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The overexpression of P-glycoprotein (P-gp/ABCB1) is a leading cause of multidrug resistance (MDR). Hence, it is crucial to discover effective pharmaceuticals that counteract ABCB1-mediated multidrug resistance. FRAX486 is a p21-activated kinase (PAK) inhibitor. The objective of this study was to investigate whether FRAX486 can reverse ABCB1-mediated multidrug resistance, while also exploring its mechanism of action. The CCK8 assay demonstrated that FRAX486 significantly reversed ABCB1-mediated multidrug resistance. Furthermore, western blotting and immunofluorescence experiments revealed that FRAX486 had no impact on expression level and intracellular localization of ABCB1. Notably, FRAX486 was found to enhance intracellular drug accumulation and reduce efflux, resulting in the reversal of multidrug resistance. Docking analysis also indicated a strong affinity between FRAX486 and ABCB1. This study highlights the ability of FRAX486 to reverse ABCB1-mediated multidrug resistance and provides valuable insights for its clinical application.

Radiotherapy (RT) can potentially induce systemic immune responses by initiating immunogenic cell death (ICD) of tumor cells. However, RT-induced antitumor immunologic responses are sporadic and insufficient against cancer metastases. Herein, we construct multifunctional self-sufficient nanoparticles (MARS) with dual-enzyme activity (GOx and peroxidase-like) to trigger radical storms and activate the cascade-amplified systemic immune responses to suppress both local tumors and metastatic relapse. In addition to limiting the Warburg effect to actualize starvation therapy, MARS catalyzes glucose to produce hydrogen peroxide (H2O2), which is then used in the Cu+-mediated Fenton-like reaction and RT sensitization. RT and chemodynamic therapy produce reactive oxygen species in the form of radical storms, which have a robust ICD impact on mobilizing the immune system. Thus, when MARS is combined with RT, potent systemic antitumor immunity can be generated by activating antigen-presenting cells, promoting dendritic cells maturation, increasing the infiltration of cytotoxic T lymphocytes, and reprogramming the immunosuppressive tumor microenvironment. Furthermore, the synergistic therapy of RT and MARS effectively suppresses local tumor growth, increases mouse longevity, and results in a 90% reduction in lung metastasis and postoperative recurrence. Overall, we provide a viable approach to treating cancer by inducing radical storms and activating cascade-amplified systemic immunity.

Toxic metal contamination in soils poses significant hazards to the environment and human health; thus, quantitative assessment of the sources and risks of metal contaminants are urgently needed. A hybrid model that integrates the positive matrix factorization (PMF) and random forest (RF) methods was proposed to quantify the sources of toxic metals in soils by combining diverse environmental variables (source proxies) in this study. In addition, a health risk assessment and Monte Carlo simulations were integrated to estimate the source-oriented stochastic health risk. The results suggested that, except for Ni, which exhibited moderate contamination, other toxic metals (As, Cd, Cr, Hg and Pb) presented slight contamination. Four sources (agricultural activities loaded heavily by As, atmospheric deposition loaded heavily by Hg and Pb, natural sources and mining activities loaded heavily by Cr and Ni, and industrial activities loaded heavily by Cd) were defined and explained 23.44 %, 26.65 %, 30.13 % and 19.78 % of the total variance in toxic metals, respectively. The principal route of exposure (i.e., ingestion), the population at highest risk (i.e., children), and the most hazard-inducing metals (i.e., As and Cr) were determined. Agricultural activities and the combination of natural sources and mining activities demonstrated certain degrees of noncarcinogenic risk to children, with exceedance ratios of 2.20 % and 2.56 %, respectively. Additionally, the combination of natural sources and mining activities demonstrated probabilities for significant carcinogenic risk to adults and children of 0.59 % and 3.76 %, respectively. To reduce the health risks of toxic metals in soils and to protect food and ecological safety, strict regulations should be established to control the discharge of waste from mining and agricultural activities.

Abstract Tumor‐associated chronic inflammation severely restricts the efficacy of immunotherapy in cold tumors. Here, a programmable release hydrogel‐based engineering scaffold with multi‐stimulation and reactive oxygen species (ROS)‐response (PHOENIX) is demonstrated to break the chronic inflammatory balance in cold tumors to induce potent immunity. PHOENIX can undergo programmable release of resiquimod and anti‐OX40 under ROS. Resiquimod is first released, leading to antigen‐presenting cell maturation and the transformation of myeloid‐derived suppressor cells and M2 macrophages into an antitumor immune phenotype. Subsequently, anti‐OX40 is transported into the tumor microenvironment, leading to effector T‐cell activation and inhibition of Treg function. PHOENIX consequently breaks the chronic inflammation in the tumor microenvironment and leads to a potent immune response. In mice bearing subcutaneous triple‐negative breast cancer and metastasis models, PHOENIX effectively inhibited 80% and 60% of tumor growth, respectively. Moreover, PHOENIX protected 100% of the mice against TNBC tumor rechallenge by electing a robust long‐term antigen‐specific immune response. An excellent inhibition and prolonged survival in PHOENIX‐treated mice with colorectal cancer and melanoma is also observed. This work presents a potent therapeutic scaffold to improve immunotherapy efficiency, representing a generalizable and facile regimen for cold tumors.

Abstract Background Photothermal therapy (PTT) is taken as a promising strategy for cancer therapy, however, its applicability is hampered by cellular thermoresistance of heat shock response and insufficient accumulation of photothermal transduction agents in the tumor region. In consideration of those limitations, a multifunctional “Golden Cicada” nanoplatform (MGCN) with efficient gene delivery ability and excellent photothermal effects is constructed, overcoming the thermoresistance of tumor cells and improving the accumulation of indocyanine green (ICG). Results Down-regulation of heat shock protein 70 (HSP70) makes tumor cells more susceptible to PTT, and a better therapeutic effect is achieved through such cascade augmented synergistic effects. MGCN has attractive features with prolonged circulation in blood, dual-targeting capability of CD44 and sialic acid (SA) receptors, and agile responsiveness of enzyme achieving size and charge double-variable transformation. It proves that, on the one hand, MGCN performs excellent capability for HSP70-shRNA delivery, resulting in breaking the cellular thermoresistance mechanism, on the other hand, ICG enriches in tumor site specifically and possesses a great thermal property to promoted PTT. Conclusions In short, MGCN breaks the protective mechanism of cellular heat stress response by downregulating the expression of HSP70 proteins and significantly augments synergistic effects of photothermal/gene therapy via cascade augmented synergistic effects.

Abstract Coevolution of tumor cells and surrounding stroma results in protective protumoral environment, in which abundant vessel, stiff structure and immunosuppression promote each other, cooperatively incurring deterioration and treatment compromise. Reversing suchenvironment may transform tumors from treatment‐resistant to treatment‐vulnerable. However, effective reversion requires synergistic comprehensive regression of such environment under precise control. Here, the first attempt to collaboratively retrograde coevolutionary tumor environment to pre‐oncogenesis status, defined as tumor environment regression therapy, is made for vigorous immune response eruption by a switchable prune‐to‐essence nanoplatform (Pres) with simplified composition and fabrication process. Through magnetic targeting and multimodal imaging of Pres, tumor environment regression therapy is guided, optimized and accomplished in a trinity way: Antiangiogenesis is executed to rarefy vessels to impede tumor progression. By seizing the time, cancer associated fibroblasts are eliminated to diminish collagen and loosen the stiff structure for deep penetration of Pres, which alternately functioned in deeper tumors, forming a positive feedback loop. Through this loop, immune cell infiltration, immunosuppression mitigation and immunogenic cells death induction are all fulfilled and further escalated in the regressed environment. These transformations consequently unleashed systemic immune responses and generated immune memory against carcinoma. This study provides new insights intotreatment of solid tumors.

Neoadjuvant chemotherapy has become an indispensable weapon against high-risk resectable cancers, which benefits from tumor downstaging. However, the utility of chemotherapeutics alone as a neoadjuvant agent is incapable of generating durable therapeutic benefits to prevent postsurgical tumor metastasis and recurrence. Herein, a tactical nanomissile (TALE), equipped with a guidance system (PD-L1 monoclonal antibody), ammunition (mitoxantrone, Mit), and projectile bodies (tertiary amines modified azobenzene derivatives), is designed as a neoadjuvant chemo-immunotherapy setting, which aims at targeting tumor cells, and fast-releasing Mit owing to the intracellular azoreductase, thereby inducing immunogenic tumor cells death, and forming an in situ tumor vaccine containing damage-associated molecular patterns and multiple tumor antigen epitopes to mobilize the immune system. The formed in situ tumor vaccine can recruit and activate antigen-presenting cells, and ultimately increase the infiltration of CD8+ T cells while reversing the immunosuppression microenvironment. Moreover, this approach provokes a robust systemic immune response and immunological memory, as evidenced by preventing 83.3% of mice from postsurgical metastasis or recurrence in the B16–F10 tumor mouse model. Collectively, our results highlight the potential of TALE as a neoadjuvant chemo-immunotherapy paradigm that can not only debulk tumors but generate a long-term immunosurveillance to maximize the durable benefits of neoadjuvant chemotherapy.

Global climate change is a serious threat to food and energy security. Crop growth modelling is an important tool for simulating crop food production and assisting in decision making. Planting date is one of the important model parameters. Larger-scale spatial distribution with high accuracy for planting dates is essential for the widespread application of crop growth models. In this study, a planting date prediction method based on environmental similarity was developed in accordance with the third law of geography. Spring maize planting date observations from 124 agricultural meteorological experiment stations in China over the years 1992–2010 were used as the data source. Samples spanning from 1992 to 2009 were allocated as training data, while samples from 2010 constituted the independent validation set. The results indicated that the root mean square error (RMSE) for spring maize planting date based on environmental similarity was 10 days, which is better than that of multiple regression analysis (RMSE = 13 days) in 2010. Additionally, when applied at varying scales, the accuracy of national-scale prediction was better than that of regional-scale prediction in areas with large differences in planting dates. Consequently, the method based on environmental similarity can effectively and accurately estimate planting date parameters at multiple scales and provide reasonable parameter support for large-scale crop growth modelling.

The absorption and scattering properties of water can cause various distortions in underwater images, which limit the ability to investigate underwater resources. In this paper, we propose a two-stage network called WaterFormer to address this issue using deep learning and an underwater physical imaging model. The first stage of WaterFormer uses the Soft Reconstruction Network (SRN) to reconstruct underwater images based on the Jaffe–McGramery model, while the second stage uses the Hard Enhancement Network (HEN) to estimate the global residual between the original image and the reconstructed result to further enhance the images. To capture long dependencies between pixels, we designed the encoder and decoder of WaterFormer using the Transformer structure. Additionally, we propose the Locally Intended Multiple Layer Perceptron (LIMP) to help the network process local information more effectively, considering the significance of adjacent pixels in enhancing distorted underwater images. We also proposed the Channel-Wise Self-Attention module (CSA) to help the network learn more details of the distorted underwater images by considering the correlated and different distortions in RGB channels. To overcome the drawbacks of physical underwater image enhancement (UIE) methods, where extra errors are introduced when estimating multiple physical parameters separately, we proposed the Joint Parameter Estimation method (JPE). In this method, we integrated multiple parameters in the Jaffe–McGramery model into one joint parameter (JP) through a special mathematical transform, which allowed for physical reconstruction based on the joint parameter (JP). Our experimental results show that WaterFormer can effectively restore the color and texture details of underwater images in various underwater scenes with stable performance.

Cultivated land quality is directly related to national food security; hence, it is necessary to determine the spatial–temporal characteristics and factors that influence its variation. This study analyzed the soil properties and cultivated land quality in the Hang-Jia-Hu Plain, the most important grain production base in Zhejiang Province, located in the lower reaches of the Yangtze River, from 2017 to 2020. In addition, the factors that influenced cultivated land quality variation were explored. The results showed that soil pH and soil organic matter (SOM) significantly improved from 6.32 and 29.07 g/kg in 2017 to 6.38 and 31.54 g/kg in 2020, whereas the variations in available phosphorus (AP) and available potassium (AK) were not significant. More than 60% of the cultivated land still had the potential for soil nutrient status improvement. The cultivated land quality indicator (CLQI) calculated based on the national standard (GB/T 33469-2016) significantly increased from 0.90 in 2017 to 0.91 in 2020. According to the CLQI classification, approximately three quarters of the cultivated land was defined as high-yielding fields. Although the spatial pattern for CLQI was similar between 2017 and 2020, more than 75% of the cultivated land quality showed an increasing trend that was mainly located in the northeastern and central areas. The results of influential factor detection indicated that the improvement in SOM and available soil nutrients including AP and AK was the main reason for the CLQI increase, whereas the climate, topography, and socioeconomic factors had little influence on the change in CLQI. In addition, when influential factors interacted, a significant increase in the explanatory ability for CLQI was obtained, especially for the interaction of SOM and AP variation, which explained 41% of the CLQI variation. This study provides basic foundations and references for cultivated land quality monitoring and improvement in the lower reaches of the Yangtze River, China.

Abstract Immune checkpoint blockade (ICB) is an attractive option in cancer therapy, but its efficacy is still less than expected due to the transient and incomplete blocking and the low responsiveness. Herein, an unprecedented programmable unlocking nano‐matryoshka‐CRISPR system (PUN) targeting programmed cell death ligand 1 (PD‐L1) and protein tyrosine phosphatase N2 (PTPN2) is fabricated for permanent and complete and highly responsive immunotherapy. While PUN is inert at normal physiological conditions, enzyme‐abundant tumor microenvironment and preternatural intracellular oxidative stress sequentially trigger programmable unlocking of PUN to realize a nano‐matryoshka‐like release of CRISPR/Cas9. The successful nucleus localization of CRISPR/Cas9 ensures the highly efficient disruption of PD‐L1 and PTPN2 to unleash cascade amplified adaptive immune response via revoking the immune checkpoint effect. PD‐L1 downregulation in tumor cells not only disrupts PD‐1/PD‐L1 interaction to attenuate the immunosurveillance evasion but also spurs potent immune T cell responses to enhance adaptive immunity. Synchronously, inhibition of JAK/STAT pathway is relieved by deleting PTPN2, which promotes tumor susceptibility to CD8+ T cells depending on IFN‐γ, thus further amplifying adaptive immune responses. Combining these advances together, PUN exhibits optimal antitumor efficiency and long‐term immune memory with negligible toxicity, which provides a promising alternative to current ICB therapy.

Process-based land surface models are important tools to study the historical and future effects of climate change and land use change. The planting date has a considerable effect on crop growth and consequently on dynamic parameters used in land surface models, for example albedo and actual evapotranspiration. If planting dates can be related to climate, scenarios can use this relation to estimate planting dates. Such a relation is expected to differ according to agro-ecological zone. In this study, spring and summer maize planting date observations at 188 agricultural meteorological experiment stations of China, as well as monthly weather records, over the years 1992−2010 were used as the data source. In order to quantify the relation between planting dates and climate parameters, growing season monthly average minimum temperature (Tmin), mean temperature (T), and precipitation (P) were used. The time trend analysis of planting dates and weather data, principal component analysis (PCA) of weather data, and multivariate regression of planting dates as affected by weather data were used. Both Tmin and T increased during this period in most zones, whereas precipitation showed no trend. In southwest and northwest China, maize planting dates advanced significantly for both spring and summer maize. However, in the north China plain (summer maize) and northeast China (spring maize), the planting date was significantly delayed. Ordinary least squares multivariate regression models were able to explain 33% and 59% of the variance of planting dates in the southwest China (i.e., the humid subtropics zone) for spring and summer maize, respectively. However, only 3% could be explained in the Loess Plateau. Thus, adjusting planting dates in scenario analysis using land surface models is indicated for some zones, but not others, where socioeconomic factors are dominant.