Using Caenorhabditis elegans as a model organism for evaluating extracellular signal-regulated kinase docking domain inhibitors

We have recently identified several novel ATP-independent inhibitors that target the extracellular signal-regulated kinase-2 (ERK2) protein and inhibit substrate phosphorylation. To further characterize these compounds, we describe the use of C. elegans as a model organism. C. elegans is recognized as a versatile and cost effective model for use in drug development. These studies take advantage of the well characterized process of vulva development and egg laying, which requires MPK-1, the homolog to human ERK2. It is shown that treatment of C. elegans eggs or larvae prior to vulva formation with a previously identified lead compound (76) caused up to 50% reduction in the number of eggs produced from the adult worm. In contrast, compound 76 had no effect on egg laying in young adult or adult worms with fully formed vulva. The reduction in egg laying by the test compound was not due to effects on C. elegans life span, general toxicity, or non-specific stress. However, compound 76 did show selective inhibition of phosphorylation of LIN-1, a MPK-1 substrate essential for vulva precursor cell formation. Moreover, compound 76 inhibited cell fusion necessary for vulva maturation and reduced the multivulva phenotype in LET-60 (Ras) mutant worms that have constitutive activation of MPK-1. These findings support the use of C. elegans as a model organism to evaluate the selectivity and specificity of novel ERK targeted compounds

Constitutive hyperproduction of sorbicillinoids in Trichoderma reesei ZC121

Abstract Background In addition to its outstanding cellulase production ability, Trichoderma reesei produces a wide variety of valuable secondary metabolites, the production of which has not received much attention to date. Among them, sorbicillinoids, a large group of hexaketide secondary metabolites derived from polyketides, are drawing a growing interest from researchers because they exhibit a variety of important biological functions, including anticancer, antioxidant, antiviral, and antimicrobial properties. The development of fungi strains with constitutive, hyperproduction of sorbicillinoids is thus desired for future industry application but is not well-studied. Moreover, although T. reesei has been demonstrated to produce sorbicillinoids with the corresponding gene cluster and biosynthesis pathway proposed, the underlying molecular mechanism governing sorbicillinoid biosynthesis remains unknown. Results Recombinant T. reesei ZC121 was constructed from strain RUT-C30 by the insertion of the gene 12121-knockout cassette at the telomere of T. reesei chromosome IV in consideration of the off-target mutagenesis encountered during the unsuccessful deletion of gene 121121. Strain ZC121, when grown on cellulose, showed a sharp reduction of cellulase production, but yet a remarkable enhancement of sorbicillinoids production as compared to strain RUT-C30. The hyperproduction of sorbicillinoids is a constitutive process, independent of culture conditions such as carbon source, light, pH, and temperature. To the best of our knowledge, strain ZC121 displays record sorbicillinoid production levels when grown on both glucose and cellulose. Sorbicillinol and bisvertinolone are the two major sorbicillinoid compounds produced. ZC121 displayed a different morphology and markedly reduced sporulation compared to RUT-C30 but had a similar growth rate and biomass. Transcriptome analysis showed that most genes involved in cellulase production were downregulated significantly in ZC121 grown on cellulose, whereas remarkably all genes in the sorbicillinoid gene cluster were upregulated on both cellulose and glucose. Conclusion A constitutive sorbicillinoid-hyperproduction strain T. reesei ZC121 was obtained by off-target mutagenesis, displaying an overwhelming shift from cellulase production to sorbicillinoid production on cellulose, leading to a record for sorbicillinoid production. For the first time, T. reesei degraded cellulose to produce platform chemical compounds other than protein in high yield. We propose that the off-target mutagenesis occurring at the telomere region might cause chromosome remodeling and subsequently alter the cell structure and the global gene expression pattern of strain ZC121, as shown by phenotype profiling and comparative transcriptome analysis of ZC121. Overall, T. reesei ZC121 holds great promise for the industrial production of sorbicillinoids and serves as a good model to explore the regulation mechanism of sorbicillinoids’ biosynthesis.https://deepblue.lib.umich.edu/bitstream/2027.42/146139/1/13068_2018_Article_1296.pd

An Integrative Model for Soil Biogeochemistry and Methane Processes. II: Warming and Elevated CO2 Effects on Peatland CH4 Emissions

Peatlands are one of the largest natural sources for atmospheric methane (CH4), a potent greenhouse gas. Climate warming and elevated atmospheric carbon dioxide (CO2) are two important environmental factors that have been confirmed to stimulate peatland CH4 emissions; however, the mechanisms underlying enhanced emissions remain elusive. A data-model integration approach was applied to understand the CH4 processes in a northern temperate peatland under a gradient of warming and doubled atmospheric CO2 concentration. We found that warming and elevated CO2 stimulated CH4 emissions through different mechanisms. Warming initially stimulated but then suppressed vegetative productivity while stimulating soil organic matter (SOM) mineralization and dissolved organic carbon (DOC) fermentation, which led to higher acetate production and enhanced acetoclastic and hydrogenotrophic methanogenesis. Warming also enhanced surface CH4 emissions, which combined with warming-caused decreases in CH4 solubility led to slightly lower dissolved CH4 concentrations through the soil profiles. Elevated CO2 enhanced ecosystem productivity and SOM mineralization, resulting in higher DOC and acetate concentrations. Higher DOC and acetate concentrations increased acetoclastic and hydrogenotrophic methanogenesis and led to higher dissolved CH4 concentrations and CH4 emissions. Both warming and elevated CO2 had minor impacts on CH4 oxidation. A meta-analysis of warming and elevated CO2 impacts on carbon cycling in wetlands agreed well with a majority of the modeled mechanisms. This mechanistic understanding of the stimulating impacts of warming and elevated CO2 on peatland CH4 emissions enhances our predictability on the climate-ecosystem feedback

The impacts of recent permafrost thaw on land–atmosphere greenhouse gas exchange

© The Author(s), 2014. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Environmental Research Letters 9 (2014): 045005, doi:10.1088/1748-9326/9/4/045005.Permafrost thaw and the subsequent mobilization of carbon (C) stored in previously frozen soil organic matter (SOM) have the potential to be a strong positive feedback to climate. As the northern permafrost region experiences as much as a doubling of the rate of warming as the rest of the Earth, the vast amount of C in permafrost soils is vulnerable to thaw, decomposition and release as atmospheric greenhouse gases. Diagnostic and predictive estimates of high-latitude terrestrial C fluxes vary widely among different models depending on how dynamics in permafrost, and the seasonally thawed 'active layer' above it, are represented. Here, we employ a process-based model simulation experiment to assess the net effect of active layer dynamics on this 'permafrost carbon feedback' in recent decades, from 1970 to 2006, over the circumpolar domain of continuous and discontinuous permafrost. Over this time period, the model estimates a mean increase of 6.8 cm in active layer thickness across the domain, which exposes a total of 11.6 Pg C of thawed SOM to decomposition. According to our simulation experiment, mobilization of this previously frozen C results in an estimated cumulative net source of 3.7 Pg C to the atmosphere since 1970 directly tied to active layer dynamics. Enhanced decomposition from the newly exposed SOM accounts for the release of both CO2 (4.0 Pg C) and CH4 (0.03 Pg C), but is partially compensated by CO2 uptake (0.3 Pg C) associated with enhanced net primary production of vegetation. This estimated net C transfer to the atmosphere from permafrost thaw represents a significant factor in the overall ecosystem carbon budget of the Pan-Arctic, and a non-trivial additional contribution on top of the combined fossil fuel emissions from the eight Arctic nations over this time period.This study was supported through grants provided as part of the National Science Foundation’s Arctic System Science Program (NSF OPP0531047), a Department of Energy (DOE) Early Career Award (DOEBER #3ERKP818), the National Aeronautics and Space Administration’s New Investigator Program (NNX10AT66G) and the NextGeneration Ecosystem Experiments (NGEE Arctic) project supported by the Office of Biological and Environmental Research in the DOE Office of Science

Hydrological Feedbacks on Peatland CH4 Emission Under Warming and Elevated CO2: A Modeling Study

Peatland carbon cycling is critical for the land–atmosphere exchange of greenhouse gases, particularly under changing environments. Warming and elevated atmospheric carbon dioxide (eCO2) concentrations directly enhance peatland methane (CH4) emission, and indirectly affect CH4 processes by altering hydrological conditions. An ecosystem model ELM-SPRUCE, the land model of the E3SM model, was used to understand the hydrological feedback mechanisms on CH4 emission in a temperate peatland under a warming gradient and eCO2 treatments. We found that the water table level was a critical regulator of hydrological feedbacks that affect peatland CH4 dynamics; the simulated water table levels dropped as warming intensified but slightly increased under eCO2. Evaporation and vegetation transpiration determined the water table level in peatland ecosystems. Although warming significantly stimulated CH4 emission, the hydrological feedbacks leading to a reduced water table mitigated the stimulating effects of warming on CH4 emission. The hydrological feedback for eCO2 effects was weak. The comparison between modeled results with data from a field experiment and a global synthesis of observations supports the model simulation of hydrological feedbacks in projecting CH4 flux under warming and eCO2. The ELM-SPRUCE model showed relatively small parameter-induced uncertainties on hydrological variables and their impacts on CH4 fluxes. A sensitivity analysis confirmed a strong hydrological feedback in the first three years and the feedback diminished after four years of warming. Hydrology-moderated warming impacts on CH4 cycling suggest that the indirect effect of warming on hydrological feedbacks is fundamental for accurately projecting peatland CH4 flux under climate warming

Modeling Analysis of Primary Controls on Net Ecosystem Productivity of Seven Boreal and Temperate Coniferous Forests Across a Continental Transect

Process-based models are effective tools to synthesize and/or extrapolate measured carbon (C) exchanges from individual sites to large scales. In this study, we used a C- and nitrogen (N)-cycle coupled ecosystem model named CN-CLASS (Carbon Nitrogen-Canadian Land Surface Scheme) to study the role of primary climatic controls and site-specific C stocks on the net ecosystem productivity (NEP) of seven intermediate-aged to mature coniferous forest sites across an east–west continental transect in Canada. The model was parameterized using a common set of parameters, except for two used in empirical canopy conductance–assimilation, and leaf area–sapwood relationships, and then validated using observed eddy covariance flux data. Leaf Rubisco-N dynamics that are associated with soil–plant N cycling, and depend on canopy temperature, enabled the model to simulate site-specific gross ecosystem productivity (GEP) reasonably well for all seven sites. Overall GEP simulations had relatively smaller differences compared with observations vs. ecosystem respiration (RE), which was the sum of many plant and soil components with larger variability and/or uncertainty associated with them. Both observed and simulated data showed that, on an annual basis, boreal forest sites were either carbon-neutral or a weak C sink, ranging from 30 to 180 g C m−2 yr−1; while temperate forests were either a medium or strong C sink, ranging from 150 to 500 g C m−2 yr−1, depending on forest age and climatic regime. Model sensitivity tests illustrated that air temperature, among climate variables, and aboveground biomass, among major C stocks, were dominant factors impacting annual NEP. Vegetation biomass effects on annual GEP, RE and NEP showed similar patterns of variability at four boreal and three temperate forests. Air temperature showed different impacts on GEP and RE, and the response varied considerably from site to site. Higher solar radiation enhanced GEP, while precipitation differences had a minor effect. Magnitude of forest litter content and soil organic matter (SOM) affected RE. SOM also affected GEP, but only at low levels of SOM, because of low N mineralization that limited soil nutrient (N) availability. The results of this study will help to evaluate the impact of future climatic changes and/or forest C stock variations on C uptake and loss in forest ecosystems growing in diverse environments.Earth and Planetary Science

Anomalous extensive landfast sea ice in the vicinity of Inexpressible Island, Antarctica

On 10 December 2017, a Chinese research vessel R/V Xuelong encountered an extensive area of landfast ice offshore Inexpressible Island (Antarctica) near the location where the fifth Chinese Antarctic research station is to be built. Using multi-source satellite images and weather data, we analyzed the ice conditions during the event season and reconstructed the development of landfast ice. Two stages in late September and early October were identified as contributing to the final ice extent. These two events are highly related to local- and large-scale weather conditions. Satellite images from 2003 to 2017 showed that four in fifteen years experienced severe landfast ice conditions, suggesting that it is not a rare phenomenon

Feature-based Transferable Disruption Prediction for future tokamaks using domain adaptation

The high acquisition cost and the significant demand for disruptive discharges for data-driven disruption prediction models in future tokamaks pose an inherent contradiction in disruption prediction research. In this paper, we demonstrated a novel approach to predict disruption in a future tokamak only using a few discharges based on a domain adaptation algorithm called CORAL. It is the first attempt at applying domain adaptation in the disruption prediction task. In this paper, this disruption prediction approach aligns a few data from the future tokamak (target domain) and a large amount of data from the existing tokamak (source domain) to train a machine learning model in the existing tokamak. To simulate the existing and future tokamak case, we selected J-TEXT as the existing tokamak and EAST as the future tokamak. To simulate the lack of disruptive data in future tokamak, we only selected 100 non-disruptive discharges and 10 disruptive discharges from EAST as the target domain training data. We have improved CORAL to make it more suitable for the disruption prediction task, called supervised CORAL. Compared to the model trained by mixing data from the two tokamaks, the supervised CORAL model can enhance the disruption prediction performance for future tokamaks (AUC value from 0.764 to 0.890). Through interpretable analysis, we discovered that using the supervised CORAL enables the transformation of data distribution to be more similar to future tokamak. An assessment method for evaluating whether a model has learned a trend of similar features is designed based on SHAP analysis. It demonstrates that the supervised CORAL model exhibits more similarities to the model trained on large data sizes of EAST. FTDP provides a light, interpretable, and few-data-required way by aligning features to predict disruption using small data sizes from the future tokamak.Comment: 15 pages, 9 figure

Evolution combined with genomic study elucidates genetic bases of isobutanol tolerance in Escherichia coli

<p>Abstract</p> <p>Background</p> <p>Isobutanol is a promising next-generation biofuel with demonstrated high yield microbial production, but the toxicity of this molecule reduces fermentation volumetric productivity and final titer. Organic solvent tolerance is a complex, multigenic phenotype that has been recalcitrant to rational engineering approaches. We apply experimental evolution followed by genome resequencing and a gene expression study to elucidate genetic bases of adaptation to exogenous isobutanol stress.</p> <p>Results</p> <p>The adaptations acquired in our evolved lineages exhibit antagonistic pleiotropy between minimal and rich medium, and appear to be specific to the effects of longer chain alcohols. By examining genotypic adaptation in multiple independent lineages, we find evidence of parallel evolution in <it>marC</it>, <it>hfq</it>, <it>mdh</it>, <it>acrAB, gatYZABCD</it>, and <it>rph </it>genes. Many isobutanol tolerant lineages show reduced RpoS activity, perhaps related to mutations in <it>hfq </it>or <it>acrAB</it>. Consistent with the complex, multigenic nature of solvent tolerance, we observe adaptations in a diversity of cellular processes. Many adaptations appear to involve epistasis between different mutations, implying a rugged fitness landscape for isobutanol tolerance. We observe a trend of evolution targeting post-transcriptional regulation and high centrality nodes of biochemical networks. Collectively, the genotypic adaptations we observe suggest mechanisms of adaptation to isobutanol stress based on remodeling the cell envelope and surprisingly, stress response attenuation.</p> <p>Conclusions</p> <p>We have discovered a set of genotypic adaptations that confer increased tolerance to exogenous isobutanol stress. Our results are immediately useful to further efforts to engineer more isobutanol tolerant host strains of <it>E. coli </it>for isobutanol production. We suggest that <it>rpoS </it>and post-transcriptional regulators, such as <it>hfq</it>, RNA helicases, and sRNAs may be interesting mutagenesis targets for future global phenotype engineering.</p

COVID-19 causes record decline in global CO2 emissions

The considerable cessation of human activities during the COVID-19 pandemic has affected global energy use and CO2 emissions. Here we show the unprecedented decrease in global fossil CO2 emissions from January to April 2020 was of 7.8% (938 Mt CO2 with a +6.8% of 2-{\sigma} uncertainty) when compared with the period last year. In addition other emerging estimates of COVID impacts based on monthly energy supply or estimated parameters, this study contributes to another step that constructed the near-real-time daily CO2 emission inventories based on activity from power generation (for 29 countries), industry (for 73 countries), road transportation (for 406 cities), aviation and maritime transportation and commercial and residential sectors emissions (for 206 countries). The estimates distinguished the decline of CO2 due to COVID-19 from the daily, weekly and seasonal variations as well as the holiday events. The COVID-related decreases in CO2 emissions in road transportation (340.4 Mt CO2, -15.5%), power (292.5 Mt CO2, -6.4% compared to 2019), industry (136.2 Mt CO2, -4.4%), aviation (92.8 Mt CO2, -28.9%), residential (43.4 Mt CO2, -2.7%), and international shipping (35.9Mt CO2, -15%). Regionally, decreases in China were the largest and earliest (234.5 Mt CO2,-6.9%), followed by Europe (EU-27 & UK) (138.3 Mt CO2, -12.0%) and the U.S. (162.4 Mt CO2, -9.5%). The declines of CO2 are consistent with regional nitrogen oxides concentrations observed by satellites and ground-based networks, but the calculated signal of emissions decreases (about 1Gt CO2) will have little impacts (less than 0.13ppm by April 30, 2020) on the overserved global CO2 concertation. However, with observed fast CO2 recovery in China and partial re-opening globally, our findings suggest the longer-term effects on CO2 emissions are unknown and should be carefully monitored using multiple measures