A new regulatory mechanism of protein phosphatase 2A activity via SET in acute myeloid leukemia

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy. Although novel emerging drugs are available, the overall prognosis remains poor and new therapeutic approaches are required. PP2A phosphatase is a key regulator of cell homeostasis and is recurrently inactivated in AML. The anticancer activity of several PP2A-activating drugs (e.g., FTY720) depends on their interaction with the SET oncoprotein, an endogenous PP2A inhibitor that is overexpressed in 30% of AML cases. Elucidation of SET regulatory mechanisms may therefore provide novel targeted therapies for SET-overexpressing AMLs. Here, we show that upregulation of protein kinase p38 beta is a common event in AML. We provide evidence that p38 beta potentiates SET-mediated PP2A inactivation by two mechanisms: facilitating SET cytoplasmic translocation through CK2 phosphorylation, and directly binding to and stabilizing the SET protein. We demonstrate the importance of this new regulatory mechanism in primary AML cells from patients and in zebrafish xenograft models. Accordingly, combination of the CK2 inhibitor CX-4945, which retains SET in the nucleus, and FTY720, which disrupts the SET-PP2A binding in the cytoplasm, significantly reduces the viability and migration of AML cells. In conclusion, we show that the p38 beta/CK2/SET axis represents a new potential therapeutic pathway in AML patients with SET-dependent PP2A inactivation

Biochar as a tool to reduce the agricultural greenhouse-gas burden – knowns, unknowns and future research needs

Agriculture and land use change has significantly increased atmospheric emissions of the non-CO2 green-house gases (GHG) nitrous oxide (N2O) and methane (CH4). Since human nutritional and bioenergy needs continue to increase, at a shrinking global land area for production, novel land management strategies are required that reduce the GHG footprint per unit of yield. Here we review the potential of biochar to reduce N2O and CH4 emissions from agricultural practices including potential mechanisms behind observed effects. Furthermore, we investigate alternative uses of biochar in agricultural land management that may significantly reduce the GHG-emissions-per-unit-of-product footprint, such as (i) pyrolysis of manures as hygienic alternative to direct soil application, (ii) using biochar as fertilizer carrier matrix for underfoot fertilization, biochar use (iii) as composting additive or (iv) as feed additive in animal husbandry or for manure treatment. We conclude that the largest future research needs lay in conducting life-cycle GHG assessments when using biochar as an on-farm management tool for nutrient-rich biomass waste streams

Tnfa Signaling Through Tnfr2 Protects Skin Against Oxidative Stress-Induced Inflammation

TNFα overexpression has been associated with several chronic inflammatory diseases, including psoriasis, lichen planus, rheumatoid arthritis, and inflammatory bowel disease. Paradoxically, numerous studies have reported new-onset psoriasis and lichen planus following TNFα antagonist therapy. Here, we show that genetic inhibition of Tnfa and Tnfr2 in zebrafish results in the mobilization of neutrophils to the skin. Using combinations of fluorescent reporter transgenes, fluorescence microscopy, and flow cytometry, we identified the local production of dual oxidase 1 (Duox1)-derived H2O2 by Tnfa- and Tnfr2-deficient keratinocytes as a trigger for the activation of the master inflammation transcription factor NF-κB, which then promotes the induction of genes encoding pro-inflammatory molecules. In addition, pharmacological inhibition of Duox1 completely abrogated skin inflammation, placing Duox1-derived H2O2 upstream of this positive feedback inflammatory loop. Strikingly, DUOX1 was drastically induced in the skin lesions of psoriasis and lichen planus patients. These results reveal a crucial role for TNFα/TNFR2 axis in the protection of the skin against DUOX1-mediated oxidative stress and could establish new therapeutic targets for skin inflammatory disorders

Strategies for greenhouse gas emissions mitigation in Mediterranean agriculture: A review

[EN] An integrated assessment of the potential of different management practices for mitigating specific components of the total GHG budget (N2O and CH4 emissions and C sequestration) of Mediterranean agrosystems was performed in this study. Their suitability regarding both yield and environmental (e.g. nitrate leaching and ammonia volatilization) sustainability, and regional barriers and opportunities for their implementation were also considered. Based on its results best strategies to abate GHG emissions in Mediterranean agro-systems were proposed. Adjusting N fertilization to crop needs in both irrigated and rain-fed systems could reduce N2O emissions up to 50% compared with a non-adjusted practice. Substitution of N synthetic fertilizers by solid manure can be also implemented in those systems, and may abate N2O emissions by about 20% under Mediterranean conditions, with additional indirect benefits associated to energy savings and positive effects in crop yields. The use of urease and nitrification inhibitors enhances N use efficiency of the cropping systems and may mitigate N2O emissions up to 80% and 50%, respectively. The type of irrigation may also have a great mitigation potential in the Mediterranean region. Drip-irrigated systems have on average 80% lower N2O emissions than sprinkler systems and drip-irrigation combined with optimized fertilization showed a reduction in direct N2O emissions up to 50%. Methane fluxes have a relatively small contribution to the total GHG budget of Mediterranean crops, which can mostly be controlled by careful management of the water table and organic inputs in paddies. Reduced soil tillage, improved management of crop residues and agro-industry by-products, and cover cropping in orchards, are the most suitable interventions to enhance organic C stocks in Mediterranean agricultural soils. The adoption of the proposed agricultural practices will require farmers training. The global analysis of life cycle emissions associated to irrigation type (drip, sprinkle and furrow) and N fertilization rate (100 and 300 kg N ha(-1) yr(-1)) revealed that these factors may outweigh the reduction in GHG emissions beyond the plot scale. The analysis of the impact of some structural changes on top-down mitigation of GHG emissions revealed that 3-15% of N2O emissions could be suppressed by avoiding food waste at the end-consumer level. A 40% reduction in meat and dairy consumption could reduce GHG emissions by 20-30%. Reintroducing the Mediterranean diet (i.e. similar to 35% intake of animal protein) would therefore result in a significant decrease of GHG emissions from agricultural production systems under Mediterranean conditions. (C) 2016 Elsevier B.V. All rights reserved.The authors would like to thank the Spanish National R+D+i Plan (AGL2012-37815-C05-01, AGL2012-37815-C05-04) and very specifically the workshop held in December 2016 in Butron (Bizkaia) to synthesize the most promising measures to reduce N2O emissions from Spanish agricultural soils. BC3 is sponsored by the Basque Government. M. L. Cayuela thanks Fundacion Seneca for financing the project 19281/PI/14.Sanz-Cobeña, A.; Lassaletta, L.; Aguilera, E.; Del Prado, A.; Garnier, J.; Billen, G.; Iglesias, A.... (2017). Strategies for greenhouse gas emissions mitigation in Mediterranean agriculture: A review. Agriculture Ecosystems & Environment. 238:5-24. https://doi.org/10.1016/j.agee.2016.09.038S52423

The molar H: Corg ratio of biochar is a key factor in mitigating N2O emissions from soil

A previously published meta-analysis of biochar impacts on soil N2O emissions by Cayuela et al. (2014) found a “grand mean” reduction in N2O emissions of 54 ± 6% following biochar application to soil. Here we update this analysis to include 26 additional manuscripts bringing the total to 56 articles. The updated meta-analysis confirms that biochar reduces soil N2O emissions by 49 ± 5% (mean ± 95% confidence interval). Importantly, this meta-analysis has sufficient data to investigate the impact of biochar under field conditions, showing a statistically significant lower average reduction in the field (28 ± 16%) compared to controlled laboratory studies (54 ± 3%). A key finding is the importance of the molar H:Corg ratio of biochar in determining mitigation of N2O. Biochars with a molar H:Corg ratio 0.5 were less effective at 40 ± 16%. Together with previously published information, our new results suggest that a key mitigation mechanism is linked to the degree of polymerization and aromaticity of biochar

Residues of bioenergy production chains as soil amendments: Immediate and temporal phytotoxicity

The current shift towards bioenergy production increases streams of bioenergy rest-products (RPs), which are likely to end-up as soil amendments. However, their impact on soil remains unclear. In this study we evaluated crop phytotoxicity of 15 RPs from common bioenergy chains (biogas, biodiesel, bioethanol and pyrolysis). The RPs were mixed into a sandy soil and the seedling root and shoot elongation of lettuce (Lactuca sativa L.), radish (Raphanus sativus L.), and wheat (Triticum aestivum L.) were measured. Immediate phytotoxic effects were observed with biodiesel and bioethanol RPs (root elongation reduced to 14-60% for the three crops;

The molar H: Corg ratio of biochar is a key factor in mitigating N2O emissions from soil

A previously published meta-analysis of biochar impacts on soil N2O emissions by Cayuela et al. (2014) found a “grand mean” reduction in N2O emissions of 54 ± 6% following biochar application to soil. Here we update this analysis to include 26 additional manuscripts bringing the total to 56 articles. The updated meta-analysis confirms that biochar reduces soil N2O emissions by 49 ± 5% (mean ± 95% confidence interval). Importantly, this meta-analysis has sufficient data to investigate the impact of biochar under field conditions, showing a statistically significant lower average reduction in the field (28 ± 16%) compared to controlled laboratory studies (54 ± 3%). A key finding is the importance of the molar H:Corg ratio of biochar in determining mitigation of N2O. Biochars with a molar H:Corg ratio 0.5 were less effective at 40 ± 16%. Together with previously published information, our new results suggest that a key mitigation mechanism is linked to the degree of polymerization and aromaticity of biochar

Bioenergy from cattle manure? Implications of anaerobic digestion and subsequent pyrolysis for carbon and nitrogen dynamics in soil

Cattle manure can be processed to produce bioenergy, resulting in by-products with different physicochemical characteristics. To evaluate whether application of such bioenergy by-products to soils would be beneficial compared with their unprocessed counterpart, we quantified differences in greenhouse gas emissions and carbon (C) and nitrogen (N) dynamics in soil. Three by-products (15N-labeled cattle manure, from which anaerobic digestate was obtained, which was subsequently pyrolysed) were applied to a loess and a sandy soil in a laboratory incubation study. The highest losses of soil C from biological activity (CO2 respiration) were observed in manure treatments (39% and 32% for loess and sandy soil), followed by digestate (31% and and 18%), and biochar (15% and and 7%). Emissions of nitrous oxide (N2O) ranged from 0.6% of applied N from biochar to 4.0% from manure. Isotope labeling indicated that manure N was most readily mineralized, contributing 50% to soil inorganic N. The anaerobic digestate was the only by-product increasing the mineral N pool, while reducing emissions of N2O compared with manure. In biochar treatments, less than 18.3% of soil mineral N derived from the biochar, while it did not constrain mineralization of native soil N. By-products of anaerobic digestion and pyrolysis revealed soil fertility in addition to environmental benefits. However, the reported advantages lessen when the declining yields of C and N over the bioenergy chain are considered

Bioenergy from cattle manure? Implications of anaerobic digestion and subsequent pyrolysis for carbon and nitrogen dynamics in soil

Cattle manure can be processed to produce bioenergy, resulting in by-products with different physicochemical characteristics. To evaluate whether application of such bioenergy by-products to soils would be beneficial compared with their unprocessed counterpart, we quantified differences in greenhouse gas emissions and carbon (C) and nitrogen (N) dynamics in soil. Three by-products (15N-labeled cattle manure, from which anaerobic digestate was obtained, which was subsequently pyrolysed) were applied to a loess and a sandy soil in a laboratory incubation study. The highest losses of soil C from biological activity (CO2 respiration) were observed in manure treatments (39% and 32% for loess and sandy soil), followed by digestate (31% and and 18%), and biochar (15% and and 7%). Emissions of nitrous oxide (N2O) ranged from 0.6% of applied N from biochar to 4.0% from manure. Isotope labeling indicated that manure N was most readily mineralized, contributing 50% to soil inorganic N. The anaerobic digestate was the only by-product increasing the mineral N pool, while reducing emissions of N2O compared with manure. In biochar treatments, less than 18.3% of soil mineral N derived from the biochar, while it did not constrain mineralization of native soil N. By-products of anaerobic digestion and pyrolysis revealed soil fertility in addition to environmental benefits. However, the reported advantages lessen when the declining yields of C and N over the bioenergy chain are considered