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In advanced hepatocellular carcinoma (HCC) tissues, M2-like tumor-associated macrophages (TAMs) are in the majority and promotes HCC progression. Contrary to the pro-tumor effect of M2-like TAMs, M1-like TAMs account for a small proportion and have anti-tumor effects. Since TAMs can switch from one type to another, reprogramming TAMs may be an important treatment for HCC therapy. However, the mechanisms of phenotypic switch and reprogramming TAMs are still obscure. In this study, we analyzed differential genes in normal macrophages and TAMs, and found that loss of MANF in TAMs accompanied by high levels of downstream genes negatively regulated by MANF. MANF reprogrammed TAMs into M1 phenotype. Meanwhile, loss of MANF promoted HCC progression in HCC patients and mice HCC model, especially tumor neovascularization. Additionally, macrophages with MANF supplement suppressed HCC progression in mice, suggesting MANF supplement in macrophage was an effective treatment for HCC. Mechanistically, MANF enhanced the HSF1–HSP70-1 interaction, restricted HSF1 in the cytoplasm of macrophages, and decreased both mRNA and protein levels of HSP70-1, which in turn led to reprogramming TAMs, and suppressing neovascularization of HCC. Our study contributes to the exploration the mechanism of TAMs reprogramming, which may provide insights for future therapeutic exploitation of HCC neovascularization.

Abstract Combining edge devices with intelligent inspection for transmission lines can fulfill the demand for real‐time defect detection in the field. However, there has been limited research on algorithms suitable for edge devices with low computational power and memory, and the existing research primarily focuses on CPU optimization. To address these issues, this paper proposes a real‐time defect detection method for transmission line endpoints based on YOLO‐GSS (YOLOv8 with Mosaic‐9, G‐GhostNet, S‐FPN, and Spatial Intersection over Union (SIoU) modifications). First, the authors improve the input of the YOLOv8 network using Mosaic‐9 to increase the number of input features in the training phase and enhance algorithm robustness. Next, the authors introduce G‐GhostNet and S‐FPN to enhance the backbone and neck sections while improving inference speed and accuracy. Finally, the authors modify the Complete Intersection over Union loss function of YOLOv8 using SIoU to further improve the detection accuracy. Experimental results demonstrate that compared to the original YOLOv8, the proposed method achieves a 5x increase in inference speed on Nvidia Jetson NX edge devices and a 7.7% improvement in accuracy, meeting the real‐time defect detection requirements for transmission line field inspections.

Abstract Objective This study aimed to examine the clinical and multimodal ultrasonic characteristics differences between carotid web (CW) and CW with plaque as well as the potential risk factors for stroke caused by CW. Methods We retrospectively enrolled patients diagnosed with CW by CTA or high-resolution MRI (HRMRI) and simultaneously underwent contrast enhanced ultrasound (CEUS) and superb microvascular imaging examinations from January 2015 to October 2022. The CW angle was measured using computer-aided software. The variations between CW and CW with plaque were evaluated, and univariable and multivariable logistic regressions were utilized to identify possible risk predictors for stroke caused by CW. Results Two hundred ninety-nine patients with an average age of 60.85 (± 8.77) years were included. Sex, age, history of smoking, alcohol, hypertension, diabetes mellitus, homocysteine level, and treatment, as well as web length and thickness, luminal stenosis, location wall, number, CW angle, and CEUS enhancement, were quite different among CW and CW with plaque patients (p

Abstract Simultaneous improvement of strength and conductivity is urgently demanded but challenging for bimetallic materials. Here we show by creating a self-assembled lamellar (SAL) architecture in W-Cu system, enhancement in strength and electrical conductivity is able to be achieved at the same time. The SAL architecture features alternately stacked Cu layers and W lamellae containing high-density dislocations. This unique layout not only enables predominant stress partitioning in the W phase, but also promotes hetero-deformation induced strengthening. In addition, the SAL architecture possesses strong crack-buffering effect and damage tolerance. Meanwhile, it provides continuous conducting channels for electrons and reduces interface scattering. As a result, a yield strength that doubles the value of the counterpart, an increased electrical conductivity, and a large plasticity were achieved simultaneously in the SAL W-Cu composite. This study proposes a flexible strategy of architecture design and an effective method for manufacturing bimetallic composites with excellent integrated properties.

Abstract Background Fatigue is a common symptom of long COVID syndrome. Compared to male survivors, females have a higher incidence of post-COVID fatigue. Therefore, long-term follow-up is necessary to understand which groups of females are more vulnerable to post-COVID fatigue. Methods This is a nested case–control study of female COVID-19 survivors who were discharged from two designated hospitals in Wuhan, China in 2020, and received 2-year follow-up from March 1 to April 6, 2022. All patients completed the Checklist Individual Strength-subscale subjective fatigue (CIS-fatigue), a chronic obstructive pulmonary disease (COPD) assessment test (CAT), and the Hospital Anxiety and Depression Scale (HADS; including the HADS-Anxiety [HADS-A] and the HADS-Depression [HADS-D]). Individuals with CIS-fatigue scores of 27 or higher were classified as cases. The risk factors for fatigue was analysed with multivariable logistic regression analysis. Results A total of 899 female COVID-19 survivors were enrolled for analysis, including 47 cases and 852 controls. Compared with controls, cases had higher CAT, HADS-A and HADS-D scores, and showed a higher prevalence of symptoms, including anxiety (cases vs. controls, 44.7% vs. 4.0%, p

The additions of microbial organic fertilizer (MOF), a microbial inoculant (MI), and quicklime (Q) are considered to be sustainable practices to restore land that has been damaged by continuous cropping of pepper (Capsicum annuum L.). However, the combined effects of these three additives on pepper yield, soil chemical properties, and soil microbial communities were unclear. The experimental design consists of 13 treatment groups: the untreated soil (control); soil amended solely with three treatments for each of MOF (1875–5625 kg ha−1), MI (150–450 mL plant−1), and Q (1500–4500 kg ha−1); and soil amended with combinations of MOF, MI, and Q at three comparable concentrations. A significant increase in pepper fruit diameter, length, yield, and soil available nitrogen, phosphorus, and potassium contents occurs upon exclusive and combined applications of MOF, MI, and Q. Pepper yield was greatest (29.89% more than control values) in the combined treatment with concentrations of 1875 kg ha−1 MOF, 150 mL plant−1 MI, and 1500 kg ha−1 Q. The application of Q increased soil pH and reduced soil–fungal richness. The application of MOF, MI, and Q increased the relative abundance of bacterial genera and the complexity of bacterial and fungal co-occurrence networks compared with control levels. The combined application of MOF, MI, and Q resulted in the greatest microbial network complexity. A Mantel test revealed the key role of soil available nitrogen content and bacterial diversity in the regulation of pepper growth and yield. We conclude that the combined application of MOF, MI, and Q improves soil nutrient availability and modifies soil microbial community composition, significantly promoting plant growth and pepper yield during continuous cultivation.

Traditional path planning algorithms typically focus only on path length, which fails to meet the low energy consumption requirements for wall-climbing robots in bridge inspection. This paper proposes an improved sparrow search algorithm based on logistic–tent chaotic mapping and differential evolution, aimed at addressing the issue of the sparrow search algorithm’s tendency to fall into local optima, thereby optimizing path planning for bridge inspection. First, the initial population is optimized using logistic–tent chaotic mapping and refracted opposition-based learning, with dynamic adjustments to the population size during the iterative process. Second, improvements are made to the position updating formulas of both discoverers and followers. Finally, the differential evolution algorithm is introduced to enhance the global search capability of the algorithm, thereby reducing the robot’s energy consumption. Benchmark function tests verify that the proposed algorithm exhibits superior optimization capabilities. Further path planning simulation experiments demonstrate the algorithm’s effectiveness, with the planned paths not only consuming less energy but also exhibiting shorter path lengths, fewer turns, and smaller steering angles.

The mesencephalic astrocyte-derived neurotrophic factor (MANF) has been recently identified as a neurotrophic factor, but its role in hepatic fibrosis is unknown. Here, we found that MANF was upregulated in the fibrotic liver tissues of the patients with chronic liver diseases and of mice treated with CCl4. MANF deficiency in either hepatocytes or hepatic mono-macrophages, particularly in hepatic mono-macrophages, clearly exacerbated hepatic fibrosis. Myeloid-specific MANF knockout increased the population of hepatic Ly6Chigh macrophages and promoted HSCs activation. Furthermore, MANF-sufficient macrophages (from WT mice) transfusion ameliorated CCl4-induced hepatic fibrosis in myeloid cells-specific MANF knockout (MKO) mice. Mechanistically, MANF interacted with S100A8 to competitively block S100A8/A9 heterodimer formation and inhibited S100A8/A9-mediated TLR4–NF-κB signal activation. Pharmacologically, systemic administration of recombinant human MANF significantly alleviated CCl4-induced hepatic fibrosis in both WT and hepatocytes-specific MANF knockout (HKO) mice. This study reveals a mechanism by which MANF targets S100A8/A9-TLR4 as a “brake” on the upstream of NF-κB pathway, which exerts an impact on macrophage differentiation and shed light on hepatic fibrosis treatment.

Corneal endothelial keratoplasty has been the primary treatment method of endothelial decompensation, but it is often limited in clinical practice due to global shortage of donor cornea. Here, we explored using an ultra-thin allogeneic cornea-derived matrix (uACM) films as a substrate for constructing bioengineered corneal endothelial grafts. We evaluated the films' optical, mechanical, and structural properties, and measured the composition of the extracellular matrix. The uACM was an ultrathin and curved cornea-shaped film with favorable optical and mechanical properties. The fabrication process efficiently preserved corneal extracellular matrix composition and significantly decreased cellular components. Moreover, human corneal endothelial cells and rabbit corneal endothelial cells (RCECs) can adhere and grow on the uACM films with a positive expression of the corneal endothelial functional markers Na+/K+-ATPase and ZO-1. The successful transplantation of uACM with RCECs grafts into the rabbit model of endothelial dysfunction via Descemet membrane endothelial keratoplasty resulted in prompt restoration of corneal transparency and thickness. During the four-week follow-up period, the uACM with RCECs implanted eyes exhibited comparable corneal transparency, central corneal thickness, and endothelial cell count to that of the healthy rabbit. Histologic examination revealed that the grafts were successfully attached and integrated onto the posterior surface of the corneal stroma. The uACM achieved biomimetic reconstruction in terms of both composition and structure, and can be used to construct the bioengineered corneal endothelial grafts. These results indicate that constructing bioengineered corneal endothelial grafts from discarded human corneal tissues may pave the way for generating high-quality corneal endothelial grafts for transplantation.

Abstract Background Chromatin-associated phase separation proteins establish various biomolecular condensates via liquid–liquid phase separation (LLPS), which regulates vital biological processes spatially and temporally. However, the widely used methods to characterize phase separation proteins are still based on low-throughput experiments, which consume time and could not be used to explore protein LLPS properties in bulk. Results By combining gradient 1,6-hexanediol (1,6-HD) elution and quantitative proteomics, we developed chromatin enriching hexanediol separation coupled with liquid chromatography-mass spectrometry (CHS-MS) to explore the LLPS properties of different chromatin-associated proteins (CAPs). First, we found that CAPs were enriched more effectively in the 1,6-HD treatment group than in the isotonic solution treatment group. Further analysis showed that the 1,6-HD treatment group could effectively enrich CAPs prone to LLPS. Finally, we compared the representative proteins eluted by different gradients of 1,6-HD and found that the representative proteins of the 2% 1,6-HD treatment group had the highest percentage of IDRs and LCDs, whereas the 10% 1,6-HD treatment group had the opposite trend. Conclusion This study provides a convenient high-throughput experimental method called CHS-MS. This method can efficiently enrich proteins prone to LLPS and can be extended to explore LLPS properties of CAPs in different biological systems.

The challenge of fabricating nanostructured W–Cu composites by powder metallurgy has been solved by means of modulated phase separation. A hierarchically nanostructured (HN) W–Cu composite was prepared using intermediary Al through sluggish asynchronous phase separation. In addition to a dual network composed of a Cu phase and the W–Cu nanostructure, dense Al-containing nanoprecipitates with a body-centered cubic (bcc) structure are distributed in the W matrix. Compared with a pristine W/Cu interface, the newly formed W/Cu interfaces modulated by Al and the coherent W/Al-containing particle interfaces possess lower energy and enhanced bonding strength due to efficient electron transfer and strong coupling interactions. With a large number of stable heterogeneous interfaces and a “self-locking” geometry, the HN W–Cu composite exhibits excellent resistance against plastic deformation. The combination of the presented composite’s hardness and compressive strength outperforms all other sintered W–Cu composites with the same Cu content. Under a reciprocating sliding load, the reactive Al prevents excessive oxidation. The excellent synergy of the hardness and toughness of the friction-induced surface endows the HN composite with high abrasion resistance. This study provides a new strategy to modulate the structure and energy state of interfaces in metallic composites containing immiscible components in order to achieve high mechanical performance.

In order to ensure the accuracy and reliability of high resolution mass spectrometry for the determination of sildenafil derivatives in aphrodisiac oral liquid, it is necessary to evaluate the uncertainty of the determination results. In this study, the content of 6 sildenafil derivatives in oral liquid health food was determined by ultra-high performance liquid chromatography with quadrupole/electrostatic field Orbitrap high resolution mass spectrometry (UPLC-Q/Orbitrap HRMS). The mathematical model was established and the measurement uncertainty was evaluated according to JJF 1059.1-2012 “Evaluation and Expression of Measurement Uncertainty”. When the contents of N-demethyl sildenafil, dimethyl thiosildenafil, dimethyl sildenafil, hydroxythiocarmo sildenafil, thiocarmo sildenafil and thiosildenafil in oral solution were 0.90, 1.04, 1.22, 2.01, 1.51 and 1.14 mg/kg, the extended uncertainties were 0.07, 0.09, 0.10, 0.16, 0.13 and 0.09 mg/kg (k=2), respectively. The results show that the uncertainty mainly comes from UPLC-Q/Orbitrap HRMS, standard solution preparation, recovery and random effect.

Transcranial sonography (TCS) has been introduced to assess hyper-echogenicity in the substantia nigra of the midbrain for Parkinson’s disease (PD); however, its subjective and resource-demanding nature has impeded its widespread application. An AI-empowered TCS-based PD classification tool is greatly demanding, yet relevant research is severely scarce. Therefore, we proposed a novel dual-channel CNXV2-DANet for TCS-based PD classification using a large cohort. A total of 1176 TCS images from 588 subjects were retrospectively enrolled from Beijing Tiantan Hospital, encompassing both the left and right side of the midbrain for each subject. The entire dataset was divided into a training/validation/testing set at a ratio of 70%/15%/15%. Development of the proposed CNXV2-DANet was performed on the training set with comparisons between the single-channel and dual-channel input settings; model evaluation was conducted on the independent testing set. The proposed dual-channel CNXV2-DANet was compared against three state-of-the-art networks (ConvNeXtV2, ConvNeXt, Swin Transformer). The results demonstrated that both CNXV2-DANet and ConvNeXt V2 performed more superiorly under dual-channel inputs than the single-channel input. The dual-channel CNXV2-DANet outperformed the single-channel, achieving superior average metrics for accuracy (0.839 ± 0.028), precision (0.849 ± 0.014), recall (0.845 ± 0.043), F1-score (0.820 ± 0.038), and AUC (0.906 ± 0.013) compared with the single channel metrics for accuracy (0.784 ± 0.037), precision (0.817 ± 0.090), recall (0.748 ± 0.093), F1-score (0.773 ± 0.037), and AUC (0.861 ± 0.047). Furthermore, the dual-channel CNXV2-DANet outperformed all other networks (all p-values < 0.001). These findings suggest that the proposed dual-channel CNXV2-DANet may provide the community with an AI-empowered TCS-based tool for PD assessment.

Background The management of nonacute symptomatic internal carotid artery occlusion remains unsatisfactory. Endovascular recanalization has been reported to be feasible but associated with a noteworthy risk of postprocedural complications in patients with symptomatic internal carotid artery occlusion. The present study aimed to investigate whether successful recanalization exerts clinical benefits over procedural risks. Methods We analyzed consecutive patients who underwent endovascular treatment of nonacute symptomatic internal carotid artery occlusion in a nationwide prospective registry. The primary outcome was the ipsilateral ischemic stroke recurrence. Other outcomes of interest included all strokes and death during follow‐up, and 30‐day symptomatic intracranial hemorrhage, and all strokes after intervention. Results The final analysis included 511 patients. Endovascular revascularization was successful in 300 patients (58.7%) but failed in 211 patients (41.3%). Patients with successful recanalization had less time from the last ischemic event to the endovascular treatment as compared with patients with failed recanalization (median [interquartile range] days, 18 [12–33] versus 22 [14–50]; P=0.003). Successful recanalization was associated with a higher rate of symptomatic intracranial hemorrhage within 30 days after intervention (odds ratio [OR], 7.99 [95% CI, 1.02–62.39]; P=0.047). Thirty‐day all strokes (OR, 1.91 [95% CI, 0.83–4.40]; P=0.128) and ischemic stroke (OR, 0.90 [95% CI, 0.33–2.46]; P=0.839) did not differ significantly. During a median follow‐up of 37 months, patients with successful recanalization demonstrated a reduced risk of ipsilateral ischemic stroke (adjusted hazard ratio, 0.28 [95% CI, 0.13–0.59]; P

Artificial intelligence of things systems equipped with flexible sensors can autonomously and intelligently detect the condition of the surroundings. However, current intelligent monitoring systems always rely on an external computer with the capability of machine learning rather than integrating it into the sensing device. The computer-assisted intelligent system is hampered by energy inefficiencies, privacy issues, and bandwidth restrictions. Here, a flexible, large-scale sensing array with the capability of low-power in-sensor intelligence based on a compression hypervector encoder is proposed for real-time recognition. The system with in-sensor intelligence can accommodate different individuals and learn new postures without additional computer processing. Both the communication bandwidth requirement and energy consumption of this system are significantly reduced by 1,024 and 500 times, respectively. The capability for in-sensor inference and learning eliminates the necessity to transmit raw data externally, thereby effectively addressing privacy concerns. Furthermore, the system possesses a rapid recognition speed (a few hundred milliseconds) and a high recognition accuracy (about 99%), comparing with support vector machine and other hyperdimensional computing methods. The research holds marked potential for applications in the integration of artificial intelligence of things and flexible electronics.

Abstract Lumbar disc herniation is a common disease that causes low back pain. Due to the high cost of medical diagnosis, as well as a shortage and uneven distribution of medical resources, a system that can automatically analyze and diagnose lumbar spine Magnetic Resonance Imaging (MRI) is becoming an urgent need. This study uses deep learning methods to establish a classifier to diagnose lumbar disc herniation. An MRI classification dataset of lumbar disc herniation consisting of public MRI images is presented and is used to train the proposed classifier. Because a common difficulty in applying computer vision technology to medical images is labeling training data, we use a semi-supervised model training method, while multilayer transverse axial MRI images are used as the model input. In this method, we first use unlabelled MRI images for random self-supervised pre-training and the pre-trained model as a feature extractor for MRI images. Then, all marked cross-sections of each intervertebral disc are used to calculate the feature vector through the feature extractor. The information of all feature vectors is integrated, while a multilayer perceptron is used for classification training. After training, the model achieved 87.11 $$\%$$ % accuracy, 87.50 $$\%$$ % sensitivity, 86.72 $$\%$$ % specificity and 0.9487 AUC (Area Under the ROC Curve) index on the test set. To analyze the rationality of the diagnostic results more quickly, we output the severity of degenerative changes in each region using a heatmap.

Abstract To deal with thrusters’ faults of autonomous underwater vehicle (AUV), an iterative learning algorithm fault‐tolerant control (FTC) based on the linear extended states observer (LESO) is proposed. In this control scheme, the non‐linear feedback mechanism of the LESO is transplanted into iterative learning processes to estimate fault. Compared to our previous work, LESO is used to substitute classic non‐linear extended state observer to make the establishment of the whole system more structured; moreover, the number of parameters need to be tuned can be reduced by the conception of observer bandwidth of LESO. To enhance the controllability and robustness of whole scheme, a new saturated sliding mode controller is proposed based on the Lyapunov theory. Then to achieve online parameter self‐tuning for the control system, fuzzy logic controllers are introduced to find optimal relationship between LESO's parameter and tracking errors. The performance of the proposed controller is tested by some comparison experiments on Zhuhai A18D AUV; the results show that the proposed control scheme can ensure better stability than classical control and our previous control scheme when AUV suffers faults.

A new type of grain-interior planar defect in a ceramic phase in TiC doped cemented tungsten carbides was discovered. It is unique in that the monolayers of metal atoms exist stably in ceramic grains. The planar defects were induced by the ordered heteroatoms distributing on certain crystal planes of the matrix, which are distinct from the known planar defects such as phase-, grain-, and twin-boundaries, stacking faults, and complexions. Detailed characterization on the atomic scale was performed for the composition, structure, and crystallography of the planar defects, and their energy state and stability were evaluated by modeling. It was found that the Ti monolayer assists nucleation of the new WC crystal along the normal direction to its basal plane. Due to the disturbance of the heteroatom layer, the deposition of W and C atoms deviates from the regular sites occupied in the perfect crystal lattice, resulting in variations of the W–C arrangement in the grain structure. Experiments confirmed that tailoring the distribution density of the planar defects could give the best comprehensive mechanical performance with simultaneously outstanding strength and fracture toughness in the materials containing the grain-interior planar defects. This study provides a new strategy to greatly enhance the mechanical properties of materials by introducing and tailoring planar defects in the grain interiors.

IntroductionResveratrol is an immune modulator that can reduce M1 macrophage polarization in vitro. Reducing macrophage recruitment and M1 polarization can prevent corneal allograft rejection (CGR). In this study, rat corneal allograft rejection models were established to explore the effects of resveratrol on CGR and macrophages and the underlying mechanisms after corneal transplantation.MethodsCorneal allograft models were established, and 100 mg/kg resveratrol was injected intraperitoneally. The corneal allografts were assessed clinically using the Holland rejection scoring system, anterior segment photography, and anterior segment optical coherence tomography. Corneal macrophages, pro-inflammatory cytokines, and corneal lymphatic vessels were detected using hematoxylin and eosin staining, immunofluorescence staining, and real-time quantitative polymerase chain reaction (qRT-PCR). Dendritic cells (DCs) in cervical lymph nodes were explored using flow cytometry. RNA sequencing experiments were conducted to identify the mechanisms through which resveratrol affected CGR. The results were verified using Simple Western analysis. Pro-inflammatory cytokines by macrophages in vitro were measured using qRT-PCR and enzyme-linked immunosorbent assays.ResultsResveratrol significantly prolonged the survival of corneal grafts and reduced graft edema and central corneal thickness. Corneal macrophage recruitment and M1 macrophage polarization decreased significantly after corneal transplantation in the resveratrol group. Resveratrol also reduced pro-inflammatory cytokines in corneal grafts and suppressed the early generation of cornea lymphatic vessels and the recruitment of cornea inflammatory cells 14 days after surgery. Resveratrol decreased the proportion of DCs in ipsilateral cervical lymph nodes. The effect of resveratrol on CGR was related to the phosphatidylinositol 3-kinase/protein kinase-B (PI3K/Akt) pathway. Resveratrol reduced the secretion of pro-inflammatory cytokines by M1 macrophages in vitro.ConclusionOur findings suggest that resveratrol can reduce corneal macrophage recruitment and M1 macrophage polarization after corneal transplantation in rats and prevent CGR. The PI3K/Akt pathway may be an important mechanism that warrants further research.

BackgroundPneumonia remains the leading cause of death among children aged 1–59 months. The early prediction of poor outcomes (PO) is of critical concern. This study aimed to explore the risk factors relating to PO in severe community-acquired pneumonia (SCAP) and build a PO-predictive nomogram model for children with SCAP.MethodsWe retrospectively identified 300 Chinese pediatric patients diagnosed with SCAP who were hospitalized in the Affiliated Hospital of Southwest Medical University from August 1, 2018, to October 31, 2021. Children were divided into the PO and the non-PO groups. The occurrence of PO was designated as the dependent variable. Univariate and multivariate logistic regression analyses were used to identify the risk factors of PO. A nomogram model was constructed from the multivariate logistic regression analysis and internally validated for model discrimination and calibration. The performance of the nomogram was estimated using the concordance index (C-index).ResultsAccording to the efficacy evaluation criteria, 56 of 300 children demonstrated PO. The multivariate logistic regression analysis resulted in the following independent risk factors for PO: co-morbidity (OR: 8.032, 95% CI: 3.556–18.140, P

Background: Dihydropteridone derivatives represent a novel class of PLK1 inhibitors, exhibiting promising anticancer activity and potential as chemotherapeutic drugs for glioblastoma.Objective: The aim of this study is to develop 2D and 3D-QSAR models to validate the anticancer activity of dihydropteridone derivatives and identify optimal structural characteristics for the design of new therapeutic agents.Methods: The Heuristic method (HM) was employed to construct a 2D-linear QSAR model, while the gene expression programming (GEP) algorithm was utilized to develop a 2D-nonlinear QSAR model. Additionally, the CoMSIA approach was introduced to investigate the impact of drug structure on activity. A total of 200 novel anti-glioma dihydropteridone compounds were designed, and their activity levels were predicted using chemical descriptors and molecular field maps. The compounds with the highest activity were subjected to molecular docking to confirm their binding affinity.Results: Within the analytical purview, the coefficient of determination (R2) for the HM linear model is elucidated at 0.6682, accompanied by an R2cv of 0.5669 and a residual sum of squares (S2) of 0.0199. The GEP nonlinear model delineates coefficients of determination for the training and validation sets at 0.79 and 0.76, respectively. Empirical modeling outcomes underscore the preeminence of the 3D-QSAR model, succeeded by the GEP nonlinear model, whilst the HM linear model manifested suboptimal efficacy. The 3D paradigm evinced an exemplary fit, characterized by formidable Q2 (0.628) and R2 (0.928) values, complemented by an impressive F-value (12.194) and a minimized standard error of estimate (SEE) at 0.160. The most significant molecular descriptor in the 2D model, which included six descriptors, was identified as “Min exchange energy for a C-N bond” (MECN). By combining the MECN descriptor with the hydrophobic field, suggestions for the creation of novel medications were generated. This led to the identification of compound 21E.153, a novel dihydropteridone derivative, which exhibited outstanding antitumor properties and docking capabilities.Conclusion: The development of 2D and 3D-QSAR models, along with the innovative integration of contour maps and molecular descriptors, offer novel concepts and techniques for the design of glioblastoma chemotherapeutic agents.

Abstract Background Degrons are short linear motifs, bound by E3 ubiquitin ligase to target protein substrates to be degraded by the ubiquitin-proteasome system. Mutations leading to deregulation of degron functionality disrupt control of protein abundance due to mistargeting of proteins destined for degradation and often result in pathologies. Targeting degrons by small molecules also emerges as an exciting drug design strategy to upregulate the expression of specific proteins. Despite their essential function and disease targetability, reliable identification of degrons remains a conundrum. Here, we developed a deep learning-based model named Degpred that predicts general degrons directly from protein sequences. Results We showed that the BERT-based model performed well in predicting degrons singly from protein sequences. Then, we used the deep learning model Degpred to predict degrons proteome-widely. Degpred successfully captured typical degron-related sequence properties and predicted degrons beyond those from motif-based methods which use a handful of E3 motifs to match possible degrons. Furthermore, we calculated E3 motifs using predicted degrons on the substrates in our collected E3-substrate interaction dataset and constructed a regulatory network of protein degradation by assigning predicted degrons to specific E3s with calculated motifs. Critically, we experimentally verified that a predicted SPOP binding degron on CBX6 prompts CBX6 degradation and mediates the interaction with SPOP. We also showed that the protein degradation regulatory system is important in tumorigenesis by surveying degron-related mutations in TCGA. Conclusions Degpred provides an efficient tool to proteome-wide prediction of degrons and binding E3s singly from protein sequences. Degpred successfully captures typical degron-related sequence properties and predicts degrons beyond those from previously used motif-based methods, thus greatly expanding the degron landscape, which should advance the understanding of protein degradation, and allow exploration of uncharacterized alterations of proteins in diseases. To make it easier for readers to access collected and predicted datasets, we integrated these data into the website http://degron.phasep.pro/ .

To study the deterioration mechanisms of anhydrite rock under the freeze-thaw weathering process, the physico-mechanical characteristics and microstructure evolutions of anhydrite samples were determined by a series of laboratory tests. Then, a descriptive-behavioral model was used to measure the integrity loss in anhydrite samples caused by cyclic freeze-thaw. Finally, the freeze-thaw damage mechanisms of anhydrite rock were revealed from the macro and micro aspects. The results show that the pore size of the anhydrite rock is mainly concentrated in the range of 0.001–10 μm. As the number of freeze-thaw cycles increases, there is a growth in the proportion of macropores and mesopores. However, the proportion of micropores shows a declining trend. The relations of the uniaxial compressive strength, triaxial compressive strength, cohesion, and elastic modulus versus freeze-thaw cycles can be fitted by a decreasing exponential function, while the internal friction angle is basically unchanged with freeze-thaw cycles. With the increase of confining pressure, the disintegration rates of the compressive strength and the elastic modulus decrease, and the corresponding half-life values increase, which reveals that the increase of confining pressures could inhibit freeze-thaw damage to rocks. Moreover, it has been proven that the water chemical softening mechanism plays an essential role in the freeze-thaw damage to anhydrite rock. Furtherly, it is concluded that the freeze-thaw weathering process significantly influences the macroscopic and microscopic damages of anhydrite rock.

Abstract Six chest leads are the standardized clinical devices of diagnosing cardiac diseases. Emerging epidermal electronics technology shift the dangling wires and bulky devices to imperceptible wearing, achieving both comfortable experience and high-fidelity measuring. Extending small areas of current epidermal electronics to the chest scale requires eliminating interference from long epidermal interconnects and rendering the data acquisition (DAQ) portable. Herein, we developed a chest-scale epidermal electronic system (EES) for standard precordial-lead ECG and hydration monitoring, including the only μm-thick substrate-free epidermal sensing module and the soft wireless DAQ module. An electrical compensation strategy using double channels within the DAQ module and epidermal compensated branches (ECB) is proposed to eliminate unwanted signals from the long epidermal interconnects and to achieve the desired ECG. In this way, the EES works stably and precisely under different levels of exercise. Patients with sinus arrhythmias have been tested, demonstrating the prospect of EES in cardiac diseases.

Seminoma is the most common subtype of testicular germ cell tumor, with an increasing incidence worldwide. Clusterin (CLU) expression was found to be downregulated in testicular seminoma in our previous study. We now expanded the sample size, and further indicated that CLU expression correlates with tumor stage. Tcam-2 cell line was used to investigate the CLU function in testicular seminoma, and CLU was found to inhibit the proliferation and metastasis abilities. Besides, extracellular matrix protein COL15a1 was demonstrated as the downstream of CLU to affect the epithelial-mesenchymal transition (EMT) process via competitively binding to DDR1 with COL1A1 and inhibiting the phosphorylation of PYK2. MEF2A was found to interact with CLU and bind to the promoter of COL15a1 and so upregulate its expression. This is the first study using testicular xenografts in situ to simulate testicular seminoma metastatic and proliferative capacities. In conclusion, CLU acts as a tumor suppressor to inhibit the metastasis of testicular seminoma by interacting with MEF2A to upregulate COL15a1 and blocking the EMT process.

ObjectiveIn this study, we aimed to characterize the plasma metabolic profiles of brain atrophy and alcohol dependence (s) and to identify the underlying pathogenesis of brain atrophy related to alcohol dependence.MethodsWe acquired the plasma samples of alcohol-dependent patients and performed non-targeted metabolomic profiling analysis to identify alterations of key metabolites in the plasma of BA-ADPs. Machine learning algorithms and bioinformatic analysis were also used to identify predictive biomarkers and investigate their possible roles in brain atrophy related to alcohol dependence.ResultsA total of 26 plasma metabolites were significantly altered in the BA-ADPs group when compared with a group featuring alcohol-dependent patients without brain atrophy (NBA-ADPs). Nine of these differential metabolites were further identified as potential biomarkers for BA-ADPs. Receiver operating characteristic curves demonstrated that these potential biomarkers exhibited good sensitivity and specificity for distinguishing BA-ADPs from NBA-ADPs. Moreover, metabolic pathway analysis suggested that glycerophospholipid metabolism may be highly involved in the pathogenesis of alcohol-induced brain atrophy.ConclusionThis plasma metabolomic study provides a valuable resource for enhancing our understanding of alcohol-induced brain atrophy and offers potential targets for therapeutic intervention.

Background Liquid-liquid phase separation (LLPS) is an important organizing principle for biomolecular condensation and chromosome compartmentalization. However, while many proteins have been reported to undergo LLPS, quantitative and global analysis of chromatin LLPS property remains absent. Results Here, by combining chromatin-associated protein pull-down, quantitative proteomics and 1,6-hexanediol (1,6-HD) treatment, we develop Hi-MS and define an anti-1,6-HD index of chromatin-associated proteins (AICAP) to quantify 1,6-HD sensitivity of chromatin-associated proteins under physiological conditions. Compared with known physicochemical properties involved in phase separation, we find that proteins with lower AICAP are associated with higher content of disordered regions, higher hydrophobic residue preference, higher mobility and higher predicted LLPS potential. We also construct BL-Hi-C libraries following 1,6-HD treatment to study the sensitivity of chromatin conformation to 1,6-HD treatment. We find that the active chromatin and high-order structures, as well as the proteins enriched in corresponding regions, are more sensitive to 1,6-HD treatment. Conclusions Our work provides a global quantitative measurement of LLPS properties of chromatin-associated proteins and higher-order chromatin structure. Hi-MS and AICAP data provide an experimental tool and quantitative resources valuable for future studies of biomolecular condensates.

Background and purposeThis study aimed to explore the association between triglyceride–glucose (TyG) index and stroke recurrence in elderly patients with ischemic stroke in China.MethodsWe enrolled ischemic stroke patients aged ≥ 65 years from the Nanjing Stroke Registry Program. The primary endpoint was defined as recurrent stroke within one year after the index stroke. We used multivariable Cox proportional hazards regression models to investigate the association between TyG index and stroke recurrence. We assessed the discriminative ability of TyG index with the receiver operative characteristic and the area under the curve.ResultsA total of 955 patients (median age, 70.0 [67.0, 75.0]; male sex, 67.2%) from the Nanjing Stroke Registry Program were enrolled. During one year follow-up, 97 (10.2%) elderly patients experienced stroke recurrence. In multivariable analyses, the association between TyG index and stroke recurrence remained significant after adjusting for confounders (quartile 4 versus quartile 1; hazard ratio, 2.073, 95% confidence interval, 1.158-3.711; P = 0.014). The restricted cubic spline showed an increasing trend for TyG index and stroke recurrence (P for non-linearity = 0.072). The area under the curve to predict stroke recurrence with TyG index was 0.719 (95% confidence interval, 0.666-0.772). Besides, TyG index slightly improved the prediction for stroke recurrence.ConclusionElevated TyG index was associated with stroke recurrence in elderly patients with ischemic stroke. Further studies are warranted to assess the role of TyG index in the development of stroke recurrence in the elderly.

Cold atmospheric plasma has been widely applied in medical treatment clinically, especially skin diseases. However, the mechanism of cold atmospheric plasma on the treatment of skin diseases is still undefined. In this study, dinitrofluorobenzene-induced atopic dermatitis mice model was constructed. Cold atmospheric plasma was able to decrease skin cells apoptosis, relieve skin inflammation, ER stress and oxidative stress caused by dinitrofluorobenzene stimulation, which was mediated by cold atmospheric plasma-induced MANF expression. In terms of mechanism, hypoxia-inducible factor-1α expression was increased intracellularly after cold atmospheric plasma treatment, which further bound to the promoter region of manf gene and enhanced MANF transcriptional expression. This study reveals that cold atmospheric plasma has a positive effect on atopic dermatitis treatment, also demonstrates the regulatory mechanism of cold atmospheric plasma on MANF expression via HIF-1α, which indicates the potential medical application of cold atmospheric plasma for atopic dermatitis treatment.

In a vascular interventional surgery robot system, accurately pushing the guidewire into the patient-specific branch vessel is the core step of the entire operation, so it has become the focus of the master-slave co-control of the guidewire propulsion and manipulation mechanism. Some vascular interventional surgery robots have been used for delivery of the guidewire; however, problems such as the inability to reliably clamp the guidewire and the lack of accurate force feedback prevent doctors from using robots for accurate delivery. In addition, failure to disinfect surgical robots quickly and completely increases the risk of surgery. This article introduces a new type of master-slave vascular interventional robot with reliable clamping of the catheter/guidewire, accurate perception of the lead-in force of the guidewire for precise delivery and fast disinfection. In response to the problem of the nonlinear and uncertain disturbance of the catheter/guidewire resistance affecting the delivery mechanism, an adaptive sliding controller based on master-slave tracking is designed. Through experiments and analysis of the fuzzy sliding mode controller (FSMC) experimental platform, the results show that a vascular interventional robot control system with good tracking performance and strong robustness has been designed.

ObjectiveThe study aimed to investigate the serum antigenomic profiling in rheumatoid arthritis (RA) and determine potential diagnostic biomarkers using label-free proteomic technology implemented with machine-learning algorithm.MethodSerum antigens were captured from a cohort consisting of 60 RA patients (45 ACPA-positive RA patients and 15 ACPA-negative RA patients), together with sex- and age-matched 30 osteoarthritis (OA) patients and 30 healthy controls. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was then performed. The significantly upregulated and downregulated proteins with fold change > 1.5 (p < 0.05) were selected. Based on these differentially expressed proteins (DEPs), a machine learning model was trained and validated to classify RA, ACPA-positive RA, and ACPA-negative RA.ResultsWe identified 62, 71, and 49 DEPs in RA, ACPA-positive RA, and ACPA-negative RA, respectively, as compared to OA and healthy controls. Typical pathway enrichment and protein–protein interaction networks were shown among these DEPs. Three panels were constructed to classify RA, ACPA-positive RA, and ACPA-negative RA using random forest models algorithm based on the molecular signature of DEPs, whose area under curve (AUC) were calculated as 0.9949 (95% CI = 0.9792–1), 0.9913 (95% CI = 0.9653–1), and 1.0 (95% CI = 1–1).ConclusionThis study illustrated the serum auto-antigen profiling of RA. Among them, three panels of antigens were identified as diagnostic biomarkers to classify RA, ACPA-positive, and ACPA-negative RA patients.

The effective removal of oxytetracycline hydrochloride (OTC) from the water environment is of great importance. Adsorption as a simple, stable, and cost-effective technology is regarded as an important method for removing OTC. Herein, a low-cost biochar with a developed mesoporous structure was synthesized via pyrolysis of poplar leaf with potassium bicarbonate (KHCO3) as the activator. KHCO3 can endow biochar with abundant mesopores, but excessive KHCO3 cannot continuously promote the formation of mesoporous structures. In comparison with all of the prepared biochars, PKC-4 (biochar with a poplar leaf to KHCO3 mass ratio of 5:4) shows the highest adsorption performance for OTC as it has the largest surface area and richest mesoporous structure. The pseudo-second-order kinetic model and the Freundlich equilibrium model are more consistent with the experimental data, which implies that the adsorption process is multi-mechanism and multi-layered. In addition, the maximum adsorption capacities of biochar are slightly affected by pH changes, different metal ions, and different water matrices. Moreover, the biochar can be regenerated by pyrolysis, and its adsorption capacity only decreases by approximately 6% after four cycles. The adsorption of biochar for OTC is mainly controlled by pore filling, though electrostatic interactions, hydrogen bonding, and π-π interaction are also involved. This study realizes biomass waste recycling and highlights the potential of poplar leaf-based biochar for the adsorption of antibiotics.

Background: Non-small-cell lung cancer (NSCLC) with STK11 mutation showed primary resistance to immune checkpoint inhibitors (ICIs). The glucose-lowering drug metformin exerted anti-cancer effect and enhanced efficacy of chemotherapy in NSCLC with KRAS/STK11 co-mutation, yet it is unknown whether metformin may enhance ICI efficacy in STK11 mutant NSCLC.Methods: We studied the impact of metformin on ICI efficacy in STK11 mutant NSCLC in vitro and in vivo using colony formation assay, cell viability assay, Ki67 staining, ELISA, CRISPR/Cas9-mediated knockout, and animal experiments.Results: Through colony formation assay, Ki67 incorporation assay, and CCK-8 assay, we found that metformin significantly enhanced the killing of H460 cells and A549 cells by T cells. In NOD-SCID xenografts, metformin in combination with PD-1 inhibitor pembrolizumab effectively decreased tumor growth and increased infiltration of CD8+ T cells. Metformin enhanced stabilization of STING and activation of its downstream signaling pathway. siRNA-mediated knockdown of STING abolished the effect of metformin on T cell-mediated killing of tumor cells. Next, we found that CRISPR/Cas9-mediated knockout of the scaffold protein AXIN-1 abolished the effect of metformin on T cell-mediated killing and STING stabilization. Immunoprecipitation and confocal macroscopy revealed that metformin enhanced the interaction and colocalization between AXIN-1 and STING. Protein-protein interaction modeling indicated that AXIN-1 may directly bind to STING at its K150 site. Next, we found that metformin decreased K48-linked ubiquitination of STING and inhibited the interaction of E3-ligand RNF5 and STING. Moreover, in AXIN-1−/− H460 cells, metformin failed to alter the interaction of RNF5 and STING.Conclusion: Metformin combining PD-1 inhibitor enhanced anti-tumor efficacy in STK11 mutant lung cancer through inhibition of RNF5-mediated K48-linked ubiquitination of STING, which was dependent on AXIN-1.

Dietary intervention is crucial for the prevention and control of diabetes. China has the largest diabetic population in the world, yet no one dietary strategy matches the eating habits of the Chinese people. To explore an effective and acceptable dietary pattern, this study uses oat and buckwheat compound (OBC) as a staple food substitute and explored its effects on diabetic Sprague–Dawley rats. The model of diabetic rats was established by combining high-calorie feed and streptozotocin (STZ) injection. The dietary intervention for the seven groups, including a normal control group, a model control group, a metformin control group, a wheat flour control group, and three OBC groups with different doses, started from the beginning of the experiment and lasted for 11 weeks, two consecutive injections of STZ in small doses were operated at the 6th week. General states, glucose metabolism, and lipid metabolism indexes were measured. Antioxidant and inflammatory indexes and pathologic changes of kidney and liver tissues were tested. Changes in kidney and ileum ultramicrostructure were detected. What's more, ileal epithelial tight junction proteins and gut microbiota were analyzed. Significant decreases in fasting blood glucose (FBG), glucose tolerance, serum insulin, and insulin resistance were observed in rats intervened with OBC, and these rats also showed a higher level of superoxide dismutase (SOD) together with improved lipid metabolism, attenuated inflammation, and liver and kidney injuries. In addition, in OBC groups, the intestinal barrier was improved, and the disturbance of gut microbiota was reduced. These results suggest that OBC has health-promoting effects for diabetic rats, and since oat and buckwheat are traditionally consumed grains in China, OBC could be a potential and easy-to-accept staple food substitute for the dietary pattern for Chinese.

W–Cu composites are commonly subjected to coupled multiple fields in service, which imposes high requirements on their overall performance. In this study, the ultrafine-grained W–Cu composite was fabricated using the combination of electroless plating and spark plasma sintering. The wear resistance and high-temperature compressive properties of the ultrafine-grained W–Cu composite were investigated and compared with those of the commercial coarse-grained counterpart. Moreover, the underlying strengthening and wear mechanisms were also discussed. Here we show that the ultrafine-grained W–Cu composite exhibits superior integrated mechanical performance, making it a potential alternative to commercial W–Cu composites.

Nutritional intervention is a basic way to prevent and treat diabetes mellitus. Appropriate whole grain intake daily is recommended. The study aimed to explore the feasibility of a kind of buckwheat–oat–pea composite flour (BOP, quality ratio of buckwheat:oats:peas = 6:1:1) as a stable food substitution and its underlying mechanisms. High-fat food (HFD) and streptozotocin injection were used to induce diabetes in rats, and buckwheat, oats, and three different doses of BOP were added to the HFD separately for diet intervention. The whole study lasted for 10 weeks, and the glucose tolerance test, lipids, liver injury, and gut microbiota were evaluated in the last week. The diabetic rat model was successfully induced. The BOP significantly changed the glucose and lipids metabolism, decreased liver injury, and changed the composition of the gut microbiota of diabetic rats. The outcomes of the current study revealed that BOP is a potential stable food substitution.

Objective To evaluate the therapeutic effect of Traditional Chinese Medicine (TCM), specifically Fuzheng Qingdu (FZQD) therapy, on the survival time of metastatic GC patients. Patients and Methods Databases of medical records of 6 hospitals showed that 432 patients with stage IV GC were enrolled from March 1, 2012 to October 31, 2020. Propensity score matching (PSM) was used to reduce the bias caused by confounding factors in the comparison between the TCM and the non-TCM users. We used a Cox multivariate regression model to compare the hazard ratio (HR) value for mortality risk, and Kaplan-Meier survival curve for the survival time of GC patients Results The same number of subjects from the non-TCM group were matched with 122 TCM-treated patients after PSM to evaluate their overall survival (OS) and progression-free survival (PFS). Median time of OS of TCM and non-TCM users were 16.53 and 9.10 months, respectively. TCM and non-TCM groups demonstrated a 1-year survival rate of 68.5% and 34.5%, 2-year survival rate of 28.6% and 3.5%, and 3-year survival rate of 17.8% and 0.0%, respectively. A statistical difference exists in OS between the 2 groups (χ 2 = 33.39 and P

Using the typical WC–Co cemented carbide as an example, the interactions of dislocations within the ceramic matrix and the binder metal, as well as the possible cooperation and competition between the matrix and binder during deformation of the nanocrystalline cermets, were studied by molecular dynamics simulations. It was found that at the same level of strain, the dislocations in Co have more complex configurations in the cermet with higher Co content. With loading, the ratio between mobile and sessile dislocations in Co becomes stable earlier in the high-Co cermet. The strain threshold for the nucleation of dislocations in WC increases with Co content. At the later stage of deformation, the growth rate of WC dislocation density increases more rapidly in the cermet with lower Co content, which exhibits an opposite tendency compared with Co dislocation density. The relative contribution of Co and WC to the plasticity of the cermet varies in the deformation process. With a low Co content, the density of WC dislocations becomes higher than that of Co dislocations at larger strains, indicating that WC may contribute more than Co to the plasticity of the nanocrystalline cermet at the final deformation stage. The findings in the present work will be applicable to a large variety of ceramic–metal composite materials.

Background: Recently, the cognitive impairment of patients with alcohol dependence has attracted more and more attention. The combination of Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and event-related potentials (ERPs) for evaluating the degree of cognitive impairment in patients with alcohol dependence has not undergone enough in-depth investigation.Method: Sixty patients with alcohol dependence were selected as alcohol-dependence group, whereas 40 healthy volunteers served as a normal control group. The original scores of the RBANS sub-items, the incubation period, and volatility of ERPs between the two groups were compared, and the correlation among the above indicators in the alcohol-dependence group was further analyzed.Results: The RBANS test showed that the original scores of speech function, attention function, delayed memory, and immediate attention in the alcohol-dependence group were significantly lower than those in the normal control group. Compared with the normal control group, the latencies of P200 and P300 in the alcohol-dependence group were significantly prolonged, and the amplitude of P200 and P300 was significantly reduced. Correlation analysis between RBANS and ERPs in alcohol-dependence group showed that immediate attention score was positively correlated with P300 and P200 amplitude, visual breadth score was positively correlated with P200 latency, and attention function score was negatively correlated with P300 latency.Conclusion: As RBANS scale was highly correlated with the results of ERPs, the combined use of these two scales may serve as an objective basis for early diagnosis of cognitive impairment in patients with alcohol dependence.

The facial expressions are a mirror of the elusive emotion hidden in the mind, and thus, capturing expressions is a crucial way of merging the inward world and virtual world. However, typical facial expression recognition (FER) systems are restricted by environments where faces must be clearly seen for computer vision, or rigid devices that are not suitable for the time-dynamic, curvilinear faces. Here, we present a robust, highly wearable FER system that is based on deep-learning-assisted, soft epidermal electronics. The epidermal electronics that can fully conform on faces enable high-fidelity biosignal acquisition without hindering spontaneous facial expressions, releasing the constraint of movement, space, and light. The deep learning method can significantly enhance the recognition accuracy of facial expression types and intensities based on a small sample. The proposed wearable FER system is superior for wide applicability and high accuracy. The FER system is suitable for the individual and shows essential robustness to different light, occlusion, and various face poses. It is totally different from but complementary to the computer vision technology that is merely suitable for simultaneous FER of multiple individuals in a specific place. This wearable FER system is successfully applied to human-avatar emotion interaction and verbal communication disambiguation in a real-life environment, enabling promising human-computer interaction applications.

Protective layer mining, as a dominating method for preventing coal and gas outburst, is generally adopted in highly gassy coal mines. In the absence of a suitable thickness coal seam to serve as the protective layer, the rock-coal composite protective layer was proposed in this paper. We conducted a series of simulations and engineering measurements to investigate the protective effect under the mining of the rock-coal composite protective layer of the Zhongtai coal mine located in the Hebi area of Henan, China. The numerical simulation analysis showed that, after the completion of protective layer mining, the minimum vertical stress of the No. 2-1 coal seam had been reduced to 3.46 MPa. The maximum vertical displacement of the No. 2-1 coal seam is 455.01 mm. The maximum expansion deformation of the No. 2-1 coal seam is 9.77‰; the effective pressure relief range is as long as 160 m. The similarity simulation experiment revealed that, after the completion of protective layer mining, the minimum vertical stress of the No. 2-1 coal seam is 4.0 MPa. The maximum vertical displacement of the No. 2-1 coal seam is 640 mm. The maximum expansion deformation of the No. 2-1 coal seam is 26.37‰; the effective protection range reaches 130 m. The engineering measurements demonstrated that the variation law of gas drainage parameters in the protected layer corresponds to the protected layer's vertical stress distribution law in numerical simulation and similarity simulation. With the exploitation of the composite protective layer, the protective layer’s pressure begins to release. The average gas drainage concentration is 2-3 times of that before the composite protective layer mining.

Background. Recent research found that N5-methylcytosine (m5C) was involved in the development and occurrence of numerous cancers. However, the function and mechanism of m5C RNA methylation regulators in clear cell renal cell carcinoma (ccRCC) remains undiscovered. This study is aimed at investigating the predictive and clinical value of these m5C-related genes in ccRCC. Methods. Based on The Cancer Genome Atlas (TCGA) database, the expression patterns of twelve m5C regulators and matched clinicopathological characteristics were downloaded and analyzed. To reveal the relationships between the expression levels of m5C-related genes and the prognosis value in ccRCC, consensus clustering analysis was carried out. By univariate Cox analysis and last absolute shrinkage and selection operator (LASSO) Cox regression algorithm, a m5C-related risk signature was constructed in the training group and further validated in the testing group and the entire cohort. Then, the predictive ability of survival of this m5C-related risk signature was analyzed by Cox regression analysis and nomogram. Functional annotation and single-sample Gene Set Enrichment Analysis (ssGSEA) were applied to further explore the biological function and potential signaling pathways. Furthermore, we performed qRT-PCR experiments and measured global m5C RNA methylation level to validate this signature in vitro and tissue samples. Results. In the TCGA-KIRC cohort, we found significant differences in the expression of m5C RNA methylation-related genes between ccRCC tissues and normal kidney tissues. Consensus cluster analysis was conducted to separate patients into two m5C RNA methylation subtypes. Significantly better outcomes were observed in ccRCC patients in cluster 1 than in cluster 2. m5C RNA methylation-related risk score was calculated to evaluate the prognosis of ccRCC patients by seven screened m5C RNA methylation regulators (NOP2, NSUN2, NSUN3, NSUN4, NSUN5, TET2, and DNMT3B) in the training cohort. The AUC for the 1-, 2-, and 3-year survival in the training cohort were 0.792, 0.675, and 0.709, respectively, indicating that the risk signature had an excellent prognosis prediction in ccRCC. Additionally, univariate and multivariate Cox regression analyses revealed that the risk signature could be an independent prognostic factor in ccRCC. The results of ssGSEA suggested that the immune cells with different infiltration degrees between the high-risk and low-risk groups were T cells including follicular helper T cells, Th1_cells, Th2_cells, and CD8+_T_cells, and the main differences in immune-related functions between the two groups were the interferon response and T cell costimulation. In addition, qRT-PCR experiments confirmed our results in renal cell lines and tissue samples. Conclusions. According to the seven selected regulatory factors of m5C RNA methylation, a risk signature associated with m5C methylation that can independently predict prognosis in patients with ccRCC was developed and further verified the predictive efficiency.

Background: Apolipoprotein C1 (APOC1) has been proved to play a critical role in gastric, breast, lung, and pancreatic cancer. However, the relationship between APOC1 and urinary tumors remains unclear. This study aimed to assess the diagnostic and prognostic value of APOC1 in urinary tumors.Methods: We performed a pan analysis of APOC1 mRNA expression in urinary cancer using the Gene Expression Profiling Interactive Analysis (GEPIA) database. To further investigate the prognostic value of APOC1 expression in urinary cancers, the Kaplan-Meier plotter database was used. Furthermore, we collected the tumor and adjacent normal samples of 32 ccRCC patients to perform qRT-PCR and western blotting assays. A total of 72 cases with ccRCC were analyzed using tissue microarrays (TMAs).Results: Our results based on Kaplan-Meier plotter database indicated that a high expression of APOC1 may lead to poor overall survival (OS, p = 0.0019) in patients with ccRCC. Furthermore, the cancer stages and tumor grade of ccRCC appeared to be strongly linked with APOC1 expression according to UALCAN database. Hence, we reached a preliminary conclusion that APOC1 may play a key role in the tumorigenesis and progression of ccRCC. Furthermore, the Kaplan-Meier survival curve analyses of 72 clinical patients indicated that high expression of APOC1 was associated with poor progression-free survival (PFS, p = 0.007) and OS (p = 0.022). In addition, univariate Cox regression analysis confirmed the significant relationship between APOC1 expression and survival (p = 0.038). The TMAs analysis in combination with the patients' clinicopathological features was also performed. The expression of APOC1 was found to be significantly correlated with the tumor size (p = 0.018) and histological grade (p = 0.016).Conclusions: In conclusion, the findings of our study suggest that APOC1 may serve as a novel diagnostic and prognostic biomarker for ccRCC. Further evidence on the mechanism of APOC1 promoting tumor progression may transform it to a new therapeutic target for the treatment of ccRCC.

A novel alumina-assisted treatment process was proposed to manufacture fully densified and perfectly spherical WC-Co particles for thermal spraying applications. In as-sprayed coating, the decarburization phenomenon common in previous studies was almost entirely eliminated, and a unique binder structure with nanocrystalline and amorphous Co co-existing was obtained. Owing to the strengthening effects of nanocrystalline Co and WC/Co interfacial bonding, the wear resistance of the new coating was 4 times higher than that of the conventional coating prepared with a porous feedstock. Instead of plastic deformation, interface fracture and micro-cutting that mainly occurred in conventional WC-based coatings, fracture of WC grains and subsequent oxidation dominated wear failure of the new WC-Co coating. The present work opens up new opportunities for the fabrication of dense ceramic-metal composite particles and wear-resistance enhancement of cermet coatings.

Hydraulic punching technology has recently developed into an effective pressure relief measure and permeability enhancement method for soft and low permeability coalbeds. Different coal outputs directly affect the shape and size of boreholes as well as the effective extraction radius. Taking the Zhongmacun mine as an example, the influence of different coal outputs and different extraction periods on effective extraction radius was analyzed and studied through field tests and numerical simulation. The results show that the increase in coal outputs from hydraulic punching can improve the effective extraction radius of the boreholes. For example, when the gas extraction reaches 90 days, with a coal output of 0.5 t/m, 1.0 t/m, and 1.5 t/m, the effective extraction radius is 3.08 m, 3.46 m, and 3.83 m, respectively. The difference in gas extraction effect of different coal output boreholes increases significantly with the extension of the extraction time, but the speed of growth gradually decreases, which is consistent with the conclusions obtained on-site. This result has important practical significance for optimizing the technical parameters of hydraulic punching, guiding the accurate layout of extraction and drilling, and enhancing the effect of gas control in mines.

The fracture behavior of ultrafine WC–Co cemented carbide was demonstrated by in situ tensile tests in a transmission electron microscope. Using two kinds of cemented carbide samples with and without previously introduced microcracks, the process from deformation till fracture was studied. Particularly, the development and interaction of dislocations within Co and WC, as well as the alternation of dislocation motion between the two phases, was demonstrated, and the features of crack propagation in cemented carbide were disclosed. The finding of the dislocation characteristics and its correlation with the fracture behavior proposed the mechanisms of the ultrahigh fracture strength of the cemented carbide.

Permeability is an essential indicator for predicting gas drainage yield and preventing mine gas disasters, which is significantly influenced by the stress paths and the integrity of coal. Conventional research on permeability mainly focused on the permeability evolution of initial undamaged or fractured (prefabricated fractures) coal under various stress paths; little attention has been paid to post-strength coal (stress-induced damage), especially for soft coal. To determine the permeability evolution and gas flow law of post-strength soft coal samples under various stress paths, we used the experimental method combined with the numerical method in this study. The results showed that when the confining pressure and axial pressure of post-strength soft coal samples were unloaded, the permeability increased by 1.25−1.32 times; when the coal samples were loaded into the secondary damage, the permeability first decreased and then increased. The simulation part in this study found that the development of the fracture of coal samples under triaxial compression was divided into four stages. Gas flow law of post-strength soft coal was significantly influenced by fracture locations, and the gas pressure and gas flow field near the fracture were disturbed.

The study was aimed to determine whether treatment with oat oligopeptides (OOPs) could modulate hyperglycemia related to type 2 diabetes mellitus (T2DM) in Sprague⁻Dawley (SD) rats. Diabetic SD rats modeling by a joint effect of high-calorie diet for 45 days and twice intraperitoneal injection of 30 mg/kg streptozotocin at one-week interval were observed with or without OOPs administration (0.25, 0.50, 1.00, and 2.00 g/kg Body Weight) for 12 weeks. Fasting blood glucose (FBG), oral glucose test tolerance (OGTT), serum insulin, level of antioxidant, and hepatic enzymes were measured. In addition, frequency of micturition was recorded in this study for the first time. It was observed that the administration of OOPs (2.00 g/kg Body Weight) resulted in a significant decrease (p < 0.05) in FBG since 6th week and a significant decrease (p < 0.05) in the OGTT-AUC on 6th and 10th week. In addition, the administration of OOPs (2.00 g/kg Body Weight) reduced HOMA-IR index and 24-h urine volume significantly (p < 0.05) whereas increased SOD activity significantly (p < 0.05). These results suggested that OOPs may have a hypoglycemic effect in diabetic rats.

The high maintenance costs and low reliability of automatic production line are attributed to the complexity of maintenance management. In the present study, a preventive maintenance strategy for the automatic production line was developed based on the group maintenance method. The criticality of machines in the production line was evaluated, and then the machines were classified into three groups: the most critical machines, the secondary critical machines and the general machines. The general machines were performed on the breakdown maintenance. The preventive maintenance model of the most critical machines was established with the shortest shutdown time as decision objective on basis of the Delay-time theory. The maintenance model of the secondary critical machine was established based on the considering of reliability-maintenance cost. A case study on an automotive part automatic production line was carried out to verify the proposed preventive maintenance strategy based on the production line data, and the maintenance periods of the most and secondary critical machines were gained; meanwhile, the machines all satisfied the reliability requirements during the maintenance periods.