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Multifunctional therapeutics have emerged as a solution to the constraints imposed by drugs with singular or insufficient therapeutic effects. The primary challenge is to integrate diverse pharmacophores within a single-molecule framework. To address this, we introduced DeepSA, a novel edit-based generative framework that utilizes deep simulated annealing for the modification of articaine, a well-known local anesthetic. DeepSA integrates deep neural networks into metaheuristics, effectively constraining molecular space during compound generation. This framework employs a sophisticated objective function that accounts for scaffold preservation, anti-inflammatory properties, and covalent constraints. Through a sequence of local editing to navigate the molecular space, DeepSA successfully identified AT-17, a derivative exhibiting potent analgesic properties and significant anti-inflammatory activity in various animal models. Mechanistic insights into AT-17 revealed its dual mode of action: selective inhibition of NaV1.7 and 1.8 channels, contributing to its prolonged local anesthetic effects, and suppression of inflammatory mediators via modulation of the NLRP3 inflammasome pathway. These findings not only highlight the efficacy of AT-17 as a multifunctional drug candidate but also highlight the potential of DeepSA in facilitating AI-enhanced drug discovery, particularly within stringent chemical constraints.

In recent years, China's advanced light sources have entered a period of rapid construction and development. As modern X-ray detectors and data acquisition technologies advance, these facilities are expected to generate massive volumes of data annually, presenting significant challenges in data management and utilization. These challenges encompass data storage, metadata handling, data transfer and user data access. In response, the Data Organization Management Access Software (DOMAS) has been designed as a framework to address these issues. DOMAS encapsulates four fundamental modules of data management software, including metadata catalogue, metadata acquisition, data transfer and data service. For light source facilities, building a data management system only requires parameter configuration and minimal code development within DOMAS. This paper firstly discusses the development of advanced light sources in China and the associated demands and challenges in data management, prompting a reconsideration of data management software framework design. It then outlines the architecture of the framework, detailing its components and functions. Lastly, it highlights the application progress and effectiveness of DOMAS when deployed for the High Energy Photon Source (HEPS) and Beijing Synchrotron Radiation Facility (BSRF).

State-of-health (SOH) estimation of lithium-ion batteries stands as a fundamental metric within the battery management system. It reflects the current level of battery aging and is important for early warning of battery failure to avoid unsafe battery behavior. Therefore, accurate SOH estimation can ensure safe and reliable battery operation. In this paper, the capacity data of the discharge phase are used as the input of the SOH estimation model, and a gray wolf optimization (GWO)–variable mode decomposition (VMD)-transformer-based SOH estimation method for lithium-ion batteries is proposed in a data-driven framework. First, the GWO algorithm is adopted to optimize VMD to decompose the original battery capacity degradation sequence into a series of intrinsic mode functions (IMFs). Then, the transformer is used to separately predict each of these IMFs. Finally, the predicted values of each IMF are integrated to obtain the final prediction of the battery capacity degradation sequence. The model undergoes testing across various datasets, and comparative evaluations are conducted against other data-driven prediction models. The experimental findings underscore the superior SOH estimation performance of the proposed method, along with its robustness when confronted with diverse types of lithium-ion batteries, spanning distinct operational conditions and different aging degrees.

Abstract Objectives To compare the efficacy, overall survival (OS) and safety of drug-eluting beads-TACE (DEB-TACE) and C-TACE as initial treatment in advanced hepatocellular carcinoma (HCC) patients with main portal vein tumor thrombus (mPVTT). Methods The medical records of consecutive advanced HCC patients with mPVTT who underwent initial DEB-TACE or C-TACE from September 2015 to October 2021 were retrospectively evaluated. Treatment crossover was allowed in this retrospective research. The adverse events, disease control rate (DCR), time to tumor progression (TTP) and OS of patients who underwent DEB-TACE were compared with those of patients who underwent C-TACE. Results Eighty-three patients were included: 42 patients in DEB-TACE group and 41 patients in C-TACE group. DEB-TACE could be safely performed in HCC patients with mPVTT, and they gained a better DCR than those submitted to the C-TACE (76.2% vs. 53.7%, P = 0.031), which might have resulted in longer TTP (median TTP: 9.0 months vs. 3.0 months, P

Background: Hypoxia has been shown to induce cancer cells to become dormant meanwhile these cells inclined to disseminate and eventually cause metastasis. However, the molecular mechanism is still elusive. The purpose is to explore whether dormancy-associated microRNAs (DmiRs) get involved in hypoxia-induced cell dormancy of salivary adenoid cystic carcinoma (SACC). Material and Methods: This study performed multi-perspective investigation of the biological effects of miR-922/DEC2 on SACC based on clinical samples, 2D and 3D in vitro model and nude mice in vivo model, based on our previous study of overexpression of DEC2 inducing SACC cellular dormancy. Results: According to the existing microRNA array of SACC tissue, we found that miR-922 was upregulated in SACC tissue and was inversely correlated with DEC2, suggesting that miR-922 might participate in the activation of SACC cell dormancy as a DmiR. Then, we found miR-922 low SACC cells exhibited cell dormancy and a low level of fatty acid oxidation with propensity for lipid droplets accumulation through DEC2. Moreover, HIF1a downregulated the level of miR-922 to induce SACC cell dormancy. In addition, in xenografts of nude mice the inhibition of miR-922 attenuated the growth of primary tumor and the lung metastasis of SACC. Conclusions: miR-922/DEC2 axis was necessary to hypoxia-induced cell dormancy and played an important role in the lipid metabolism reprogramming of SACC.

Background Although the roles of PD-L1 in promoting tumor escape from immunosurveillance have been extensively addressed, its non-immune effects on tumor cells remain unclear.Methods The spatial heterogeneity of PD-L1 staining in human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) tissues was identified by immunohistochemistry. Three-dimensional (3D) specific cell-led invasion assay and 3D cancer spheroid model were used to investigate the roles of PD-L1hileader cells in collective invasion. The impact of M1 macrophages on specific PD-L1 expression in leader cells and its mechanisms were further studied. Finally, the effect of combination therapy of anti-PD-L1 and CDK4 inhibitor on HPV-positive tumors were evaluated on a mice model.Results Here, we observed a distinctive marginal pattern of PD-L1 expression in HPV-positive HNSCC tissues. By mimicking this spatial pattern of PD-L1 expression in the 3D invasion assay, we found that PD-L1hi cells led the tumor collective invasion. M1 macrophages induced specific PD-L1 expression in leader cells, and depletion of macrophages in tumor-bearing mice abrogated PD-L1hileader cells and collective invasion. Mechanistically, TNF-α secreted by M1 macrophages markedly increased the abundance of PD-L1 via CDK4/ubiquitin-specific peptidase 14-mediated deubiquitination of PD-L1. We also found that suppression of CDK4 enhanced the efficacy of anti-PD-L1 therapy in an E6/E7 murine model.Conclusions Our study identified TNF-α/CDK4/ubiquitin-specific peptidase 14-mediated PD-L1 stability as a novel mechanism underlying M1 macrophage-induced PD-L1hileader cells and collective tumor invasion, and highlighted the potential of the combination therapy of anti-PD-L1 and CDK4 inhibitor for HPV-positive HNSCC.

Abstract Spinal cord injury (SCI) can result in irreversible sensory and motor disability with no effective treatment currently. After SCI, infiltrated macrophages accumulate in epicenter through destructed blood-spinal cord barrier (BSCB). Further, great majority of macrophages are preferentially polarized to M1 phenotype, with only a few transient M2 phenotype. The purpose of this study was to explore roles of vascular endothelial cells in microglia/macrophages polarization and the underlying mechanism. Lipopolysaccharide (LPS) was used to pretreat BV2 microglia and RAW264.7 macrophages followed by administration of conditioned medium from microvascular endothelial cell line bEnd.3 cells (ECM). Analyses were then performed to determine the effects of exosomes on microglia/macrophages polarization and mitochondrial function. The findings demonstrated that administration of ECM shifted microglia/macrophages towards M2 polarization, ameliorated mitochondrial impairment, and reduced reactive oxygen species (ROS) production in vitro. Notably, administration of GW4869, an exosomal secretion inhibitor, significantly reversed these observed benefits. Further results revealed that exosomes derived from bEnd.3 cells (Exos) promote motor rehabilitation and M2 polarization of microglia/macrophages in vivo. Ubiquitin-specific protease 13 (USP13) was shown to be significantly enriched in BV2 microglia treated with Exos. USP13 binds to, deubiquitinates and stabilizes the NF-κB inhibitor alpha (IκBα), thus regulating microglia/macrophages polarization. Administration of the selective IκBα inhibitor betulinic acid (BA) inhibited the beneficial effect of Exos in vivo. These findings uncovered the potential mechanism underlying the communications between vascular endothelial cells and microglia/macrophages after SCI. In addition, this study indicates exosomes might be a promising therapeutic strategy for SCI treatment.

Background The incidence and mortality of hepatocellular carcinoma (HCC) had increased globally over the past decades. Previous studies found that transarterial chemoembolization (TACE) combined with lenvatinib had also shown efficacy in the unresectable HCC. We aimed to evaluate the safety and efficacy of TACE combined with lenvatinib and camrelizumab to treat unresectable multiple nodular and large HCC (>5 cm). Materials and methods Between November 2018 and June 2021, we retrospectively recruited 82 patients with unresectable multiple nodular and large HCC (BCLC stage B or C with a single nodular diameter of >5 cm). Of the patients who had not previously been treated, 33 patients received TACE + lenvatinib + camrelizumab (group A, TLC), and 49 patients treated with TACE + lenvatinib (group B, TLB) as the initial treatment. Related efficacy and safety results were recorded and assessed. Results The median follow-up periods of groups A and B were 14.5 ± 7.9 months (range, 3-36) and 12.5 ± 8.2 months (range, 3-32), respectively (P = 0.799). The progression-free survival (PFS) of groups A and B was 9.4 months and 5.9 months (P 5 cm), TACE combined with target therapy and immunotherapy is safe and effective.

Background and aim: Percutaneous transhepatic biliary drainage (PTBD) does not always lead to a reduction in serum total bilirubin (TBil) level in patients with hepatocellular carcinoma and obstructive jaundice. We aimed to develop a model for pre-PTBD prediction of post-procedural TBil decrease in these patients. Materials and methods: Retrospective database searches were conducted at four teaching hospitals (reference period: January 2010 to December 2018), and baseline characteristics of eligible patients were extracted. Any decrease in TBil after PTBD and the lowest level of TBil post-PTBD

Abstract Background Conventional-transarterial chemoembolization (C-TACE) was proven to improve overall survival (OS) in hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT), drug-eluting microsphere-TACE (DEM-TACE) was supposed to provide more benefit than C-TACE in this respect. Purpose To compare the safety and efficacy between DEM-TACE and C-TACE as the initial treatment in HCC patients with PVTT and to identify prognostic factors of OS. Methods The medical records of advanced HCC patients with PVTT who underwent DEM-TACE or C-TACE as the initial thearpy from September 2015 with mean follow-up time 14.9 ± 1.2 (95% CI 12.6–17.2) months were retrospectively evaluated. A total of 97 patients were included, 49 patients in the DEM-TACE group and 48 in the C-TACE group. Adverse events (AEs) related to TACE were compared. Tumor and PVTT radiologic response, time to tumor progression (TTP) and OS were calculated and compared in both groups. Results Patients in DEM-TACE group had a better radiologic response (Tumr response: 89.8% vs. 75.0%; PVTT response: 85.7% vs. 70.8%; overall response: 79.6% vs. 58.3%, P = 0.024) and longer TTP (7.0 months vs. 4.0 months, P = 0.040) than patients in C-TACE group. A lower incidence of abdominal pain was found in the DEM-TACE group than in C-TACE group (21 vs. 31, P = 0.032), but there were no significant differences between DEM-TACE and C-TACE patients in any other AEs reported. When compared to C-TACE, DEM-TACE also showed significant OS benefits (12.0 months vs. 9.0 months, P = 0.027). DEM-TACE treatment, the absence of arterioportal shunt (APS), lower AFP value and better PVTT radiologic response were the independent prognostic factors for OS in univariate/multivariate analyses, which provided us with a guide for better patient selection. Conclusions Based on our retrospective study, DEM-TACE can be performed safely and might be superior to C-TACE as the initial treatment for HCC patients with PVTT. Trial registration Retrospectively registered.

Abstract The uptake of hexavalent chromium (Cr(VI)) ions from wastewater is of great significance for environmental remediation and resource utilization. In this study, a self‐designed instrument equipped with an oxidized mesoporous carbon monolith (o‐MCM) as an electro‐adsorbent is developed. o‐MCM with a super hydrophilic surface displayed a high specific surface area (up to 686.5 m2 g−1). With the assistance of an electric field (0.5 V), the removal capacity of Cr(VI) ions is as high as 126.6 mg g−1, much higher than that without an electric field (49.5 mg g−1). During this process, no reduction reaction of Cr(VI) to Cr(III) ions is observed. After adsorption, the reverse electrode with 10 V is used to efficiently desorb the ions on the carbon surface. Meanwhile, the in situ regeneration of carbon adsorbents can be obtained even after ten recycles. On this basis, the enrichment of Cr(VI) ions in a special solution is achieved with the assistance of an electric field. This work lays a foundation for the uptake of heavy metal ions from wastewater with the assistance of the electric field.

In this study, a portable spectral analysis instrument based on spontaneous emission spectroscopy (SES) was developed for the in situ, non-intrusive, and quantitative measurement of gaseous Na inside ZD coal-fired boilers, which is mainly applied for predicting slagging in furnaces. This technology is needed urgently because the problem of fouling and slagging caused by high alkali metals in ZD coal restricts the rational utilization of this coal. The relative extended uncertainty for the measurement of gaseous Na concentration is Urel = 10%, k = 2, which indicates that measurement data are reliable under working conditions. It was found that there is a clear linear relationship between the concentration of gaseous Na and fouling in high-alkali coal boilers. Therefore, a fast and efficient method for predicting the slagging and fouling of high-alkali coal boilers can be established by using this in situ online real-time optical measurement.

The large-scale deployment of carbon capture and storage (CCS) is becoming increasingly urgent in the global path toward net zero emissions; however, global CCS deployment is significantly lagging behind its expected contribution to greenhouse gas emission reduction. Reviewing and learning from the examples and history of successful CCS practices in advanced countries will help other countries, including China, to promote and deploy CCS projects using scientific methods. This paper shows that the establishment of major science and technology CCS infrastructures in advanced countries has become the main source of CCS technological innovation, cost reduction, risk reduction, commercial promotion, and talent training in the development and demonstration of key CCS technologies. Sound development of CCS requires a transition from pilot-scale science and technology infrastructures to large-scale commercial infrastructures, in addition to incentive policies; otherwise, it will be difficult to overcome the technical barriers between small-scale demonstrations and the implementation of million-tonne-scale CCS and ten-million-tonne-scale CCS hubs. Geological CO2 storage is the ultimate goal of CCS projects and the driving force of CO2 capture. Further improving the accuracy of technologies for the measurement, monitoring, and verification (MMV) of CO2 storage capacity, emission reduction, and safety remains a problem for geological storage. CO2 storage in saline aquifers can better couple multiple carbon emission sources and is currently a priority direction for development. Reducing the energy consumption of low-concentration CO2 capture and the depletion of chemical absorbents and improving the operational efficiency and stability of post-combustion CO2 capture systems have become the key constraints to large-scale CCS deployment. Enhanced oil recovery (EOR) is also important in order for countries to maximize fossil fuel extraction instead of importing oil from less environmentally friendly oil-producing countries.

Accurate characterization of land use and land cover changes (LULCC) is essential for numerical models to capture LULCC-induced effects on regional meteorology and air quality, while outdated LULC dataset largely limits model capability in reproducing land surface parameters, particularly for complex terrain. In this study, we incorporate land cover data from MODIS in 2019 into the Weather Research and Forecasting (WRF) model to simulate the impacts of LULC on meteorological parameters over the Sichuan Basin (SCB). Further, we conduct Community Multiscale Air Quality (CMAQ) simulations with WRF default LULC and MODIS 2019 to probe the effects on regional air quality. Despite consistency found between meteorological observations and WRF-CMAQ simulations, the default WRF land cover data does not accurately capture rapid urbanization over time compared with MODIS. Modeling results indicate that magnitude changes trigged by LULCC are highly varied across SCB and the impacts of LULCC are more pronounced over extended metropolitan areas due to alteration by urbanization, featured by elevating 2-m temperature up to 2°C and increased planetary boundary layer height (PBLH) up to 400 m. For air quality implications, it is found that LULCC leads to basin-wide O3 enhancements with maximum reaching 21.6 μg/m3 and 57.2 μg/m3 in the daytime and nighttime, respectively, which is mainly attributed to weakening NOx titration effects at night. This work contributes modeling insights into quantitative assessment for impacts of LULCC on regional meteorology and air quality which pinpoints optimization of the meteorology-air quality model.

Rapid urbanization has the potential to fundamentally perturb energy budget and alter urban air quality. While it is clear that urban meteorological parameters are sensitive to urbanization-induced changes in landscapes, a gap exists in our knowledge about how changes in land use and land cover affect the dynamics of urban air quality. Herein, we simulated a severe O3 episode (10–16 July 2017) and a highly polluted PM2.5 episode (25–30 December 2017) and assessed the changes of meteorological phenomenon and evolution of air pollutants induced by urbanization. We found that the urban expansion area (i.e., land use transition from natural to urban surfaces between 2000 and 2017, UEA) has a significant increase in nocturnal 2-m temperature (T2) with maximum values reaching 3 and 4°C in summer and winter, respectively. In contrast, UEA experienced cooling in the daytime with stronger reductions of T2 in winter than in summer. The T2 variability is primarily attributed to the intense thermal inertia and high heat capacity of the urban canopy and the shadowing effect caused by urbanization. Owing to increased surface roughness and decreased surface albedo as well as shadowing effects, the ventilation index (VI) of UEA increased up to 1,200 m2/s in winter while decreased up to 950 m2/s in summer. Changes in meteorological phenomenon alter physical and chemical processes associated with variations in PM2.5 and O3 concentrations. Urbanization leads to enhanced vertical advection process and weakened aerosol production, subsequently causing PM2.5 levels to decrease by 33.2 μg/m3 during the day and 4.6 μg/m3 at night, respectively. Meanwhile, O3 levels increased by 61.4 μg/m3 at 20:00 due to the reduction of horizontal advection induced by urbanization, while O3 concentrations changed insignificantly at other times. This work provides valuable insights into the effects of urbanization on urban meteorology and air quality over typical megacities, which support informed decision-making for urban heat and air pollution mitigation.

Head and neck squamous cell carcinomas (HNSCCs) are closely linked with immunosuppression, accompanied by complex immune cell functional activities. The abnormal competition between costimulatory and coinhibitory signal molecules plays an important role in the malignant progression of HNSCC. This review will summarize the features of costimulatory molecules (including CD137, OX40 as well as CD40) and coinhibitory molecules (including CTLA-4, PD-1, LAG3, and TIM3), analyze the underlying mechanism behind these molecules' regulation of the progression of HNSCC, and introduce the clinic application. Vaccines, such as those targeting STING while working synergistically with monoclonal antibodies, are also discussed. A deep understanding of the tumor immune landscape will help find new and improved tumor immunotherapy for HNSCC.