Nitrogen fertilization modulates rice phyllosphere functional genes and pathogens through fungal communities.

The phyllosphere is a vital yet often neglected habitat hosting diverse microorganisms with various functions. However, studies regarding how the composition and functions of the phyllosphere microbiome respond to agricultural practices, like nitrogen fertilization, are limited. This study investigated the effects of long-term nitrogen fertilization with different levels (CK, N90, N210, N330) on the functional genes and pathogens of the rice phyllosphere microbiome. Results showed that the relative abundance of many microbial functional genes in the rice phyllosphere was significantly affected by nitrogen fertilization, especially those involved in C fixation and denitrification genes. Different nitrogen fertilization levels have greater effects on fungal communities than bacteria communities in the rice phyllosphere, and network analysis and structural equation models further elucidate that fungal communities not only changed bacterial-fungal inter-kingdom interactions in the phyllosphere but also contributed to the variation of biogeochemical cycle potential. Besides, the moderate nitrogen fertilization level (N210) was associated with an enrichment of beneficial microbes in the phyllosphere, while also resulting in the lowest abundance of pathogenic fungi (1.14 %). In contrast, the highest abundance of pathogenic fungi (1.64 %) was observed in the highest nitrogen fertilization level (N330). This enrichment of pathogen due to high nitrogen level was also regulated by the fungal communities, as revealed through SEM analysis. Together, we demonstrated that the phyllosphere fungal communities were more sensitive to the nitrogen fertilization levels and played a crucial role in influencing phyllosphere functional profiles including element cycling potential and pathogen abundance. This study expands our knowledge regarding the role of phyllosphere fungal communities in modulating the element cycling and plant health in sustainable agriculture.

Spacer Conformation Induced Multiple Hydrogen Bonds in 2D Perovskite toward Highly Efficient Optoelectronic Devices.

Two-dimensional (2D) Dion-Jacobson (DJ) perovskites typically outperform Ruddlesden-Popper (RP) analogs in terms of photodetection (PD). However, the mechanism behind this enhanced performance remains elusive. Theoretical calculations for elucidating interlayer spacer conformation-induced multiple hydrogen bonds in 2D perovskite are presented, along with the synthesis of DPAPbBr4 (DPB) single crystals (SCs) and their PD properties under X-ray/ultraviolet (UV) excitation. The high-quality DPB SC enhances PD with exceptional photoresponse attributes, including a high on/off ratio (4.89 × 104), high responsivity (2.44 A W⁻1), along with large dynamic linear range (154 dB) and low detection limit (7.1 nW cm⁻2), which are currently the best results among 2D perovskite SC detectors, respectively. Importantly, high-resolution images are obtained under UV illumination with weak light levels. The SC X-ray detector exhibits a high sensitivity of 663 µC Gyair⁻1 cm-2 at 10 V and a detection limit of 1.44 µGyair s⁻1. This study explores 2D DJ perovskites for efficient and innovative optoelectronic applications.

Transcriptomic and metabolomic analysis provides insight into imazethapyr toxicity to non-target plants.

Imazethapyr is a widely used imidazolinone herbicide worldwide, and its potential adverse effects on non-target plants have raised concerns. Understanding the mechanisms of imazethapyr phytotoxicity is crucial for its agro-ecological risk assessment. Here, the comprehensive molecular responses and metabolic alterations of Arabidopsis in response to imazethapyr were investigated. Our results showed that root exposure to imazethapyr inhibited shoot growth, reduced chlorophyll contents, induced photoinhibition and decreased photosynthetic activity. By non-target metabolomic analysis, we identified 75 metabolites that were significantly changed after imazethapyr exposure, and they are mainly enriched in carbohydrate, lipid and amino acid metabolism. Transcriptomic analysis confirmed that imazethapyr significantly downregulated the genes involved in photosynthetic electron transport and the carbon cycle. In detail, 48 genes in the photosynthetic lightreaction and 11 genes in Calvin cycle were downregulated. Additionally, the downregulation of genes related to electron transport in mitochondria provides strong evidence for imazethapyr inhibiting photosynthetic carbon fixation and cellular energy metabolism as one of mechanisms of toxicity. These results revealed the molecular and metabolic basis of imazethapyr toxicity on non-target plants, contributing to environmental risk assessment and mitigate negative impact of imazethapyr residues in agricultural soils.

Design, Synthesis, and Antitumor Activity Evaluation of Novel VISTA Small Molecule Inhibitors.

VISTA (V-domain Ig suppressor of T cell activation) is a novel immune checkpoint protein and represents a promising target for cancer immunotherapy. Here, we report the design, synthesis, and evaluation of a series of methoxy-pyrimidine-based VISTA small molecule inhibitors with potent antitumor activity. By employing molecular docking and microscale thermophoresis (MST) assay, we identified a lead compound A1 that binds to VISTA protein with high affinity and optimized its structure. A4 was then obtained, which exhibited the strongest binding ability to VISTA protein, with a KD value of 0.49 ± 0.20 µM. In vitro, A4 significantly activated peripheral blood mononuclear cells (PBMCs) induced the release of cytokines such as IFN-γ and enhanced the cytotoxicity of PBMCs against tumor cells. In vivo, A4 displayed potent antitumor activity and synergized with PD-L1 antibody to enhance the therapeutic effect against cancer. These results suggest that compound A4 is an effective VISTA small molecule inhibitor, providing a basis for the future development of VISTA-targeted drugs.

Propofol Ameliorates Spinal Cord Injury Process by Mediating miR-672-3p/TNIP2 Axis.

Propofol has been found to have a protective effect against spinal cord injury (SCI). However, the underlying molecular mechanism of propofol regulating SCI process remains unclear. In this study, lipopolysaccharide (LPS)-induced PC12 cells were used to build SCI cell models. Cell viability and apoptosis were determined by cell counting kit 8 assay, flow cytometry, and caspase-3 activity detection. The protein levels of apoptosis-related markers and TNFAIP3 interacting protein 2 (TNIP2) were assessed using western blot analysis, and the levels of inflammatory factors were detected using ELISA. Cell oxidative stress was evaluated by measuring malondialdehyde (MDA) and reactive oxygen species (ROS) levels. The expression of microRNA (miR)-672-3p was examined by quantitative real-time PCR. SCI rat models were constructed to assess the effect of propofol in vivo. We found that propofol treatment promoted viability, while inhibited apoptosis, inflammation and oxidative stress of LPS-induced PC12 cells. Propofol decreased miR-672-3p expression, and miR-672-3p overexpression eliminated the inhibiting effect of propofol on LPS-induced PC12 cell injury. Besides, miR-672-3p targeted TNIP2, and TNIP2 knockdown reversed the protective effect of miR-672-3p inhibitor or propofol against LPS-induced PC12 cell injury. In vivo experiments, propofol treatment enhanced the motor function recovery and inhibited apoptosis of SCI rat models. In conclusion, propofol increased TNIP2 level by reducing miR-672-3p expression, thereby alleviating LPS-induced PC12 cell injury and improving the motor function of SCI rat models.

A cancer cell nanotherapy method based on GHz film bulk acoustic resonator and nanoscale CaO2.

Sonodynamic therapy (SDT) is an emerging cancer treatment method in recent years. However, the ultrasound signal utilized for SDT is usually located at a low-frequency spectrum (<2 MHz), and in the field of SDT research, few studies have focused on the exploration and development of ultrasound frequency. Studies have shown that the GHz-level ultrasound can increase cell membrane permeability and have a negligible effect on cell vitality. Herein, we reported the study of a GHz thin film bulk acoustic resonator as an ultrasound source for synergistic treatment with nanoscale calcium peroxide (CaO2). It was discovered that this ultrasound source ultimately achieved an efficient therapeutic outcome on mouse breast cancer cell line 4T1. Such GHz-level ultrasound application in SDT is of high significance to broaden the cognition and application scope of SDT.

Bispecific antibodies in cancer therapy: Target selection and regulatory requirements.

In recent years, the development of bispecific antibodies (bsAbs) has been rapid, with many new structures and target combinations being created. The boom in bsAbs has led to the successive issuance of industry guidance for their development in the US and China. However, there is a high degree of similarity in target selection, which could affect the development of diversity in bsAbs. This review presents a classification of various bsAbs for cancer therapy based on structure and target selection and examines the advantages of bsAbs over monoclonal antibodies (mAbs). Through database research, we have identified the preferences of available bsAbs combinations, suggesting rational target selection options and warning of potential wastage of medical resources. We have also compared the US and Chinese guidelines for bsAbs in order to provide a reference for their development.

Enantioselective uptake and translocation of atenolol in higher plants.

The presence of pharmaceuticals in surface water and wastewater has been an increasing area of research since they can represent a possible route for human exposure when these waters are used to irrigate crops. The concentration of these drugs in crops depends on their uptake and translocation within plants. A less recognized question is that over 50 % of pharmaceuticals are chiral compounds, but there is little knowledge about their enantioselectivity in plants. In this study, we evaluated the uptake, bioconcentration, and translocation of enantiomers of atenolol, a commonly used beta-blocker, in Arabidopsis thaliana cells and Lactuca sativa plants under hydroponic conditions. Atenolol was taken up by Arabidopsis thaliana cells during 120 h of exposure to solutions with 1 mg/L of R/S-(±)-atenolol. A moderate preference for R-(+)-atenolol over S-(-)-atenolol was observed, with the enantiomeric fraction (EF) reaching 0.532 ± 0.002 for the R enantiomer. Atenolol was also taken up and translocated by Lactuca sativa after hydroponic cultivation in nutrient solutions containing 1 or 10 µg/L R/S-(±)-atenolol. Moderate enantioselectivity was detected in the treatment with 10 µg/L, and the EF after 168 h was 0.42 ± 0.01, suggesting that S-(-)-atenolol was preferentially accumulated. Selectivity was also observed in the translocation factor (TF), calculated as the ratio of the concentration in the leaves over that in the roots. As many emerging contaminants are chiral, our findings highlight the importance to consider their fate and risks in terrestrial ecosystems at the enantiomer scale.

Imazethapyr disrupts plant phosphorus homeostasis and acquisition strategies.

The deficiency of essential mineral nutrients caused by xenobiotics often results in plant mortality or an inability to complete its life cycle. Imazethapyr, a widely utilized imidazolinone herbicide, has a long-lasting presence in the soil-plant system and can induce toxicity in non-target plants. However, the effects of imazethapyr on mineral nutrient homeostasis remain poorly comprehended. In this study, Arabidopsis seedlings exposed to concentrations of 4 and 10 µg/L imazethapyr showed noticeable reductions in shoot development and displayed a distinct dark purple color, which is commonly associated with phosphorus (P) deficiency in crops. Additionally, the total P content in both the shoots and roots of Arabidopsis significantly decreased following imazethapyr treatment when compared to the control groups. Through the complementary use of physiological and molecular analyses, we discovered that imazethapyr hinders the abundance and functionality of inorganic phosphorus (Pi) transporters and acid phosphatase. Furthermore, imazethapyr impairs the plant's Pi-deficiency adaptation strategies, such as inhibiting Pi transporter activities and impeding root hair development, which ultimately exacerbate P starvation. These results provide compelling evidence that residues of imazethapyr have the potential to disrupt plant P homeostasis and acquisition strategies. These findings offer valuable insights for risk assessment and highlight the need to reconsider the indiscriminate use of imazethapyr, particularly under specific scenarios such as nutrient deficiency.

Azospirillum brasilense activates peroxidase-mediated cell wall modification to inhibit root cell elongation.

The molecular mechanism of beneficial bacterium Azospirillum brasilense-mediated root developmental remain elusive. A. brasilense elicited extensively transcriptional changes but inhibited primary root elongation in Arabidopsis. By analyzing root cell type-specific developmental markers, we demonstrated that A. brasilense affected neither overall organization nor cell division of primary root meristem. The cessation of primary root resulted from reduction of cell elongation, which is probably because of bacterially activated peroxidase that will lead to cell wall cross-linking at consuming of H2O2. The activated peroxidase combined with downregulated cell wall loosening enzymes consequently led to cell wall thickness, whereas inhibiting peroxidase restored root growth under A. brasilense inoculation. We further showed that peroxidase activity was probably promoted by cadaverine secreted by A. brasilense. These results suggest that A. brasilense inhibits root elongation by activating peroxidase and inducing cell wall modification in Arabidopsis, in which cadaverine released by A. brasilense is a potential signal compound.

Targeting polyketide synthase 13 for the treatment of tuberculosis.

Tuberculosis (TB) is one of the most threatening diseases for humans, however, the drug treatment strategy for TB has been stagnant and inadequate, which could not meet current treatment needs. TB is caused by Mycobacterial tuberculosis, which has a unique cell wall that plays a crucial role in its growth, virulence, and drug resistance. Polyketide synthase 13 (Pks13) is an essential enzyme that catalyzes the biosynthesis of the cell wall and its critical role is only found in Mycobacteria. Therefore, Pks13 is a promising target for developing novel anti-TB drugs. In this review, we first introduced the mechanism of targeting Pks13 for TB treatment. Subsequently, we focused on summarizing the recent advance of Pks13 inhibitors, including the challenges encountered during their discovery and the rational design strategies employed to overcome these obstacles, which could be helpful for the development of novel Pks13 inhibitors in the future.

A Survival Model for Patients with Upper Tract Urothelial Carcinoma.

OBJECTIVES: We aimed to establish a survival model for patients with upper tract urothelial carcinoma (UTUC). METHODS: A total of 241 patients with UTUC treated from January 2010 to December 2018 were selected. Their general clinical data were collected, and urological indices were measured. They were followed up after discharge, and divided into a death group (n = 51) and a survival group (n = 190) to compare the clinical data. Multivariate logistic regression analysis was performed to analyze the independent risk factors for postoperative death, based on which a nomogram prediction model was established and then validated. RESULTS: The death group had significantly older age, larger tumor diameter, and higher tumor grade, pathological stage and proportion of no adjuvant chemotherapy than those of the control group (p < 0.01). The results of multivariate logistic analysis suggested that high tumor grade, tumor located in the ureter, large tumor diameter, high pathological stage, and lymph node metastasis were independent risk factors for postoperative death. A nomogram prediction model was established based on the prognostic independent risk factors. The area under the curve of receiver operating characteristic curve was 0.828 (95% confidence interval (CI): 0.801-0.845), so the model had good discrimination. The calibration curve showed that the model had high consistency. CONCLUSIONS: The established nomogram model can be used to predict the mortality risk of patients with UTUC and postoperative survival, and to develop individualized treatment plans for improving the prognosis and survival.

A Survival Model for Patients with Upper Tract Urothelial Carcinoma

Objectives: We aimed to establish a survival model for patients with upper tract urothelial carcinoma (UTUC). Methods: A total of 241 patients with UTUC treated from January 2010 to December 2018 were selected. Their general clinical data were collected, and urological indices were measured. They were followed up after discharge, and divided into a death group (n = 51) and a survival group (n = 190) to compare the clinical data. Multivariate logistic regression analysis was performed to analyze the independent risk factors for postoperative death, based on which a nomogram prediction model was established and then validated. Results: The death group had significantly older age, larger tumor diameter, and higher tumor grade, pathological stage and proportion of no adjuvant chemotherapy than those of the control group (p < 0.01). The results of multivariate logistic analysis suggested that high tumor grade, tumor located in the ureter, large tumor diameter, high pathological stage, and lymph node metastasis were independent risk factors for postoperative death. A nomogram prediction model was established based on the prognostic independent risk factors. The area under the curve of receiver operating characteristic curve was 0.828 (95% confidence interval (CI): 0.801–0.845), so the model had good discrimination. The calibration curve showed that the model had high consistency. Conclusions: The established nomogram model can be used to predict the mortality risk of patients with UTUC and postoperative survival, and to develop individualized treatment plans for improving the prognosis and survival (AU)

Boosting Performance of SAW Resonator via AlN/ScAlN Composite Films and Dual Reflectors.

Surface acoustic wave (SAW) resonators based on aluminum nitride (AlN)/scandium-doped AlN (ScAlN) composite thin films with dual reflection structures demonstrate substantial improvement in acoustic performance. In this work, the factors affecting the final electrical performance of SAW are analyzed from the aspects of piezoelectric thin film, device structure design, and fabrication process. AlN/ScAlN composite films can effectively solve the problem of abnormal grains of ScAlN, improve the crystal orientation, and reduce the intrinsic loss and etching defects. The double acoustic reflection structure of the grating and groove reflector can not only reflect the acoustic wave more thoroughly, but also helps to release the film stress. Both structures are beneficial to obtain a higher Q value. The new stack and design results in large Qp and figure of merit among SAW devices working at 446.47 MHz on silicon up to 8241 and 18.1, respectively.

Design and Analysis of Lithium-Niobate-Based Laterally Excited Bulk Acoustic Wave Resonator with Pentagon Spiral Electrodes.

In this paper, we present a comprehensive study on the propagation and dispersion characteristics of A1 mode propagating in Z-cut LiNbO3 membrane. The A1 mode resonators with pentagon spiral electrodes utilizing Z-cut lithium niobate (LiNbO3) thin film are designed and fabricated. The proposed structure excites the A1 mode waves in both x- and y-direction by utilizing both the piezoelectric constants e24 and e15 due to applying voltage along both the x- and y-direction by arranging pentagon spiral electrode. The fabricated resonator operates at 5.43 GHz with no spurious mode and effective electromechanical coupling coefficient (Keff2) of 21.3%, when the width of electrode is 1 µm and the pitch is 5 µm. Moreover, we present a comprehensive study of the effect of different structure parameters on resonance frequency and Keff2 of XBAR. The Keff2 keeps a constant with varied thickness of LiNbO3 thin film and different electrode rotation angles, while it declines with the increase of p from 5 to 20 µm. The proposed XBAR with pentagon spiral electrodes realize high frequency response with no spurious mode and tunable Keff2, which shows promising prospects to satisfy the needs of various 5 G high-band application.

Preparation, Characterization, and Application of AlN/ScAlN Composite Thin Films.

Piezoelectric aluminum nitride (AlN) thin film, as a commonly used material for high-frequency acoustic resonators, has been a research hotspot in the RF field. Doping Sc elements in AlN is one of most effective methods to improve the piezoelectricity of the material. In this work, the first principal calculation and Mori-Tanaka model are used to obtain the piezoelectric constants of AlN, ScAlN, and AlN/ScAlN composites. Then, five types of AlN/ScAlN thin films are prepared on 8 inch silicon substrates. The crystal quality, roughness, and stress distribution are measured to characterize the film quality. The results show that composite film can effectively solve the problem of abnormal grains and reduce the roughness. Finally, a lamb wave resonator with an AlN/Sc0.2Al0.8N composite working at 2.33 GHz is fabricated. The effective electromechanical coupling coefficient Keff2 is calculated to be 6.19%, which has the potential to design high-frequency broadband filters.

Aluminum Nitride-Based Adjustable Effective Electromechanical Coupling Coefficient Film Bulk Acoustic Resonator.

The arrival of the 5G era has promoted the need for filters of different bandwidths. Thin-film bulk acoustic resonators have become the mainstream product for applications due to their excellent performance. The Keff2 of the FBAR greatly influences the bandwidth of the filter. In this paper, we designed an AlN-based adjustable Keff2 FBAR by designing parallel capacitors around the active area of the resonator. The parallel capacitance is introduced through the support column structure, which is compatible with conventional FBAR processes. The effects of different support column widths on Keff2 were verified by finite element simulation and experimental fabrication. The measured results show that the designed FBAR with support columns can achieve a Keff2 value that is 25.9% adjustable.

Lipid peroxide-derived short-chain aldehydes promote programmed cell death in wheat roots under aluminum stress.

Lipid peroxidation is a primary event in plant roots exposed to aluminum (Al) toxicity, which leads to the formation of reactive aldehydes. Current evidence demonstrates that the resultant aldehydes are integrated components of cellular damage in plants. Here, we investigated the roles of aldehydes in mediating Al-induced damage, particularly cell death, using two wheat genotypes with different Al resistances. Aluminum treatment significantly induced cell death, which was accompanied by decreased root activity and cell length. Al-induced cell death displayed granular nuclei and internucleosomal fragmentation of nuclear DNA, suggesting these cells underwent programmed cell death (PCD). During this process, caspase-3-like protease activity was extensively enhanced and showed a significant difference between these two wheat genotypes. Further experiments showed that Al-induced cell death was positively correlated with aldehydes levels. Al-induced representative diagnostic markers for PCD, such as TUNEL-positive nuclei and DNA fragmentation, were further enhanced by the aldehyde donor (E)-2-hexenal, but significantly suppressed by the aldehyde scavenger carnosine. As the crucial executioner of Al-induced PCD, the activity of caspase-3-like protease was further enhanced by (E)-2-hexenal but inhibited by carnosine in wheat roots. These results suggest that reactive aldehydes sourced from lipid peroxidation mediate Al-initiated PCD probably through activating caspase-3-like protease in wheat roots.

Novel Small-Molecule PD-L1 Inhibitor Induces PD-L1 Internalization and Optimizes the Immune Microenvironment.

Blocking the PD-1/PD-L1 interaction has become an important strategy for tumor therapy, which has shown outstanding therapeutic effects in clinical settings. However, unsatisfactory response rates and immune-related adverse effects limit the use of anti-PD1/PD-L1 antibodies. Here, we report the discovery and identification of S4-1, an innovative small-molecule inhibitor of PD-L1. In vitro, S4-1 effectively altered the PD-L1/PD-1 interaction, induced PD-L1 dimerization and internalization, improved its localization to endoplasmic reticulum, and thus enhanced the cytotoxicity of peripheral blood mononuclear cells toward tumor cells. In vivo, S4-1 significantly inhibited tumor growth in both lung and colorectal cancer models, particularly in colorectal cancer, where it led to complete clearance of a portion of the tumor cells. Furthermore, S4-1 induced T-cell activation and inversed the inhibitory tumor microenvironment, consistent with the PD-L1/PD-1 pathway blockade. These data support the continued evaluation of S4-1 as an alternative ICB therapeutic strategy.

Demonstration of Thin Film Bulk Acoustic Resonator Based on AlN/AlScN Composite Film with a Feasible Keff2.

Film bulk acoustic resonators (FBARs) with a desired effective electromechanical coupling coefficient (Keff2) are essential for designing filter devices. Using AlN/AlScN composite film with the adjustable thickness ratio can be a feasible approach to obtain the required Keff2. In this work, we research the resonant characteristics of FBARs based on AlN/AlScN composite films with different thickness ratios by finite element method and fabricate FBAR devices in a micro-electromechanical systems process. Benefiting from the large piezoelectric constants, with a 1 µm-thick Al0.8Sc0.2N film, Keff2 can be twice compared with that of FBAR based on pure AlN films. For the composite films with different thickness ratios, Keff2 can be adjusted in a relatively wide range. In this case, a filter with the specific N77 sub-band is demonstrated using AlN/Al0.8Sc0.2N composite film, which verifies the enormous potential for AlN/AlScN composite film in design filters.