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The full potential of tumor-infiltrating lymphocyte (TIL) therapy has been hampered by the inadequate activation and low persistence of TILs, as well as inefficient neoantigen presentation by tumors. We transformed tumor cells into artificial antigen-presenting cells (aAPCs) by infecting them with a herpes simplex virus 1 (HSV-1)-based oncolytic virus encoding OX40L and IL12 (OV-OX40L/IL12) to provide local signals for optimum T cell activation. The infected tumor cells displayed increased expression of antigen-presenting cell-related markers and induced enhanced T cell activation and killing in coculture with TILs. Combining OV-OX40L/IL12 and TIL therapy induced complete tumor regression in patient-derived xenograft and syngeneic mouse tumor models and elicited an antitumor immunological memory. In addition, the combination therapy produced aAPC properties in tumor cells, activated T cells, and reprogrammed macrophages to a more M1-like phenotype in the tumor microenvironment. This combination strategy unleashes the full potential of TIL therapy and warrants further evaluation in clinical studies.

Vogt-Koyanagi-Harada (VKH) disease, a major blinding eye disease, is characterized by an autoimmune response against melanocytes in multiple organs throughout the body. Currently, the aetiology and pathogenesis of VKH disease are unclear, and the treatment strategy needs to be further optimized. The retinal pigment epithelium (RPE), a monolayer of pigmented cells of the fundus, is essential for maintaining normal visual function and is involved in both the acute and chronic stages of VKH disease. Therefore, the functions of the RPE may play a critical role in the aetiology and treatment of VKH disease. Herein, we established a human induced pluripotent stem cell (hiPSC) RPE model of VKH disease by reprogramming peripheral blood mononuclear cells (PBMCs) into iPSCs and then differentiating them into RPE cells. Patient-derived RPE cells exhibited barrier disruption, impaired phagocytosis, and depigmentation compared with those from normal controls, which was consistent with the features of VKH disease. Furthermore, a small molecular compound targeting EGR2 was found to rescue the barrier and phagocytic functions of the hiPSC-RPE cells through high-throughput virtual screening and functional studies, suggesting a promising strategy for the treatment of VKH disease.

Spatial targeting plays a key role in improving the efficiency of payment for ecosystem services (PES). However, the risk of grassland degradation after implementing PES increases uncertainty about the efficiency of PES. Here, we identified the spatial heterogeneity of grassland degradation risk using Future Land Use Simulation (FLUS) model, then incorporated grassland degradation risk as a criterion into PES spatial targeting using cost-benefit analysis and ranking optimization. The framework was applied to a case study of the Three-River-Source National Park, China. We found that grasslands in the study area continued to degrade between 2015 and 2025, and the area of degraded grasslands increased by 26%. Compared with spatial targeting of PES without considering grassland degradation risk, PES spatial targeting that considered grassland degradation risk was significantly different (the overlap area accounted for only 75%, 82%, and 94% of the PES area within 25%, 50%, and 75% of the total protection cost budget). When the grassland degradation risk was considered as a targeting criterion, PES efficiency increased by 154%, 116%, 124%, and 99%, respectively, within 25%, 50%, 75%, and 100% of the total protection cost budget. Our results demonstrate that considering grassland degradation risk in the spatial targeting of PES increases efficiency because it helps to target areas with greater environmental benefits.

Ginsenoside Rg1 is the active ingredient of Chinese herbal medicine ginseng and sanqi, which has remarkable effects on anti-inflammation and anti-diabetes. In this study, we explored the molecular mechanism of ginsenoside Rg1 against diabetes in rat subjected to insulin resistance induced by high-fat and high-sugar (HFHS). Biochemical analysis revealed that ginsenoside Rg1 significantly decreased the serum levels of alanine transaminase, aspartate transaminase, alkaline phosphatase, total cholesterol, triglyceride, low-density lipoprotein and increased the serum levels of high-density lipoprotein, which indicated ginsenoside Rg1 improved the extent of hepatic steatosis. Furthermore, ginsenoside Rg1 suppressed the expression of IL-1β, IL-6,TNF-α,NF-κB and G6Pase, however, p-Akt was up-regulated. These results suggested that ginsenosideRg1 improved insulin resistance through suppressing inflammatory response and glucose output, which may be a potential therapeutic strategy in protecting hepatic steatosis.

Maintaining high crop yield and meanwhile reducing the risk of environmental pollution are of paramount importance for food security and sustainability. The aims of this study were (i) quantify soil NO3− -N buffer capacity under wheat-maize cropping system in Northern China, and (ii) establish agronomic optimum and environmentally safe N rates to guide N recommendation for the region. We compiled data of 76 sets of wheat and 73 sets of maize experiments spanning about 20 years, where N rate experiments conducted and soil NO3− -N content were measured immediately after crop harvest under conventional practice. By applying linear-plateau and plateau-linear models, we computed the soil NO3− -N buffer capacity, agronomic optimum N rate and environmentally safe N rates. Soil NO3− -N buffer capacity ranged from 10 to 221 kg ha−1 for wheat season and from 14 to 212 kg ha−1 for maize season, which were mostly less than 100 kg ha−1 in the region. The agronomic optimum N rates for wheat and maize were 46–221 and 44–250 kg N ha−1 with means of 110 and 127 kg N ha−1, respectively. The environmentally safe N rates were 19–248 kg N ha−1 with mean of 107 kg N ha−1 for wheat, and 36–209 kg N ha−1 with mean of 99 kg N ha−1 for maize. It was found that agronomic optimum N rates from 61% of wheat and 52% of maize were higher than the environmentally safe N rates, implying that current N recommendation had the high potential risk of nitrate leaching. Hence, it is suggested that N recommendation should consider not only the agronomic optimum N but also environmentally safe N rate, especially in areas where are vulnerable to nitrate leaching the latter should be placed at the top priority.

Glyphosate is the active ingredient of the commercial formulation Roundup®, which is used worldwide. This study aimed to investigate the toxic effects of pure glyphosate or Roundup® on pregnant mice and their fetuses during pregnancy. From gestation days (GDs) 1-19, ICR mice were orally administered distilled water, 0.5% glyphosate solution or 0.5%-glyphosate Roundup® solution. The ovaries and serum were collected at GD19. The results showed decreases in body weight gain and, ovary and liver weight in glyphosate-treated mice. Additionally, histopathological alterations in the ovary including increased atretic follicles, interstitial fibrosis and decreased mature follicles were observed in the groups treated with glyphosate. The serum concentrations of both progesterone and estrogen were markedly altered after glyphosate exposure, and there were also changes in the expression of GnRH, LHR, FSHR, 3β-HSD and Cyp19a1 genes at the hypothalamic-pituitary-ovarian axis. Furthermore, oxidative stress was observed in the treated mice, increasing the activity of T-AOC, CAT and GSH-Px, as well as the MDA content in both the serum and ovary. With regard to litters, the sex ratio was significantly altered by pure glyphosate. These results show that glyphosate is able to cause several effects on pregnant mice, such as ovarian failure, interference with hormone secretion by affecting the steroidogenesis-related gene expression, and oxidative stress. The sex ratio of litters was also influenced by prenatal exposure to pure glyphosate.

As a drug carrier, the properties of magnetic nanoparticles for drug loading are significant. In this letter, three different shapes of magnetic nanoparticles for drug carrier systems were compared. We synthesized Fe3O4 magnetic nanospheres, nanorings and nanotubes, and plyethylene glycol was used as a surface modifier for drug loading. The structure characterization of three different shapes of Fe3O4 nanoparticles was elucidated by electron microscopy, and the composition was analyzed by Fourier transform infrared. The drug loading status and drug release of the three types of nanoparticles with different shapes were tested by Ultraviolet Spectrophometometer. The results show that the hollow Fe3O4 magnetic nanorings and nanotubes have better drug loading capacity and are more suitable for drug carriers, compared with nanospheres.

A framework that integrates Bayesian optimization (BO) and high-performance computing was developed, to automate calibration of complex hydrological models. It adopts a loosely coupled web architecture, integrating Tornado and SpringBoot, to facilitate bidirectional transfer of variables between BO and model evaluation. Extensive model evaluations were implemented on a Hadoop cluster, to wrap the model into the calculation flexibly and separate the calculation process from the algorithm execution effectively. A case study, calibrating a SWAT model in the Meichuan Basin (Jiangxi Province, China), indicated that the framework provides an ideal environment for assessment of the capability of BO to quantify the efficient estimation of SWAT parameters. Compared with that of the built-in SWAT-CUP tool, the number of executions was reduced from 1500 to 150, while maintaining similar accuracy. The framework also allows evaluation of the performance of different surrogate models and acquisition functions and provides instant visualization for searching for optimal parameters.

Understanding the temporal changes of soil organic C (SOC) pools and microbial residues is essential for clarifying SOC dynamics in agroecosystems; however, this information remains largely unclear in greenhouse vegetable production (GVP) systems. Here, based on information of SOC pools (i.e., oxidizable organic C pools) and microbial residue C (MRC, as indicated by amino sugars differentiation), a 10-year (2009–2019) field experiment with fertilization was conducted to evaluate how fertilization alters SOC dynamics in a GVP field in Tianjin, China. The experiment includes four treatments (equal N, P2O5, and K2O inputs): 100% chemical N (N100), 50% substitution of chemical N with manure-N (N50M50), straw-N (N50S50), and manure-N plus straw-N (N50M25S25). Results showed that the values of SOC, lability index, and C management index increased and decreased linearly with time in N50M50- and N100-amended soils, respectively, which were mainly induced by the changes in labile C fractions. Based on logistic regression models, we found that these indices in straw-amended soils (N50M25S25 and N50S50) were rapidly increased between 2009 and 2013, and then approach steady levels between 2015 and 2019. These findings suggested that we should guarantee enough C inputs to maintain the level and quality of SOC, otherwise it will cause C loss in the unique GVP soils. Besides, straw-amended treatments increased MRC contents and enlarged their contributions to SOC sequestration, whereas these indices in N100 treatment decreased linearly with the time of fertilization. In conclusion, long-term chemical application alone was not beneficial for SOC accumulation, whereas organic amendments brought several benefits for SOC sequestration in GVP soils. Our results implied that C sequestration in GVP soils is to a large extent determined by the amounts and time of fertilization.

This work introduces an optimization approach for the design and operation of integrated energy systems of residential structures and light industrial plants to minimize greenhouse gas (GHG) emissions going beyond the best possible results from standalone systems. Unlike previous studies, in this work, heat transfer considers temperatures of heat sources and receptors; production rates of plants are optimized to maximize GHG emissions reduction of the integrated operation. Results from case studies indicate if temperature levels are not considered, more than 33% of deemed heat transfer is infeasible. Operating the integrated plants at a steady daily production rate brings a significant reduction in GHG emissions for systems accessing the northeast U.S. grid. Further reduction of GHG emissions is accomplished by scheduling the production rate. Schedules with at most one daily production rate change have only 0.4% higher GHG emissions than the optimum, which has frequent production rate changes. When the standalone system and integrated system have the same annual total cost, the integrated system reduces GHG emissions by at least 18.8% and reduces electricity purchases by 66%. Therefore, the integrated operation can reduce GHG emissions of the system, where the maximum reduction is achieved by optimizing the design and operation of energy system equipment, considering the temperature of heating demands, and optimizing production rates of plants with constraints applied to changes of the rates.

Carbon isotope composition (indicated by leaf δ13C) reflects plants' strategies to balance carbon acquisition and water loss, which is directly linked to water use efficiency. At a large scale, leaf δ13C has been demonstrated to be closely related to climate and plant functional types; however, at a regional scale, its variation across an aridity gradient and species categories and its covariation with traits in leaf economic spectrum (LES) traits are still unclear. Here, a multivariate statistical analysis was carried out with 271 observations of leaf δ13C from 22 sampling sites on the Loess Plateau. Our results showed that (1) mean leaf δ13C did not differ significantly among life forms in C3 plants, with the maximum mean values occurring in geophytes (-26.31) and the minimum values occurring in lianas (-28.29); (2) the leaf δ13C responses of different life forms, families and species categories to climates were consistent for C3 plants, namely, they presented similar response rates to changes along the aridity gradient (represented by the moisture index); (3) climate, soil, species category, and leaf economic spectrum traits jointly explained 78.4% of the variation in leaf δ13C for C3 plants. Species category was the largest determinant of leaf δ13C variations for both C3 and C4 plants. Revealing the variation in leaf δ13C of the Loess Plateau plants not only helps us to understand plant adaptation strategies under arid conditions but also provides scientific support for ecological management in vegetation restoration regions.

Monitoring real-time heat dissipation of lighting, a major indoor heat source, is essential for determining the dynamic cooling demand of buildings, and it provides a reliable basis for sizing air-conditioning systems and saving energy. Contemporary models cannot be used to obtain the accurate real-time heat dissipation of lighting or the time-delay effect, because of which these models have critical limitations in precisely detecting dynamic cooling demand of buildings. To address this problem, a transfer function model is proposed for calculating the real-time heat dissipation of lighting in this paper. First, the model structure is determined according to the energy conservation law, heat transfer principles, and so on. Second, an experiment is conducted using a nearly adiabatic test chamber. Third, parameter identification and order reduction analyses are performed, and the real-time heat dissipation model of lighting is determined as a third-order transfer function. Experimental data of the same and different types of lighting are employed to verify the proposed model, and the maximum mean absolute percentage error (MAPE) is 7.83%. Comparing with the fixed ratio method, the proposed transfer function model not only reduces MAPE by 66.05% within 1 h after lighting is turned on but also describes a time-delay effect in the stability of lighting heat dissipation. The results of this study exhibit the promising applicability for accurately determining the cooling demand of a building during real-time operation, thus improving the indoor thermal environment and reducing energy consumption.

Hydrologic regulation is an important ecosystem service, and is easily influenced by human disturbance. Many studies have been conducted on the impacts that human activities have on flow regime and regulating capacity by a single environmental factor. However, these studies have not clarified the comprehensive effects at sub-watershed scale; these effects are important for sub-watershed management. This research was conducted to reveal the spatial heterogeneity of hydrologic regulating service and identify the impact factors in China’s Yangtze River Basin. This basin is the largest in China and frequently floods. We built a new index based on the coefficients of variation for precipitation and runoff. The proposed indicator reflected the relative strength of regulating service effectively, and distinguished the basin into two different groups (A and B) of sub-watersheds. The hydrologic regulating index was significantly and positively correlated to slope and coverage of bush and forest, and negatively correlated to hydraulic projects, farmland, and urban area. Land-use changes have the greatest contribution (more than 60%) to differences in sub-watershed hydrologic regulating service. Compared with the sub-watersheds of group A, the sub-watersheds of group B suffered more severe human activity, for which the relative contributions to hydrologic regulating service were 32.18% (hydraulic projects), 18.21% (farmland) and 6.21% (urban area). These results indicated that the ecological effects of human activities should be a concern, and that restoration of the natural environment should play an important role for hydrologic regulating capacity enhancement. Group A sub-watersheds should explore the existing massive potential of (cascade) reservoirs for improving hydrologic regulating ability. Our results not only present a useful tool for watershed hydrologic regulating assessment, but lay a foundation for exploring differentiated management strategies of flood mitigation at sub-watershed scale.

We conducted a numerical analysis on high-K dielectric passivated AlGaN/GaN Schottky barrier diodes (HPG-SBDs) with a gated edge termination (GET). The reverse blocking characteristics were significantly enhanced without the stimulation of any parasitic effect by varying the dielectric thickness dge under the GET, thickness TP, and dielectric constant er of the high-K passivation layer. The leakage current was reduced by increasing er and decreasing dge. The breakdown voltage of the device was enhanced by increasing er and TP. The highest breakdown voltage of 970 V and the lowest leakage current of 0.5 nA/mm were achieved under the conditions of er = 80, TP = 800 nm, and dge = 10 nm. C-V simulation revealed that the HPG-SBDs induced no parasitic capacitance by comparing the integrated charges of the devices with different high-K dielectrics and different dge.

Excessive phosphorus (P) fertilizer and manure application is widespread in greenhouse vegetable production, causing P accumulation and groundwater pollution. The partial substitution of chemical fertilizer with organic amendments may effectively address this problem; however, little is known about P speciation and transformation at the molecular scale. Here, we combined P K-edge X-ray absorption near-edge structure, 31P nuclear magnetic resonance spectroscopy, and chemical extraction to characterize P speciation and assess P leaching in a 10-year field experiment including chemical fertilizer (4CN) and replacement of half the chemical N fertilizer with manure (2CN+2 MN), straw (2CN+2SN), or combined manure and straw (2CN+1 MN+1SN) treatments. Compared to the 4CN treatment, organic substitution treatments resulted in 10.0–16.3% lower P accumulation and 57.3–102% higher organic P. Newberyite was detected in the organic substitution treatments, making up 6.9–13.0% of the total P, and the hydroxyapatite proportion was 7.3–15.6% lower than that in the 4CN treatment. Moreover, 2CN+2 MN treatment increased the orthophosphate diester content and labile P (Resin-P and NaHCO3–P) proportion, and 2CN+2SN treatment increased the orthophosphate monoester content and moderately labile P (NaOH–P) proportion. The 2CN+1 MN+1SN treatment exhibited the advantages of both manure and straw application. Partial least squares path modeling revealed that labile P was affected mainly by manure application and pH, and moderately labile P was influenced mainly by straw application and alkaline phosphomonoesterase activity. Compared with the 4CN treatment, the organic substitution treatments significantly decreased the total P leaching losses by 21.3–48.8%. Our results provide new insights into soil P transformation in response to different organic amendments. Combined manure, straw, and chemical fertilizer application (2CN+1 MN+1SN treatment) was a more effective practice for developing sustainable P management practices by comprehensively considering soil P transformation, vegetable yields, and environmental losses.

Increasing urbanization combined with climate change has resulted in the increased risk of flooding in cities. Thus, assessing the effect of future climate change on urban flooding and adopting effective flood management measures is becoming increasingly important. In this study, an urban rainstorm model and a scenario simulation method were applied to central Shanghai, China. We first examined the risks of flooding in the study area under the impact of future climate change using a simulation with different rainfall return periods. We then evaluated the benefits of traditional drainage system adaptation measures and Low Impact Development (LID) practices on alleviating the current urban flood hazard. Finally, we explored the effectiveness of using an integrated flood management scheme to adapt to climate change. The results show that the urban flood volume increases non-linearly with increasing rainfall intensity under climate change. The maximum flooding area also increases accordingly, and is much more sensitive to smaller rainfall events. Both traditional drainage system adaptation measures and LID practices can effectively alleviate flooding, while an integrated flood management scheme that emphasizes the combination of the two methods is shown to be the most effective in reducing flooding under future climate change.

Integration of distributed energy systems in residential buildings, commercial buildings, and light industries can decrease greenhouse gas (GHG) emissions further than the lowest emissions achieved by the most efficient standalone system. Until now, an unexplored topic is the optimal relative sizes of the entities in the integrated system. This work introduces a novel optimization model which determines optimal sizes of the entities (buildings and plant capacities) in the integrated system, optimal sizes of the equipment comprising the energy systems, and optimal production schedules. Temperature levels of the heating demands are included in the model to ensure that the heat transfers are feasible. A case study that includes a residential building, a supermarket, a confectionery plant, a bakery plant, a brewery, and electric vehicles is presented. It is shown that the maximum achievable GHG reduction is relatively constant as the sizes of the residential buildings increase, but it requires significant changes in the type and relative sizes of the industrial plants.

A properly colored cycle (path) in an edge-colored graph is a cycle (path) with consecutive edges assigned distinct colors. A monochromatic triangle is a cycle of length 3 with the edges assigned a same color. It is known that every edge-colored complete graph without monochromatic triangle always contains a properly colored Hamilton path. In this paper, we investigate the existence of properly colored cycles in edge-colored complete graphs when monochromatic triangles are forbidden. We obtain a vertex-pancyclic analogous result combined with a characterization of all the exceptions. As a consequence, we partially confirm a structural conjecture given by Bollobas and Erdős (1976) and an algorithmic conjecture given by Gutin and Kim (2009).

A high breakdown voltage GaN-on-Insulator based heterojunction field effect transistor with a partial back barrier (PB-GOI HFET) is proposed in this paper. The partial back barrier (PB) formed by AlGaN is located in the GaN channel layer, which can make the breakdown voltage improved significantly by modulating the distribution of electric field along the channel. PB-GOI HFET can not only maintain the original advantages of GOI structure, but also improve the breakdown voltage without degradation of frequency performance. Compared with a conventional GOI HFET, the proposed PB-GOI HFET with gate–drain distance of 5 μm possesses the breakdown voltage of 1200 V and the FOM of 3.12 GW/cm 2 , which increased by more than 353% and 976%. The novel PB-GOI HFET shows great prospects in power electronics applications.

In this paper, a novel high-K/low-K compound passivation AlGaN/GaN Schottky Barrier Diode (CPG-SBD) is proposed to improve the off-state characteristics of AlGaN/GaN schottky barrier diode with gated edge termination (GET-SBD) by adding low-K blocks in to the high-K passivation layer. The reverse leakage current of CPG-SBD can be reduced to 1.6 nA/mm by reducing the thickness of high-K dielectric under GET region to 5 nm, while the forward voltage and on-state resistance keep 1 V and 3.8 Ω mm, respectively. Breakdown voltage of CPG-SBDs can be improved by inducing discontinuity of the electric field at the high-K/low-K interface. The breakdown voltage of the optimized CPG-SBD with 4 blocks of low-K can reach 1084 V with anode to cathode distance of 5 μm yielding a high FOM of 5.9 GW/cm 2 . From the C-V simulation results, CPG-SBDs induce no parasitic capacitance by comparison of the GET-SBDs.

This paper optimizes the design and operation of integrated distributed energy systems of large buildings and light industrial plants. The integration reduces greenhouse gas (GHG) emissions and the annual total cost (ATC) beyond the best possible from individual energy systems and there is a sharp optimum with respect to the size of the confectionary plant, which maximizes the reduction of GHG emissions and minimizes ATC. In contrast to previous studies, the design accounts for plant heating demands at different temperature levels and sets plant production volumes as decision variables. Optimal design, operation, and production schedule have been determined via a mixed-integer nonlinear programming model. Integrated energy systems of two entities (confectionary plant and residential building) have been compared to the non-integrated entities equipped with combined cooling, heating, and power systems. The lowest ATC (−8%) of the integrated system and the maximum GHG reductions (−8.3%) occur at slightly different sizes of the plant. Such reductions require simultaneous optimization of integrated design and operation of energy systems and relative sizes of the confectionary plant and the residential building.

Over the past decades, a number of prolactin receptor (PRLR) antagonists have been developed, which can be divided into two categories, PRLR analogue and anti-PRLR antibody. However, until now, there have been no commercially available PRLR antagonists. Here, we described a new approach for the preparation of PRLR antagonist, namely internal image anti-idiotypic antibody strategy. The hybridoma technique was used to generate anti-idiotypic antibodies to PRL. Competitive ELISA, competitive receptor-binding analysis and immunofluorescence assay (IFA) were then used to screen and characterize anti-idiotypic antibodies to PRL. One internal image anti-idiotypic antibody, termed MG7, was obtained. A series of experiments demonstrated that MG7 behaved as a typical internal image anti-idiotypic antibody (Ab2β). MG7 exhibited effective antagonistic activity, which not only inhibited PRL binding to PRLR in a dose-dependent manner but also inhibited PRLR-mediated intracellular signalling. Furthermore, MG7 also blocked Nb2 cell proliferation induced by PRL. The current study suggests that MG7 has the potential application in the PRL/PRLR-related studies in future. In addition, this work also suggests that the internal image anti-idiotypic antibody may represent a novel strategy for the development of PRLR antagonist.

The combination of chemotherapy and photodynamic therapy has been proved to be a promising therapy for drug-resistant cancers. In this study, we report, for the first time, a novel two-fold interpenetration pillar-layered metal-organic frameworks (MOFs) material, using BODIPY-derivate bipyridine as linker and Photosensitizer (PS), named BBP-MOFs, was successfully synthesized to serve as a drug carrier and Photodynamic agent simultaneously. The BBP-MOFs could generate singlet oxygen (1O2) to perform PDT under 660 nm light irradiation, in the meantime, the anticancer drugs doxorubicin (DOX) could be loaded for chemotherapy. The results showed that BBP-MOFs exhibited a high drug loading content of 49.7% a controlled drug release and ideal biocompatibility. This DOX loaded BBP-MOFs was readily taken up by HeLa cells, and high levels of 1O2 were generated under light irradiation. This work provided strong evidence for BBP-MOFs as a promising new anticancer drug carrier and PDT candidate, the PDT and chemotherapy combined synergistic therapy revealed high therapeutic efficacy for cancer cells.