Discovery of Potent and Selective c-Met Degraders for Hepatocellular Carcinoma Treatment.

Targeting c-Met is a clinical trend for the precise treatment of HCC, but the potential issue of acquired drug resistance cannot be ignored. Targeted protein degradation technology has demonstrated promising prospects in disease treatment and overcoming drug resistance due to its special mechanism of action. In this study, we designed and synthesized two series of novel c-Met degraders and conducted a systematic biological evaluation of the optimal compound H11. H11 exhibited good c-Met degradation activity and anti-HCC activity. Importantly, H11 also demonstrated more potent inhibitory activity against Ba/F3-TPR-MET-D1228N and Ba/F3-TPR-MET-Y1230H cell lines than did tepotinib. In summary, H11 displayed potent anti-HCC activity as a degrader and may overcome resistance to type Ib inhibitors, making it a new therapeutic strategy for HCC with MET alterations.

Dynamic imaging of micro-vibrations with an ultra-wide bandwidth and a femtometer noise using switchable pulsed laser interferometry.

Imaging the complex dynamics of micro-vibrations plays a fundamental role in the investigation of microelectromechanical systems (MEMS). However, it remains a challenge for achieving both a wide bandwidth and a low noise due to the high photodetector noise and electromagnetic interference at GHz frequencies. Here, we propose a pulsed laser interferometry system with an adaptable switch to image GHz vibrations based on stroboscopic mixing, while measuring lower-frequency vibrations based on the homodyne scheme. The noise power spectral density is shown in both regions from DC to 10 GHz with an average noise down to 30.8 fm/√Hz at GHz frequencies, which holds the highest resolution to the best of our knowledge. Vibrational amplitude and phase mappings of a kHz comb-drive resonator, a GHz piezoelectric transducer, and a GHz film bulk acoustic resonator are presented with animated visualizations and k-space analysis, paving a new paradigm for the first time to image and analyze various MEMS devices of a bandwidth spanning 10 orders of magnitude.

Design and Fabrication of a Film Bulk Acoustic Wave Filter for 3.0 GHz-3.2 GHz S-Band.

Film bulk acoustic-wave resonators (FBARs) are widely utilized in the field of radio frequency (RF) filters due to their excellent performance, such as high operation frequency and high quality. In this paper, we present the design, fabrication, and characterization of an FBAR filter for the 3.0 GHz-3.2 GHz S-band. Using a scandium-doped aluminum nitride (Sc0.2Al0.8N) film, the filter is designed through a combined acoustic-electromagnetic simulation method, and the FBAR and filter are fabricated using an eight-step lithographic process. The measured FBAR presents an effective electromechanical coupling coefficient (keff2) value up to 13.3%, and the measured filter demonstrates a -3 dB bandwidth of 115 MHz (from 3.013 GHz to 3.128 GHz), a low insertion loss of -2.4 dB, and good out-of-band rejection of -30 dB. The measured 1 dB compression point of the fabricated filter is 30.5 dBm, and the first series resonator burns out first as the input power increases. This work paves the way for research on high-power RF filters in mobile communication.

Design and Fabrication of 3.5 GHz Band-Pass Film Bulk Acoustic Resonator Filter.

With the development of wireless communication, increasing signal processing presents higher requirements for radio frequency (RF) systems. Piezoelectric acoustic filters, as important elements of an RF front-end, have been widely used in 5G-generation systems. In this work, we propose a Sc0.2Al0.8N-based film bulk acoustic wave resonator (FBAR) for use in the design of radio frequency filters for the 5G mid-band spectrum with a passband from 3.4 to 3.6 GHz. With the excellent piezoelectric properties of Sc0.2Al0.8N, FBAR shows a large Keff2 of 13.1%, which can meet the requirement of passband width. Based on the resonant characteristics of Sc0.2Al0.8N FBAR devices, we demonstrate and fabricate different ladder-type FBAR filters with second, third and fourth orders. The test results show that the out-of-band rejection improves and the insertion loss decreases slightly as the filter order increases, although the frequency of the passband is lower than the predicted ones due to fabrication deviation. The passband from 3.27 to 3.47 GHz is achieved with a 200 MHz bandwidth and insertion loss lower than 2 dB. This work provides a potential approach using ScAlN-based FBAR technology to meet the band-pass filter requirements of 5G mid-band frequencies.

MEMS Oscillators-Network-Based Ising Machine with Grouping Method.

Combinatorial optimization (CO) has a broad range of applications in various fields, including operations research, computer science, and artificial intelligence. However, many of these problems are classified as nondeterministic polynomial-time (NP)-complete or NP-hard problems, which are known for their computational complexity and cannot be solved in polynomial time on traditional digital computers. To address this challenge, continuous-time Ising machine solvers have been developed, utilizing different physical principles to map CO problems to ground state finding. However, most Ising machine prototypes operate at speeds comparable to digital hardware and rely on binarizing node states, resulting in increased system complexity and further limiting operating speed. To tackle these issues, a novel device-algorithm co-design method is proposed for fast sub-optimal solution finding with low hardware complexity. On the device side, a piezoelectric lithium niobate (LiNbO3) microelectromechanical system (MEMS) oscillator network-based Ising machine without second-harmonic injection locking (SHIL) is devised to solve Max-cut and graph coloring problems. The LiNbO3 oscillator operates at speeds greater than 9 GHz, making it one of the fastest oscillatory Ising machines. System-wise, an innovative grouping method is used that achieves a performance guarantee of 0.878 for Max-cut and 0.658 for graph coloring problems, which is comparable to Ising machines that utilize binarization.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 (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.