of canagliflozin was the first study to demonstrate renal protection with a sodium glucose co-transporter 2 inhibitor in patients with T2DM and CKD, and these results could have important implications for clinical practice. Summary: In CREDENCE, participants with T2DM and estimated glomerular filtration rate 30–2 and urinary albumin-creatinine ratio >300–5,000 mg/g who were treated with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker for ≥4 weeks prior to randomization at either the maximum labeled or tolerated dose were randomized to receive either canagliflozin 100 mg or placebo. Canagliflozin significantly reduced the risk of the primary composite outcome of doubling of serum creatinine, end-stage kidney disease, or renal or cardiovascular (CV) death compared with placebo (hazard ratio 0.70, 95% CI 0.59–0.82; p = 0.00001). Canagliflozin also reduced the risk of secondary renal and CV outcomes. The safety profile of canagliflozin in CREDENCE was generally similar to previous studies of canagliflozin. No imbalances were observed between canagliflozin and placebo in the risk of amputation or fracture in the CREDENCE population. Key Messages: The positive renal and CV effects of canagliflozin observed in the ­CREDENCE trial could have a substantial impact on improving outcomes for patients with T2DM and CKD.

Background The immunotherapeutic drug dinutuximab, which binds to disialoganglioside (GD2) and activates natural killer (NK) cells, is part of the standard regimen in high-risk neuroblastoma (NB) patients. However, dinutuximab only results in tumor reduction in a subset of patients, and survival rates of high-risk neuroblastoma patients are below 60%. Novel immunotherapies are therefore needed. Current in vitro models lack the ability to study novel immunotherapies with high-throughput screening (HTS). We aimed to optimize NB organoid-lymphocyte cocultures for HTS, and possibly personalized testing, of novel antibody-mediated and cellular immunotherapies. Materials and Methods Two patient-derived organoids (691B: GD2+MHC-I- and 691T: GD2-MHC-I+) were transduced with an endogenous luciferase construct to use D-luciferin-induced bioluminescence as readout for cell growth. The growth rate, optimal seeding density and optimal pre-culture time per organoid were determined by density curves, and the number of needed cells was downscaled to facilitate HTS. After pre-culture, the luciferase-transduced organoids were co-cultured with primary PBMCs from healthy donors, PRAME-TCR transduced T cells or CAR-T cells.1 Several effector:target (E:T) ratios and timepoints were tested to identify the optimal window for read-out of dinutuximab-induced antibody-dependent cytotoxicity (ADCC) and T-cell mediated cytotoxicity. The required number of immune cells per ratio was calculated based on the expansion rate of organoid cells after 48 and 72 hours. Results The density screens showed an optimal seeding density of 5000-10.000 organoid cells per well, yielding a high luminescence signal while minimizing the number of cells needed. Already at the lowest E:T ratio (1:3), we observed killing of the MHC-I expressing 691T organoid, likely based on allogeneic recognition of the organoids by T cells. The killing efficacy increased with higher E:T ratios and co-culture time. Pre-culturing of organoids for 72 hours before addition of effector cells resulted in formation of larger 3D spheres, which reduced the killing efficacy for all E:T ratios. ADCC effects of dinutuximab were studied in GD2+MHC-I- 691B organoids. Addition of dinutuximab resulted in 25% increase of killing after 24 hours and reached up to 70% increase after 72 hours for 10:1 and 20:1 E:T ratios. Higher E:T ratios were likely needed because NK cells make up a smaller proportion of PBMCs than T cells. Dinutuximab did not increase killing of the GD2- organoid, confirming specificity of the antibody. T cell mediated killing was almost 100% for MHC-I+691T organoids after 24 hours of culturing with PRAME-TCR transduced T cells and CAR-T cells at a 1:3 E:T ratio, showing the high anti-tumor cytotoxicity of these cells and potential for HTS at very low E:T ratios. Conclusions We have developed a robust in vitro bioluminescence-based organoid/lymphocyte co-culture assay with a low cell input, to facilitate high-throughput screening of novel antibody-based or cellular immunotherapies, possibly combined with chemotherapeutic or targeted compounds. In the future this method may be applied for personalized drug screens. Reference Avital L Amir, et al. PRAME-Specific Allo-HLA-restricted T cells with potent antitumor reactivity useful for therapeutic T-cell receptor gene transfer. Clin Cancer Res 2011. Disclosure Information F. van den Ham: None. W.M. Kholosy: None. K. Ober: None. A.M. Cornel: None. S. Nierkens: None. J. Anderson: None. J.J. Molenaar: None. J. Wienke: None.

Background:Joint arthrodesis often employs autograft to promote union; graft harvesting can lead to perioperative morbidity. A Canadian randomized controlled trial (RCT) demonstrated that recombinant human platelet–derived growth factor BB homodimer (rhPDGF-BB) combined with beta-tricalcium phosphate (β-TCP)-collagen was a safe, effective alternative to autograft. This multicenter North American RCT compared the safety and efficacy of rhPDGF-BB/β-TCP-collagen with autograft for ankle and hindfoot fusion. Subclassification using propensity scores (PS) incorporated patients from previous trials for enhanced statistical power for noninferiority testing and broader review of treatments.Methods:Patients requiring ankle or hindfoot arthrodesis and supplemental bone graft were treated with rhPDGF-BB/β-TCP-collagen ( n = 69) or autograft ( n = 35). Outcomes included joint fusion on computed tomography (24 weeks), clinical healing status, visual analog scale (VAS) pain, Short-Form 12 (SF-12), American Orthopaedic Foot & Ankle Society (AOFAS) Ankle-Hindfoot Scale, and Foot Function Index (FFI) scores over 52 weeks. PS methodology addressed potential selection bias arising from pooling data among these patients and 2 previous RCTs with similar inclusion criteria, surgical techniques, graft harvest techniques, and outcomes. All 132 rhPDGF-BB/β-TCP-collagen–treated patients and 167 of 189 candidate autograft-treated controls were selected for comparison by an independent statistician blinded to outcomes.Results:In the PS subclassification, 68.1% treatment patients and 68.4% controls achieved >50% osseous bridging at fusion sites. Clinical healing status was achieved in 84.8% of treated patients and 90.7% of controls at 52 weeks. Clinical, functional, and quality of life results demonstrated noninferiority of rhPDGF-BB/β-TCP-collagen to autograft. Safety-related outcomes were equivalent.Conclusion:PS subclassification analysis of 3 RCTs demonstrated that rhPDGF-BB/β-TCP-collagen was as effective as autograft for ankle and hindfoot fusions, with less pain and morbidity than treatment with autograft.Level of Evidence:Level I, prospective randomized study.

Lake metabolism and associated emissions of CO in lakes are heavily subsidized by terrestrial carbon but the role of climate forcing remains unclear. The carbon stable isotope composition of zoopla...

Amplification of MYCN is the driving oncogenic change in a subset of high-risk neuroblastomas. The MYCN protein and the Aurora-A kinase form a complex during the S phase that stabilizes MYCN. Here we show that MYCN activates Aurora-A on chromatin, which phosphorylates histone H3 at serine 10 in the S phase, promotes the deposition of histone H3.3 and suppresses R-loop formation. Inhibition of Aurora-A induces transcription–replication conflicts and activates ataxia telangiectasia and Rad3-related (ATR) kinase, which limits double-strand break accumulation upon Aurora-A inhibition. Combined inhibition of Aurora-A and ATR kinases induces rampant tumor-specific apoptosis and tumor regression in mouse models of neuroblastoma, leading to permanent eradication in a subset of mice. The therapeutic efficacy is due to both tumor cell-intrinsic and immune cell-mediated mechanisms. We propose that targeting the ability of Aurora-A to resolve transcription–replication conflicts is an effective therapy for MYCN-driven neuroblastoma. Eilers and colleagues report that Aurora-A suppresses transcription–replication conflicts in MYCN-driven neuroblastoma, a vulnerability that can be targeted with a combination of Aurora-A and ATR kinase inhibitors.

Although the oxygen isotope composition (δ18O) of calcite (δ18Ocalcite) and, to a lesser extent, diatom silica (δ18Odiatom) are widely used tracers of past hydroclimates (especially temperature and surface water hydrology), the degree to which these two hosts simultaneously acquire their isotope signals in modern lacustrine environments, or how these are altered during initial sedimentation, is poorly understood. Here, we present a unique dataset from a natural limnological laboratory to explore these issues. This study compares oxygen and hydrogen isotope data (δ18O, δ2H) of contemporary lake water samples at ~2-weekly intervals over a 2-year period (2010–12) with matching collections of diatoms (δ18Odiatom) and calcite (δ18Ocalcite) from sediment traps (at 10 m and 25 m) at Rostherne Mere (maximum depth 30 m), a well-monitored, eutrophic, seasonally stratified monomictic lake in the UK. The epilimnion shows a seasonal pattern of rising temperature and summer evaporative enrichment in 18O, and while there is a temperature imprint in both δ18Odiatom and δ18Ocalcite, there is significant inter-annual variability in both of these signals. The interpretation of δ18Odiatom and δ18Ocalcite values is complicated due to in-lake processes (e.g. non-equilibrium calcite precipitation, especially in spring, leading to significant 18Ocalcite depletion), and for δ18Odiatom, by post-mortem, depositional and possibly dissolution or diagenetic effects. For 2010 and 2011 respectively, there is a strong temperature dependence of δ18Ocalcite and δ18Odiatom in fresh trap material, with the fractionation slope for δ18Odiatom of ca. −0.2‰/°C, in agreement with several other studies. The δ18Odiatom data indicate the initiation of rapid post-mortem secondary alteration of fresh diatom silica (within ~6 months), with some trap material undergoing partial maturation in situ. Diatom δ18O of the trap material is also influenced by resuspension of diatom frustules from surface sediments (notably in summer 2011), with the net effect seen as an enrichment of deep-trap 18Odiatom by about +0.7‰ relative to shallow-trap values. Contact with anoxic water and anaerobic bacteria are potentially key to initiating this silica maturation process, as deep-trap samples that were removed prior to anoxia developing do not show enrichment. Dissolution (perhaps enhanced by anaerobic bacterial communities) may also be responsible for changes to δ18Odiatom that lead to increasing, but potentially predictable, error in inferred temperatures using this proxy. High resolution, multi-year monitoring can shed light on the complex dynamics affecting δ18Odiatom and δ18Ocalcite and supports the careful use of sedimentary δ18Odiatom and δ18Ocalcite as containing valuable hydroclimatic signals especially at a multi-annual resolution, although there remain substantial challenges to developing a reliable geothermometer on paired δ18Odiatom and δ18Ocalcite. In particular, δ18Odiatom needs cautious interpretation where silica post-mortem secondary alteration is incomplete and diatom preservation is not perfect, and we recommend dissolution be routinely assessed on diatom samples used for isotopic analyses.

The Stratospheric Aerosol and Gas Experiment III (SAGE III, 2018) instrument was launched on 19 February 2017 from the NASA Kennedy Space Center and was integrated aboard the International Space Station (ISS). SAGE III-ISS has been providing ozone profile measurements since June 2017. This paper presents an early validation of the Level 2 solar and lunar occultation ozone data products using ground-based lidar and ozonesondes from Hohenpeißenberg and Lauder as well as satellite ozone vertical products from the Atmospheric Chemistry Experiment Fourier Transform Spectrometer (ACE-FTS) instrument. Average differences in the ozone concentration between SAGE III-ISS and Hohenpeißenberg lidar observations for 1 year are less than 10 % between 16 and 42 km and less than 5 % between 20 and 40 km. Hohenpeißenberg ozonesonde comparisons are mostly within 10 % between 18 and 30 km. The Lauder lidar comparison results are less than 10 % between 17 and 37 km, and the Lauder ozonesonde comparison results are less than 10 % between 19 and 31 km. The seasonal average differences in the ozone concentration between SAGE III-ISS and ACE-FTS are mostly less than 5 % between 20 and 45 km for both the Northern Hemisphere and Southern Hemisphere. All results from these comparisons show that the SAGE III-ISS ozone solar data compare well with correlative measurements throughout the stratosphere. With few comparisons available, the percentage difference between the SAGE III-ISS lunar ozone data and the ozonesonde data is less than 10 % between 19 and 27 km. The percentage difference between the SAGE III-ISS lunar ozone data and the ACE-FTS ozone data is less than 10 % between 20 and 40 km.

The HIV genome is rich in A but not G or U and deficient in C. This nucleotide bias controls HIV phenotype by determining the highly unusual composition of all major HIV proteins. The bias is also responsible for the high frequency of narrow DNA minor groove sites in the double-stranded HIV genome as compared to cellular protein coding sequences and the bulk of the human genome. Since drugs that bind in the DNA minor groove disrupt nucleosomes on sequences that contain closely spaced oligo-A tracts which are prevalent in HIV DNA because of its bias, it was of interest to determine if these drugs exert this selective inhibitory effect on HIV chromatin. To test this possibility, nucleosomes were reconstituted onto five double-stranded DNA fragments from the HIV-1 pol gene in the presence and in the absence of several minor groove binding drugs (MGBDs). The results demonstrated that the MGBDs inhibited the assembly of nucleosomes onto all of the HIV-1 segments in a manner that was proportional to the A-bias, but had no detectable effect on the formation of nucleosomes on control cloned fragments or genomic DNA from chicken and human. Nucleosomes preassembled onto HIV DNA were also preferentially destabilized by the drugs as evidenced by enhanced nuclease accessibility in physiological ionic strength and by the preferential loss of the histone octamer in hyper-physiological salt solutions. The drugs also selectively disrupted HIV-containing nucleosomes in yeast as revealed by enhanced nuclease accessibility of the in vivo assembled HIV chromatin and reductions in superhelical densities of plasmid chromatin containing HIV sequences. A comparison of these results to the density of A-tracts in the HIV genome indicates that a large fraction of the nucleosomes that make up HIV chromatin should be preferred in vitro targets for the MGBDs. These results show that the MGBDs preferentially disrupt HIV-1 chromatin in vitro and in vivo and raise the possibility that non-toxic derivatives of certain MGBDs might serve as a novel class of anti-HIV agents.

Arctic lakes are poised for substantial changes to their carbon (C) cycles in the near future. Autochthonous processes in lakes which consume inorganic C and create biomass that can be sequestered in sediments are accompanied by allochthonous inputs of organic matter from the surrounding watershed. Both C sources can be mineralized and degassed as CO2, but also become recalcitrant and accumulate in pelagic waters. Using stable carbon isotope (δ13C) values and elemental ratios as geochemical proxies, we investigated diverse organic matter sources to lakes located across a hydro‐climatic gradient in Southwest Greenland. Particulate organic matter (POM) and sediments were clearly of autochthonous algal origin, while dissolved organic matter (DOM) was a mix between autochthonous macrophytes and allochthonous watershed sources. Our results imply that a warmer and drier Arctic will lead to decoupled C pools: a water column dominated by increasingly autochthonous, macrophytic DOM, and sediments dominated by autochthonous algal POM.

In this work, potassium doped and undoped Li2ZrO3-based sorbents for CO2 capture at high temperatures were synthesized through wet impregnation of Li and K salts over a colloidal suspension of zirconia nanoparticles. The synthesized sorbents were characterized by XRD and Raman spectroscopy, and the CO2 sorption/desorption properties of the sorbents were investigated by in-situ Raman spectroscopy and by thermogravimetric analysis at different temperatures and CO2 partial pressures. The stability of the doped sorbent over 30 cycles of CO2 sorption/desorption was investigated by thermogravimetric analysis and by XRD, evaluating the variations of the capture capacity, capture rate and crystallite size over the cycles. The sorbent desorption kinetics was analyzed both in N2 and in a mixture of CO2/N2, and is characterized by a relatively fast chemically controlled stage followed by a second slow stage. The second slow stage was assumed to be controlled by diffusion through the lithium zirconate layer and the amount of lithium carbonate converted in the second stage decreases when the regeneration temperature increases. The effect of potassium doping on the CO2 desorption rates in nitrogen flow was analyzed, both in the first and in the second slow stages. The influence of the CO2 concentration on the lithium carbonate conversion rates and on the sorbent capture capacity at the end of the first stage were analyzed for the doped and undoped sorbents. Finally, a zeroth order advancing interface reaction model was identified for the first stage of the CO2 desorption and, by fitting the CO2 desorption thermogravimetric data, the activation energies for both sorbents were calculated. Fil: Peltzer, Diana Jacqueline. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Investigaciones en Catálisis y Petroquímica ; Argentina Fil: Gómez Múnera, John Anderson. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Investigaciones en Catálisis y Petroquímica ; Argentina Fil: Cornaglia, Laura Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Investigaciones en Catálisis y Petroquímica ; Argentina Fil: Strumendo, M.. Università di Padova; Italia

Despite the benefits of chimeric antigen receptor (CAR)-T cell therapies against lymphoid malignancies, responses in solid tumors have been more limited and off-target toxicities have been more marked. Among the possible design limitations of CAR-T cells for cancer are unwanted tonic (antigen-independent) signaling and off-target activation. Efforts to overcome these hurdles have been blunted by a lack of mechanistic understanding. Here, we showed that single-cell analysis with time course mass cytometry provided a rapid means of assessing CAR-T cell activation. We compared signal transduction in expanded T cells to that in T cells transduced to express second-generation CARs and found that cell expansion enhanced the response to stimulation. However, expansion also induced tonic signaling and reduced network plasticity, which were associated with expression of the T cell exhaustion markers PD-1 and TIM-3. Because this was most evident in pathways downstream of CD3ζ, we performed similar analyses on γδT cells that expressed chimeric costimulatory receptors (CCRs) lacking CD3ζ but containing DAP10 stimulatory domains. These CCR-γδT cells did not exhibit tonic signaling but were efficiently activated and mounted cytotoxic responses in the presence of CCR-specific stimuli or cognate leukemic cells. Single-cell signaling analysis enabled detailed characterization of CAR-T and CCR-T cell activation to better understand their functional activities. Furthermore, we demonstrated that CCR-γδT cells may offer the potential to avoid on-target, off-tumor toxicity and allo-reactivity in the context of myeloid malignancies.

The HIV genome is rich in A but not G or U and deficient in C. This nucleotide bias controls HIV phenotype by determining the highly unusual composition of all majors HIV proteins. Since drugs that bind in the DNA minor groove disrupt nucleosomes on sequences that contain closely spaced oligo-A tracts which are prevalent in HIV DNA because of this bias, it was of interest to determine if these drugs exert this selective inhibitory effect on HIV chromatin. To test this possibility, nucleosomes were reconstituted onto five double-stranded DNA fragments from the HIV-1 pol gene in the presence and in the absence of several minor groove binding drugs (MGBDs). The results demonstrated that the MGBDs inhibited the assembly of nucleosomes onto all of the HIV-1 segments in a manner that was proportional to the A-bias, but had no detectable effect on the formation of nucleosomes on control cloned fragments or genomic DNA from chicken and human. Nucleosomes preassembled onto HIV DNA were also preferentially destabilized by the drugs as evidenced by enhanced nuclease accessibility in physiological ionic strength and by the preferential loss of the histone octamer in hyper-physiological salt solutions. The drugs also selectively disrupted HIV-containing nucleosomes in yeast as revealed by enhanced nuclease accessibility of the in vivo assembled HIV chromatin and reductions in superhelical densities of plasmid chromatin containing HIV sequences. A comparison of these results to the density of A-tracts in the HIV genome indicates that a large fraction of the nucleosomes that make up HIV chromatin should be preferred in vitro targets for the MGBDs. These results show that the MGBDs preferentially disrupt HIV-1 chromatin in vitro and in vivo and raise the possibility that non-toxic derivatives of certain MGBD might serve as a novel class of anti-HIV agents.

Across a small geographic area (

Stratospheric water vapour is a powerful greenhouse gas. The longest available record from balloon observations over Boulder, Colorado, USA shows increases in stratospheric water vapour concentrations that cannot be fully explained by observed changes in the main drivers, tropical tropopause temperatures and methane. Satellite observations could help resolve the issue, but constructing a reliable long-term data record from individual short satellite records is challenging. Here we present an approach to merge satellite data sets with the help of a chemistry–climate model nudged to observed meteorology. We use the models’ water vapour as a transfer function between data sets that overcomes issues arising from instrument drift and short overlap periods. In the lower stratosphere, our water vapour record extends back to 1988 and water vapour concentrations largely follow tropical tropopause temperatures. Lower and mid-stratospheric long-term trends are negative, and the trends from Boulder are shown not to be globally representative. In the upper stratosphere, our record extends back to 1986 and shows positive long-term trends. The altitudinal differences in the trends are explained by methane oxidation\ud together with a strengthened lower-stratospheric and a weakened upper stratospheric circulation inferred by this analysis. Our results call into question previous estimates of surface radiative forcing based on presumed global long-term increases in water vapour concentrations in the lower stratosphere.

Ozone forms in the Earth's atmosphere from the photodissociation of molecular oxygen, primarily in the tropical stratosphere. It is then transported to the extratropics by the Brewer-Dobson circulation (BDC), forming a protective ozone layer around the globe. Human emissions of halogen-containing ozone-depleting substances (hODSs) led to a decline in stratospheric ozone until they were banned by the Montreal Protocol (MP), and since 1998 ozone in the upper stratosphere shows a likely recovery. Total column ozone (TCO) measurements of ozone between the Earth's surface and the top of the atmosphere, indicate that the ozone layer has stopped declining across the globe, but no clear increase has been observed at latitudes outside the polar regions (60–90). Here we report evidence from multiple satellite measurements that ozone in the lower stratosphere between 60° S and 60° N has declined continuously since 1985. We find that, even though upper stratospheric ozone is recovering in response to the MP, the lower stratospheric changes more than compensate for this, resulting in the conclusion that, globally (60°&tinsp;S–60° N), stratospheric column ozone (StCO) continues to deplete. We find that globally, TCO appears to not have decreased because tropospheric column ozone (TrCO) increases, likely the result of human activity and harmful to respiratory health, are compensating for the stratospheric decreases. The reason for the continued reduction of lower stratospheric ozone is not clear, models do not reproduce these trends, and so the causes now urgently need to be established. Reductions in lower stratospheric ozone trends may partly lead to a small reduction in the warming of the climate, but a reduced ozone layer may also permit an increase in harmful ultra-violet (UV) radiation at the surface and would impact human and ecosystem health.

Trends in the vertical distribution of ozone are reported and compared for a number of new and recently revised data sets. The amount of ozone-depleting compounds in the stratosphere (as measured by equivalent effective stratospheric chlorine – EESC) was maximised in the second half of the 1990s. We examine the periods before and after the peak to see if any change in trend is discernible in the ozone record that might be attributable to a change in the EESC trend, though no attribution is attempted. Prior to 1998, trends in the upper stratosphere (~ 45 km, 4 hPa) are found to be −5 to −10 % per decade at mid-latitudes and closer to −5 % per decade in the tropics. No trends are found in the mid-stratosphere (28 km, 30 hPa). Negative trends are seen in the lower stratosphere at mid-latitudes in both hemispheres and in the deep tropics. However, it is hard to be categorical about the trends in the lower stratosphere for three reasons: (i) there are fewer measurements, (ii) the data quality is poorer, and (iii) the measurements in the 1990s are perturbed by aerosols from the Mt Pinatubo eruption in 1991. These findings are similar to those reported previously even though the measurements for the main satellite and ground-based records have been revised. There is no sign of a continued negative trend in the upper stratosphere since 1998: instead there is a hint of an average positive trend of ~ 2 % per decade in mid-latitudes and ~ 3 % per decade in the tropics. The significance of these upward trends is investigated using different assumptions of the independence of the trend estimates found from different data sets. The averaged upward trends are significant if the trends derived from various data sets are assumed to be independent (as in Pawson et al., 2014) but are generally not significant if the trends are not independent. This occurs because many of the underlying measurement records are used in more than one merged data set. At this point it is not possible to say which assumption is best. Including an estimate of the drift of the overall ozone observing system decreases the significance of the trends. The significance will become clearer as (i) more years are added to the observational record, (ii) further improvements are made to the historic ozone record (e.g. through algorithm development), and (iii) the data merging techniques are refined, particularly through a more rigorous treatment of uncertainties.

A key indicator of changes in the terrestrial carbon cycle is shifting dissolved organic carbon (DOC) concentrations in surface waters. Arctic permafrost holds twice as much C as the atmosphere, thus recent warming and changes in atmospheric deposition to the region raise the need for a better understanding of how DOC is changing in arctic surface waters. In Kangerlussuaq, Greenland, lakewater DOC concentrations declined by 14 to 55% (absolute changes of 1 to 24 mg L-1) between 2003 and 2013, without significant changes in quality. Lakewater sulfate concentrations, but not chloride or conductivity, increased. These results suggest that, similar to processes that have occurred at northern mid-latitudes, increases in soil ionic strength as a result of sulfate enrichment may be linked to declining surface water DOC concentrations. Such enrichment may be occurring with enhanced non-sea-salt sulfate deposition. Our results reveal that rapid changes are occurring in the carbon cycle of this region of southwest Greenland.

We present a comprehensive analysis of the trends of stratospheric ozone in the midlatitudes and subtropics. The analysis is performed using ground-based and space-based measurements over the light detection and ranging stations for the period 1985–2012. Also, trends are estimated for the zonal mean data made from a merged satellite data set, Global OZone Chemistry And Related trace gas Data records for the Stratosphere, over 1979–2012. The linear trends in stratospheric ozone are estimated using piecewise linear trend (PWLT) functions. The ozone trends during the increasing phase of halogens (before 1997) range from −0.2 ± 0.08 to −1 ± 0.07% yr−1 in the midlatitudes and −0.2 ± 0.06 to −0.7 ± 0.05 % yr−1 in the subtropics at 15–45 km, depending on altitude. In 1997–2012, the PWLT analyses show a positive trend, significantly different from zero at the 95% confidence intervals, toward ozone recovery in the middle- and low-latitude upper stratosphere (35–45 km), and the trends are about +0.5 ± 0.07% yr−1 at midlatitudes and about +0.3 ± 0.05% yr−1 at subtropical latitudes. However, negative and insignificant trends are estimated in the lower stratosphere (15–20 km) over 1997–2012 in the midlatitudes, mainly due to the dynamics, as demonstrated by the large (50–60%) contributions from the quasi-biennial oscillation, El Nino–Southern Oscillation, and planetary wave activity to recent ozone changes. This suggests that the ozone changes are governed by the interannual variations in meteorology and dynamics of the regions; these factors will influence the recovery detection time and the behavior of the recovery path to pre-1980 levels.

Fumarate-containing pharmaceuticals are potent therapeutic agents that influence multiple cellular pathways. Despite proven clinical efficacy, there is a significant lack of data that directly defines the molecular mechanisms of action of related, yet distinct fumarate compounds. We systematically compared the impact of dimethyl fumarate (DMF), monomethyl fumarate (MMF) and a mixture of monoethyl fumarate salts (Ca++, Mg++, Zn++; MEF) on defined cellular responses. We demonstrate that DMF inhibited NF-κB-driven cytokine production and nuclear translocation of p65 and p52 in an Nrf2-independent manner. Equivalent doses of MMF and MEF did not affect NF-κB signaling. These results highlight a key difference in the biological impact of related, yet distinct fumarate compounds.

Background: Some patients with refractory asthma have evidence of uncontrolled eosinophilic inflammation in the distal airways. While traditional formulations of inhaled steroids settle predominantly in the large airways, newer formulations with an extra-fine particle size have a more peripheral pattern of deposition. Specifically treating distal airway inflammation may improve asthma control. Methods: 30 patients with refractory asthma despite high dose inhaled corticosteroids were identified as having persistent airway eosinophilia. Following 2 weeks of prednisolone 30 mg, patients demonstrating an improvement in asthma control were randomised to receive either ciclesonide 320 µg twice daily or placebo in addition to usual maintenance therapy for 8 weeks. The primary outcome measure was sputum eosinophil count at week 8. Alveolar nitric oxide was measured as a marker of distal airway inflammation. Results: There was continued suppression of differential sputum eosinophil counts with ciclesonide (median 2.3%) but not placebo (median 4.5%) though the between-group difference was not significant. When patients who had changed their maintenance prednisolone dose during the trial were excluded the difference between groups was significant (1.4% vs 4.5%, p=0.028). Though alveolar nitric oxide decreased with ciclesonide the value did not reach statistical significance. Conclusions: These data demonstrate that patients with ongoing eosinophilic inflammation are not truly refractory, and that suppression of airway eosinophilia may be maintained with additional inhaled corticosteroid. Further work is needed with a focus on patient-orientated outcome measures such as exacerbation rate, with additional tests of small airway function. Trial registration number NCT01171365. Protocol available at http://www.clinicaltrials.gov.

In the framework of the SI2N (SPARC (Stratosphere-troposphere Processes And their Role in Climate)/IO3C (International Ozone Commission)/IGACO-O3 (Integrated Global Atmospheric Chemistry Observations – Ozone)/NDACC (Network for the Detection of Atmospheric Composition Change)) initiative, several long-term vertically resolved merged ozone data sets produced from satellite measurements have been analysed and compared. This paper presents an overview of the methods, assumptions, and challenges involved in constructing such merged data sets, as well as the first thorough intercomparison of seven new long-term satellite data sets. The analysis focuses on the representation of the annual cycle, interannual variability, and long-term trends for the period 1984–2011, which is common to all data sets. Overall, the best agreement amongst data sets is seen in the mid-latitude lower and middle stratosphere, with larger differences in the equatorial lower stratosphere and the upper stratosphere globally. In most cases, differences in the choice of underlying instrument records that were merged produced larger differences between data sets than the use of different merging techniques. Long-term ozone trends were calculated for the period 1984–2011 using a piecewise linear regression with a change in trend prescribed at the end of 1997. For the 1984–1997 period, trends tend to be most similar between data sets (with largest negative trends ranging from −4 to −8% decade−1 in the mid-latitude upper stratosphere), in large part due to the fact that most data sets are predominantly (or only) based on the SAGE-II record. Trends in the middle and lower stratosphere are much smaller, and, particularly for the lower stratosphere, large uncertainties remain. For the later period (1998–2011), trends vary to a greater extent, ranging from approximately −1 to +5% decade−1 in the upper stratosphere. Again, middle and lower stratospheric trends are smaller and for most data sets not significantly different from zero. Overall, however, there is a clear shift from mostly negative to mostly positive trends between the two periods over much of the profile., Atmospheric Chemistry and Physics, 15 (6), ISSN:1680-7375, ISSN:1680-7367

Rh catalysts with low Rh content were prepared by incipient wetness impregnation using [NH4]3[RhCl6]·3H2O or RhCl3·3H2O as precursor salts, on CaO–SiO2 supports. All solids showed a high stability after 48 h on stream for the dry reforming of methane with low carbon content, which made them suitable for obtaining ultrapure hydrogen in a membrane reactor. The methane conversion and hydrogen recovery were measured increasing the sweep gas flow rates to rise the driving force for hydrogen permeation. The catalyst with 0.36 wt.% of Rh showed a slight deactivation. However, the Rh(0.6)/CaO–SiO2 solid, in which the Rh impregnation was performed using [NH4]3[RhCl6]·3H2O, exhibited an increase on CH4 conversion of 77% and a hydrogen recovery equal to 84%. Nanoparticles of about 1.4–1.7 nm surface average diameter were detected for the reduced and used solids indicating that Rh is well dispersed and sintering was not produced after the catalytic tests. Rh particle sizes calculated by CO chemisorption were coincident with those measured by Transmission Electron Microscopy. Characterization by this technique and Laser Raman Spectroscopy of the solids used in membrane reactor revealed the formation of scarce carbon filaments. However, a surface re-oxidation was detected in the low loading catalyst used in the membrane reactor suggesting that it is the main cause for the decrease in the activity of the highly dispersed catalyst. Fil: Faroldi, Betina María Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Investigaciones en Catálisis y Petroquímica "Ing. José Miguel Parera". Universidad Nacional del Litoral. Instituto de Investigaciones en Catálisis y Petroquímica "Ing. José Miguel Parera"; Argentina Fil: Gómez Múnera, John Anderson. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Investigaciones en Catálisis y Petroquímica "Ing. José Miguel Parera". Universidad Nacional del Litoral. Instituto de Investigaciones en Catálisis y Petroquímica "Ing. José Miguel Parera"; Argentina Fil: Falivene, Juan Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Investigaciones en Catálisis y Petroquímica "Ing. José Miguel Parera". Universidad Nacional del Litoral. Instituto de Investigaciones en Catálisis y Petroquímica "Ing. José Miguel Parera"; Argentina Fil: Rodríguez Ramos, Inmaculada. Consejo Superior de Investigaciones Científicas. Instituto de Catálisis y Petroleoquímica; España Fil: Gutiérrez García, Álvaro. Universidad de Salamanca; España Fil: Tejedor Fernández, Loreto. Universidad de Salamanca; España Fil: González Carrazán, Silvia. Universidad de Salamanca; España Fil: Cornaglia, Laura Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Investigaciones en Catálisis y Petroquímica "Ing. José Miguel Parera". Universidad Nacional del Litoral. Instituto de Investigaciones en Catálisis y Petroquímica "Ing. José Miguel Parera"; Argentina

Snowpack chemistry, nitrate stable isotopes and net deposition fluxes for the largest ice-free region in Greenland were investigated to determine whether there are spatial gradients from the ice sheet margin to the coast linked to a gradient in precipitation. Late-season snowpack was sampled in March 2011 at 8 locations within 3 lake catchments in each of 3 regions (ice sheet margin in the east, central area near Kelly Ville and the coastal zone to the west). At the coast, snowpack accumulation averaged 181 mm snow water equivalent (SWE), compared with 36 mm SWE by the ice sheet. Coastal snowpack showed significantly greater concentrations of marine salts (Na+, Cl−, other major cations), ammonium (regional means 1.4–2.7 µmol L−1), total and non-sea salt sulfate (total 1.8–7.7, non-sea salt 1.0–1.8 µmol L−1) than the two inland regions. Nitrate (1.5–2.4 µmol L−1) showed significantly lower concentrations at the coast. Despite lower concentrations, higher precipitation at the coast results in a strong deposition gradient for NO3− as well as NH4+ and non-sea salt sulfate (nss-SO42−) increasing from the inland regions to the coast (lowest at Kelly Ville 6, 4 and 3; highest at coast 9, 17 and 11 mol ha−1 yr−1 of NO3−, NH4+ and nss-SO42− respectively). The δ(15N) of snowpack NO3− shows a significant decrease from the ice sheet margin (−7.5 ‰) to the coast (−11.3 ‰). We attribute the spatial gradient of δ(15N) in SW Greenland to post-deposition processing rather than differing sources because of (1) the climatic gradient from ice sheet margin to coast, (2) within-catchment isotopic differences between terrestrial snowpack and lake-ice snowpack, and (3) similarities between fresh snow (rather than accumulated snowpack) at Kelly Ville and the coast. Hence the δ(15N) of coastal snowpack is most representative of snowfall in SW Greenland, but after deposition the effects of photolysis, volatilization and sublimation lead to enrichment of the remaining snowpack with the greatest effect in inland areas of low precipitation and high sublimation losses.

Many arctic landscapes are rich in lakes that store large quantities of organic carbon in their sediments. While there are indications of highly efficient carbon burial in high-latitude lakes, the magnitude and efficiency of carbon burial in arctic lake sediments, and thus their potential as carbon sinks, has not been studied systematically. We therefore investigated the burial efficiency of organic carbon (OC), defined as the ratio between OC burial and OC deposition onto the sediment, in seven contrasting lakes in western Greenland representing different arctic lake types. We found that the OC burial efficiency was generally low in spite of the differences between lake types (mean 22%, range 11–32%), and comparable to lakes in other climates with similar organic matter source and oxygen exposure time. Accordingly, post-depositional degradation of sediment organic matter was evident in the organic matter C:N ratio, δ13C and δ15N values during the initial ~50 years after deposition, and proceeds simultaneously with long-term changes in, e.g., productivity and climate. Pore water profiles of dissolved methane suggest that post-depositional degradation may continue for several centuries in these lakes, at very low rates. Our results demonstrate that the regulation of the sediment OC burial efficiency is no different in arctic lakes than in other lakes, implying that the efficiency of the carbon sink in lake sediments depends similarly on environmental conditions irrespective of latitude.

Ruthenium catalysts supported on a lanthanum oxycarbonate phase (La2O2CO3) with high surface area were prepared. All solids were stable for at least 90 h on stream in the combined dry reforming and oxidation of methane reactions. The catalyst with more stable metallic Ru species was selected to be studied under the more severe conditions of membrane reactors. A double tubular membrane reactor was built using a commercial self-standing membrane or a composite Pd/NaAPSS membrane. The Pd membrane reactor exhibited a higher H2 permeated/CH4 fed ratio at 450 ◦C that could be related to its higher hydrogen permeability. The comparison of the catalytic behavior of Ru catalysts supported on high surface area lanthanum oxycarbonate and La2O3–SiO2 binary support in a membrane reactor was performed at 550 ◦C. On the retentate side, the molar composition of CO2 was similar to that of CH4 when the Ru/La2O2CO3 catalyst was employed, which suggests that this solid did not favor the RWGS reaction under DRM conditions producing a higher H2 permeated/CH4 fed ratio. The Ru catalysts showed a similar performance to that of our best Rh solids when the fractions of the reaction equilibration and H2 permeated/(CH4 fed × permeation area) ratio were compared. Fil: Faroldi, Betina María Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Investigaciones En Catalisis y Petroquímica "ing. Jose Miguel Parera". Universidad Nacional del Litoral. Instituto de Investigaciones En Catalisis y Petroquímica "ing. Jose Miguel Parera"; Argentina Fil: Bosko, María Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Investigaciones En Catalisis y Petroquímica "ing. Jose Miguel Parera". Universidad Nacional del Litoral. Instituto de Investigaciones En Catalisis y Petroquímica "ing. Jose Miguel Parera"; Argentina Fil: Múnera Agudelo, John Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Investigaciones En Catalisis y Petroquímica "ing. Jose Miguel Parera". Universidad Nacional del Litoral. Instituto de Investigaciones En Catalisis y Petroquímica "ing. Jose Miguel Parera"; Argentina Fil: Lombardo, Eduardo Agustin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Investigaciones En Catalisis y Petroquímica "ing. Jose Miguel Parera". Universidad Nacional del Litoral. Instituto de Investigaciones En Catalisis y Petroquímica "ing. Jose Miguel Parera"; Argentina Fil: Cornaglia, Laura Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Investigaciones En Catalisis y Petroquímica "ing. Jose Miguel Parera". Universidad Nacional del Litoral. Instituto de Investigaciones En Catalisis y Petroquímica "ing. Jose Miguel Parera"; Argentina

Abdul-Razak Abubakari,1 Martyn C Jones,2 William Lauder,3 Alison Kirk,4 John Anderson,5 Devasenan Devendra,6 Ebrahim K Naderali11School of Health Sciences, Liverpool Hope University, Hope Park, Liverpool, 2School of Nursing and Midwifery, University of Dundee, Dundee, 3School of Nursing and Midwifery and Health, University of Stirling, Stirling, 4Department of Sport, Culture and the Arts, University of Strathclyde, Glasgow, 5Homerton University Hospital NHS Trust, Homerton Row, London, 6West Hertfordshire Hosptials NHS Trust, Watford, UKObjectives: This study investigated ethnic differences in diabetes-specific knowledge, illness perceptions, self-management, and metabolic control among black-African, black-Caribbean,and white-British populations with type 2 diabetes. The study also examined associations between demographic/disease characteristics and diabetes-specific knowledge, illness perceptions, self-management, and metabolic control in each of the three ethnic groups.Design: Cross-sectionalSetting: Diabetes/retinal screening clinics in Hackney and Brent, London.Methods: Black-African, black-Caribbean and white-British populations with type 2 diabetes were asked to participate. Questionnaires measuring demographic/disease characteristics, diabetes-specific knowledge, self-management, and illness perceptions were used for data collection. Data for glycated hemoglobin (HbA1c) and microvascular complications were obtained from medical records. Ethnic differences in diabetes-related measures were estimated using analysis of variance/covariance. Multiple regression techniques were used to determine relationships between demographic/disease characteristics and measured diabetes-related outcomes.Results: Three hundred and fifty-nine patients participated in the study. White-British participants had high diabetes-specific knowledge compared to their black-African and black-Caribbean counterparts. Black-Africans reported better adherence to self-management recommendations than the other ethnic groups. Compared to the white-British patients, black-African and black-Caribbean participants perceived diabetes as a benign condition that could be cured. Educational status and treatment category were determinants of diabetes-specific knowledge in all three ethnic groups. However, different demographic/disease characteristics predicted adherence to self-management recommendations in each ethnic group.Conclusion: Clearly, there is disease (diabetes) knowledge-perception variation between different ethnic groups in the UK which may partly influence overall disease outcome. It is plausible to recommend screening, identifying, and dispelling misconceptions about diabetes among ethnic minority patients by health care professionals as well as emphasizing the importance of self-management in managing chronic diseases such as diabetes.Keywords: black-African, black-Caribbean, white-British, diabetes, illness perceptions, self-management

White matter lesions have detrimental effects upon older adults, while serum calcium levels have been associated with elevated vascular risk and may be associated with these lesions. Depression, a serious mental disorder characterized by disturbances in calcium metabolism, may be an important contributor to any calcium-lesion relationship. This cross-sectional pilot study examined the association between serum ionized calcium (the physiologically active form of calcium) and white matter lesion volumes in a sample of depressed and non-depressed older adults (N = 42, 60 years and older). Serum ionized calcium was determined using an ion-selective electrode technique, while lesion volumes were estimated from magnetic resonance imaging using an automated expectation-maximization segmentation. A linear regression model, controlling for age and group (depression vs. comparison), showed a trend for a positive relationship between serum ionized calcium and white matter lesion volume (β = 4.34, SE = 2.27, t = 1.91, p = 0.063). Subsample analyses with depressed participants showed a significant positive relationship between higher ionic calcium and greater lesion volume (β = 6.41, SE = 2.53, t = 2.53, p = 0.018), but no association was found for non-depressed participants. Sex-specific subsample analyses showed a significant positive relationship between higher calcium and greater lesion volume in men only (β = 7.49, SE = 3.42, t = 2.19, p = 0.041). These preliminary results indicate that serum ionized calcium may be associated with white matter lesions in older adults, particularly among men and individuals with depression. Larger studies are needed to confirm these findings.

In this work, NiMgAl and RhNiMgAl catalysts prepared from HTLCs precursors were investigated for the Partial Oxidation of Methane (POM) at 550 and 750 C. Samples have been characterized by XRD, TPR, H2 chemisorption, TPSR analyses, XPS, field emission scanning electron microscopy and Raman spectroscopy. NiMgAl catalysts with high Ni content (40 and 16 wt%) showed high stability and high methane conversion for POM. On the other hand those with lower Ni content (NiHT15 and NiHT25, with 6 and 4 wt%) exhibited low catalytic activity with low H2/CO ratio and fast deactivation. In RhNiHT25 (0.6 wt. % Rh), the Ni reducibility was improved, increasing the methane conversion and hydrogen selectivity. In addition, the noticeable increase in stability was related to the absence of carbon deposition after 30 h on stream at 550 C. These results show that RhNiHT25 is promising for application in membrane reactors to produce high purity hydrogen. Fil: Cesar, Deborah V.. Universidade Federal do Rio de Janeiro. Programa de Engenharia Quımica. Nucleo de Catalise ; Brasil Fil: Baldanza, Maria A. S.. Universidade Federal do Rio de Janeiro. Programa de Engenharia Quımica. Nucleo de Catalise; Brasil Fil: Henriques, Cristiane A.. Universidade Federal do Rio de Janeiro. Programa de Engenharia Quımica. Nucleo de Catalise; Brasil Fil: Pompeo, Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Ciencias Aplicadas "Dr. Jorge J. Ronco". Universidad Nacional de la Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Ciencias Aplicadas; Argentina Fil: Santori, Gerardo Fabian. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Ciencias Aplicadas "Dr. Jorge J. Ronco". Universidad Nacional de la Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Ciencias Aplicadas; Argentina Fil: Múnera Agudelo, John Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Investigaciones En Catalisis y Petroquímica "ing. Jose Miguel Parera". Universidad Nacional del Litoral. Instituto de Investigaciones En Catalisis y Petroquímica "ing. Jose Miguel Parera"; Argentina Fil: Lombardo, Eduardo Agustin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Investigaciones En Catalisis y Petroquímica "ing. Jose Miguel Parera". Universidad Nacional del Litoral. Instituto de Investigaciones En Catalisis y Petroquímica "ing. Jose Miguel Parera"; Argentina Fil: Schmal, Martin. Universidade Federal do Rio de Janeiro. Programa de Engenharia Quımica. Nucleo de Catalise ; Brasil Fil: Cornaglia, Laura Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Investigaciones En Catalisis y Petroquímica "ing. Jose Miguel Parera". Universidad Nacional del Litoral. Instituto de Investigaciones En Catalisis y Petroquímica "ing. Jose Miguel Parera"; Argentina Fil: Nichio, Nora Nancy. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Ciencias Aplicadas "Dr. Jorge J. Ronco". Universidad Nacional de la Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Ciencias Aplicadas; Argentina

Microsystem technologies have the potential to significantly improve the performance, reduce the cost, and extend the capabilities of solar power systems. These benefits are possible due to a number of significant beneficial scaling effects within solar cells, modules, and systems that are manifested as the size of solar cells decrease to the sub-millimeter range. To exploit these benefits, we are using advanced fabrication techniques to create solar cells from a variety of compound semiconductors and silicon that have lateral dimensions of 250 - 1000 µm and are 1 - 20 µm thick. These fabrication techniques come out of relatively mature microsystem technologies such as integrated circuits (IC) and microelectromechanical systems (MEMS) which provide added supply chain and scale-up benefits compared to even incumbent PV technologies.

The reaction cure kinetics of a novel polyoxometalate (POM) loaded epoxy nanocomposite is described. The POM is dispersed in the epoxy resin up to volume fractions of 0.1. Differential scanning calorimetry measurements show the cure of the epoxy resin to be sensitive to the POM loading. A kinetics study of the cure exotherm confirms that POM acts as a catalyst promoting cationic homopolymerization of the epoxy resin. The cure reaction is shown to propagate through two cure regimes. A fast cure at short time is shown to be propagation by the activated chain end (ACE) mechanism. A slow cure at long time is shown to be propagation by the activated monomer (AM) mechanism. The activation energies for the fast and slow cure regimes agree well with other epoxy based systems that have been confirmed to propagate by the ACE and AM mechanisms.

Floodplain lakes may play an important role in the cycling of organic matter at the landscape scale. For those lakes on the middle and lower reaches of the Yangtze (MLY) floodplain which are subjected to intense anthropogenic disturbance, carbon burial rates should, theoretically, be substantial due to the high nutrient input, increased primary production and high sediment accumulation rates. There are more than 600 lakes >1 km2 on the Yangtze floodplain including 18 lakes >100 km2 and most are shallow and eutrophic. 210Pb-dated cores were combined with total organic carbon (TOC) analyses to determine annual C accumulation rates (C AR; g C m−2 yr−1) and the total C stock (since ~1850). The sediment TOC content is relatively low with an average

Summary 1. In cultural landscapes, lake response to climate can be masked by land-use change and nutrient loss from their catchments. Palaeolimnological methods were used to reconstruct the ecological response of diatoms in a eutrophic lowland lake (White Lough, Co. Tyrone, Northern Ireland) to altered nutrient P loading and precipitation variability over c. 100 years. 2. 210Pb-dated sediment cores were analysed to determine diatom assemblage variability, biogenic silica concentration, geochemical phosphorus concentration and accumulation rate. Manure P and agricultural N surplus data were collated from documentary sources. Long-term trends in annual temperature and precipitation were derived from the Armagh Observatory. 3. Diatom community turnover from 1890 until c. 1960 was limited, and assemblages were dominated by Aulacoseira subarctica; after this date, changes primarily reflected a eutrophication sequence owing to increased diffuse nutrient inputs associated with intensification of land use (external P loading increased by a factor of three). 4. Diatom and biogenic Si profiles were compared with North Atlantic Oscillation (NAO) records, an index of regional weather patterns. Biogenic Si exhibited a c. 7-year cycle, which tracked a cycle of similar timescale in the Armagh climate record for dry summers. In turn, this cycle was related to the variation in the NAO. 5. Monitoring data from 1971 to 2007 of nitrate exports from the Blackwater River showed that these too followed a roughly 7-year cycle at least up to 2000, in which dry summers were followed by sharp increases in nitrate export. It is argued that diatom production in White Lough reflects the cyclic behaviour in nitrate loading and the constraints that nitrogen availability places on the spring diatom bloom in a lake that is dominated by cyanobacteria.

Northern forests are important ecosystems for carbon (C) cycling and lakes within them process and bury large amounts of organic-C. Current burial estimates are poorly constrained and may discount other shifts in organic-C burial driven by global change. Here we analyse a suite of northern lakes to determine trends in organic-C burial throughout the Anthropocene. We found burial rates increased significantly over the last century and are up to five times greater than previous estimates. Despite a correlation with temperature, warming alone did not explain the increase in burial, suggesting the importance of other drivers including atmospherically deposited reactive nitrogen. Upscaling mean lake burial rates for each time period to global northern forests yields up to 4.5 Pg C accumulated in the last 100 years—20% of the total burial over the Holocene. Our results indicate that lakes will become increasingly important for C burial under future global change scenarios., The rate at which carbon burial has changed in lakes in response to human-induced global change is poorly understood. Here, the authors show that carbon burial has increased significantly in remote northern lakes along with increased nitrogen deposition and warming over the last century.

The decomposition of urea nitrate (UN) was studied using adiabatic and non-isothermal calorimetry techniques. Gas species released were identified and quantified in situ using TG-infrared spectroscopy/mass spectrometry and molar proportions of these gases were evaluated. A decomposition mechanism at high temperature was proposed based on the nature and sequences of gaseous species observed combined with literature data on decomposition of intermediate products formed. Non-isothermal decomposition kinetics of urea nitrate were measured using variable heating rates to give activation energies E /kJ mol −1 = 206 and 113 with preexponential factors Ln Z /min −1 = 47 and 21, in a closed and open system, respectively. In these systems the major UN decomposition step is strongly coupled to an endothermic dissociation reaction. Species remaining after this exothermic decomposition showed only minor exothermicity at higher temperatures. This is contrasted with the onset to adiabatic decomposition which occurred ∼30 °C below the apparent melting point (155–156 °C), and where solid (condensed) species are available.

Aging and degradation of urea nitrate below the melting point, at 100 °C, was studied by using thermal analysis and spectroscopic methods including IR, Raman, 1 H and 13 C NMR techniques. It was found that urea nitrate was completely degraded after 72 h at 100 °C into a mixture of solids (69%) and released gaseous species (31%). The degradation mechanism below the melting point was clearly identified. The remaining solid mixture was composed of ammonium nitrate, urea and biuret while unreacted residual nitric and isocyanic acids as well as traces of ammonia were released as gaseous species at 100 °C. The thermal stability of urea nitrate, under extreme storage conditions (50 °C), was also examined by isothermal nano-calorimetry.

A small library of pyrrolidinesulphonylaryl molecules has been synthesized via an efficient 4-step route, and members evaluated for their ability to inhibit IL-6 signalling. One molecule (6a) was found to have promising activity against IL-6/STAT3 signalling at the low micromolar level, and to selectively inhibit phosphorylation of STAT3 (but not STAT1) in IL-6 stimulated MDA-MB-231 breast cancer and HeLa cell lines. It was also selectively cytostatic in MDA-MB-231 (STAT3-dependent) versus A4 (STAT3-null) cells suggesting STAT3-specific inhibitory properties.

Aims: Platelet-derived growth factors (PDGF) and their receptors (PDGFR) play an essential role in pathways involved in the regulation of cell proliferation, growth and function. Overexpression of PDGF/R is reported in a wide range of solid tumours. The aim was to determine levels of PDGF/R expression in paediatric fibromatoses and myofibromatosis.Methods and results: Quantitative real-time polymerase chain reaction was used to examine the expression level of alpha and beta isoforms of PDGF/R in 17 fibromatoses, four myofibromatoses and three dermatofibrosarcoma protuberans (DFSP) in children. Fifteen of 17 (88%) fibromatoses and all myofibromatoses and DFSPs demonstrated increased expression of PDGF alpha and beta compared with a panel of normal tissues. In terms of the cognate receptors, 13/17 (76%) fibromatoses demonstrated increased expression for PDGFR alpha and R beta, whereas 3/4 myofibromatoses demonstrated increased expression of PDGFR alpha and all four had increased PDGFR beta expression. All DFSPs were associated with increased expression of both PDGFR alpha and PDGFR beta compared with normal control tissues.Conclusions: Increased expression of PDGF/R alpha beta may play an important role in the mechanism of growth of these paediatric fibromatous lesions and warrants further investigation, since novel therapeutic interventions could potentially be developed in the light of the expression patterns.

A previous report demonstrated that one site in a nucleosome assembled onto a synthetic positioning sequence known as Fragment 67 is hypersensitive to permanganate. The site is required for positioning activity and is located 1.5 turns from the dyad, which is a region of high DNA curvature in the nucleosome. Here, the permanganate sensitivity of the nucleosome positioning Fragment 601 was examined in order to expand the dataset of nucleosome sequences containing KMnO(4) hypersensitive sites. The hyperreactive T residue in the six sites detected as well as the one in Fragment 67 and three in the 5 S rDNA positioning sequence were contained within a TA step. Seven of the ten sequences were of the form CTAGPuG or the related sequence TTAAPu. These motifs were also found in the binding sites of several transcriptional regulatory proteins that kink DNA. In order to assess the significance of these sites, the 10 bp positioning determinant in Fragment 67 was removed and replaced by the nine sequences from the 5 S rDNA and Fragment 601. The results demonstrated that these derivative fragments promoted high nucleosome stability and positioning as compared to a control sequence that contained an AT step in place of the TA step. The importance of the TA step was further tested by making single base-pair substitutions in Fragment 67 and the results revealed that stability and positioning activity followed the order: TA>TG>TT>/=TC approximately GG approximately GA approximately AT. Sequences flanking the TA step were also shown to be critical for nucleosome stability and positioning. Nucleosome positioning was restored to near wild-type levels with (CTG)(3), which can form slipped stranded structures and with one base bulges that kink DNA. The results of this study suggest that local DNA structures are important for positioning and that single base-pair changes at these sites could have profound effects on those genomic functions that depend on ordered nucleosomes.

The accuracy of three methods used to estimate the whole-lake accumulation rate of chemicals in sediment, the simple mean accumulation rate, regression against water depth and the mean accumulation ...

The performance of Rh/La2O3–SiO2 and Rh/CeO2 catalysts for steam reforming of ethanol was investigated in a conventional fixed-bed reactor and a membrane reactor. This reactor was built with a self-supported Pd–Ag membrane, and its performance was compared to that the conventional reactor employing the same residence time and temperature. The effect of steam to ethanol molar ratio, ethanol concentration, temperature and contact time over hydrogen permeation and hydrogen recovery was investigated. In all cases, the ethanol conversion was kept at 100%, and the products formed were only H2, CO2, CO and CH4. In the membrane reactor, the overall ethanol reforming reaction was favored without the formation of carbon deposits. The highest permeated and H2 recovery was obtained for low ethanol content in the feed (high H2O/Ethanol ratio) and the methane formation was unfavored, in agreement with the high production of hydrogen. A slight difference in the hydrogen permeated/feed ethanol ratio was observed at higher sweep gas flow rates being higher for Rh supported on CeO2 in comparison with the Rh/La2O3–SiO2 catalyst. The best results were obtained with a H2O/Ethanol molar ratio equal to 10 and the highest membrane permeation area. Under these conditions, the H2 recovery reached values of about 70% and the hydrogen produced for each mole of ethanol exhibited the highest value close to 2.8. Fil: da Silva, Adriana M.. Instituto Nacional de Tecnologia; Brasil Fil: Mattos, Lisiane V.. Universidade Federal Fluminense; Brasil Fil: Múnera Agudelo, John Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Investigaciones en Catálisis y Petroquímica ; Argentina Fil: Lombardo, Eduardo Agustin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Investigaciones en Catálisis y Petroquímica ; Argentina Fil: Noronha, Fabio B.. Instituto Nacional de Tecnologia; Brasil Fil: Cornaglia, Laura Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Investigaciones en Catálisis y Petroquímica ; Argentina

There is an increasing demand for pure H2 (CO < 10 ppm) to be used in low temperature PEM fuel cells. This puts pressure on the development of alternative routes to purify the hydrogen that is produced in reformers using feedstocks such as natural gas and ethanol. A good option is the water gas shift reaction conducted in a membrane reactor to obtain ultrapure hydrogen. This contribution critically reviews the developments that took place in this decade concerning more efficient, selective, long-lasting catalysts that do not catalyze the formation of methane, graphitic and carbonaceous residues. The membranes, highly selective to hydrogen with high permeability and resistant to poisonous gases, particularly H2S, are also critically reviewed. Also included in this analysis are the different types of membrane reactors most commonly used. Fil: Cornaglia, Laura Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Investigaciones en Catálisis y Petroquímica ; Argentina Fil: Múnera Agudelo, John Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Investigaciones en Catálisis y Petroquímica ; Argentina Fil: Lombardo, Eduardo Agustin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Investigaciones en Catálisis y Petroquímica ; Argentina

OBJECTIVE To evaluate the pharmacokinetics, tolerability and effect on endocrinology of bicalutamide given as once-daily monotherapy at doses of > 150 mg to patients with locally advanced (MO) or metastatic (M1) prostate cancer, with efficacy as a secondary endpoint. PATIENTS AND METHODS Patients were initially enrolled to receive bicalutamide 300 mg in a non-randomized phase, after which further patients were randomized to higher bicalutamide doses (in 150 mg increments) or castration. Overall, 248 patients received bicalutamide at 300 mg (21), 450 mg (95) or 600 mg (42), or castration (90). RESULTS Systemic exposure to bicalutamide stabilised at a dose of approximate to 300 mg, as determined by pharmacokinetic analysis. The tolerability of high doses of bicalutamide was similar to that of the 150 mg dose, with no increase in the incidence of adverse events. Patients receiving bicalutamide had early increases in the mean levels of oestradiol, testosterone and luteinizing hormone, which were maintained throughout the study. Levels of these hormones rapidly decreased in the castration group and remained low. From baseline (first day of treatment) to 12 weeks there was an equivalent reduction in prostate-specific antigen (PSA) levels across all four groups. At a median follow-up of 5 years, there was no significant survival difference between patients who received bicalutamide and those who received castration, either in M0 or M1 disease. CONCLUSION The low median PSA level (180 ng/mL) of patients with M1 disease might account for the lack of survival difference between the treatment groups. Further studies are needed to assess whether high-dose bicalutamide monotherapy can provide equivalent efficacy to castration in patients with M1 prostate cancer. (Less)

To the Editor: Inhaled corticosteroids (ICS) reduce airway inflammation; however, guidelines recommend titrating ICS dose based on symptoms [1], which are not closely associated with airway inflammation [2]. Once symptoms are controlled for ≥3 months, ICS reduction is recommended [3] but step-down is often not implemented. Studies suggest that the majority of patients treated with ICS can have their therapy stepped down, although there is no clear evidence on how best to achieve this [4]. We assessed whether exhaled nitric oxide fraction ( F eNO) measurements could predict a loss of symptom control or exacerbation following a reduction in ICS dose in a cohort study of people with well-controlled asthma recruited from primary care. All participants had a recorded asthma diagnosis, were aged 18–75 years, and had received at least one ICS prescription in the last year. The study was restricted to nonsmokers ( 1.5 at visit 1 (indicating poor control) were excluded. Participants were seen at the same time of day on four occasions: days 0, 14, 21 and 110. At each visit, ACQ-5, F eNO (Flex Flow; Aerocrine, Solna, Sweden) and spirometry were performed. Symptoms were assessed using the ACQ-5 [6]. Airway inflammation was measured using F eNO at 50 mL·s−1; participants were blinded to their measurements. Differential …

We investigated whether phytoplankton communities in two lakes in SW Greenland were phosphorus or nitrogen limited. The study lakes have contrasting water chemistry (mean conductivities differ ten fold) and are located near Kangerlussuaq, SW Greenland (~67°N, 51°W). A microcosm nutrient enrichment experiment was performed in June 2003 to determine whether nitrate or phosphate addition stimulated phytoplankton growth. Samples were analysed for species composition, biomass, and alkaline phosphatase activity (APA). Initially, both lakes had extremely low total phosphorus but high total nitrogen concentrations and high APA, suggesting that the phytoplankton were phosphorus limited prior to the start of the experiment. The phytoplankton composition and biomass (mainly Ochromonas spp.) responded to phosphate but not to nitrate addition. In both lakes, chlorophyll a increased significantly when phosphate was added. Furthermore, APA was significantly lower in the two lakes when phosphate was added compared to the control and the nitrogen addition treatment. The dominance of mixotrophic phytoplankton and high DOC values suggest that these lakes may be regulated by microbial loop processes.

Solar proton events (SPEs) are known to have caused changes in constituents in the Earth's neutral middle atmosphere. The highly energetic protons produce ionizations, excitations, dissociations, and dissociative ionizations of the background constituents, which lead to the production of HOx (H, OH, HO2) and NOy (N, NO, NO2, NO3, N2O5, HNO3, HO2NO2, ClONO2, BrONO2). The HOx increases lead to short-lived ozone decreases in the mesosphere and upper stratosphere due to the short lifetimes of the HOx constituents. The NOy increases lead to long-lived stratospheric ozone changes because of the long lifetime of the NOy family in this region. The past four years, 2000-2003, have been replete with SPEs and huge fluxes of high energy protons occurred in July and November 2000, September and November 2001, April 2002, and October 2003. Smaller, but still substantial, proton fluxes impacted the Earth during other months from year 2000 to 2003. The Goddard Space Flight Center (GSFC) Two-dimensional (2D) Model was used in computing the influence of the SPEs. The impact of these extremely large SPEs was calculated to be especially large in the upper stratosphere and mesosphere. The results of the GSFC 2D Model will be shown along with comparisons to the Upper Atmosphere Research Satellite (UARS) Halogen Occultation Experiment (HALOE) and Solar Backscatter Ultraviolet 2 (SBUV/2) instruments.

Neuroblastomas are the second most common solid tumor in children but the molecular mechanisms underlying the initiation and progression of this disease are poorly understood. We previously showed that the Brn-3b transcription factor is highly expressed in actively proliferating neuroblastoma cells but is significantly decreased when these cells are induced to differentiate. In this study, we analyzed the effects of manipulating Brn-3b levels in the human neuroblastoma cell line, IMR-32 and showed that constitutive overexpression of Brn-3b consistently increased cellular growth and proliferation in monolayer as well as in an anchorage-independent manner compared with controls whereas stably decreasing Brn-3b can reduce the rate of growth of these cells. Cells with high Brn-3b also fail to respond to growth inhibitory retinoic acid, as they continue to proliferate. Moreover, Brn-3b levels significantly modified tumor growth in vivo with elevated Brn-3b resulting in faster tumor growth in xenograft models whereas decreasing Brn-3b resulted in slower growth compared with controls. Interestingly, elevated Brn-3b levels also enhances the invasive capacity of these neuroblastoma cells with significantly larger numbers of migrating cells observed in overexpressing clones compared with controls. Because invasion and metastasis influence morbidity and mortality in neuroblastoma and so significantly affect the course and outcome of neuroblastomas, this finding is very important. Our results therefore suggest that Brn-3b transcription factor contributes to proliferation of neuroblastoma cells in vivo and in vitro but may also influence progression and/or invasion during tumorigenesis. It is possible that decreasing Brn-3b levels may reverse some effects on growth and proliferation of these cells.

Palaeoclimatic inferences from the Greenland ice cores suggest that Holocene climate was relatively uniform. The ice core records primarily reflect hemispheric temperature-related climate processes whereas lakes tend to reflect regional scale climatic variability. Stable isotopes in closed-basin lakes are sensitive to changes in effective precipitation. Here we report stable isotope evidence (δ 18 O and δ 13 C records from authigenic calcite in laminated lake sediments) from two oligosaline, closed-basin lakes in southern West Greenland (Sondre Stromfjord). The stable isotope profiles indicate a dynamic early to mid-Holocene climate as a strongly negative precipitation-evaporation balance from ∼7000 to 5600 cal yr BP lowered lake levels throughout the region. This interpretation of the stable isotope data is supported by a survey of modern lake-water isotopic composition and fossil shorelines around many closed-basin saline lakes which indicate higher lake levels in the past. The increased aridity during the early Holocene resulted from a shift in regional circulation patterns in the Davis Straits–Baffin Bay area. Enhanced stability of the West Greenland depression and the situation of a regional trough over the Sondre Stromfjord area caused weakened westerly airflow and strengthened outflow (i.e. winds blowing off the ice sheet), resulting in reduced precipitation in the region. Decreased precipitation, coupled with higher insolation, probably caused the negative precipitation–evaporation balance.