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Supplementary Figures 1-7 from A Small-Molecule Inhibitor of MDMX Activates p53 and Induces Apoptosis

The p53 inactivation caused by aberrant expression of its major regulators (e.g., MDM2 and MDMX) contributes to the genesis of a large number of human cancers. Recent studies have shown that restoration of p53 activity by counteracting p53 repressors is a promising anticancer strategy. Although agents (e.g., nutlin-3a) that disrupt MDM2–p53 interaction can inhibit tumor growth, they are less effective in cancer cells that express high levels of MDMX. MDMX binds to p53 and can repress the tumor suppressor function of p53 through inhibiting its trans-activation activity and/or destabilizing the protein. Here we report the identification of a benzofuroxan derivative [7-(4-methylpiperazin-1-yl)-4-nitro-1-oxido-2,1,3-benzoxadiazol-1-ium, NSC207895] that could inhibit MDMX expression in cancer cells through a reporter-based drug screening. Treatments of MCF-7 cells with this small-molecule MDMX inhibitor activated p53, resulting in elevated expression of proapoptotic genes (e.g., PUMA, BAX, and PIG3). Importantly, this novel small-molecule p53 activator caused MCF-7 cells to undergo apoptosis and acted additively with nutlin-3a to activate p53 and decrease the viability of cancer cells. These results thus show that small molecules targeting MDMX expression would be of therapeutic benefits. Mol Cancer Ther; 10(1); 69–79. ©2010 AACR.

Background Di-nitrogen oxide (N2O) emissions from soil may lead to nonpoint-source pollution in farmland. Improving the C and N content in the soil is an excellent strategy to reduce N2O emission and mitigate soil N loss. However, this method lacks a unified mathematical index or standard to evaluate its effect. Methods To quantify the impact of soil improvement (C and N) on N2O emissions, we conducted a 2-year field experiment using biochar as carbon source and fertilizer as nitrogen source, setting three treatments (fertilization (300 kg N ha−1), fertilization + biochar (30 t ha−1), control). Results Results indicate that after biochar application, the average soil water content above 20 cm increased by ∼26% and 26.92% in 2019, and ∼10% and 12.49% in 2020. The average soil temperature above 20 cm also increased by ∼2% and 3.41% in 2019. Fertigation significantly promotes the soil N2O emissions, and biochar application indeed inhibited the cumulation by approximately 52.4% in 2019 and 33.9% in 2020, respectively. N2O emissions strongly depend on the deep soil moisture and temperature (20–80 cm), in addition to the surface soil moisture and temperature (0–20 cm). Therefore, we established an exponential model between the soil moisture and N2O emissions based on theoretical analysis. We find that the N2O emissions exponentially increase with increasing soil moisture regardless of fertilization or biochar application. Furthermore, the coefficient a aRU indicates that biochar application mitigates this rate induced by fertilization. This conclusion can be verified by the sensitivity coefficient (SCB of 1.02 and 14.74; SCU of 19.18 and 20.83). Thus, we believe the model can quantify the impact of soil C and N changes on N2O emissions. We can conclude that biochar does significantly reduce N2O emissions from farmland.

Drip irrigation and brackish water irrigation are considered to be the two main ways to alleviate the current shortage of agricultural freshwater resources and have been widely used in countries around the world. Our purpose is to evaluate the effects of different irrigation methods (flood irrigation and drip irrigation) and irrigation water salinities (1.1 g·L

Water and inorganic nitrogen fertilizer have a notable impact on crop yield and greenhouse gas (GHG) emissions from soil. Reclaimed water (RW) is widely used for irrigation when there are shortages of water resources. It is very important to control yield and greenhouse gas emissions by fertilization under reclaimed water irrigation (RWI). The study consisted of a continuous test that evaluated three types of fertilizer treatments (urea, amine, and slow-release fertilizer) and a no-fertilizer treatment under three-year RWI and four fertilizer levels (150, 200, 250 and 300 kg.N.ha-1) under one-year RWI to determine the best fertilizer to support maize production and reduce GHG (CO2 and N2O) emissions from soil; further, the applicability of RWI in the DNDC model was verified. For many years, GHG emissions under RWI showed an increasing trend, but the effect was not significant. A strong correlation was found between the GHG emissions flux and fertilizer amount, and a threshold fertilization amount existed between 220 and 260 kg.N.ha-1 that minimized yield-scaled N2O emissions and the ratio of GHG cumulative emission to yield (GHG/Y). The results indicated that the optimal amounts of SF and UF under RWI were 240 and 225 kg.N.ha-1 by second-order equation and the DNDC model, respectively, and the rate better balanced the yield and GHG emissions.

The nutrient loss caused by soil erosion is the main reason for soil degradation and environmental pollution, and polyacrylamide (PAM) as a common soil amendment has a great influence on runoff and erosion processes at the slope. In order to investigate the mechanism of nutrient transport with runoff, a field experiment was conducted and a simple mathematical model was developed in this study. Four PAM application rates (0, 1, 2, and 4 g·m−2) and two rainfall intensities (50 and 80 mm·h−1) were applied in the field experiment. The results revealed that runoff rate of 2 g·m−2 PAM application treatments decreased by 5.3%-10.6% compared with the control groups, but it increased by10.9%-18.7% at 4 g·m−2 PAM application treatments. Polyacrylamide application reduced ammonium nitrogen concentrations of runoff by 10.0% to 44.3% relative to the control groups. The best performance with correlation coefficient (R2) and Nash–Sutcliffe efficiency (NSE) showed that the ammonium transport with runoff could be well described by the proposed model. Furthermore, the model parameter of the depth of the mixing layer (hm) linearly increased with an increase in flow velocity, but exponentially decreased with an increase in PAM application rate.

The combined application of different functional chemicals creates challenges both in modeling water flow in soil and quantification of water extraction by crops in dry land farming. In the present study, 2-year laboratory and field experiments were conducted in a typical dry land of northern China in order to: (i) develop a model to describe patterns of water flow in soil under two typical chemicals Superabsorbent polymer (SAP) and Fulvic acid (FA) combined applied in the soil-maize system and (ii) use the stable hydrogen and oxygen analysis method to further quantify the soil water extraction by crops as affected by SAP and FA. Two root water extraction (RWE) terms based on density of root length (DRL) and density of root nitrogen mass (DRNM), respectively, were established to describe the rate of RWE, demonstrating that the values simulated from DRNM were verified to be closer to measured values. A particular model was further developed to simulate flow of water in different soil layers, and its authenticity was confirmed for describing the patterns of soil water flow under multi-chemicals application. The results of hydrogen and oxygen isotope abundance estimated from multi-source mass balance method (IsoSource model) suggested that main depth of water extraction as affected by multi-chemicals decreased first and then increased, and mainly concentrated in the shallow soil layers, 0–20 cm soil layer for jointing stage, 20–40 cm soil layer for heading stage, 0–20 cm soil layer for grain filling stage. Combined application of SAP and FA played a synergistic role in promoting the rainfall WUE of maize.

In-depth understanding of the patterns of root water uptake (RWU) is the key to improving the water-use efficiency of plants. Superabsorbent polymers (SAPs) can repeatedly absorb and then release water to plants when needed, which substantially increases the water-use efficiency of plants in arid and semiarid farming. However, it also creates a challenge in modeling RWU due to unstable soil hydraulic parameters and the unclear response of root growth to SAP application. A controlled soil column experiment was conducted to investigate the response of two important root indexes, that is, root length density (RLD) and root nitrogen mass density (RND), to SAP application, as well as their relationships with RWU. The results showed that the use of the SAP caused a steady increase in RND, and it also substantially increased the RLD in the early stage, but the rate of increase gradually slowed over time. The effect of unstable soil hydraulic parameters on RWU was analyzed in a numerical experiment, which indicated that the time-dependent effect of SAP on soil hydraulic parameters should be considered to avoid errors in calculating RWU. A specific method for calculating the RWU source/sink term in the Richards equation was proposed and ultimately used as the theoretical value of RWU to verify the RWU models based on RLD and RND to ensure the best one was selected. The results showed that RND was better able to be used for development of the RWU model to simulate the patterns of RWU under SAP application.

In dry land farming, the use of a superabsorbent polymer (SAP) can improve rain-water use efficiency for its unique characteristic of repeatedly absorbing rainfall and slowly releasing it to crop; however, this characteristic creates challenges in modeling water movement in soils after SAPs are applied. A series of experiments were conducted in both the laboratory and the field in an attempt to (i) study the unstable effects of SAP on soil hydraulic parameters and crop root growth; and (ii) determine variation in soil hydraulic parameters after an SAP is applied. A specific model was developed to simulate soil water movement for application of SAPs. In this model, as the unsaturated diffusivity was reduced by 1.2 to 76.6% over the time of SAP application, the time variable t was included in the Richards equation to obtain the time-varying soil hydraulic parameters. The moisture content of soil layers applied with an SAP was increased by 5.5 to 14.1% after each irrigation event; meanwhile, SAPs enhanced the rate of root water uptake (RWU) to effectively use water. Model validation indicated positive effects of time-varying soil hydraulic parameters on simulating soil water movement in soils where SAP was applied, and the simulated values had good agreement with measured values. Patterns of water movement in soil layers where SAPs were applied were accurately simulated. The findings of this study provide important guidance for modeling soil water movement when any functional substances are added to soil.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic cancer derived from the malignant transformation of T-cell progenitors. Outcomes remain poor for T-ALL patients who have either primary resistance to standard-of-care chemotherapy or disease relapse. Notably, there are currently no targeted therapies available in T-ALL. This lack of next-generation therapies highlights the need for relevant preclinical disease modeling to identify and validate new targets and treatment approaches. Here, we adapted a spontaneously arising, genetically heterogeneous, thymic transplantation-based murine model of T-ALL, recapitulating key histopathological and genetic features of the human disease, to the preclinical testing of targeted and immune-directed therapies. Genetic engineering of the murine Notch1 locus aligned the spectrum of Notch1 mutations in the mouse model to that of human T-ALL and confirmed aberrant, recombination-activating gene (RAG)-mediated 5′ Notch1 recombination events as the preferred pathway in murine T-ALL development. Testing of Notch1-targeting therapeutic antibodies demonstrated T-ALL sensitivity to different classes of Notch1 blockers based on Notch1 mutational status. In contrast, genetic ablation of Notch3 did not impact T-ALL development. The T-ALL model was further applied to the testing of immunotherapeutic agents in fully immunocompetent, syngeneic mice. In line with recent clinical experience in T-cell malignancies, programmed cell death 1 (PD-1) blockade alone lacked anti-tumor activity against murine T-ALL tumors. Overall, the unique features of the spontaneous T-ALL model coupled with genetic manipulations and the application to therapeutic testing in immunocompetent backgrounds will be of great utility for the preclinical evaluation of novel therapies against T-ALL., Summary: Adapting a spontaneous, genetically heterogenous T-ALL model to preclinical testing demonstrated that response to therapeutic anti-Notch1 antibodies was determined by Notch1 mutational status and that PD-1 immune checkpoint blockade alone lacked anti-tumor activity.

Alternative irrigation between saline water and groundwater can alleviate shortages of available agricultural water while effectively slowing the adverse effects of saline water on the soil-crop system when compared with continuous irrigation with saline water and blending irrigation between saline water and groundwater. In 2018, we tested the effect on soil CO2 and N2O emissions by two types of irrigation regimes (alternating groundwater and saline water (GW-SW), and alternating groundwater, followed by two cycles of saline water (GW-SW-SW)) between groundwater and three levels of salinity of irrigation water (mineralization of 2 g/L, 3.5 g/L, and 5 g/L), analyzed the correlation between gas emissions and soil properties, calculated comprehensive global warming potential (GWP), and investigated the maize yield. The results show that, with the same alternate irrigation regime, cumulative CO2 emissions decreased with increasing irrigation water salinity, and cumulative N2O emissions increased. Cumulative CO2 emissions were higher in the GW-SW regime for the same irrigation water salinity, and cumulative N2O emissions were higher in the GW-SW-SW regime. The GW-SW-SW regime had less comprehensive GWP and maize yield as compared to the GW-SW regime. The 2 g/L salinity in both regimes showed larger comprehensive GWP and maize yield. The 3.5 g/L salinity under the GW-SW regime will be the best choice while considering that the smaller comprehensive GWP and the larger maize yield are appropriate for agricultural implication. Fertilizer type and irrigation amount can be taken into consideration in future research direction.

Brackish water has been widely used to irrigate crops to compensate for insufficient freshwater water supply for agricultural use. The goal of this research was to determine an efficient brackish water use method to increase irrigation efficiency and reduce N2O emission. To this end, we conducted a field experiment with four salinity levels of irrigation water (1.1, 2.0, 3.5, and 5.0 g&middot, L&minus, 1 with drip irrigation) at Hetao Irrigation District (Inner Mongolia, China) in 2017 and 2018. The results show that irrigation with 3.5&ndash, 5.0 g&middot, 1 water salinity increased the soil salinity compared with irrigation using 1.1&ndash, 2.0 g&middot, 1 water salinity. The soil water content with 5.0 g&middot, 1 brackish water irrigation was significantly higher than with 1.1&ndash, 3.5 g&middot, 1 water salinity due to the effect of salinity on crop water uptake. The overall soil pH increased with the increase in irrigation water salinity. Saturated soil hydraulic conductivity decreased with the increase in irrigation water salinity. These results indicate that brackish water irrigation aggravates the degree of soil salinization and alkalization. The soil N2O cumulative flux resulting from irrigation with 5.0 g&middot, 1 water salinity was 51.18&ndash, 82.86% higher than that resulting from 1.1&ndash, 3.5 g L&minus, 1 water salinity in 2017, and was 32.38&ndash, 44.79% higher than that resulting from 1.1&ndash, 1 in 2018. Irrigation with brackish water reduced maize yield, and the reduction in yield in 2018 was greater than that in 2017, but irrigation with 2.0 g&middot, 1 brackish water did not significantly reduce maize yield in 2017. These results suggest that reducing the salinity of irrigation water may effectively reduce soil N2O emission, alleviate the degree of soil salinization, and increase crop yield.

Alternative irrigation between saline water and groundwater can alleviate shortages of available agricultural water while effectively slowing the adverse effects of saline water on the soil-crop system when compared with continuous irrigation with saline water and blending irrigation between saline water and groundwater. In 2018, we tested the effect on soil CO2 and N2O emissions by two types of irrigation regimes (alternating groundwater and saline water (GW-SW), and alternating groundwater, followed by two cycles of saline water (GW-SW-SW)) between groundwater and three levels of salinity of irrigation water (mineralization of 2 g/L, 3.5 g/L, and 5 g/L), analyzed the correlation between gas emissions and soil properties, calculated comprehensive global warming potential (GWP), and investigated the maize yield. The results show that, with the same alternate irrigation regime, cumulative CO2 emissions decreased with increasing irrigation water salinity, and cumulative N2O emissions increased. Cumulative CO2 emissions were higher in the GW-SW regime for the same irrigation water salinity, and cumulative N2O emissions were higher in the GW-SW-SW regime. The GW-SW-SW regime had less comprehensive GWP and maize yield as compared to the GW-SW regime. The 2 g/L salinity in both regimes showed larger comprehensive GWP and maize yield. The 3.5 g/L salinity under the GW-SW regime will be the best choice while considering that the smaller comprehensive GWP and the larger maize yield are appropriate for agricultural implication. Fertilizer type and irrigation amount can be taken into consideration in future research direction.

The removal of nutrients by overland flow remains a major source of non-point pollution in agricultural land. In this study, a mathematical model of ammonium nitrogen transport from soil solution to overland flow was established. The model treated the mass transfer coefficient (km) as a time-dependent parameter, which was not a constant value as in previous studies, and it was evaluated with a four-slope gradient and three rainfall intensities. The kinematic-wave equation for overland flow was solved by an approximately semi-analytical solution based on Philip&rsquo, s infiltration model, while the diffusion-based mass conversation equation for overland nutrient transport was solved numerically. The results showed that the simulated runoff processes and ammonium nitrogen concentration transport to the overland flow agreed well with the experimental data. Further correlation analyses were made to determine the relationships between the slope gradient, rainfall intensity and the hydraulic and nutrient transport parameters. It turned out that these parameters could be described as a product of exponential functions of slope gradient and rainfall intensity. Finally, a diffusion-based model with a time-dependent mass transfer coefficient was established to predict the ammonium nitrogen transport processes at the experimental site under different slope gradients and rainfall intensities.

The implementation of energy conservation and emissions reduction in Beijing prompted yearly increases in the area of urban green space, leading to direct increases in urban water consumption. This aggravated an already tense situation of water shortage. Considering the low irrigation water utilization effectives of the urban green space system, the typical urban greening shrub (Ligustrum vicaryi) was selected as the research object of this study. In a pot experiment, three mulch materials were selected: gravel (CH1), pine needles + gravel (CH2), and bark + gravel (CH3). These materials were set to a uniform thickness of 3 cm, and soil water was maintained between 75% and 85% of the field capacity. Using the analytic hierarchy process and fuzzy mathematics model, the physiological and ecological response characteristics of Ligustrum vicaryi were investigated under different combinations of mulch material. The results for various processing, regarding plant growth, showed CH3 &gt, CH2 &gt, CH1 &gt, CK (Control Check). The leaf area, total leaf area, and leaf area index of CH3 were, respectively, 21.4%, 21.9%, and 62.5% larger than those of the control check (CK). Regarding physiological characteristics, photosynthetic rate, evaporation rate, stomatal conductance, and water use efficiency of CH3 were better than for the other treatments. Regarding ecological services, carbon fixation, oxygen release, cooling, and quantity of humidification of CH3 were optimal. Considered comprehensively for the landscape function, physical characteristics, and ecological services of Ligustrum vicaryi, the preliminary thought is that bark and gravel dual-element mulch, with a layer thickness of 3 cm, was the optimal soil cover treatment for the typical city greening shrub Ligustrum vicaryi. Using the analytic hierarchy process (AHP) and the fuzzy mathematical model for the evaluation of the effects of different soil cover treatments on the landscape function, ecological service function, and physiological characteristics of Ligustrum vicaryi was reliable and feasible. The model evaluation results match the actual ones.

Fractal flow channel structure as research object, based on chemical clogging condition of the physical model. It was analyzed using computational fluid dynamics (CFD) simulation and reveals the fractal flow channel internal flow characteristics of water and sediment. Fractal flow channel non-energy dissipation of the arc angle design optimization. Using standard κ-e turbulence model and the DPM model, calculated: (1) As for the hydraulic performance analysis, before optimization emitter flow exponent of 0.487, 0.489 after optimization; From the inner flow field analysis, When the pressure head from 5 m to 15 m, before optimization emitter maximum flow rate from 2.09 m/s to 3.70 m/s, the maximum flow rate to optimize the emitter from 2.15 m/s to 3.81 m/s, the maximum optimization of flow rates were increased compared to the previous 2.87%, 3.34%, 2.97%, the flow rate improved. After optimizing the eddy region, the velocity of the outer edge of the eddy region increased from (0.005–0.752 m/s) to (0.311–0.930 m/s), which improved the self-cleaning ability of the irrigator. Based on the analysis of blockage performance, the passing rate of particles is significantly improved after optimizing the flow channel. Considering the optimized emitter has excellent hydraulic performance and anti-clogging properties.

This study investigated the effect of water-saving measures on the spatiotemporal variability of water absorption and thermal state in roots. It is crucial for understanding the process of water use of plants and its importance in the functioning of hydro-ecosystem. The spatiotemporal patterns of δ18O in the water from lower soil profile and the ratio of water absorbed by cherry roots from the soil at different depths and irrigation water, under four different treatment (CK, T1, T2, T3, i.e. 100 % of designed irrigation quota + no water-saving measures, 85 % of designed irrigation quota + no measures of water preservation, plastic film mulching and mulching by branches cut-off from the trees) were analyzed in the cherry orchard by measuring the stable oxygen isotopes (δ18O) in the soil moisture, sap in the xylem stem and in the irrigation water (local groundwater) under drip irrigation conditions during 2015−2016. The obtained outcomes show that the amount of δ18O in soil water is closely related to the changes in the irrigation, water-saving measures and soil moisture content during the growth stage of cherry trees. Irrigation significantly promotes the water absorption by cherry roots from soil water in the shallow layers. In the early growth stage of cherry trees, as the cherry grows, water absorption by cherry roots mainly comes from irrigation water. In the mid growth stage of cherry trees, if water-saving measures or adequate irrigation is employed, the contribution of soil water and irrigation water increases. In their mid-growth process, cherry trees mainly absorb water from the soil at a depth of 30−60 cm and irrigation water. Water-saving irrigation is beneficial to the utilization of irrigation water. After the harvest time, the cherries entered the late growth stage in August and September, where the cherries grow slowly and the amount of water required is low. At the same time, an increase in the temperature results in higher soil temperatures. Therefore, based on comprehensive consideration of the patterns of cherry water uptake and the characteristics of soil temperature during the cherry growth period. The best water regulation and management was 100 % of design irrigation quota and plastic film mulching at the fruit growth stage; 85 % of design irrigation quota and plastic film mulching at the postharvest stage; 85 % of design irrigation quota and no mulching should be applied at the end of growth stage.