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Abstract Background Delta-like ligand 3 (DLL3) is highly expressed on the cell surface of small cell lung cancer (SCLC), one of the most lethal malignancies, but minimally or not in normal tissues, making it an attractive target for SCLC. However, none of the DLL3-targeting antibody-drug conjugates (ADCs) have been approved for SCLC therapy yet. We developed DB-1314, the new anti-DLL3 ADC composed of a novel humanized anti-DLL3 monoclonal antibody (DB131401) conjugated with eight molecules of P1021 (topoisomerase I inhibitor), and described its preclinical profiles. Methods The binding epitope for DB131401 and Rovalpituzumab was tested by biolayer interferometry. The binding affinity and specificity of DB-1314 to DLL3 and other homologous proteins were respectively measured by surface plasmon resonance and enzyme-linked immunosorbent assay. Internalization, bystander effects, and antibody-dependent cell-mediated cytotoxicity (ADCC) were assessed by respective assay. DLL3 was quantified by antibodies bound per cell assay and immunohistochemistry. In vitro and in vivo growth inhibition studies were evaluated in SCLC cell lines, and cell line/patient-derived xenograft models. The safety profile was measured in cynomolgus monkeys. Results DB-1314 induces potent, durable, and dose-dependent antitumor effects in cells in vitro and in cell/patient-derived xenograft models in vivo. The killing activity of DB-1314 mechanically arises from P1021-induced DNA damage, whereby P1021 is delivered and released within tumor cells through DLL3-specific binding and efficient internalization. Bystander effects and ADCC also contribute to the antitumor activity of DB-1314. DB-1314 displays favorable pharmacokinetic and toxicokinetic profiles in rats and cynomolgus monkeys; besides, DB-1314 is well-tolerated at a dose of up to 60 mg/kg in monkeys. Conclusions These results suggest that DB-1314 may be a candidate ADC targeting DLL3 for the treatment of DLL3-positive SCLC, supporting further evaluation in the clinical setting.

Abstract Acute myeloid leukaemia (AML) is a fatal haematopoietic malignancy and is treated with the conventional combination of cytarabine (Ara-C) and daunorubicin (Dau). The survival rate of AML patients is lower due to the cardiotoxicity of daunorubicin. Clinically, homoharringtonine (HHT) plus Ara-C has been reported to be equally effective as Dau plus Ara-C in some types of AML patients with less toxic effects. We utilized the clinical use of homoharringtonine in combination with Ara-C to test its combination mechanism. We found that the insensitivity of AML cells to cytarabine-induced apoptosis is associated with increased Mcl-1 stability and p38 inactivation. HHT downregulates Mcl-1, phosphorylates H2AX and induces apoptosis by activating p38 MAPK. Inactivation of p38 through inhibitors and siRNA blocks apoptosis, H2AX phosphorylation and Mcl-1 reduction. HHT enhances Ara-C activation of the p38 MAPK signalling pathway, overcoming Ara-C tolerance to cell apoptosis by regulating the p38/H2AX/Mcl-1 axis. The optimal ratio of HHT to Ara-C for synergistic lethality in AML cells is 1:4 (M/M). HHT synergistically induces apoptosis in combination with Ara-C in vitro and prolongs the survival of xenografts. We provide a new mechanism for AML treatment by regulating the p38 MAPK/H2AX/Mcl-1 axis to improve cytarabine therapy.

Abstract Background HER3 (ErbB3), a member of the human epidermal growth factor receptor family, is frequently overexpressed in various cancers. Multiple HER3-targeting antibodies and antibody–drug conjugates (ADCs) were developed for the solid tumor treatment, however none of HER3-targeting agent has been approved for tumor therapy yet. We developed DB-1310, a HER3 ADC composed of a novel humanized anti-HER3 monoclonal antibody covalently linked to a proprietary DNA topoisomerase I inhibitor payload (P1021), and evaluate the efficacy and safety of DB-1310 in preclinical models. Methods The binding of DB-1310 to Her3 and other HER families were measured by ELISA and SPR. The competition of binding epitope for DB-1310 and patritumab was tested by FACS. The sensitivity of breast, lung, prostate and colon cancer cell lines to DB-1310 was evaluated by in vitro cell killing assay. In vivo growth inhibition study evaluated the sensitivity of DB-1310 to Her3 + breast, lung, colon and prostate cancer xenograft models. The safety profile was also measured in cynomolgus monkey. Results DB-1310 binds HER3 via a novel epitope with high affinity and internalization capacity. In vitro, DB-1310 exhibited cytotoxicity in numerous HER3 + breast, lung, prostate and colon cancer cell lines. In vivo studies in HER3 + HCC1569 breast cancer, NCI-H441 lung cancer and Colo205 colon cancer xenograft models showed DB-1310 to have dose-dependent tumoricidal activity. Tumor suppression was also observed in HER3 + non-small cell lung cancer (NSCLC) and prostate cancer patient-derived xenograft (PDX) models. Moreover, DB-1310 showed stronger tumor growth-inhibitory activity than patritumab deruxtecan (HER3-DXd), which is another HER3 ADC in clinical development at the same dose. The tumor-suppressive activity of DB-1310 synergized with that of EGFR tyrosine kinase inhibitor, osimertinib, and exerted efficacy also in osimertinib-resistant PDX model. The preclinical assessment of safety in cynomolgus monkeys further revealed DB-1310 to have a good safety profile with a highest non severely toxic dose (HNSTD) of 45 mg/kg. Conclusions These finding demonstrated that DB-1310 exerted potent antitumor activities against HER3 + tumors in in vitro and in vivo models, and showed acceptable safety profiles in nonclinical species. Therefore, DB-1310 may be effective for the clinical treatment of HER3 + solid tumors.

Abstract Memristors are a candidate device for artificial neural systems due to their excellent conductance‐regulation ability and potential to simulate the characteristics of biological synapses. This study fabricated a Pt/TaOx/TiOy/Ti analog artificial synapse memristor that exhibits excellent multilevel storage property with a large on/off ratio of ≈660 times. The dynamic resistive switching mechanism is well expounded and validated by the reset stopping voltage dependent Schottky fitting results. Moreover, the essential biological synaptic characteristics such as long‐term potentiation/depression (LTP/D) and paired‐pulse facilitation (PPF) are successfully mimicked with a low pulse energy consumption of 12.69 nJ. A neuromorphic network constructed on the enhanced symmetry and linearity of conductance for this Pt/TaOx/TiOy/Ti memristive device can achieve 92.45% accuracy in recognizing handwritten pattern. These results demonstrate a significant potential for application Pt/TaOx/TiOy/Ti memristor in non‐volatile memory and bioinspired neuromorphic systems.

In recent years, China’s neighboring environment has experienced profound changes, and China’s external security situation has been subject to a series of shocks. Against this background, China’s neighborhood diplomacy has become increasingly prominent. Indochina has been the focus of China’s neighborhood diplomacy since the Geneva Conference in 1954. Based on the declassified archives of Kissinger’s secret visit to China in 1971, this paper examines the issue of Indochina in the negotiations between Zhou Enlai and Kissinger. The aim is to offer a valuable historical experience for China’s neighborhood diplomacy of today and the way to manage and resolve strategic disputes in its neighboring area. The study finds that during the negotiations, Zhou took a clear stance on behalf of the Chinese government in expressing support for the struggle for the national independence of the Indochinese people. This reflects China’s unshakable commitment to the Five Principles of Peaceful Coexistence and support for the international justice of anti-aggression and anti-colonialism. Additionally, through his statements, Zhou has shown us the meaning of “amity, sincerity, mutual benefit, and inclusiveness (亲诚惠容 Qin Cheng Hui Rong)” in neighborhood diplomacy. All his efforts showed us how to effectively undertake neighborhood diplomacy, which is the essence of maintaining stability in China’s neighborhood.

Excessive oxidative stress and NLRP3 inflammasome activation are considered the main drivers of inflammatory bowel disease (IBD), and inhibition of inflammasomes ameliorates clinical symptoms and morphological manifestations of IBD. Herein, we examined the roles of NLRP3 activation in IBD and modulation of NLRP3 by sulforaphane (SFN), a compound with multiple pharmacological activities that is extracted from cruciferous plants. To simulate human IBD, we established a mouse colitis model by administering dextran sodium sulfate in the drinking water. SFN (25, 50 mg·kg−1·d−1, ig) or the positive control sulfasalazine (500 mg/kg, ig) was administered to colitis-affected mice for 7 days. Model mice displayed pathological alterations in colon tissue as well as classic symptoms of colitis beyond substantial tissue inflammation. Expression of NLRP3, ASC, and caspase-1 was significantly elevated in the colonic epithelium. The expression of NLRP3 inflammasomes led to activation of downstream proteins and increases in the cytokines IL-18 and IL-1β. SFN administration either fully or partially reversed these changes, thus restoring IL-18 and IL-1β, substantially inhibiting NLRP3 activation, and decreasing inflammation. SFN alleviated the inflammation induced by LPS and NLRP3 agonists in RAW264.7 cells by decreasing the levels of reactive oxygen species. In summary, our results revealed the pathological roles of oxidative stress and NLRP3 in colitis, and indicated that SFN might serve as a natural NLRP3 inhibitor, thereby providing a new strategy for alternative colitis treatment.

Summary: Decarbonization plans depend on the rapid, large-scale deployment of batteries to sufficiently decarbonize the electricity system and on-road transport. This can take many forms, shaped by technology, materials, and supply chain selection, which will have local and global environmental and social impacts. Current knowledge gaps limit the ability of decision-makers to make choices in facilitating battery deployment that minimizes or avoids unintended environmental and social consequences. These gaps include a lack of harmonized, accessible, and up-to-date data on manufacturing and supply chains and shortcomings within sustainability and social impact assessment methods, resulting in uncertainty that limits incorporation of research into policy making. These gaps can lead to unintended detrimental effects of large-scale battery deployment. To support decarbonization goals while minimizing negative environmental and social impacts, we elucidate current barriers to tracking how decision-making for large-scale battery deployment translates to environmental and social impacts and recommend steps to overcome them.

Borderless e-commerce originated within the international trade domain and has been significantly shaped by the societal backdrop of economic globalization and the rapid advancement of internet technologies. This evolution has given rise to numerous B2C borderless e-commerce platforms. While there has been a growing recognition of the importance of service innovation, there remains an incomplete understanding and a need for further refinement in the service evaluation system. Consequently, the scientific assessment and enhancement of service innovation capabilities have become focal points of research both domestically and internationally. Existing research has predominantly focused on the development models and challenges of import e-commerce retail platforms, with theoretical studies taking precedence. However, there is relatively limited emphasis on the evaluation and empirical analysis of service innovation capabilities in borderless e-commerce platforms. This study aims to bridge the existing research gap by constructing a scientifically accurate evaluation framework and employing statistical methods to comprehensively investigate and assess the service innovation levels of Chinese import borderless e-commerce retail platforms. To address this gap in understanding, this study has selected four import borderless e-commerce retail platforms in China as research subjects. Subsequently, an evaluation model for these import borderless e-commerce retail platforms was constructed through factor analysis to establish an evaluation index system. Then, the service innovation abilities of these four platforms were calculated and ranked within this index system using the TOPSIS model. This process facilitates a deeper exploration of the underlying reasons for their differences and provides clear developmental pathways for these platforms to bolster their service innovation capabilities. The results indicate that there exists a direct correlation between the market share and popularity of e-commerce platforms and their service innovation capabilities. Furthermore, luxury brand marketing and high market share can significantly enhance their service performance. These findings carry valuable implications for guiding the development of borderless e-commerce import platforms.

In the trend of spectrometer miniaturization, the design of combining computational imaging with the metasurfaces has been proved to be an efficient and feasible solution. Nevertheless, determining the optimal filter array design remains a compelling subject for ongoing research. A computational microspectrometer consisting of a planar array of broadband optical filters is proposed, which are formed by low-loss freeform dielectric metasurfaces. Diverse metasurface designs are obtained by using binary graph generation technology, and rich spectral responses are obtained. The final performance of microspectrometer depends on the trade-offs between reconstruction time, relative error, footprint, and resolution. To optimize these trade-offs, we have improved the existing freeform metasurface design scheme and optimized the filter array design. Simulation results show the proposed microspectrometer can successfully reconstruct the spectra over the 380 to 680 nm spectral range with a resolution of 1 nm. In summary, we propose an integrated design including meta-pixel design, filter combinations and simulation test flow, which leads to an impressive performance microspectrometer.

Abstract Nuclear receptors (NRs) are important transcriptional factors that mediate autophagy, preventing podocyte injury and the progression of diabetic kidney disease (DKD). However, the role of nuclear receptor coactivators that are powerful enhancers for the transcriptional activity of NRs in DKD remains unclear. In this study, a significant decrease in Nuclear Receptor Coactivator 3 (NCOA3) is observed in injured podocytes caused by high glucose treatment. Additionally, NCOA3 overexpression counteracts podocyte damage by improving autophagy. Further, Src family member, Fyn is identified to be the target of NCOA3 that mediates the podocyte autophagy process. Mechanistically, NCOA3 regulates the transcription of Fyn in a nuclear receptor, PPAR‐γ dependent way. Podocyte‐specific NCOA3 knockout aggravates albuminuria, glomerular sclerosis, podocyte injury, and autophagy in DKD mice. However, the Fyn inhibitor, AZD0530, rescues podocyte injury of NCOA3 knockout DKD mice. Renal NCOA3 overexpression with lentivirus can ameliorate podocyte damage and improve podocyte autophagy in DKD mice. Taken together, the findings highlight a novel target, NCOA3, that protects podocytes from high glucose injury by maintaining autophagy.

Mesotrione, topramezone, tembotrione, and sulcotrione are four types of 4-hydroxyphenylpyruvate dioxidase (HPPD) inhibitor herbicides that are extensively employed in agricultural practices, but their usage also leads to environmental pollution and poses risks to human health. A probe (E)−1-((2-(pyridin-2-yl) hydrazineylidene) methyl) naphthalen-2-ol (CHMN) based on chelation enhancement (CHEF) effect synthesized. CHMN was first chelated with Zn2+ to form a probe system with green, which can be further used to detect mesotrione, topramezone, tembotrione and sulcotrione in complicated environment. CHMN-Zn2+ detection of four pesticides was accurate, with an excellent linear relationship between 0 and 100 μM. The detection limits were LODmesotrione = 7.79 μM, LODtopramezone = 1.91 μM, LODtembotrione = 1.38 μM and LODsulcotrione = 2.43 μM. The detection time is 1 min, and it is successfully applied in real water sample and bioimaging. This work can provide a novel method for studying the migration and behavior of environmental pollutants.

Understanding the physiological effects of herbicides on crops is crucial for crop production and environmental management. The effects of 4-hydroxyphenylpyruvate dioxygenase inhibitor (HPPDi) herbicides at different concentrations on chlorophyll content in maize leaves, fresh weight of roots, stems and leaves, and fluorescence substances and functional groups in root exudates (REs) were studied by UV-Vis absorption spectroscopy, fluorescence spectroscopy, Fourier transform infrared spectroscopy (FTIR) and two-dimensional correlation analysis (2D-COS). The results showed that 5 mg/L and 10 mg/L HPPDi herbicides inhibited the synthesis of chlorophyll in maize leaves. The weight of roots, stems and leaves of maize after application was lighter than that of the control group. HPPDi herbicides affected the early growth of maize seedlings, and the effect was most obvious at high concentration. Synchronous fluorescence spectrum and three-dimensional (3D) fluorescence spectrum revealed that the fluorescence intensity of protein, fulvic acid and humic acid in maize REs changed prominently. With the increase of HPPDi herbicides concentration, the fluorescence intensity decreased gradually. Through FTIR and 2D-COS, functional groups such as C-H, CO, Cl, NO3-, C-O and O-H were found to participate in the interaction between HPPDi herbicides and maize REs as binding sites. C-O, C-Cl and C-C have the strongest binding ability, while CC and CO of aromatic rings, quinones or ketones first take part in the binding between HPPDi herbicides and maize REs. The results can provide a theoretical basis for evaluating the safety of HPPDi herbicides on maize and a method for discovering the effects of pesticides on environmental media and plant physiological effects.

Abstract The maternal-fetal interface shares similarities with tumor tissues in terms of the immune microenvironment. Normal pregnancy is maintained due to the immunosuppressed state, but pyroptosis induced by MITA can trigger the body’s immune response and disrupt the immunosuppressed state of the maternal-fetal interface, leading to abortion. In this study, we explored the role of MITA and TRIM38 in regulating pyroptosis and maintaining the immune tolerance of the maternal-fetal interface during pregnancy. Our findings show that the interaction between MITA and TRIM38 plays a crucial role in maintaining the immunosuppressed state of the maternal-fetal interface. Specifically, we observed that TRIM38-mediated K48 ubiquitination of MITA was higher in M2 macrophages, leading to low expression levels of MITA and thus inhibiting pyroptosis. Conversely, in M1 macrophages, the ubiquitination of K48 was lower, resulting in higher expression levels of MITA and promoting pyroptosis. Our results also indicated that pyroptosis played an important role in hindering the transformation of M1 to M2 and maintaining the immunosuppressed state of the maternal-fetal interface. These discoveries help elucidate the mechanisms that support the preservation of the immune tolerance microenvironment at the maternal-fetal interface, playing a vital role in ensuring successful pregnancy.

This study makes a significant contribution to the field of groundwater potential mapping (GWPM) by exploring the application of ensemble learning models (ELMs), specifically boosting ensemble models (BEMs), which have not been fully utilized in GWPM. By employing six ELMs (random forest, AdaBoost, XGBoost, CatBoost, GBDT, and LightGBM), along with Tree-structured Parzen Estimator in Luoning County, China, this study identifies key indicators (topographic position index, distance to rivers, and topographic wetness index) and demonstrates the superior model performance of XGBoost compared to other ELMs. Additionally, correlation analysis confirms the accuracy of XGBoost in predicting relationships between important indicators and groundwater potentials. Finally, the findings provide valuable insights for sustainable groundwater management strategies in Luoning County and emphasize the need for further exploration of ELMs, development of comprehensive performance evaluation and indicator systems, reduction of the inconsistencies between indicators and predication results and practical research to support future sustainable groundwater management.

Abstract Electric motors in electric and hybrid vehicles generate mid-frequency noise and vibration. These factors cause drivers to experience discomfort while traveling. Active mounting techniques have been extensively researched and developed to effectively address this issue. The optimal placement of an active mounting system is essential for enhancing NVH performance when an active mounting system is utilized. In order to propose optimal location criteria for active paths, this paper concentrates on developing an analytical model based on both dynamic and static analysis. The secondary forces along active trajectories are mathematically determined when a structure is subjected to an excitation force. These locations are considered optimal for the active mounting system if the secondary forces are comparatively minimal. Simulations and feasibility experiments are also conducted in order to validate the proposed method. In addition, the results are compared with the case of beam structure. It has been determined through this procedure that the active path’s control performance will be enhanced if it is positioned in the optimal location and less control force is required than in the case of beam.

Abstract The vibration and noise caused by electric motors in hybrid and electric vehicles (EVs) generate complex signals with a mid-frequency band, which causes uncomfortable vibration and noise. In order to isolate the vibration and noise, active engine mounting systems based on smart structures have attracted attention. Thus, in this study, the vibration attenuation performance was validated through simulation and feasibility experiments by applying an active mounting system using a piezoelectric stack actuator. A plate structure with three paths, consisting of two passive paths and one active path, was modeled using the lumped parameter method. The source part was excited by a sinusoidal and modulated signal with a mid-frequency band to validate the vibration attenuation performance. Furthermore, (1) mathematical modeling with a source-path-receiver structure was proposed based on lumped parameter modeling, (2) normalized least mean square (NLMS) and multi-NLMS algorithms were applied to implement motion control, and (3) a principal experimental setup was designed to validate the simulation results. Through this process, the vibration attenuation performance of the proposed active mount structure was validated.

Abstract Background Mental health disorders affect millions of US adults, however, the trends and related factors for mental health care utilization in the US remain unknown. Aims Our study aimed to assess the trend of mental health utilization and related socio-demographic factors in the US. Methods The study included 55,052 individuals from the National Health and Nutrition Examination Survey (NHANES) in 1999–2018. Temporal trends in the percentages of mental health care utilizers were estimated across survey cycles. Trends and linked factors of mental health care utilization were assessed by a logistic regression model, while the non-linearity was estimated by restricted cubic splines. Results From 1999 to 2018, the percentage of mental health care utilizers in the US adult population increased from 7.0 to 11.3% (P

A compact eight-element frame antenna array covering the 5G n79 frequency band (4.4–5.0 GHz) has been proposed in this paper. Considering the demands in the application of 5G ultrathin smartphones, the antenna unit has been miniaturized and designed with a low profile. Each antenna unit occupies a distance of 11.1 mm on the long edge, and the profile height of each unit is only 3 mm. The antenna array consists of 8 identical monopole antennas. By loading an inverted E-shaped slot on the ground plane and arranging the positions of the antenna units reasonably without the need for a decoupling structure, the antenna can achieve a low profile and compact design. Simultaneously, it can achieve excellent isolation and cover the entire n79 frequency band. The processed eight-element antenna array has a −6 dB bandwidth ranging from 4.38 to 5.19 GHz. The isolation between all antennas is better than −13.9 dB. The total efficiency is between 48.66% and 90.57%, with an average efficiency of 68.6%. The ECC (envelope correlation coefficient) is less than 0.066. The antenna array is characterized by its small size, low profile, simple structure, easy manufacturing, and excellent radiation performance. It holds significant application value in the design of MIMO antennas for 5G ultrathin smartphones.

BackgroundDiffuse large B-cell lymphoma (DLBCL) is the most common B-cell lymphoma in adults. CDGSH iron sulfur domain 2 (CISD2) is an iron–sulfur protein and plays a critical role of cell proliferation. The aberrant expression of CISD2 is associated with the progression of multiple cancers. However, its role in DLBCL remains unclear.MethodsThe differential expression of CISD2 was identified via public databases, and quantitative real-time PCR (qRT-PCR) and western blot were used to identifed the expression of CISD2. We estimated the impact of CISD2 on clinical prognosis using the Kaplan-Meier plotter. Meanwhile, the drug sensitivity of CISD2 was assessed using CellMiner database. The 100 CISD2-related genes from STRING obtained and analyzed using the LASSO Cox regression. A CISD2 related signature for risk model (CISD2Risk) was established. The PPI network of CISD2Risk was performed, and functional enrichment was conducted through the DAVID database. The impacts of CISD2Risk on clinical features were analyzed. ESTIMATE, CIBERSORT, and MCP-counter algorithm were used to identify CISD2Risk associated with immune infiltration. Subsequently, Univariate and multivariate Cox regression analysis were applied, and a prognostic nomogram, accompanied by a calibration curve, was constructed to predict 1-, 3-, and 5-years survival probabilities.ResultsCISD2 was upregulated in DLBCL patients comparing with normal controls via public datasets, similarly, CISD2 was highly expressed in DLBCL cell lines. Overexpression of CISD2 was associated with poor prognosis in DLBCL patients based on the GSE31312, the GSE32918, and GSE93984 datasets (P

During the process of developing and utilizing geothermal resources, various challenges are encountered. One such challenge is the decrease in temperature and pressure of the geothermal reservoir as a result of the increasing geothermal exploitation and duration. In addition, the discharge of geothermal tail water poses a risk of thermal pollution, leading to environmental concerns. To address these issues effectively, reinjection of geothermal fluids into the reservoir can be implemented as a viable solution. Prior to initiating the geothermal development and utilization, it is crucial to conduct scientifical and rational planning of the layout of production and reinjection wells. This involves exploring optimal strategies for the production-reinjection scheme that prevents the premature thermal breakthrough and maximize the efficient utilization of geothermal resources, thereby extending the lifespan of the geothermal reservoir. The Fengpei Basin, a Cenozoic rift basin that developed since the Paleogene period, exhibits a widespread distribution of geothermal reservoirs, primarily composed of the Ordovician limestone with karst and fracture characteristics. Building upon the geothermal resource exploration results in the Anguo Town in Peixian County in Jiangsu Province, this study utilizes key parameters obtained from pumping tests and reinjection experiments, such as well spacing and the reinjection-to-production ratio. This paper establishes a 3D coupled numerical model of geothermal water seepage and heat transfer by using the Feflow6.2 software. The recoverable reserves of geothermal fluid within the geothermal reservoir are simulated and predictd, specifically the Ordovician limestone formation. Furthermore, a simulated optimization of the development and utilization scheme for the production-reinjection wells is conducted. The results reveal that an appropriate well spacing of 389 m between the producing well (RPX01) and the reinjection well (RPX02) is recommended. Moreover, the reinjection-to-production ratio, namely the ratio of average aquifer hydraulic conductivity, is determined to be 1.29, supporting a sustainable approach of one-for-one pumping and reinjection. With a stabilized drawdown of 50.61 m, the production well has a capacity to recover 1000 m3/d of geothermal resources. Under the conditions of a production rate and a reinjection rate of 1000 m3/d, as well as a reinjection temperature of 40 °C, the simulation predicts a decrease in groundwater level by 45.49 m and a temperature reduction of 1.44 °C after ten heating seasons. This represents the optimal cyclic development and utilization scheme among the simulated scenarios. The above results provide a scientific basis for decision-making in the construction of the clean energy heating demonstration area in rural northern Jiangsu. They contribute to the establishment of a scientifically sound and sustainable approach for utilizing geothermal resources, while considering the challenges associated with the thermal breakthrough and the environmental impact of geothermal tail water discharge.

Metasurface holograms, with the capability to manipulate spatial light amplitudes and phases, are considered next-generation solutions for holographic imaging. However, conventional fabrication approaches for meta-atoms are heavily dependent on electron-beam lithography (EBL), a technique known for its expensive and time-consuming nature. In this paper, a polarization-insensitive metasurface hologram is proposed using a cost-effective and rapid nanoimprinting method with titanium dioxide (TiO2) nanoparticle loaded polymer (NLP). Based on a simulation, it has been found that, despite a reduction in the aspect ratio of meta-atoms of nearly 20%, which is beneficial to silicon master etching, NLP filling, and the mold release processes, imaging efficiency can go up to 54% at wavelength of 532 nm. In addition, it demonstrates acceptable imaging quality at wavelengths of 473 and 671 nm. Moreover, the influence of fabrication errors and nanoimprinting material degradation in terms of residual layer thickness, meta-atom loss or fracture, thermal-induced dimensional variation, non-uniform distribution of TiO2 particles, etc., on the performance is investigated. The simulation results indicate that the proposed device exhibits a high tolerance to these defects, proving its applicability and robustness in practice.

Silicon nitride (SiN) is emerging as a material of choice for photonic integrated circuits (PICs) due to its ultralow optical losses, absence of two-photon absorption in telecommunication bands, strong Kerr nonlinearity and high-power handling capability. These properties make SiN particularly well-suited for applications such as delay lines, chip-scale frequency combs and narrow-linewidth lasers, especially when implemented with thick SiN waveguides, which is achieved through low-pressure chemical vapor deposition (LPCVD). However, a significant challenge arises when the LPCVD SiN film thickness exceeds 300 nm on an 8-inch wafer, as this can result in cracking due to high stress. In this work, we successfully develop a damascene process to fabricate 800 nm-thick SiN photonics devices on an 8-inch wafer in a pilot line, overcoming cracking challenges. The resulting 2 × 2 multimode interference (MMI) coupler exhibits low excess loss (−0.1 dB) and imbalance (0.06 dB) at the wavelength of 1310 nm. Furthermore, the dispersion-engineered SiN micro-ring resonator exhibits a quality (Q) factor exceeding 1 × 106, enabling the generation of optical frequency combs. Our demonstration of photonics devices utilizing the photonics damascene process sets the stage for high-volume manufacturing and widespread deployment.

Abstract Background Postoperative lung cancer patients belong to the high-risk group for venous thromboembolism (VTE). The standardized preventive measures for perioperative VTE in lung cancer are not perfect, especially for the prevention and treatment of catheter-related thrombosis (CRT) caused by carried central venous catheters (CVCs) in lung cancer surgery. Patients and methods This study included 460 patients with lung cancer undergoing video-assisted thoracic surgery (VATS) in our center from July 2020 to June 2021. Patients were randomized into two groups, and intraoperatively-placed CVCs would be carried to discharge. During hospitalization, the control group was treated with low-molecular-weight heparin (LMWH), and the experimental group with LMWH + intermittent pneumatic compression (IPC). Vascular ultrasound was performed at three time points which included before surgery, before discharge, and one month after discharge. The incidence of VTE between the two groups was studied by the Log-binomial regression model. Results CRT occurred in 71.7% of the experimental group and 79.7% of the control group. The multivariate regression showed that the risk of developing CRT in the experimental group was lower than in the control group (Adjusted RR = 0.889 [95%CI0.799–0.989], p = 0.031), with no heterogeneity in subgroups (P for Interaction > 0.05). Moreover, the fibrinogen of patients in the experimental group was lower than control group at follow-up (P = 0.019). Conclusion IPC reduced the incidence of CRT during hospitalization in lung cancer patients after surgery. Trial registration No. ChiCTR2000034511.

BackgroundThe impact of inflammatory factors on the development of Ankylosing Spondylitis (AS) is widely recognized, but the exact causal relationship remains unclear.MethodsThe bidirectional mendelian-randomization study utilized genetic data from a genome-wide association study (GWAS) of 186 AS cases and 456,162 controls of European ancestry. Inflammatory cytokines were obtained from a GWAS summary of 8,293 healthy participants. Causal associations were primarily investigated using the inverse variance-weighted method, supplemented by MR Egger, weighted median and weighted mode analyses. Heterogeneity in the results was assessed using the Cochrane Q test. Horizontal pleiotropy was evaluated through the MR-Egger intercept test and the MR pleiotropy residual sum and outliers (MR-PRESSO) test. Sensitivity analysis was conducted through leave-one-out analysis.ResultsThe results suggest a genetically predicted potential association between beta-nerve growth factor (βNGF), Interleukin-1-beta (IL-1β), and TNF-related apoptosis inducing ligand (TRAIL) with the risk of AS (OR: 2.17, 95% CI: 1.13-4.16; OR: 0.41, 95% CI: 0.18-0.95,; OR: 1.47, 95% CI: 1.02-2.13).Additionally, Interleukin-12p70 (IL-12p70), Interleukin-17 (IL-17), Interleukin-6 (IL-6), Interleukin-4 (IL-4), Stromal-cell-derived factor 1 alpha (SDF−1α), Macrophage inflammatory protein 1β (MIP1β), Monocyte chemoattractant protein-3 (MCP-3), Platelet-derived growth factor bb (PDGFbb), Granulocyte-colony stimulating factor (GCSF), Fibroblast growth factor basic (bFGF), TNF-related apoptosis inducing ligand (TRAIL), and Interferon-gamma (IFN -γ) are suggested as consequences of AS in genetically prediction.No evidence of horizontal pleiotropy or heterogeneity between the genetic variants was found (P>0.05), and a leave-one-out test confirmed the stability and robustness of this association.ConclusionThese findings suggest that βNGF, IL-1β, and TRAIL may play a crucial role in the pathogenesis of AS. Additionally, AS may impact the expression of cytokines such as IL-12p70, IL-17, IL-6, IL-4, SDF−1α, MIP1β, MCP-3, PDGFbb,GCSF, bFGF,TRAIL,and IFN-γ. Further investigations are warranted to determine whether these biomarkers can be utilized for the prevention or treatment of AS.

Abstract Recently, research into the development of hybrid and electric vehicles has been vigorously undertaken, indicating a trend toward the replacement of internal combustion engine vehicles. However, while high efficiency and light weight are crucial in the development of vehicles, they increase the excitation force of the engine. In addition, sensor placement in future mobility is very important since it causes malfunctioning of autonomous driving systems when the location and orientation of sensors are changed due to excessive vehicle vibration. To reduce the structure-borne noise and vibration caused by engine excitation, an active engine mounting system must be installed in an optimal location. Thus, in this study, to determine the optimal location for an active engine mounting system applied to a beam structure, a series of simulations with two different methodologies are performed. The overall beam structure with two active mounting systems is modeled based on the lumped parameter model. To determine the optimal position of the active mounting system, it is moved to equal intervals, and the force and phase of the active mounts at each location combination are calculated based on static and dynamic methods. The optimal position is suggested such that the vibration reduction is maximized, while the applied force is minimized. Additionally, a feasibility experiment is conducted to validate the proposed criteria and confirm the simulation results. The results demonstrate that the optimal location of the active engine mounting system with a minimized force requirement and maximized vibration reduction can be identified.

Abstract Acute myeloid leukemia (AML) patients with FLT3-ITD mutations are associated with poor prognosis. FLT3-ITD inhibitors are developed and result in transient disease remission, but generally resistance develops. We propose that resistance occurs due to apoptosis evasion. We compared the abilities of five clinically used FLT3-ITD inhibitors, namely, midostaurin, crenolanib, gilteritinib, quizartinib, and sorafenib, to induce apoptosis. These drugs inhibit FLT3-ITD and induce apoptosis. Apoptosis induction is associated with GSK3β activation, Mcl-1 downregulation, and Bim upregulation. Sorafenib-resistant MOLM-13/sor cells have the secondary D835Y mutation and increased Axl signaling pathway with cross-resistance to quizartinib. Gilteritinib and crenolanib inhibit both FLT3-ITD and Axl and induce apoptosis in MOLM-13/sor cells, in which they activate GSK3β and downregulate Mcl-1. Inactivation of GSK3β through phosphorylation and inhibitors blocks apoptosis and Mcl-1 reduction. The Axl/GSK3β/Mcl-1 axis works as a feedback mechanism to attenuate apoptosis of FLT3-ITD inhibition. Homoharringtonine decreases the protein levels of Mcl-1, FLT3-ITD, and Axl. Moreover, it synergistically induces apoptosis with gilteritinib in vitro and prolongs survival of MOLM-13/sor xenografts. The GSK3β/Mcl-1 axis works as the hub of FLT3-ITD inhibitors and plays a critical role in resistance against FLT3-ITD AML-targeted therapy.

Podocyte injury can disrupt the glomerular filtration barrier (GFB), leading to podocytopathies that emphasize podocytes as the glomerulus’s key organizer. The coordinated cytoskeleton is essential for supporting the elegant structure and complete functions of podocytes. Therefore, cytoskeleton rearrangement is closely related to the pathogenesis of podocytopathies. In podocytopathies, the rearrangement of the cytoskeleton refers to significant alterations in a string of slit diaphragm (SD) and focal adhesion proteins such as the signaling node nephrin, calcium influx via transient receptor potential channel 6 (TRPC6), and regulation of the Rho family, eventually leading to the disorganization of the original cytoskeletal architecture. Thus, it is imperative to focus on these proteins and signaling pathways to probe the cytoskeleton rearrangement in podocytopathies. In this review, we describe podocytopathies and the podocyte cytoskeleton, then discuss the molecular mechanisms involved in cytoskeleton rearrangement in podocytopathies and summarize the effects of currently existing drugs on regulating the podocyte cytoskeleton.

The Kingdom of Saudi Arabia (KSA) has pledged to achieve net-zero greenhouse gas emissions by 2060. Direct air carbon capture and storage (DACCS) is critical for the country to meet its net-zero target given its reliance on fossil fuels and limited options for carbon dioxide removal (CDR). However, the role of DACCS in KSA’s national climate change mitigation has not been studied in the literature. In this study, we aim to understand the potential role of DACCS and the effect of its deployment timing in KSA’s transition toward its net-zero target using the Global Change Analysis Model (GCAM)-KSA, which is a version of GCAM with KSA split out as an individual region. We find that the annual DACCS CO _2 sequestration in KSA reaches 0.28–0.33 Gt yr ^−1 by 2060 depending on its deployment timing. Early DACCS deployment, driven by its early and rapid cost reduction worldwide, could bring significant savings (∼420 billion USD during 2020–2060) in the cost of climate change mitigation in KSA, approximately 17% reduction relative to delayed DACCS deployment. Our study suggests a strong role for KSA to proactively invest in the R&D of DACCS, initiate early DACCS deployment, and explore a broad suite of CDR options.

Magnetoelectric (ME) sensors cannot effectively detect broadband magnetic field signals due to their narrow bandwidth, and existing readout circuits are unable to vary the bandwidth of the sensors. To expand the bandwidth, this paper introduces a negative-feedback readout circuit, fabricated by introducing a negative-feedback compensation circuit based on the direct readout circuit of the ME sensor. The negative-feedback compensation circuit contains a current amplifier, a feedback resistor, and a feedback coil. For this purpose, a Metglas/PVDF/Metglas ME sensor was prepared. Experimental measurements show that there is a six-fold difference between the maximum and minimum values of the ME voltage coefficients in the 6–39 kHz frequency band for the ME sensor without the negative-feedback compensation circuit when the sensor operates at the optimal bias magnetic field. However, the ME voltage coefficient in this band remains stable, at 900 V/T, after the charge amplification of the direct-reading circuit and the negative-feedback circuit. In addition, experimental results show that this negative-feedback readout circuit does not increase the equivalent magnetic noise of the sensor, with a noise level of 240 pT/√Hz in the frequency band lower than 25 kHz, 63 pT/√Hz around the resonance frequency of 30 kHz, and 620 pT/√Hz at 39 kHz. This paper proposes a negative-feedback readout circuit based on the direct readout circuit, which greatly increases the bandwidth of ME sensors and promotes the widespread application of ME sensors in the fields of broadband weak magnetic signal detection and DBS electrode positioning.

Gravel mulch is an agricultural water conservation practice that has been widely used in the semi-arid region of northwest China, but its effectiveness is now lessening due to soil degradation caused by long-term gravel mulching. In this study, we report on a 6-year-long gravel mulch experiment conducted in the northwestern Loess Plateau to evaluate the impact of gravel mulch on soil physicochemical properties and microbial communities, with the objective of clarifying the causes of long-term gravel mulching-induced land degradation. After 6 years mulching, we found that gravel mulched soil contained significantly higher concentrations of total carbon and total organic carbon than non-mulched soil (control). Long-term gravel mulching significantly changed the soil microbial diversity and abundance distribution of bacterial and fungal communities. Notably, the relative abundance of Acidobacteria was significantly higher under gravel mulching than the control (no mulching), being significantly greater in the AG treatment (small-sized gravel, 2–5 mm) than all other treatments. Conversely, the relative abundance of Actinobacteria was significantly lower under gravel mulching than the control, being the lowest in the BG treatment (large-sized gravel, 40–60 mm). At the same time, the relative abundance of Bacteroidetes was significantly lower in AG yet higher in BG vis-à-vis the other treatments. Of the various factors examined, on a 6-year scale, the capture of dust by gravel mulch and altered carbon and nitrogen components in soil play major contributing roles in the compositional change of soil microorganisms. These results suggest that modified soil material input from gravel mulching may be the key factor leading to soil degradation. More long-term experimental studies at different sites are now needed to elucidate the mechanisms responsible for soil degradation under gravel mulching.

Gansu Province is a district renowned for the cultivation of Angelica sinensis (Oliv.) Diels, accounting for greater than 90% of China's total annual production. However, virus infection has caused a reduction in A. sinensis yield. Here, we collected suspected virus-infected A. sinensis leaf samples from Gansu Province's A. sinensis cultivation area. For the first time, using small RNA deep sequencing and RT-PCR, lychnis mottle virus (LycMoV) was found to naturally infect A. sinensis. The coat protein (cp) gene of the Gansu A. sinensis LycMoV isolate was obtained through cloning, where its nucleotide and amino acid identity was highest while having the closest affinity to the China Pearl (i.e., Prunus persica) isolate. Recombination analysis indicated that genetic recombination had only a limited influencing effect on the molecular evolution of LycMoV. Moreover, results from genetic diversity analysis indicated that the host, geographic isolation, and genetic drift may be the main factors that contributed to the formation of genetic diversity and differentiation in LycMoV. Furthermore, the LycMoV population trend was expansionary. Selection pressure may also be the main driver for the evolution of the entire LycMoV population, while the driving effect of genetic recombination is limited. This study marks a new LycMoV host (i.e., A. sinensis) for the first time and provides scientific support for the identification, prevention, and control of LycMoV.

microRNAs (miRNAs), a subclass of noncoding short RNAs, direct cells fate decisions that are important for cell proliferation and cell lineage decisions. Adipogenic differentiation contributes greatly to the development of white adipose tissue, involving of highly organized regulation by miRNAs. In the present study, we screened and identified 78 differently expressed miRNAs of porcine BMSCs during adipogenic differentiation. Of which, the role of miR-29c in regulating the proliferation and adipogenic differentiation was proved and detailed. Specifically, over-expression miR-29c inhibits the proliferation and adipogenic differentiation of BMSCs, which were reversed upon miR-29c inhibitor. Interference of IGF1 inhibits the proliferation and adipogenic differentiation of BMSCs. Mechanistically, miR-29c regulates the proliferation and adipogenic differentiation of BMSCs by targeting IGF1 and further regulating the MAPK pathway and the PI3K-AKT-mTOR pathway, respectively. In conclusion, we highlight the important role of miR-29c in regulating proliferation and adipogenic differentiation of BMSCs.

In mm-wave massive Multiple Input Multiple Output (MIMO) systems, in order to further improve the spectral efficiency of hybrid precoding in fully connected structure, an Alternate Minimization based on Gradient Descent (GD-AltMin) hybrid precoding algorithm is proposed. Firstly, the right singular vector of the channel matrix is used to initialize the analog precoding matrix. Secondly, digital and analog precoding matrices are updated by least square criterion and gradient descent method respectively. Then, under the principle of alternating minimization, the digital and analog precoding matrices are updated iteratively until the optimal digital and analog precoding matrices are obtained. Through theoretical analysis and numerical simulation, the spectral efficiency of several classical algorithms are compared under different signal-to-noise-ratio, number of radio frequency links and number of transmitting antennas. The results show that the spectral efficiency of the proposed algorithm is closer to the optimal unconstrained precoding algorithm than alternate minimization algorithm using phase extraction and channel singular value decomposition algorithm, especially when the number of radio frequency links is greater than the number of data streams.

Abstract Background Shaoyao Decoction (SYD) is a canonical herbal medicine prescription formulated by Liu Wan-Su in AD 1186. SYD has been widely used to treat inflammatory bowel disease by clearing heat and damp, removing stasis toxin in the intestine; however, the precise mechanisms and therapeutic material basis remain largely unclear. In the present study, we measured the effects of SYD on colitis symptom, epithelial barrier function, epithelial ferroptosis, colonic protein and mRNA expression of glutathione peroxidase 4 (GPX4) in colitis model, and determined whether SYD restored barrier loss in colitis by modulation of GPX4-regulated ferroptosis pathway. Methods Colitis was established by infusion with 1 mL 2,4,6-trinitrobenzene sulfonic acid (TNBS) dissolved in ethanol (40% v/v) in rats at a 125 mg/kg dose. Ferroptosis in epithelial cells was determined by flow cytometer. GPX4 promoter-firefly luciferase fusion construct was transfected to Caco-2 cell to determine GPX4 transcription. MS analysis was used to identified ingredients in SYD. Results Different doses of SYD significantly alleviated colitis, decreased ferroptosis in epithelial cells, knockout of GPX4 significantly reversed SYD-induced alleviation effects on colitis, restoration of epithelial barrier function, and epithelial ferroptosis. Wogonoside, wogonin, palmatine, paeoniflorin and liquiritin were identified as active ingredients of SYD-exerted alleviation effects of colitis based on GPX4 agonistic transcription. Conclusion SYD alleviated chemically induced colitis by activation of GPX4, inhibition of ferroptosis in epithelial cells and further restoration of barrier function. Wogonoside, wogonin, palmatine, paeoniflorin and liquiritin were identified as the key therapeutic material basis of SYD-exerted anti-colitis effects. The findings provide a scientific basis for the therapeutic effect of SYD on colitis.

Objective This study was performed to explore the function and mechanism of Dvl3 in RA-FLS by exosome intervention. Methods The expression pattern of Dvl3 was examined by IHC, WB, and qPCR. Modified exosomes obtained from culturing supernatant of RA-FLS infected with Dvl3 over expression (OE) lentivirus were administrated to the target RA-FLS. The ability of survival, migration, and the production of inflammatory factor influenced by exosomal Dvl3 were detected by CKK8 kits, Tunel, migration test, qPCR, and enzyme-linked immunosorbent assay (ELISA) respectively; Flow cytometry analysis was conducted to explorer the inflammatory moderate role of exosomes on CD4+ T cells. The possible downstream pathways of Dvl3 were screened by qPCR and WB and verified by double luciferase reporter experiment. Results The expression level of Dvl3 was significantly increased in RA and CIA. Exosomes from the OE group could significantly promote cell proliferation activity, migration/invasion ability. The augment of TNF-α, IL-1β, IL-17, and IL-21 was observed in exosomal Dvl3-OE group. Th1 and Th17 cells polarisation and cytokines related were both enhanced by Exosomal Dvl3. Over expression of Dvl3 was accompanied by the significant increase of β-catenin and RhoA activities. Conclusion This study discovered the high expression of Dvl3 of exosomes derived from RA patients which may possessed the ability to promote phenotypic transformation of RA-FLS through Wnt pathway.

A composite Air Health Index (AHI) is helpful for separately emphasizing the health risks of multiple stimuli and communicating the overall risks of an adverse atmospheric environment to the public. We aimed to establish a new AHI by integrating daily mortality risks due to air pollution with those due to non-optimum temperature in China. Based on the exposure-response (E-R) coefficients obtained from time-series models, the new AHI was constructed as the sum of excess mortality risk associated with air pollutants and non-optimum temperature in 272 Chinese cities from 2013 to 2015. We examined the association between the “total AHI” (based on total mortality) and total mortality, and further compared the ability of the “total AHI” to predict specific cardiopulmonary mortality with that of “specific AHIs” (based on specific mortalities). On average, air pollution and non-optimum temperature were associated with 28.23% of daily excess mortality, of which 23.47% was associated with non-optimum temperature while the remainder was associated with fine particulate matter (PM2.5) (1.12%), NO2 (2.29%,), and O3 (2.29%). The new AHI uses a 10-point scale and shows an average across all 272 cities of 6 points. The E-R curve for AHI and mortality is approximately linear, without any thresholds. Each one unit increase in “total AHI” is associated with a 0.84% increase in all-cause mortality and 1.01%, 0.98%, 1.02%, 1.66%, and 1.71% increases in cardiovascular disease, coronary heart disease, stroke, respiratory diseases, and chronic obstructive pulmonary disease mortality, respectively. Cause-specific mortality risk estimates using the “total AHI” are similar to those predicted by “specific AHIs.” In conclusion, the “total AHI” proposed herein could be a promising tool for communicating health risks related to exposure to the ambient environment to the public.

New study concludes that environmental tradeoffs of direct air capture and sequestration technologies are linked to the energy system in which they will operate, and their deployment should not equate to a relaxation of decarbonization or resource use efficiency targets.

Summary: RNA interference (RNAi) is a well-established antiviral immunity. However, for mammalian somatic cells, antiviral RNAi becomes evident only when viral suppressors of RNAi (VSRs) are disabled by mutations or VSR-targeting drugs, thereby limiting its scope as a mammalian immunity. We find that a wild-type alphavirus, Semliki Forest virus (SFV), triggers the Dicer-dependent production of virus-derived small interfering RNAs (vsiRNAs) in both mammalian somatic cells and adult mice. These SFV-vsiRNAs are located at a particular region within the 5′ terminus of the SFV genome, Argonaute loaded, and active in conferring effective anti-SFV activity. Sindbis virus, another alphavirus, also induces vsiRNA production in mammalian somatic cells. Moreover, treatment with enoxacin, an RNAi enhancer, inhibits SFV replication dependent on RNAi response in vitro and in vivo and protects mice from SFV-induced neuropathogenesis and lethality. These findings show that alphaviruses trigger the production of active vsiRNA in mammalian somatic cells, highlighting the functional importance and therapeutic potential of antiviral RNAi in mammals.

Abstract Lithium–air batteries (LABs), owing to their ultrahigh theoretical energy density, are recognized as one of the next‐generation energy storage techniques. However, it remains a tricky problem to find highly active cathode catalyst operating within ambient air. In this contribution, a highly active Fe2Mo3O12 (FeMoO) garnet cathode catalyst for LABs is reported. The experimental and theoretical analysis demonstrate that the highly stable polyhedral framework, composed of FeO octahedrons and MO tetrahedrons, provides a highly effective air catalytic activity and long‐term stability, and meanwhile keeps good structural stability. The FeMoO electrode delivers a cycle life of over 1800 h by applying a simple half‐sealed condition in ambient air. It is found that surface‐rich Fe vacancy can act as an O2 pump to accelerate the catalytic reaction. Furthermore, the FeMoO catalyst exhibits a superior catalytic capability for the decomposition of Li2CO3. H2O in the air can be regarded as the main contribution to the anode corrosion and the deterioration of LAB cells could be attributed to the formation of LiOH·H2O at the end of cycling. The present work provides in‐depth insights to understand the catalytic mechanism in air and constitutes a conceptual breakthrough in catalyst design for efficient cell structure in practical LABs.

Acute kidney injury (AKI) is a common clinical complication. Cisplatin (Cis) is an effective chemotherapeutic drug; however, its acute nephrotoxicity often limits its application. The role of liraglutide (Lir), an agonist of the glucagon-like peptide-1 receptor (GLP-1R), has recently attracted increasing attention beyond glycemic regulation. This study showed that Lir significantly ameliorated Cis-induced kidney dysfunction and renal damage. However, this renoprotective effect was partially abolished in GLP-1R knockout (GLP-1R-/-) mice. Furthermore, we synthesized Lir metabolites, GLP-1 (9−37) and GLP-1 (28−37), and found that they also exerted reno-protective effects that were not impaired in GLP-1R-/- mice. We also demonstrated that Lir and its metabolites reduced cisplatin-induced apoptosis in human renal tubular epithelial cells (HK-2). After silencing GLP-1R expression in HK-2 cells with small interfering ribose nucleic acid (siRNA), the protective effect of Lir on HK-2 cells was inhibited, while the protective effects of GLP-1 (9−37) and GLP-1 (28−37) were not affected. Additionally, we demonstrated that Lir and its metabolites inhibited Cis-induced high-mobility group box 1 (HMGB1) nuclear-cytoplasmic translocation and release, and reduced inflammatory cytokines and HMGB1 receptor expression. The exogenous use of recombinant HMGB1 (rHMGB1) dramatically weakened the protective effects of Lir and its metabolites. In conclusion, our study shows that Lir significantly attenuated Cis-induced AKI through GLP-1R dependent and independent pathways, mediated by inhibiting nuclear-cytoplasmic translocation and release of HMGB1. Lir and its metabolites may be effective drugs for treating cisplatin-induced nephrotoxicity.

IntroductionThe ketogenic diet (KD), as a dietary intervention, has gained importance in the treatment of solid organ structural remodeling, but its role in renal fibrosis has not been explored.MethodsMale C57BL/6 mice were fed a normal diet or a KD for 6 weeks prior to unilateral ureteral obstruction (UUO), a well-established in vivo model of renal fibrosis in rodents. Seven days after UUO, serum and kidney samples were collected. Serum β-hydroxybutyrate (β-OHB) concentrations and renal fibrosis were assessed. NRK52E cells were treated with TGFβ1, a fibrosis-inducing cytokine, and with or without β-OHB, a ketone body metabolized by KD, to investigate the mechanism underlying renal fibrosis.ResultsKD significantly enhanced serum β-OHB levels in mice. Histological analysis revealed that KD alleviated structural destruction and fibrosis in obstructed kidneys and reduced the expression of the fibrosis protein markers α-SMA, Col1a1, and Col3a1. Expression of the rate-limiting enzymes involved in fatty acid oxidation (FAO), Cpt1a and Acox1, significantly decreased after UUO and were upregulated by KD. However, the protective effect of KD was abolished by etomoxir (a Cpt1a inhibitor). Besides, our study observed that KD significantly suppressed UUO-induced macrophage infiltration and the expression of IL-6 in the obstructive kidneys. In NRK52E cells, fibrosis-related signaling was increased by TGFβ1 and reduced by β-OHB. β-OHB treatment restored the impaired expression of Cpt1a. The effect of β-OHB was blocked by siRNA targeting free fatty acid receptor 3 (FFAR3), suggesting that β-OHB might function through the FFAR3-dependent pathway.DiscussionOur results highlight that KD attenuates UUO-induced renal fibrosis by enhancing FAO via the FFAR3-dependent pathway, which provides a promising dietary therapy for renal fibrosis.

The development and utilization of land in the main urban area have significantly impacted the stability of the regional geological environment through various means, such as increased load and subway construction, primarily manifested as rock and soil mass deformation leading to geological hazards. Therefore, it is worth exploring how to reduce the occurrence of karst ground subsidence (KGS) through reasonable land development and control measures in the main urban areas with large-scale developments of buried karst formations. This study focuses on the main urban area of Wuhan City. An evaluation model for KGS was constructed using the analytic hierarchy process (AHP) and comprehensive index evaluation method by analyzing the geological conditions that affect KGS. The susceptibility zoning of KGS was obtained with GIS spatial analysis technology. The results show that the susceptible areas can be divided into extreme, high, medium, and weak susceptibility, accounting for 4.93%, 15.30%, 33.21%, and 46.56%, respectively, which are consistent with the distribution density of past KSGs. Furthermore, by selecting the subway construction as a human activity type, it indirectly discusses the influence of land development intensity on KGS. The results show that past KSGs are mainly concentrated in areas with high engineering construction density and significant land development intensity. Based on the above, strategies for regional land development and prevention and control of KGSs are proposed.

Groundwater function zoning is an important means to ensure that groundwater plays its various functions, which can provide a scientific basis for the protection and development of groundwater resources. Water resources are scarce in the Central Plains Urban Agglomeration (CPUA), so it is of great significance to evaluate groundwater vulnerability and to zone groundwater function in this area. In this study, the resource supply function (RSF), eco-environment function (EEF), and geo-environment function (GEF) of groundwater were analyzed using the analytic hierarchy process (AHP), maximum method, and dominant mark method, so as to divide the shallow groundwater function in the plain of the CPUA. The results show that the reservation areas (32.0%) are distributed in the areas from Luoning County to Yanjin County, Changyuan County to Xinzheng County, and the areas near mountainous in the south of the CPUA. The geological-disaster-prone areas (29.5%) are distributed in the areas from Ruyang County to Luohe City, Weihui County to Jiyuan City, Xingyang County to Changge County, Changyuan County to Yuanyang County, and Kaifeng City. The development and utilization areas (6.4%) are distributed near mountainous areas in the CPUA. The ecologically vulnerable areas (7.5%) are distributed in the east of Kaifeng City and the northeast of Xinxiang City. The conservation areas (24.6%) are distributed in the areas from Ruyang County to Wuyang County, Xinzheng County to Xingyang County, the north of Xuchang City, the east of Luohe City, Kaifeng City, and Xinxiang City. In order to better manage the groundwater, this study evaluates the vulnerability of the groundwater using the DRASTIC model and makes a single indicator sensitivity analysis. The results show that the accuracies of indicators D, A, and I are particularly important for this vulnerability evaluation. According to the groundwater vulnerability and the land use types, some suggestions were put forward. The research results can provide a reference for groundwater management and development in the CPUA and other areas.

Hot compression tests are carried out for the 2219 Al alloys, which are prepared by conventional direct chill casting and internal electromagnetic stirring direct chill casting respectively. The processing maps are constructed and the as-deformed microstructures are observed to investigate the effects of internal electromagnetic stirring on the hot deformation of 2219 Al alloy. The results show that the internal electromagnetic stirring expends of stability domain, especially increasing the corresponding range of strain temperature. The suitable deformation parameters of internal electromagnetic stirring direct chill casting 2219 Al alloy includes a relatively lower strain temperature and a relatively higher strain rate. The internal electromagnetic stirring promotes the formation of more homogeneous as-deformed microstructures and more dynamic recrystallization grains.

ABSTRACT Herpes simplex virus 1 (HSV-1) is a DNA virus belonging to the family Herpesviridae. HSV-1 infection causes severe neurological disease in the central nervous system (CNS), including encephalitis. Ferroptosis is a nonapoptotic form of programmed cell death that contributes to different neurological inflammatory diseases. However, whether HSV-1 induces ferroptosis in the CNS and the role of ferroptosis in viral pathogenesis remain unclear. Here, we demonstrate that HSV-1 induces ferroptosis, as hallmarks of ferroptosis, including Fe2+ overload, reactive oxygen species (ROS) accumulation, glutathione (GSH) depletion, lipid peroxidation, and mitochondrion shrinkage, are observed in HSV-1-infected cultured human astrocytes, microglia cells, and murine brains. Moreover, HSV-1 infection enhances the E3 ubiquitin ligase Keap1 (Kelch-like ECH-related protein 1)-mediated ubiquitination and degradation of nuclear factor E2-related factor 2 (Nrf2), a transcription factor that regulates the expression of antioxidative genes, thereby disturbing cellular redox homeostasis and promoting ferroptosis. Furthermore, HSV-1-induced ferroptosis is tightly associated with the process of viral encephalitis in a mouse model, and the ferroptosis-activated upregulation of prostaglandin-endoperoxide synthase 2 (PTGS2) and prostaglandin E2 (PGE2) plays an important role in HSV-1-caused inflammation and encephalitis. Importantly, the inhibition of ferroptosis by a ferroptosis inhibitor or a proteasome inhibitor to suppress Nrf2 degradation effectively alleviated HSV-1 encephalitis. Together, our findings demonstrate the interaction between HSV-1 infection and ferroptosis and provide novel insights into the pathogenesis of HSV-1 encephalitis. IMPORTANCE Ferroptosis is a nonapoptotic form of programmed cell death that contributes to different neurological inflammatory diseases. However, whether HSV-1 induces ferroptosis in the CNS and the role of ferroptosis in viral pathogenesis remain unclear. In the current study, we demonstrate that HSV-1 infection induces ferroptosis, as Fe2+ overload, ROS accumulation, GSH depletion, lipid peroxidation, and mitochondrion shrinkage, all of which are hallmarks of ferroptosis, are observed in human cultured astrocytes, microglia cells, and murine brains infected with HSV-1. Moreover, HSV-1 infection enhances Keap1-dependent Nrf2 ubiquitination and degradation, which results in substantial reductions in the expression levels of antiferroptotic genes downstream of Nrf2, thereby disturbing cellular redox homeostasis and promoting ferroptosis. Furthermore, HSV-1-induced ferroptosis is tightly associated with the process of viral encephalitis in a mouse model, and the ferroptosis-activated upregulation of PTGS2 and PGE2 plays an important role in HSV-1-caused inflammation and encephalitis. Importantly, the inhibition of ferroptosis by either a ferroptosis inhibitor or a proteasome inhibitor to suppress HSV-1-induced Nrf2 degradation effectively alleviates HSV-1-caused neuro-damage and inflammation in infected mice. Overall, our findings uncover the interaction between HSV-1 infection and ferroptosis, shed novel light on the physiological impacts of ferroptosis on the pathogenesis of HSV-1 infection and encephalitis, and provide a promising therapeutic strategy to treat this important infectious disease with a worldwide distribution.

BackgroundWhen thyroid cancer invades the trachea, tumor resection and trachea reconstruction are required. Although the traditional way of anesthesia and tracheal intubation can maintain the necessary ventilation function during the operation, tracheal intubation affects the surgical field of vision and is not conducive to the protection of the recurrent laryngeal nerve beside the trachea during the operation.Case presentationExtracorporeal membrane oxygenation (ECMO) is used to replace traditional tracheal intubation in the process of resection and end-to-end anastomosis of tracheal tumors, and complete tracheal tumor resection and trachea reconstruction are achieved.ConclusionUsing ECMO for thyroid carcinoma resection, invaded trachea resection, and trachea reconstruction is safe and effective, which reduces the obstruction of endotracheal intubation on the operative field, guarantees the rapid and efficient end-to-end anastomosis in the upper trachea, and clearly avoids laryngeal recurrent nerve injury in the process of anastomosis.

Abstract Podocyte injury and loss are critical events in diabetic nephropathy (DN); however, the underlying molecular mechanisms remain unclear. Here, we demonstrate that asparaginyl endopeptidase (AEP) protects against podocyte injury through modulating the dynamics of the cytoskeleton. AEP was highly upregulated in diabetic glomeruli and hyperglycemic stimuli treated-podocytes; however, AEP gene knockout and its compound inhibitor treatment accelerated DN in streptozotocin-induced diabetic mice, whereas specific induction of AEP in glomerular cells attenuated podocyte injury and renal function deterioration. In vitro, elevated AEP was involved in actin cytoskeleton maintenance and anti-apoptosis effects. Mechanistically, we found that AEP directly cleaved the actin-binding protein cofilin-1 after the asparagine 138 (N138) site. The protein levels of endogenous cofilin-1 1-138 fragments were upregulated in diabetic podocytes, consistent with the changes in AEP levels. Importantly, we found that cofilin-1 1-138 fragments were remarkably unphosphorylated than full-length cofilin-1, indicating the enhanced cytoskeleton maintenance activity of cofilin-1 1-138. Then we validated cofilin-1 1-138 could rescue podocytes from cytoskeleton disarrangement and injury in diabetic conditions. Taken together, our data suggest a protective role of elevated AEP in podocyte injury during DN progression through cleaving cofilin-1 to maintain podocyte cytoskeleton dynamics and defend damage.

Abstract Background A key issue for implementation of CRISPR-Cas9 genome editing for plant trait improvement and gene function analysis is to efficiently deliver the components, including guide RNAs (gRNAs) and Cas9, into plants. Plant virus-based gRNA delivery strategy has proven to be an important tool for genome editing. However, its application in soybean which is an important crop has not been reported yet. ALSV (apple latent spherical virus) is highly infectious virus and could be explored for delivering elements for genome editing. Results To develop a ALSV-based gRNA delivery system, the Cas9-based Csy4-processed ALSV Carry (CCAC) system was developed. In this system, we engineered the soybean-infecting ALSV to carry and deliver gRNA(s). The endoribonuclease Csy4 effectively releases gRNAs that function efficiently in Cas9-mediated genome editing. Genome editing of endogenous phytoene desaturase (PDS) loci and exogenous 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) sequence in Nicotiana. benthamiana (N. benthamiana) through CCAC was confirmed using Sanger sequencing. Furthermore, CCAC-induced mutagenesis in two soybean endogenous GW2 paralogs was detected. Conclusions With the aid of the CCAC system, the target-specific gRNA(s) can be easily manipulated and efficiently delivered into soybean plant cells by viral infection. This is the first virus-based gRNA delivery system for soybean for genome editing and can be used for gene function study and trait improvement.

Abstract Objective: To investigate the involvement of IL-6/STAT3 signaling pathway activation in macrophage polarization and bone destruction related to apical periodontitis (AP) stimulated by Porphyromonas gingivalis. Methodology: Macrophage polarization, IL-6/STAT3 expression, and the presence of P. gingivalis were detected in human AP tissues via RT-qPCR, western blotting, and immunohistochemistry staining. Murine bone marrow derived macrophages were isolated and cultured with P. gingivalis W83 in vitro, and levels of macrophage IL-6 expression, STAT3 phosphorylation, and macrophage polarization with or without the selective STAT3 phosphorylation inhibitor Stattic (5 μM) were detected via ELISA, western blotting, RT-qPCR, and flow cytometry, respectively. P. gingivalis-induced murine AP models were constructed, and bone destruction and macrophage polarization in the apical region were evaluated. Transwell co-culture systems were used to investigate the effects of macrophages infected with P. gingivalis on osteogenesis and osteoclastogenesis. Results: P. gingivalis was detected in human AP tissues that highly expressed IL-6/STAT3, and the M1 subtype of macrophages was more abundant in these tissues. P. gingivalis infection induced IL-6 expression, STAT3 phosphorylation, and M1 polarization of macrophages, while 5 μM of Stattic partially abolished these activation effects. Systemic STAT3 blockade via oral administration of Stattic at a dose of 25 mg kg-1 alleviated murine periapical bone resorption and apical infiltration of M1 macrophages induced by P. gingivalis infection in vivo. Furthermore, macrophages infected with P. gingivalis promoted bone destruction via secretion of IL-6, TNF-α, and RANKL, which hinder pre-osteoblast expression of Runx2 and accelerate pre-osteoclast expression of NFAT2. Conclusions: The activation of IL-6/STAT3 signaling pathway is involved in mediating macrophages M1 polarization in the P. gingivalis induced apical inflammatory context and may also be intimately involved in the bone loss caused by P. gingivalis infection, directing the M1 macrophage infiltration during the progression of AP.