Technical note: Novel estimates of the leaf relative uptake rate of carbonyl sulfide from optimality theory

In order to estimate the gross primary productivity (GPP) of terrestrial ecosystems from the canopy uptake of carbonyl sulfide (COS), the leaf relative uptake rate (LRU) of COS with respect to carbon dioxide needs to be known a priori. Currently, the variability of the LRU between plant species in different biomes of the world is poorly understood, making the choice of an appropriate LRU uncertain and hampering further progress towards developing COS as an alternative tracer of GPP. Here we propose a novel approach for estimating LRU based on plant optimality principles, validate it against in situ leaf gas exchange measurements and provide global monthly climatological estimates. The global vegetation season average simulated LRUs fall into the range of 0.5&ndash;1.4 and are thus lower than any other published global estimates. We advocate these LRU estimates to be adopted by global modellers in order to test to what degree these are compatible with our current understanding of the sources and sinks in the global COS budget.</p

Technical Note: Novel Estimates of the Leaf Relative Uptake Rate of Carbonyl Sulfide from Optimality Theory

In order to estimate the gross primary productivity (GPP) of terrestrial ecosystems from the canopy uptake of carbonyl sulfide (COS), the leaf relative uptake rate (LRU) of COS with respect to carbon dioxide needs to be known a priori. Currently, the variability of the LRU between plant species in different biomes of the world is poorly understood, making the choice of an appropriate LRU uncertain and hampering further progress towards developing COS as an alternative tracer of GPP. Here we propose a novel approach for estimating LRU based on plant optimality principles, validate it against in situ leaf gas exchange measurements and provide global monthly climatological estimates. The global vegetation season average simulated LRUs fall into the range of 0.5-1.4 and are thus lower than any other published global estimates. We advocate these LRU estimates to be adopted by global modellers in order to test to what degree these are compatible with our current understanding of the sources and sinks in the global COS budget

Soil carbonyl sulfide exchange in relation to microbial community composition: Insights from a managed grassland soil amendment experiment

The viability of carbonyl sulfide (COS) measurements for partitioning ecosystem-scale net carbon dioxide (CO2) fluxes into photosynthesis and respiration critically depends on our knowledge of non-leaf sinks and sources of COS in ecosystems. We combined soil gas exchange measurements of COS and CO2 with next-generation sequencing technology (NGS) to investigate the role of soil microbiota for soil COS exchange. We applied different treatments (litter and glucose addition, enzyme inhibition and gamma sterilization) to soil samples from a temperate grassland to manipulate microbial composition and activity. While untreated soil was characterized by consistent COS uptake, other treatments reduced COS uptake and even turned the soil into a net COS source. Removing biotic processes through sterilization led to positive or zero fluxes. We used NGS to link changes in the COS response to alterations in the microbial community composition, with bacterial data having a higher explanatory power for the measured COS fluxes than fungal data. We found that the genera Arthrobacter and Streptomyces were particularly abundant in samples exhibiting high COS emissions. Our results indicate cooccurring abiotic production and biotic consumption of COS in untreated soil, the latter linked to carbonic anhydrase activity, and a strong dependency of the COS flux on the activity, identity, abundance of and substrate available to microorganisms.Austrian National Science Fund (FWF) | Ref. P27176-B16Tyrolean Science Fund (TWF) | Ref. UNI-0404/1801Ministerio de Economía y Competitividad | Ref. RYC-2016-2123

Randomized controlled phase 2 trial of hydroxychloroquine in childhood interstitial lung disease

Background No results of controlled trials are available for any of the few treatments offered to children with interstitial lung diseases (chILD). We evaluated hydroxychloroquine (HCQ) in a phase 2, prospective, multicentre, 1:1-randomized, double-blind, placebo-controlled, parallel-group/crossover trial. HCQ (START arm) or placebo were given for 4 weeks. Then all subjects received HCQ for another 4 weeks. In the STOP arm subjects already taking HCQ were randomized to 12 weeks of HCQ or placebo (= withdrawal of HCQ). Then all subjects stopped treatment and were observed for another 12 weeks. Results 26 subjects were included in the START arm, 9 in the STOP arm, of these four subjects participated in both arms. The primary endpoint, presence or absence of a response to treatment, assessed as oxygenation (calculated from a change in transcutaneous O 2 -saturation of ≥ 5%, respiratory rate ≥ 20% or level of respiratory support), did not differ between placebo and HCQ groups. Secondary endpoints including change of O 2 -saturation ≥ 3%, health related quality of life, pulmonary function and 6-min-walk-test distance, were not different between groups. Finally combining all placebo and all HCQ treatment periods did not identify significant treatment effects. Overall effect sizes were small. HCQ was well tolerated, adverse events were not different between placebo and HCQ. Conclusions Acknowledging important shortcomings of the study, including a small study population, the treatment duration, lack of outcomes like lung function testing below age of 6 years, the small effect size of HCQ treatment observed requires careful reassessments of prescriptions in everyday practice (EudraCT-Nr.: 2013-003714-40, www.clinicaltrialsregister.eu , registered 02.07.2013)

Pitfalls in mutational testing and reporting of common KIT and PDGFRA mutations in gastrointestinal stromal tumors

<p>Abstract</p> <p>Background</p> <p>Mutation analysis of <it>KIT </it>and <it>PDGFRA </it>genes in gastrointestinal stromal tumors is gaining increasing importance for prognosis of GISTs and for prediction of treatment response. Several groups have identified specific mutational subtypes in <it>KIT </it>exon 11 associated with an increased risk of metastatic disease whereas GISTs with <it>PDGFRA </it>mutations often behave less aggressive. Furthermore, in advanced GIST disease with proven <it>KIT </it>exon 9 mutation the doubled daily dose of 800 mg imatinib increases the progression free survival and is now recommended both in the European and the American Guidelines. In Germany, there are still no general rules how to perform mutational analysis.</p> <p>Methods</p> <p>When comparing results from six different molecular laboratories we recognized the need of standardisation. Six German university laboratories with experience in mutation analysis in GISTs joined together to develop recommendations for the mutation analysis of the most common and clinically relevant hot spots, i. e. <it>KIT </it>exons 9 and 11 and <it>PDGFRA </it>exon 18. We performed a three-phased interlaboratory trial to identify pitfalls in performing molecular analysis in GISTs.</p> <p>Results</p> <p>We developed a design for a continuous external laboratory trial. In 2009 this external trial was conducted by 19 laboratories via the initiative for quality assurance in pathology (QuiP) of the German Society of Pathology and the Professional Association of German Pathologists.</p> <p>Conclusions</p> <p>By performing a three-phased internal interlaboratory trial and conducting an external trial in Germany we were able to identify potential pitfalls when performing KIT and PDGFRA mutational analysis in gastrointestinal stromal tumors. We developed standard operation procedures which are provided with the manuscript to allow other laboratories to prevent these pitfalls.</p

The histone methyltransferase DOT1L is required for proper DNA damage response, DNA repair, and modulates chemotherapy responsiveness

Abstract Background Disruptor of telomeric silencing 1-like (DOT1L) is a non-SET domain containing methyltransferase known to catalyze mono-, di-, and tri-methylation of histone 3 on lysine 79 (H3K79me). DOT1L-mediated H3K79me has been implicated in chromatin-associated functions including gene transcription, heterochromatin formation, and DNA repair. Recent studies have uncovered a role for DOT1L in the initiation and progression of leukemia and other solid tumors. The development and availability of small molecule inhibitors of DOT1L may provide new and unique therapeutic options for certain types or subgroups of cancer. Methods In this study, we examined the role of DOT1L in DNA double-strand break (DSB) response and repair by depleting DOT1L using siRNA or inhibiting its methyltransferase activity using small molecule inhibitors in colorectal cancer cells. Cells were treated with different agents to induce DNA damage in DOT1L-depleted or -inhibited cells and analyzed for DNA repair efficiency and survival. Further, rectal cancer patient samples were analyzed for H3K79me3 levels in order to determine whether it may serve as a potential marker for personalized therapy. Results Our results indicate that DOT1L is required for a proper DNA damage response following DNA double-strand breaks by regulating the phosphorylation of the variant histone H2AX (γH2AX) and repair via homologous recombination (HR). Importantly, we show that small molecule inhibitors of DOT1L combined with chemotherapeutic agents that are used to treat colorectal cancers show additive effects. Furthermore, examination of H3K79me3 levels in rectal cancer patients demonstrates that lower levels correlate with a poorer prognosis. Conclusions In this study, we conclude that DOT1L plays an important role in an early DNA damage response and repair of DNA double-strand breaks via the HR pathway. Moreover, DOT1L inhibition leads to increased sensitivity to chemotherapeutic agents and PARP inhibition, which further highlights its potential clinical utility. Our results further suggest that H3K79me3 can be useful as a predictive and or prognostic marker for rectal cancer patients

Global modelling of soil carbonyl sulfide exchanges

International audienceCarbonyl sulfide (COS) is an atmospheric trace gas of interest for C cycle research because COS uptake by continental vegetation is strongly related to terrestrial gross primary productivity (GPP), the largest and most uncertain flux in atmospheric CO2 budgets. However, to use atmospheric COS as an additional tracer of GPP, an accurate quantification of COS exchange by soils is also needed. At present, the atmospheric COS budget is unbalanced globally, with total COS flux estimates from oxic and anoxic soils that vary between -409 and -89 GgS yr(-1). This uncertainty hampers the use of atmospheric COS concentrations to constrain GPP estimates through atmospheric transport inversions. In this study we implemented a mechanistic soil COS model in the ORCHIDEE (Organising Carbon and Hydrology In Dynamic Ecosystems) land surface model to simulate COS fluxes in oxic and anoxic soils. Evaluation of the model against flux measurements at seven sites yields a mean root mean square deviation of 1.6 pmolm(-2)s(-1), instead of 2 pmol m(-2)s(-1) when using a previous empirical approach that links soil COS uptake to soil heterotrophic respiration. However, soil COS model evaluation is still limited by the scarcity of observation sites and long-term measurement periods, with all sites located in a latitudinal band between 39 and 62 degrees N and no observations during wintertime in this study. The new model predicts that, globally and over the 2009-2016 period, oxic soils act as a net uptake of -126 GgS yr(-1) and anoxic soils are a source of +96 GgS yr(-1), leading to a global net soil sink of only -30 GgS yr(-1), i.e. much smaller than previous estimates. The small magnitude of the soil fluxes suggests that the error in the COS budget is dominated by the much larger fluxes from plants, oceans, and industrial activities. The predicted spatial distribution of soil COS fluxes, with large emissions from oxic (up to 68.2 pmol COS m(-2) s(-1)) and anoxic (up to 36.8 pmol COS m(-2) S-1) soils in the tropics, especially in India and in the Sahel region, marginally improves the latitudinal gradient of atmospheric COS concentrations, after transport by the LMDZ (Laboratoire de Meteorologie Dynamique) atmospheric transport model. The impact of different soil COS flux representations on the latitudinal gradient of the atmospheric COS concentrations is strongest in the Northern Hemisphere. We also implemented spatiotemporal variations in near-ground atmospheric COS concentrations in the modelling of biospheric COS fluxes, which helped reduce the imbalance of the atmospheric COS budget by lowering soil COS uptake by 10 % and plant COS uptake by 8 % globally (with a revised mean vegetation budget of -576 GgS yr(-1) over 2009-2016). Sensitivity analyses highlighted the different parameters to which each soil COS flux model is the most responsive, selected in a parameter optimization framework. Having both vegetation and soil COS fluxes modelled within ORCHIDEE opens the way for using observed ecosystem COS fluxes and larger-scale atmospheric COS mixing ratios to improve the simulated GPP, through data assimilation techniques