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Blue sky often represents better air quality and lower air pollution. Using satellite aerosol optical depth (AOD) data of Beijing, Tianjin and Hebei Province from 2000 to 2023, combined with the blue-sky data observed at noon time in 2023, a blue-sky grade index is established based on satellite AOD, in which the monitoring index of blue-sky grade is the AOD at 550 nm less than 0.36, and that of deep blue-sky grade is the AOD at 550 nm less than 0.2.Spatial and temporal characteristics of blue-sky grade days in Beijing-Tianjin-Hebei Region from 2000 to 2023 are investigated. Results show that the multi-year average blue-sky days in Beijing, Tianjin, and Hebei are 144.2 d·a-1, 96.3 d·a-1, and 119.6 d·a-1, respectively, with the highest number of blue-sky days for Beijing, followed by Hebei and the lowest number is recorded in Tianjin. In terms of spatial distribution, the northern part of Hebei has the highest annual average of blue-sky days, while the southern part of Hebei has the lowest number of blue-sky days. The number of blue-sky days in Beijing-Tianjin-Hebei exhibits noticeable seasonal changes, with the highest number of blue-sky days in winter and autumn, followed by spring, and the lowest in summer.From 2001 to 2023, the average annual number of clear-sky days in Beijing, Tianjin, and Hebei takes on an increasing trend, with an increase of 18.1 d, 22.3 d and 16.3 d per decade, respectively. There is no significant trend change from 2001 to 2013. However, the annual average blue-sky days in Beijing-Tianjin-Hebei from 2013 to 2023 all show increasing trends, with increments of 26.9 d, 46.5 d, and 36.4 d per decade, respectively. The annual average blue-sky days and deep blue-sky days in Beijing-Tianjin-Hebei from 2013 to 2023 are higher than those in 2001-2013, with the annual average blue-sky days in Beijing, Tianjin, and Hebei of 153.5 d, 107.5 d, and 128.5 d, respectively, which are 17.5 d, 21.8 d, and 16.9 d higher than those in 2001-2013. It may be largely due to the implementation of regional air pollution prevention and control measures, which have led to a reduction in atmospheric particulate matter concentration since 2013.

Abstract Carbon-based metal-free catalysts are promising green catalysts for photocatalysis and electrocatalysis due to their low cost and environmental friendliness. A key challenge in utilizing these catalysts is identifying their active sites, given their poor crystallinity and complex structures. Here we demonstrate the key structure of the double-bonded conjugated carbon group as a metal-free active site, enabling efficient O2 photoreduction to H2O2 through a cascaded water oxidation − O2 reduction process. Using ethylenediaminetetraacetic acid as a precursor, we synthesized various carbon-based photocatalysts and analyzed their structural evolution. Under the polymerization conditions of 260 °C to 400 °C, an N-ethyl-2-piperazinone-like structure was formed on the surface of the catalyst, resulting in high photocatalytic H2O2 photoproduction (2884.7 μmol g−1h−1) under visible light. A series of control experiments and theoretical calculations further confirm that the double-bond conjugated carbonyl structure is the key and universal feature of the active site of metal-free photocatalysts.

Abstract The investigation of aberrations in lipid metabolism within tumor has become a burgeoning field of study that has garnered significant attention in recent years. Lipids can serve as a potent source of highly energetic fuel to support the rapid growth of neoplasia, in where the ER-mitochondrial membrane domains (ERMMDs) provide an interactive network for facilitating communication between ER and mitochondria as well as their intermembrane space and adjunctive proteins. In this review, we discuss fatty acids (FAs) anabolic and catabolic metabolism, as well as how CPT1A-VDAC-ACSL clusters on ERMMDs participate in FAs transport, with a major focus on ERMMDs mediated collaborative loop of FAO, Ca2+ transmission in TCA cycle and OXPHOS process. Here, we present a comprehensive perspective on the regulation of aberrant lipid metabolism through ERMMDs conducted tumor physiology might be a promising and potential target for tumor starvation therapy.

Abstract Background Myocardial ischemia-reperfusion injury (MIRI) is caused by reperfusion after ischemic heart disease. LncRNA Snhg1 regulates the progression of various diseases. N6-methyladenosine (m6A) is the frequent RNA modification and plays a critical role in MIRI. However, it is unclear whether lncRNA Snhg1 regulates MIRI progression and whether the lncRNA Snhg1 was modified by m6A methylation. Methods Mouse cardiomyocytes HL-1 cells were utilized to construct the hypoxia/reoxygenation (H/R) injury model. HL-1 cell viability was evaluated utilizing CCK-8 method. Cell apoptosis, mitochondrial reactive oxygen species (ROS), and mitochondrial membrane potential (MMP) were quantitated utilizing flow cytometry. RNA immunoprecipitation and dual-luciferase reporter assays were applied to measure the m6A methylation and the interactions between lncRNA Snhg1 and targeted miRNA or target miRNAs and its target gene. The I/R mouse model was constructed with adenovirus expressing lncRNA Snhg1. HE and TUNEL staining were used to evaluate myocardial tissue damage and apoptosis. Results LncRNA Snhg1 was down-regulated after H/R injury, and overexpressed lncRNA Snhg1 suppressed H/R-stimulated cell apoptosis, mitochondrial ROS level and polarization. Besides, lncRNA Snhg1 could target miR-361-5p, and miR-361-5p targeted OPA1. Overexpressed lncRNA Snhg1 suppressed H/R-stimulated cell apoptosis, mitochondrial ROS level and polarization though the miR-361-5p/OPA1 axis. Furthermore, WTAP induced lncRNA Snhg1 m6A modification in H/R-stimulated HL-1 cells. Moreover, enforced lncRNA Snhg1 repressed I/R-stimulated myocardial tissue damage and apoptosis and regulated the miR-361-5p and OPA1 levels. Conclusion WTAP-mediated m6A modification of lncRNA Snhg1 regulated MIRI progression through modulating myocardial apoptosis, mitochondrial ROS production, and mitochondrial polarization via miR-361-5p/OPA1 axis, providing the evidence for lncRNA as the prospective target for alleviating MIRI progression.

Summary: Early prediction of acute pancreatitis (AP) with acute kidney injury (AKI) using abdominal contrast-enhanced CT could effectively reduce the mortality and the economic burden on patients and society. However, this challenge is limited by the imaging manifestations of early-stage AP that are not clearly visible to the naked eye. To address this, we developed a machine learning model using imperceptible variations in the structural changes of pancreas and peripancreatic region, extracted by radiomics and artificial intelligence technology, to screen and stratify the high-risk AP patients at the early stage of AP. The results demonstrate that the machine learning model could screen the high-risk AP with AKI patients with an area under the curve (AUC) of 0.82 for the external cohort, superior to the human radiologists. This finding confirms the significant potential of machine learning in the screening of acute pancreatitis and contributes to personalized treatment and management for AP patients.

Background: Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by poor prognosis due to the absence of effective targeted therapies. Emerging evidence indicates that the gut microbiota and its metabolites play a key role in the occurrence and development of TNBC. This study aimed to explore the metabolic changes and potential mechanisms associated with TNBC. Objectives: This study aimed to explore the potential relationship between targeted metabolites and the gut microbiota in TNBC. Design: We recruited 8 participants, including 4 with TNBC and 4 with benign fibroadenomas as controls. Methods: The gut microbiota was analyzed using metagenomics on fecal samples. Liquid chromatography–mass spectrometry (LC-MS) was employed to identify differential metabolites in serum and fecal samples. The correlation between the gut microbiota and metabolites was analyzed using Spearman’s correlation analysis. Results: Analysis of altered serum metabolites in the TNBC group revealed changes, particularly in carboxylic acids and derivatives, benzene, and substituted derivatives. Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic pathway analysis revealed significant enrichment in 18 pathways. Regarding fecal metabolites, differences between the 2 groups also included carboxylic acids and derivatives, benzene, and substituted derivatives, with 28 metabolic pathways enriched based on KEGG pathway analysis. Metagenomics analysis showed differences in the relative abundance of Anaerococcus , Fischerella , and Schizosaccharomyces at the genus level, which have been previously associated with breast cancer. Furthermore, 4 serum metabolites—L-glutamine, citrate, creatinine, and creatine—along with 9 fecal metabolites, were associated with the aforementioned microbiota. Conclusion: Our findings highlight distinct metabolite profiles in the serum and feces of patients with TNBC. The identification of gut microbiota and their associated metabolites provides new insights into the pathophysiological mechanisms underlying TNBC.

Hepatocellular carcinoma (HCC) remains the fourth leading cause of cancer-associated death globally with a lack of efficient therapy. The pathogenesis of HCC is a complex and multistep process, highly reliant on de novo lipogenesis, from which tumor cells can incorporate fatty acids to satisfy the necessary energy demands of rapid proliferation and provide survival advantages. Triptolide (TP) is a bioactive ingredient exhibiting potent abilities of anti-proliferation and lipid metabolism regulation, but its clinical application is constrained because of its toxicity and non-specific distribution. The present study has developed galactosylated bovine serum albumin nanoparticles loaded with TP (Gal-BSA-TP NPs) to alleviate systemic toxicity and increase tumor-targeting and antitumor efficacy. Furthermore, Gal-BSA-TP NPs could inhibit de novo lipogenesis via the p53-SREBP1C-FASN pathway to deprive the fuel supply of HCC, offering a specific strategy for HCC treatment. In general, this study provided a biocompatible delivery platform for targeted therapy for HCC from the perspective of de novo lipogenesis.

This study employs grounded theory methodology, utilizing open coding, axial coding, and selective coding techniques, to conduct a systematic analysis of Pang Xunqin's "Chinese Decorative Pattern Collection." A theoretical framework is constructed to explore the fusion of traditional Chinese patterns with modern decorative art design. As a pioneer in this domain, Pang Xunqin's oeuvre not only bridges historical gaps in Chinese decorative arts, but also offers innovative insights for the progression of contemporary Chinese art and design. The coding analysis of the study reveals the adept integration of traditional patterns into modern design practices by Pang Xunqin, thereby enhancing cultural identity and artistic vigor. Additionally, a dynamic model is introduced, charting innovative pathways for the modern evolution of traditional patterns and fostering their global cultural dissemination and innovation. This model enriches our comprehension of the amalgamation of tradition and modernity and presents a novel perspective for the observation and application of traditional culture in contemporary settings.

Abstract Currently, cancer is still a leading cause of human death globally. Tumor deterioration comprises multiple events including metastasis, therapeutic resistance and immune evasion, all of which are tightly related to the phenotypic plasticity especially epithelial–mesenchymal plasticity (EMP). Tumor cells with EMP are manifest in three states as epithelial–mesenchymal transition (EMT), partial EMT, and mesenchymal–epithelial transition, which orchestrate the phenotypic switch and heterogeneity of tumor cells via transcriptional regulation and a series of signaling pathways, including transforming growth factor‐β, Wnt/β‐catenin, and Notch. However, due to the complicated nature of EMP, the diverse process of EMP is still not fully understood. In this review, we systematically conclude the biological background, regulating mechanisms of EMP as well as the role of EMP in therapy response. We also summarize a range of small molecule inhibitors, immune‐related therapeutic approaches, and combination therapies that have been developed to target EMP for the outstanding role of EMP‐driven tumor deterioration. Additionally, we explore the potential technique for EMP‐based tumor mechanistic investigation and therapeutic research, which may burst vigorous prospects. Overall, we elucidate the multifaceted aspects of EMP in tumor progression and suggest a promising direction of cancer treatment based on targeting EMP.

How we view the passage of past time determines how we face time itself as well as our futures, which has a strong impact particularly during the highly creative and malleable college years. Chinese culture cherishes time deeply, and for centuries there has been a tradition of “educating children and youth to inspect the passage of time.” However, in today’s age of information and intelligence, time has shown a trend toward fragmentation. How do contemporary Chinese college students view the passage of time, and what structures or content does it contain? The answer to this question remains uncertain, necessitating further exploration. Following Flavell’s theory of metacognitive knowledge (MK), we adopted a semi-structured interview method and used the results to first outline the basic structure of Chinese college students’ view of time passing, identifying four major aspects: priming aftereffect, life touching, positive promotion, and negative inhibition. Then, using the initial four-dimensional structure as a starting point, we developed the Metacognitive Knowledge of Time Passing Scale (MKTPS), and carried out exploratory factor analysis and confirmatory factor analysis to test its fit. The results showed that the four-factor scale and its 22 items had a good fit to the data. Third, the reliability and validity of the self-developed scale were tested. The results show that the internal consistency, split-half, and retest reliability of the MKTPS are good (all rs > 0.60). The construct validity of the MKTPS is also good (rbetween subscales is 0.33–0.60, rbetween subscales and total scale is 0.64–0.87), the convergent validity with Zimbardo’s negative past time perspective is high (r = 0.37), and the discriminant validity with Zimbardo’s future time perspective is significant (r = 0.18). Regarding criterion correlation validity, the total scores of the MKTPS have a significantly higher positive correlation with those of the time management disposition (TMD) scale (r = 0.45). Future points for studying the view of time passing in adults of all ages and across cultures field and shortcomings of the current study are also discussed.

Triptolide (TP) is the principal bioactive compound of Tripterygium wilfordii with significant anti-tumor, anti-inflammatory and immunosuppressive activities. However, its severe hepatotoxicity greatly limits its clinical use. The underlying mechanism of TP-induced liver damage is still poorly understood. Here, we estimate the role of the gut microbiota in TP hepatotoxicity and investigate the bile acid metabolism mechanisms involved. The results of the antibiotic cocktail (ABX) and fecal microbiota transplantation (FMT) experiment demonstrate the involvement of intestinal flora in TP hepatotoxicity. Moreover, TP treatment significantly perturbed gut microbial composition and reduced the relative abundances of Lactobacillus rhamnosus GG (LGG). Supplementation with LGG reversed TP-induced hepatotoxicity by increasing bile salt hydrolase (BSH) activity and reducing the increased conjugated bile acids (BA). LGG supplementation upregulates hepatic FXR expression and inhibits NLRP3 inflammasome activation in TP-treated mice. In summary, this study found that gut microbiota is involved in TP hepatotoxicity. LGG supplementation protects mice against TP-induced liver damage. The underlying mechanism was associated with the gut microbiota-BA-FXR axis. Therefore, LGG holds the potential to prevent and treat TP hepatotoxicity in the clinic.

Abstract Mitochondrial permeability transition (mPT)-mediated mitochondrial dysfunction plays a pivotal role in various human diseases. However, the intricate details of its mechanisms and the sequence of events remain elusive, primarily due to the interference caused by Bax/Bak-induced mitochondrial outer membrane permeabilization (MOMP). To address these, we have developed a methodology that utilizes nano-flow cytometry (nFCM) to quantitatively analyze the opening of mitochondrial permeability transition pore (mPTP), dissipation of mitochondrial membrane potential ( $$\Delta$$ Δ Ψm), release of cytochrome c (Cyt c), and other molecular alternations of isolated mitochondria in response to mPT induction at the single-mitochondrion level. It was identified that betulinic acid (BetA) and antimycin A can directly induce mitochondrial dysfunction through mPT-mediated mechanisms, while cisplatin and staurosporine cannot. In addition, the nFCM analysis also revealed that BetA primarily induces mPTP opening through a reduction in Bcl-2 and Bcl-xL protein levels, along with an elevation in ROS content. Employing dose and time-dependent strategies of BetA, for the first time, we experimentally verified the sequential occurrence of mPTP opening and $$\Delta$$ Δ Ψm depolarization prior to the release of Cyt c during mPT-mediated mitochondrial dysfunction. Notably, our study uncovers a simultaneous release of cell-death-associated factors, including Cyt c, AIF, PNPT1, and mtDNA during mPT, implying the initiation of multiple cell death pathways. Intriguingly, BetA induces caspase-independent cell death, even in the absence of Bax/Bak, thereby overcoming drug resistance. The presented findings offer new insights into mPT-mediated mitochondrial dysfunction using nFCM, emphasizing the potential for targeting such dysfunction in innovative cancer therapies and interventions.

Abstract Tumors desmoplastic microenvironments are characterized by abundant stromal cells and extracellular matrix (ECM) deposition. Cancer-associated fibroblasts (CAFs), as the most abundant of all stromal cells, play significant role in mediating microenvironments, which not only remodel ECM to establish unique pathological barriers to hinder drug delivery in desmoplastic tumors, but also talk with immune cells and cancer cells to promote immunosuppression and cancer stem cells-mediated drug resistance. Thus, CAFs mediated desmoplastic microenvironments will be emerging as promising strategy to treat desmoplastic tumors. However, due to the complexity of microenvironments and the heterogeneity of CAFs in such tumors, an effective deliver system should be fully considered when designing the strategy of targeting CAFs mediated microenvironments. Engineered exosomes own powerful intercellular communication, cargoes delivery, penetration and targeted property of desired sites, which endow them with powerful theranostic potential in desmoplastic tumors. Here, we illustrate the significance of CAFs in tumors desmoplastic microenvironments and the theranostic potential of engineered exosomes targeting CAFs mediated desmoplastic microenvironments in next generation personalized nano-drugs development. Graphical Abstract

Abstract Background The study set out to develop an accurate and clinically valuable prognostic nomogram to assess the risk of in-hospital death in patients with acute decompensated chronic heart failure (ADCHF) and diabetes. Methods We extracted clinical data of patients diagnosed with ADCHF and diabetes from the Medical Information Mart for Intensive Care III database. Risk variables were selected utilizing least absolute shrinkage and selection operator regression analysis, and were included in multivariate logistic regression and presented in nomogram. bootstrap was used for internal validation. The discriminative power and predictive accuracy of the nomogram were estimated using the area under the receiver operating characteristic curve (AUC), calibration curve and decision curve analysis (DCA). Results Among 867 patients with ADCHF and diabetes, In-hospital death occurred in 81 (9.3%) patients. Age, heart rate, systolic blood pressure, red blood cell distribution width, shock, β-blockers, angiotensin converting enzyme inhibitors or angiotensin receptor blockers, assisted ventilation, and blood urea nitrogen were brought into the nomogram model. The calibration curves suggested that the nomogram was well calibrated. The AUC of the nomogram was 0.873 (95% CI: 0.834–0.911), which was higher that of the Simplified Acute Physiology Score II [0.761 (95% CI: 0.711–0.810)] and sequential organ failure assessment score [0.699 (95% CI: 0.642–0.756)], and Guidelines-Heart Failure score [0.782 (95% CI: 0.731–0.835)], indicating that the nomogram had better ability to predict in-hospital mortality. In addition, the internally validated C-index was 0.857 (95% CI: 0.825–0.891), which again verified the validity of this model. Conclusions This study constructed a simple and accurate nomogram for predicting in-hospital mortality in patients with ADCHF and diabetes, especially in those who admitted to the intensive care unit for more than 48 hours, which contributed clinicians to assess the risk and individualize the treatment of patients, thereby reducing in-hospital mortality.

Tantalum disilicide (TaSi2) has been widely studied for its excellent physical properties such as high hardness, high temperature oxidation resistance and low resistivity. Here, we aim to investigate the effects of different sintering temperatures and pressures on the microstructure and physical properties of TaSi2 ceramics. We successfully prepared dense TaSi2 ceramics using high-pressure and high-temperature (HPHT) sintering techniques. Characterization results show that TaSi2 ceramic properties are strongly influenced by the sintering temperature. The density, Vickers hardness and fracture toughness of TaSi2 sintered samples reaches a maximum value of 9.182 g/cm3, 11.34 GPa and 11.97 MPa m1/2, respectively. The fracture toughness of TaSi2 sintered samples was significantly improved and also exhibited excellent high-temperature oxidation resistance. Meanwhile, we also investigated the microstructure and grain size variation of TaSi2 sintered samples with sintering conditions using scanning electron microscopy (SEM) and electron backscatter diffraction (EBSD). The results show that HPHT sintering can effectively refine the grains of TaSi2 ceramics. It provides effective data and ideas for more efficient utilization of TaSi2 and preparation of other high-performance ceramics.

Gut microbiota dysbiosis is involved in cholestatic liver diseases. However, the mechanisms remain to be elucidated. The purpose of this study was to examine the effects and mechanisms of Lactobacillus acidophilus (L. acidophilus) on cholestatic liver injury in both animals and humans. Bile duct ligation (BDL) was performed to mimic cholestatic liver injury in mice and serum liver function was tested. Gut microbiota were analyzed by 16S rRNA sequencing. Fecal bacteria transplantation (FMT) was used to evaluate the role of gut microbiota in cholestasis. Bile acids (BAs) profiles were analyzed by targeted metabolomics. Effects of L. acidophilus in cholestatic patients were evaluated by a randomized controlled clinical trial (NO: ChiCTR2200063330). BDL induced different severity of liver injury, which was associated with gut microbiota. 16S rRNA sequencing of feces confirmed the gut flora differences between groups, of which L. acidophilus was the most distinguished genus. Administration of L. acidophilus after BDL significantly attenuated hepatic injury in mice, decreased liver total BAs and increased fecal total BAs. Furthermore, after L. acidophilus treatment, inhibition of hepatic Cholesterol 7α-hydroxylase (CYP7α1), restored ileum Fibroblast growth factor 15 (FGF15) and Small heterodimer partner (SHP) accounted for BAs synthesis decrease, whereas enhanced BAs excretion was attributed to the increase of unconjugated BAs by enriched bile salt hydrolase (BSH) enzymes in feces. Similarly, in cholestasis patients, supplementation of L. acidophilus promoted the recovery of liver function and negatively correlated with liver function indicators, possibly in relationship with the changes in BAs profiles and gut microbiota composition. L. acidophilus treatment ameliorates cholestatic liver injury through inhibited hepatic BAs synthesis and enhances fecal BAs excretion.

Objective: To systematically evaluate the efficacy and safety of integrated traditional Chinese and Western medicine(TCM-WM) for the treatment of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Materials and methods: An independent search of electronic databases (PubMed, Excerpta Medica Database, Cochrane Central Register of Controlled Trials, OVID Medline, China National Knowledge Infrastructure, WanFang Data, VIP Data databases, and China Biology Medicine disc) from inception to June 25, 2024 was performed to identify studies treating RA-ILD that used combined Chinese and Western medicine treatment compared to Western medicine. Two researchers independently audited each article, and the quality was assessed using the Cochrane Risk of Bias Assessment Tool 2 and the modified Jadad. Meta-analyses were performed using Review Manager 5.4 and Stata 16.0 software to analyze data. Sample certainty and conclusiveness of evidence were assessed using the Grading of Recommendations Assessment, Development, and Evaluation Profiler (GRADEPRO) and trial sequential analysis(TSA) 0.9.5.10 beta. Results: Eighteen randomised controlled trials (RCT), including 1353 patients, were abstracted. Integrated traditional Chinese and Western medicine was significantly more effective than Western medicine in improving lung function in patients with rheumatoid arthritis-associated interstitial lung disease, including forced vital capacity (FVC) (Standardized Mean Difference (SMD) = 1.44, 95 % CI 0.93 to 1.95, P

Triptolide (TP), a diterpene from Tripterygium wilfordii, exhibits potent anti-inflammatory, immunomodulatory, and antitumor properties but is limited by severe hepatotoxicity. This study investigates sex differences in TP-induced liver injury and the protective role of estradiol (E2) in modulating macrophage-mediated inflammation and hepatocyte function. An acute liver injury model was established in male and female Balb/c mice using intraperitoneal TP injection. Liver function tests, histological analyses, and immunohistochemical staining were performed. THP-1 macrophage and various liver cell lines were used to study the effects of TP and E2 in vitro. Virtual screening, molecular docking, luciferase assays, and qPCR were employed to identify potential targets and elucidate underlying mechanisms. TP caused more severe liver injury in female mice, evidenced by increased liver indices, aspartate aminotransferase (AST) levels, and extensive hepatocyte damage. TP promoted M1 macrophage polarization, enhancing inflammation, particularly in female mice. E2 mitigated TP-induced inflammatory responses by downregulating pro-inflammatory cytokines and macrophage activation markers. Molecular docking and functional assays identified Nuclear receptor subfamily 1 group I member 2 (NR1I2) as a key target mediating the protective effects of E2. The study highlights significant sex differences in TP-induced hepatotoxicity, with females being more susceptible. E2 exerts protective effects against TP-induced liver injury by modulating immune responses, presenting a potential therapeutic approach to mitigate drug-induced liver injury (DILI). Further research on NR1I2 could lead to targeted therapies for reducing drug-induced liver damage.

Abstract Objective To assess the efficacy of Phyllanthus emblica extract in alleviating halitosis and reducing the inflammatory response to halitosis-related bacteria. Methodology This investigation, using Phyllanthus emblica fruit extract (PE), involved four aspects. First, we evaluated the effect on growth and aggregation of halitosis-related bacteria, including Fusobacterium nucleatum, Porphyromonas gingivalis, and Solobacterium moorei, using a microdilution assay and scanning electron microscopy. Second, volatile sulfur compound (VSC) levels were measured on individuals with halitosis in randomized short-term (26 participants) and double-blind randomized long-term trials (18 participants in each group) after rinsing with PE for 3, 6, and 12 h, and 28 days. Third, we analyzed pro-inflammatory cytokine expression in TR146 cells using quantitative real-time PCR and enzyme-linked immunosorbent assays. Lastly, we assessed pro-inflammatory cytokine secretion and Toll-like receptor (TLR) 2 mRNA expression via the same experimental methods in a three-dimensional oral mucosal epithelial model (3D OMEM). Results PE extract dose-dependently inhibited the growth of F. nucleatum (50% inhibition concentration [IC50]=0.079%), P. gingivalis (IC50=0.65%), and S. moorei (IC50=0.07%) and effectively prevented bacterial aggregation. Furthermore, VSC contents decreased significantly at 3, 6, and 12 h after rinsing with 5% PE compared with those in the control. Long-term use of mouthwash containing 5% PE for 28 days led to a significant decrease in VSC contents. PE attenuated the F. nucleatum- or P. gingivalis-stimulated mRNA expression and protein release of interleukin (IL)-6 and IL-8 in TR146 cells. It also suppressed IL-8 and prostaglandin E2 secretion and TLR2 mRNA expression in F. nucleatum-induced OMEMs. Conclusion Our findings support the use of PE in oral care products to alleviate halitosis and it may reduce inflammation.

Summary: Background: Contrast-enhanced CT scans provide a means to detect unsuspected colorectal cancer. However, colorectal cancers in contrast-enhanced CT without bowel preparation may elude detection by radiologists. We aimed to develop a deep learning (DL) model for accurate detection of colorectal cancer, and evaluate whether it could improve the detection performance of radiologists. Methods: We developed a DL model using a manually annotated dataset (1196 cancer vs 1034 normal). The DL model was tested using an internal test set (98 vs 115), two external test sets (202 vs 265 in 1, and 252 vs 481 in 2), and a real-world test set (53 vs 1524). We compared the detection performance of the DL model with radiologists, and evaluated its capacity to enhance radiologists’ detection performance. Findings: In the four test sets, the DL model had the area under the receiver operating characteristic curves (AUCs) ranging between 0.957 and 0.994. In both the internal test set and external test set 1, the DL model yielded higher accuracy than that of radiologists (97.2% vs 86.0%, p 0.99), and it detected 2 cases that had been missed by radiologists. Interpretation: The developed DL model can accurately detect colorectal cancer and improve radiologists’ detection performance, showing its potential as an effective computer-aided detection tool. Funding: This study was supported by National Science Fund for Distinguished Young Scholars of China (No. 81925023); Regional Innovation and Development Joint Fund of National Natural Science Foundation of China (No. U22A20345); National Natural Science Foundation of China (No. 82072090 and No. 82371954); Guangdong Provincial Key Laboratory of Artificial Intelligence in Medical Image Analysis and Application (No. 2022B1212010011); High-level Hospital Construction Project (No. DFJHBF202105).

Background and objective: Spatial interaction between tumor-infiltrating lymphocytes (TILs) and tumor cells is valuable in predicting the effectiveness of immune response and prognosis amongst patients with lung adenocarcinoma (LUAD). Recent evidence suggests that the spatial distance between tumor cells and lymphocytes also influences the immune responses, but the distance analysis based on Hematoxylin and Eosin (H&E) -stained whole-slide images (WSIs) remains insufficient. To address this issue, we aim to explore the relationship between distance and prognosis prediction of patients with LUAD in this study. Methods: We recruited patients with resectable LUAD from three independent cohorts in this multi-center study. We proposed a simple but effective deep learning-driven workflow to automatically segment different cell types in the tumor region using the HoVer-Net model, and quantified the spatial distance (DIST) between tumor cells and lymphocytes based on H&E-stained WSIs. The association of DIST with disease-free survival (DFS) was explored in the discovery set (D1, n = 276) and the two validation sets (V1, n = 139; V2, n = 115). Results: In multivariable analysis, the low DIST group was associated with significantly better DFS in the discovery set (D1, HR, 0.61; 95 % CI, 0.40–0.94; p = 0.027) and the two validation sets (V1, HR, 0.54; 95 % CI, 0.32–0.91; p = 0.022; V2, HR, 0.44; 95 % CI, 0.24–0.81; p = 0.009). By integrating the DIST with clinicopathological factors, the integrated model (full model) had better discrimination for DFS in the discovery set (C-index, D1, 0.745 vs. 0.723) and the two validation sets (V1, 0.621 vs. 0.596; V2, 0.671 vs. 0.650). Furthermore, the computerized DIST was associated with immune phenotypes such as immune-desert and inflamed phenotypes. Conclusions: The integration of DIST with clinicopathological factors could improve the stratification performance of patients with resectable LUAD, was beneficial for the prognosis prediction of LUAD patients, and was also expected to assist physicians in individualized treatment.

Objective(s): Inadequate cytotrophoblast migration and invasion are speculated to result in preeclampsia, which is a pro-inflammatory condition. Sodium dichloroacetate (DCA) exerts anti-inflammatory actions. Thus,we sought to investigate the effect of DCA on the migration function of the lipopolysaccharide (LPS)-stimulated human-trophoblast-derived cell line (HTR-8/SVneo).Materials and Methods: HTR-8/SVneo cells were treated with LPS to suppress cell migration. Cell migration was examined by both scratch wound healing assay and transwell migration assay. Western blotting was used to analyze the expression levels of toll-like receptor-4 (TLR4), nuclear factor-κB (NF-κB), TNF-α, IL-1β, and IL-6 in the cells.Results: DCA reversed LPS-induced inhibition of migration in HTR-8/SVneo cells. Furthermore, DCA significantly suppressed LPS-induced activation of TLR4, phosphorylation of NF-κB (p65), translocation of p65 into the nucleus, and the production of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6). Treatment with inhibitors of TLR4 signal transduction (CLI095 or MD2-TLR-4-IN-1) reduced LPS-induced overexpression of pro-inflammatory cytokines, and a synergistic effect was found between TLR4 inhibitors and DCA in HTR-8/SVneo cells. Conclusion: DCA improved trophoblast cell migration function by suppressing LPS-induced inflammation, at least in part, via the TLR4/NF-κB signaling pathway. This result indicates that DCA might be a potential therapeutic candidate for human pregnancy-related complications associated with trophoblast disorder.

Background: Breast cancer is one of the most common cancer type of women in the world. miR-301b-3p/5p were paired miRNAs derived from the same pre-miRNA, which may have different clinical roles in tumor and requires more exploration and research. Methods: In order to investigate the differential expression, clinical significance, diagnostic and prognostic value of miR-301b-3p/5p and explore their function in breast cancer, we extracted information of miRNAs from TCGA data sets for clinical correlation analysis, and the potential function was explored by GO、KEGG enrichment and immunoinfiltration analysis. Results: miR-301b-3p/5p were both highly expressed in breast cancer, there is a positive correlation between them. miR-301b-3p and miR-301b-5p have different clinical features. In breast cancer, miR-301b-3p can be used as a potential diagnostic marker while miR-301b-5p can be used as a prognostic molecule. GO, KEGG enrichment and immunoinfiltration analysis reveals that miR-301b-3p focuses on molecular functions, miR-301b-5p focuses on regulation of angiogenesis, and it is correlated with immune cells. Conclusions: miR-301b-3p and miR-301b-5p are both tumor promoter in breast cancer, miR-301b-3p can be used as a potential diagnostic marker, while miR-301b-5p can be used as a prognostic molecule and an underlying therapy target. Although miR-301b-3p/5p is a pair of miRNAs from two arms of the same pre-miRNA, they may promote the progression of breast cancer together through different pathway.

To address the weak real-time control, poor decision-making ability, nonintuitive process monitoring, and unclear operation situation problems in a special transformer production workshop, a new digital twin system architecture is discussed for the workshop, focusing on digital twin modeling, knowledge information fusion, operation reliability analysis, and visual representation. The modeling and expression of the digital twin were based on the “Five dimensions–Four perspectives” engine, where the “Five dimensions” refer to physical entities, virtual objects, twin data, connection mapping, and services and the “Four perspectives” refer to geometric, physical, behavioral, and rule models, with high-performance computing power and immersive visualization technology. This paper describes the method of 3D modeling, data mapping, computing power development, and visual expression for the digital twin. A deep fusion method between knowledge and digital twin was studied based on the principle of tree growth. This model includes two key parts. First, a design of the index system having a hierarchical structure based on the principle of tree growth was proposed. Indices were divided into four levels—workshop, production line, station, and equipment levels—based on the workshop scale, vertically constituting the main branches of the index tree model. From the perspective of the life cycle of production activities, indices were divided into planning parameters, process parameters, work order parameters, quality parameters, equipment parameters, and so on. Thus, a complete index system of the digital twin workshop was established. Furthermore, the photosynthesis and the transport of organic products in the tree were simulated by formally describing the deep fusion mechanism of knowledge and digital twin in transformer workshops, and diverse intelligent computing units were built to mine knowledge and identify information from disorganized workshop operation big data. Finally, a multilevel and complex model was constructed to integrate the knowledge and digital twin of a special transformer workshop based on the computation model, and the real-time monitoring and control of the workshop were realized. An operational reliability analysis model of the digital twin system for special transformer workshops based on composite matter element information entropy was also proposed, which combines the analytical hierarchy process and the correlation entropy method. A composite matter element model was systematically built based on the historical operational data of the transformer workshop, which can be used for the real-time monitoring of the operational reliability and the evolution of any trends in the operational parameters. Thus, a prototype digital twin system was developed, and its rationality and effectiveness were verified using the special transformer workshop as the application case. The research results have an outstanding reference for the construction of digital twin systems and the intelligent management of transformer workshops.

In this paper, we present a novel method to enhance the sum-rate effectiveness in full-duplex unmanned aerial vehicle (UAV)-assisted communication networks. Existing approaches often couple uplink and downlink associations, resulting in suboptimal performance, particularly in dynamic environments where user demands and network conditions are unpredictable. To overcome these limitations, we propose a decoupling of uplink and downlink associations for ground-based users (GBUs), significantly improving network efficiency. We formulate a comprehensive optimization problem that integrates UAV trajectory design and user association, aiming to maximize the overall sum-rate efficiency of the network. Due to the problem’s non-convexity, we reformulate it as a Partially Observable Markov Decision Process (POMDP), enabling UAVs to make real-time decisions based on local observations without requiring complete global information. Our framework employs multi-agent deep reinforcement learning (MADRL), specifically the Multi-Agent Deep Deterministic Policy Gradient (MADDPG) algorithm, which balances centralized training with distributed execution. This allows UAVs to efficiently learn optimal user associations and trajectory controls while dynamically adapting to local conditions. The proposed solution is particularly suited for critical applications such as disaster response and search and rescue missions, highlighting the practical significance of utilizing UAVs for rapid network deployment in emergencies. By addressing the limitations of existing centralized and distributed solutions, our hybrid model combines the benefits of centralized training with the adaptability of distributed inference, ensuring optimal UAV operations in real-time scenarios.

Triptolide (TP) has various pharmacological activities, but its hepatotoxicity limits its therapeutic potential. Licorice has been evaluated to harmonize various medicines, and its active ingredient glycyrrhizic acid (GA) has been identified for its detoxification effect. In this study, we demonstrated that the combination of GA and TP (G&T) could mitigate TP-induced hepatotoxicity. To explore TP toxicity and G&T detoxification mechanisms, transcriptomics and proteomics have been utilized. TP was found to promote the expression of PKCα and FIS1, accompanied by an increase in mitochondrial fission. After pretreatment with GA, improvements were observed in TP-induced mitochondrial fission, as well as the expression of active-caspase3, and cytochrome c release. Silencing PKCα and FIS1 has a similar effect to GA on the regulation of mitochondria-dependent apoptosis and mitochondrial fission. In conclusion, PKCα and FIS1-involved mitochondrial dynamic regulation is associated with TP-induced hepatotoxicity. The G&T combination may be an effective strategy for ameliorating TP-induced toxicity.

We investigate the generation of bright-dark solitons in erbium-doped mode-locked fiber lasers based on ZrTe2 as saturable absorber. By adjusting the pump power and polarization state appropriately, three dual-wavelength mode-locked operations, namely bright soliton, bright-dark soliton pairs, and dark soliton are acquired. At pump power of 230 mW, bright solitons with central wavelengths of 1567.3 and 1568.1 nm, corresponding to 3-dB bandwidths of 0.15 and 0.2 nm, are obtained. For the bright-dark soliton pairs operation, the maximum average output power and largest single-pulse energy are 7.2 mW and 0.69 nJ, respectively. In addition, stable dark solitons with pump power of 300 mW at the fundamental rate of 10.47 MHz are achieved. Our research results indicate that ZrTe2 can operate as excellent saturable absorber for bright-dark soliton generation and will promote the development of ultrafast optics.

Abstract Integrated traditional Chinese medicine (TCM) and Western medicine (WM) is a new medical science grounded in the knowledge bases of both TCM and WM, which then forms a unique modern medical system in China. Integrated TCM and WM has a long history in China, and has made important achievements in the process of clinical diagnosis and treatment. However, the methodological defects in currently published clinical practice guidelines limit its development. The organic integration of TCM and WM is a deeper integration of TCM and WM. To realize the progression of "integration" to "organic integration", a targeted and standardized guideline development methodology is needed. Therefore, the purpose of this study is to establish a standardized development procedure for clinical practice guidelines for the organic integration of TCM and WM to promote the systematic integration of TCM and WM research results into clinical practice guidelines in order to achieve optimal results as the whole is greater than the sum of the parts.

The primary objective of this research is to investigate the structure and tribological properties of NiCr–Mo–Ag–O/Mo–V–Ag–O bilayer films in a wide temperature range (RT-1000 °C). The bilayer films were prepared by pulsed laser deposition (PLD) technology, so as to provide the theoretical basis and experimental guidance for the study of the synergistic lubricating effect of Mo and V bimetallic lubricating oxides. The NiCr–Mo–Ag–O composite target was fabricated by the hot-press sintering technique. Subsequently, a NiCr–Mo–Ag–O/Mo–V–Ag–O bilayer film was deposited on Inconel 718 by pulsed laser deposition (PLD). The tribological properties of the film were evaluated by HRT-1000 high-temperature ball-on-disc configuration at RT-1000 °C. The obtained results reveal that the NiCr–Mo–Ag–O target is marked by a compact structure and homogeneous composition. Furthermore, the composite film exhibits a smooth surface and dense structure, comprised of polycrystalline and amorphous phases. The measured hardness and elastic modulus of the film approximated 4.9 GPa and 153.5 GPa, respectively. Additionally, the lowest friction coefficient of the film is about 0.28 at 800 °C. Upon reaching this temperature, the cooperative lubrication resulting from NiMoO4, Ag2Mo2O7, and AgVO3 contributed effectively towards reducing the film's friction coefficient.

Abstract Purpose The objective of this systematic review and meta-analysis was to assess the efficacy of the Ilizarov method in the treatment of radius and ulna bone defects. Methods The PubMed, Embase, Web of Science, Cochrane Library, Ovid MEDLINE, and Scopus databases were searched for articles published up to May 2023. The quality of the studies was evaluated using a modified version of the Newcastle–Ottawa scale. The effect size and confidence intervals at 95% for the main results were calculated. The heterogeneity was evaluated. The demographic data, defect size (DS), external fixation time (EFT), external fixation index (EFI), and complications were extracted and analyzed using the Stata version 16. Results This meta-analysis identified and included seven studies involving 98 patients. The union rate of 100% was reported in all studies. According to the findings of the single-arm meta-analysis, the pooled DS was 3.42 cm (95% CI [2.64, 4.21], I 2 = 53.5%, P = 0.045), EFT was 148.43 days (95% CI [97.49, 199.38], I 2 = 91.9%, P = 0.000), and EFI was 41.32 days/cm (95% CI [35.72, 46.91], I 2 = 62.2%, P = 0.021). Pin tract infection was the most common complication, as reported in six studies. Conclusion The findings of the present meta-analysis indicate that the Ilizarov technique is a successful treatment option for bone defects in the radius and ulna. This method has demonstrated efficacy in achieving expected clinical outcomes.

The cable-stiffened single-layer latticed shell is an innovative structural design that achieves a perfect balance between lightweight and stability by combining cables and a latticed shell. However, the study on dynamic response and failure mechanism of cable-stiffened single-layer latticed shell under seismic action is still lacking. Therefore, small-scale shaking table tests of two kinds of single-layer spherical latticed shells are carried out; the dynamic response and failure mode of the two shells under sine wave earthquake are investigated by using time history analysis. The conclusions show that the introduction of the prestressed cable plays an important role in improving the seismic performance of the single-layer latticed shell, and the cable-stiffened single-layer latticed shell has better load capacity and seismic performance under earthquake action than the ordinary single-layer latticed shell structure.

Multiple emulsions can dissolve some substances with different properties, such as hydrophilicity and lipophilicity, into different phases. They play an important role in protection, controlled release and targeted release of the encapsulated substances. However, it’s poor stability has always been one of the main problems restricting its application in the food industry. For this reason, a heat-induced aggregate (HIA) of Maillard graft product of isomalto-oligosaccharides (IMO), as well as egg white protein (EWP), was used as hydrophilic emulsifier to improve the stability of W1/O/W2 emulsions. Moreover, gelatin was added into the internal aqueous phase (W1) to construct W1/O/W2 emulsion-gels system. The encapsulation efficiency of HIA-stabilized W1/O/W2 emulsions remained nearly unaltered, dropping by only 0.86%, significantly outperforming the conjugates and physical mixture of IMO and EWP in terms of encapsulation stability. The emulsion-gels system was constructed by adding 5% gelatin in the W1, and had the highest EE% and good salt and heat stability after 30 days of storage. This experiment provides guidance for improving the stability of W1/O/W2 emulsions system and its application in the package delivery of functional substances in the food field.

The application of blockchain technology in industrial product quality traceability is analyzed to construct a new model of product quality traceability that is mainly based on blockchain technology and supplemented by an identity system. The blockchain-enabled overall technical architecture of an industrial product quality traceability system is explored, and a blockchain-based industrial product full life cycle information traceability system is constructed. First, the weights of the information indicators of different links of the industrial equipment information traceability system were calculated using the EAHP hierarchical analysis method. The manufacturing link had the largest weight, with a value of 18.8%. Second, the system’s functional module design is based on the weights. We designed and developed the industrial product information traceability platform based on the hybrid blockchain chain structure of private chain + alliance chain. Finally, a manufacturing enterprise in the Xinjiang region is taken as the research object, query validation is carried out for the products produced by the enterprise, and the average query time of the system is measured to be 65.376 ms. It can meet the traceability needs of consumers and enterprise users. The research can provide theoretical support and reference for the whole life cycle information traceability of industrial products.

Abstract Background Cook Stage extubation is a tool developed by Cook Medical for patients with difficult airways. Multiple clinical studies demonstrated the effectiveness and safety of Cook Stage extubation Set (CSES). Currently, no systematic review evidence has been published in this field. Therefore, this study aimed to review the clinical success rate, safety, and tolerability of CSES in patients with difficult airways. Method The inclusion criteria were based on the population, intervention, comparator, outcomes, and study designs. An electronic search was conducted, and the following databases were used: PubMed, EMBASE, Cochrane Library, and Web of Science. Search keywords included difficult airway and CSES. The primary outcome was the CSES clinical success rate.The Joanna Briggs Institute Critical Appraisal tools for Case Series were used to assess the risk of bias in the included studies. R studio, version 4.2.2. was used to perform the statistical analysis. The Cochrane Q and I 2 statistics were used to test the heterogeneity among all studies. Details of the included case reports were summarized in the systematic review part. Results Five studies were eligible for meta-analysis, and 7 case reports were included for systematic review. The pooled overall CSES clinical success rate was 93% (95% CI: 85%, 97%). The CSES intolerable and complication incidence rates were 9% (95% CI: 5%, 18%) and 5% (95% CI: 2%, 12%), respectively. CSES clinical success rate was influenced by the study center and study design. The success rate of CSES was higher in multicenter and prospective design studies. Seven case reports have documented the successful operation of CSES intubation in obese, tall, oncologist, and pediatric patients. Discussion This meta-analysis suggested that CSES have achieved a high clinical success rate in adult and pediatric patients with different physical conditions and types of surgery. The results of all original studies and meta-analysis confirmed a remarkably high tolerance rate and low overall complication rate. However, regardless of the tools chosen, a personalized, safe intubation strategy and a highly qualified anesthesiologist should be considered as the fundamental guarantee of a high clinical success rate. Future studies should also focus on the success rate of reintubation using CSES in patients with airway difficulties.

The long-term precision of shearer independent positioning device is an important research content of intelligent mining. The current shearer positioning accuracy is hard to meet the demands of automatic mining, and we established a fusion positioning model based on IMU/UWB, and proposed autonomous correction to compensate the drift error of inertial navigation device for the coal mine working face by using the fusion results of IMU/UWB to correct the position and posture of inertial positioning system. It can compensate the deviation of IMU in real time, and realize long-term high-precision autonomous cycle cutting of the shearer. To reduce the influence of uncertain measurement noise on the positioning results, we use variational Bayesian unscented Kalman filter (VB-UKF) technique to smooth the positioning results in order to further improve the fusion positioning accuracy. To verify the positioning accuracy of the mining face end, fusion positioning experiments are conducted in Taiyuan Heavy Machinery Co., Ltd on the ground and Shandong Energy Group coal mine working face in the underground, respectively. The experimental results demonstrate that, the accuracy of IMU/UWB fusion positioning is higher than that of the single UWB solution. After smoothing via the VB-UKF algorithm, the error in the x-axis and z-axis orientation of the IMU/UWB fusion localization for underground experiments decreased from 0.0102 m and 0.194 m to 0.082 m and 0.158 m, respectively, and the corresponding average accuracy improved by 19.6% and 18.6%. The error of the three pose angles is less than 2°, because the error extended Kalman filter compensates and modifies the IMU bias in the fusion localization model, which can effectively suppress the drift of the IMU posture angle. The underground field experiment proves the effectiveness of the positioning method of coal mining face end, which provides better reference and experience for the further application in underground coalmine by using IMU/UWB fusion positioning.

Abstract Chemoradiation is a common therapeutic regimen for human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). However, not all patients benefit from chemotherapy, especially patients with low-risk characteristics. We aim to develop and validate a prognostic and predictive radiomic image signature (pRiS) to inform survival and chemotherapy benefit using computed tomography (CT) scans from 491 stage I and II HPV-associated OPSCC, which were divided into three cohorts D1–D3. The prognostic performance of pRiS was evaluated on two test sets (D2, n = 162; D3, n = 269) using concordance index. Patients from D2 and D3 who received either radiotherapy alone or chemoradiation were used to validate pRiS as predictive of added benefit of chemotherapy. Seven features were selected to construct pRiS, which was found to be prognostic of overall survival (OS) on univariate analysis in D2 (hazard ratio [HR] = 2.14, 95% confidence interval [CI], 1.1–4.16, p = 0.02) and D3 (HR = 2.74, 95% CI, 1.34–5.62, p = 0.006). Chemotherapy was associated with improved OS for high-pRiS patients in D2 (radiation vs chemoradiation, HR = 4.47, 95% CI, 1.73–11.6, p = 0.002) and D3 (radiation vs chemoradiation, HR = 2.99, 95% CI, 1.04–8.63, p = 0.04). In contrast, chemotherapy did not improve OS for low-pRiS patients, which indicates these patients did not derive additional benefit from chemotherapy and could be considered for treatment de-escalation. The proposed radiomic signature was prognostic of patient survival and informed benefit from chemotherapy for stage I and II HPV-associated OPSCC patients.

Abstract The tumor immune composition influences prognosis and treatment sensitivity in lung cancer. The presence of effective adaptive immune responses is associated with increased clinical benefit after immune checkpoint blockers. Conversely, immunotherapy resistance can occur as a consequence of local T-cell exhaustion/dysfunction and upregulation of immunosuppressive signals and regulatory cells. Consequently, merely measuring the amount of tumor-infiltrating lymphocytes (TILs) may not accurately reflect the complexity of tumor-immune interactions and T-cell functional states and may not be valuable as a treatment-specific biomarker. In this work, we investigate an immune-related biomarker (PhenoTIL) and its value in associating with treatment-specific outcomes in non-small cell lung cancer (NSCLC). PhenoTIL is a novel computational pathology approach that uses machine learning to capture spatial interplay and infer functional features of immune cell niches associated with tumor rejection and patient outcomes. PhenoTIL’s advantage is the computational characterization of the tumor immune microenvironment extracted from H&E-stained preparations. Association with clinical outcome and major non-small cell lung cancer (NSCLC) histology variants was studied in baseline tumor specimens from 1,774 lung cancer patients treated with immunotherapy and/or chemotherapy, including the clinical trial Checkmate 057 (NCT01673867).

Abstract Prognostic markers currently utilized in clinical practice for estrogen receptor-positive (ER+) and lymph node-negative (LN−) invasive breast cancer (IBC) patients include the Nottingham grading system and Oncotype Dx (ODx). However, these biomarkers are not always optimal and remain subject to inter-/intra-observer variability and high cost. In this study, we evaluated the association between computationally derived image features from H&E images and disease-free survival (DFS) in ER+ and LN− IBC. H&E images from a total of n = 321 patients with ER+ and LN− IBC from three cohorts were employed for this study (Training set: D1 (n = 116), Validation sets: D2 (n = 121) and D3 (n = 84)). A total of 343 features relating to nuclear morphology, mitotic activity, and tubule formation were computationally extracted from each slide image. A Cox regression model (IbRiS) was trained to identify significant predictors of DFS and predict a high/low-risk category using D1 and was validated on independent testing sets D2 and D3 as well as within each ODx risk category. IbRiS was significantly prognostic of DFS with a hazard ratio (HR) of 2.33 (95% confidence interval (95% CI) = 1.02–5.32, p = 0.045) on D2 and a HR of 2.94 (95% CI = 1.18–7.35, p = 0.0208) on D3. In addition, IbRiS yielded significant risk stratification within high ODx risk categories (D1 + D2: HR = 10.35, 95% CI = 1.20–89.18, p = 0.0106; D1: p = 0.0238; D2: p = 0.0389), potentially providing more granular risk stratification than offered by ODx alone.

Hepatocellular carcinoma (HCC) was characterized as being hypervascular. In the present study, we generated a single-cell spatial transcriptomic landscape of the vasculogenic etiology of HCC and illustrated overexpressed Golgi phosphoprotein 73 (GP73) HCC cells exerting cellular communication with vascular endothelial cells with high pro-angiogenesis potential via multiple receptor–ligand interactions in the process of tumor vascular development. Specifically, we uncovered an interactive GP73-mediated regulatory network coordinated with c-Myc, lactate, Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway, and endoplasmic reticulum stress (ERS) signals in HCC cells and elucidated its pro-angiogenic roles in vitro and in vivo. Mechanistically, we found that GP73, the pivotal hub gene, was activated by histone lactylation and c-Myc, which stimulated the phosphorylation of downstream STAT3 by directly binding STAT3 and simultaneously enhancing glucose-regulated protein 78 (GRP78)-induced ERS. STAT3 potentiates GP73-mediated pro-angiogenic functions. Clinically, serum GP73 levels were positively correlated with HCC response to anti-angiogenic regimens and were essential for a prognostic nomogram showing good predictive performance for determining 6-month and 1-year survival in patients with HCC treated with anti-angiogenic therapy. Taken together, the aforementioned data characterized the pro-angiogenic roles and mechanisms of a GP73-mediated network and proved that GP73 is a crucial tumor angiogenesis niche gene with favorable anti-angiogenic potential in the treatment of HCC.

Site specific biotinylation of AviTagged recombinant proteins using BirA enzyme is a widely used protein labeling technology. However, due to the incomplete biotinylation reactions and the lack of a purification method specific for the biotinylated proteins, it is challenging to purify the biotinylated sample when mixed with the non-biotinylated byproduct. Here, we have developed a monoclonal antibody that specifically recognizes the non-biotinylated AviTag but not the biotinylated sequence. After a ten-minute incubation with the resin that is conjugated with the antibody, the non-biotinylated AviTagged protein is trapped on the resin while the fully biotinylated material freely passes through. Therefore, our AviTrap (anti-AviTag antibody conjugated resin) provides an efficient solution for enriching biotinylated AviTagged proteins via a simple one-step purification.

Samples suitable for electron diffraction studies must satisfy certain characteristics such as having a thickness in the range of 10–100 nm. We report, to our knowledge, the first successful synthesis technique of nanometer-thin sheets of single-crystalline thymine suitable for electron diffraction and spectroscopy studies. This development provides a well-defined system to explore issues related to UV photochemistry of DNA and high intrinsic stability essential to maintaining integrity of genetic information. The crystals are grown using the evaporation technique, and the nanometer-thin sheets are obtained via microtoming. The sample is characterized via x-ray diffraction and is subsequently studied using electron diffraction via a transmission electron microscope. Thymine is found to be more radiation resistant than similar molecular moieties (e.g., carbamazepine) by a factor of 5. This raises interesting questions about the role of the fast relaxation processes of electron scattering-induced excited states, extending the concept of radiation hardening beyond photoexcited states. The high stability of thymine in particular opens the door for further studies of these ultrafast relaxation processes giving rise to the high stability of DNA to UV radiation.

Abstract Liver is one of the most common sites for metastases, which can occur on account of primary tumors from multiple sites of origin. Identifying the primary site of origin (PSO) of a metastasis can help in guiding therapeutic options for liver metastases. In this pilot study, we hypothesized that computer extracted handcrafted (HC) histomorphometric features can be utilized to identify the PSO of liver metastases. Cellular features, including tumor nuclei morphological and graph features as well as cytoplasm texture features, were extracted by computer algorithms from 175 slides (114 patients). The study comprised three experiments: (1) comparing and (2) fusing a machine learning (ML) model trained with HC pathomic features and deep learning (DL)‐based classifiers to predict site of origin; (3) identifying the section of the primary tumor from which metastases were derived. For experiment 1, we divided the cohort into training sets composed of primary and matched liver metastases [60 patients, 121 whole slide images (WSIs)], and a hold‐out validation set (54 patients, 54 WSIs) composed solely of liver metastases of known site of origin. Using the extracted HC features of the training set, a combination of supervised machine classifiers and unsupervised clustering was applied to identify the PSO. A random forest classifier achieved areas under the curve (AUCs) of 0.83, 0.64, 0.82, and 0.64 in classifying the metastatic tumor from colon, esophagus, breast, and pancreas on the validation set. The top features related to nuclear and peri‐nuclear shape and textural attributes. We also trained a DL network to serve as a direct comparison to our method. The DL model achieved AUCs for colon: 0.94, esophagus: 0.66, breast: 0.79, and pancreas: 0.67 in identifying PSO. A decision fusion‐based strategy was deployed to fuse the trained ML and DL classifiers and achieved slightly better results than ML or DL classifier alone (colon: 0.93, esophagus: 0.68, breast: 0.81, and pancreas: 0.69). For the third experiment, WSI‐level attention maps were also generated using a trained DL network to generate a composite feature similarity heat map between paired primaries and their associated metastases. Our experiments revealed that epithelium‐rich and moderately differentiated tumor regions of primary tumors were quantitatively similar to paired metastatic tumors. Our findings suggest that a combination of HC and DL features could potentially help identify the PSO for liver metastases while at the same time also potentially identify the spatial sites of origin for the metastases within primary tumors.

Objective: This study explored prophylactic central compartment lymph node dissection (pCCLND) for patients with cN0 papillary thyroid carcinoma (PTC) and the effect of carbon nanoparticles (CNP) on surgical outcomes. Methods: This retrospective study reviewed PTC cases treated at our tertiary medical institution between January 2019 and December 2022. Only patients with indications for total thyroidectomy and cN0 disease were included. CNP has been associated with a higher number of harvested lymph nodes and a lower rate of accidental parathyroid gland (PTG) removal. Patients who used CNP in this study were classified as group 1, while those who denied its use were classified as group 2. Results: In total, 116 cases were included, with 80 patients in group 1 and 36 in group 2. Most patients were in stage T1, with 68 (85.0 %) patients in group 1 and 31 (86.1 %) in group 2. Postoperative hoarseness occurred in 3 (3.8 %) patients in group 1 and 1 (2.8 %) in group 2, which recovered within two months. In group 2, 250 nodes were harvested, 72 (28.8 %) of which were metastatic; in group 1, 889 nodes were harvested, 316 (35.5 %) of which were metastatic; the difference regarding the rates of metastatic lymph nodes between the 2 groups was statistically significant (P = 0.047). Differences in postoperative blood calcium and parathyroid hormone levels between the two groups were statistically significant (P = 0.035 and P = 0.034, respectively). There were symptoms of hypocalcemia in 6 (16.7 %) patients in group 2 but in only 2 (2.5 %) in group 1, all of which recovered within three months; the difference was statistically significant (p = 0.017). Conclusion: pCCLND is worth undertaking for cN0 PTC. CNP is beneficial for achieving more thorough dissection and reducing temporary hypoparathyroidism.

BackgroundAcute liver injury (ALI) is an important global health concern, primarily caused by widespread hepatocyte cell death, coupled with a complex immune response and a lack of effective remedies. This study explores the underlying mechanisms, immune infiltration patterns, and potential targets for intervention and treatment ALI.MethodsThe datasets of acetaminophen (APAP), carbon tetrachloride (CCl4), and lipopolysaccharide (LPS)-induced ALI were obtained from the GEO database. Differentially expressed genes (DEGs) were individually identified using the limma packages. Functional enrichment analysis was performed using KEGG, GO, and GSEA methods. The overlapping genes were extracted from the three datasets, and hub genes were identified using MCODE and CytoHubba algorithms. Additionally, PPI networks were constructed based on the String database. Immune cell infiltration analysis was conducted using ImmuCellAI, and the correlation between hub genes and immune cells was determined using the Spearman method. The relationship between hub genes, immune cells, and biochemical indicators of liver function (ALT, AST) was validated using APAP and triptolide (TP) -induced ALI mouse models.ResultsFunctional enrichment analysis indicated that all three ALI models were enriched in pathways linked to fatty acid metabolism, drug metabolism, inflammatory response, and immune regulation. Immune analysis revealed a significant rise in macrophage infiltration. A total of 79 overlapping genes were obtained, and 10 hub genes were identified that were consistent with the results of the biological information analysis after screening and validation. Among them, Clec4n, Ms4a6d, and Lilrb4 exhibited strong associations with macrophage infiltration and ALI.

AbstractBackground Cancer-associated fibroblasts (CAFs) are the most important components of the tumor microenvironment (TME). CAFs are heterogeneous and involved in tumor tumorigenesis and drug resistance, contributing to TME remodeling and predicting clinical outcomes as prognostic factors. However, the effect of CAFs the TME and the prognosis of patients with breast cancer (BC) is not fully understood. This study investigated the correlation between CAFs-activating biomarkers immune cell infiltration and survival in patients with breast cancer.Methods RNA sequencing data and survival information for patients with breast cancer were downloaded from The Cancer Genome Atlas (TCGA) using R software. We then analyzed the correlation between CAFs-expressing biomarkers and immune cells using the clusterProfiler package, and evaluated the prognostic role of appealing genes using the Survminer package. Immunohistochemical (IHC) staining was used to determine the expression levels of TNC in 160 breast cancer samples pathologically diagnosed as invasive ductal carcinoma that were not otherwise specified (IDC-NOS).Results Data analysis showed that CAFs-expressing genes was higher than in normal tissues (p

DNMT1 (DNA methyltransferase 1) is the predominant member of the DNMT family and the most abundant DNMT in various cell types. It functions as a maintenance DNMT and is involved in various diseases, including cancer and nervous system diseases. Programmed cell death (PCD) is a fundamental mechanism that regulates cell proliferation and maintains the development and homeostasis of multicellular organisms. DNMT1 plays a regulatory role in various types of PCD, including apoptosis, autophagy, necroptosis, ferroptosis, and others. DNMT1 is closely associated with the development of various diseases by regulating key genes and pathways involved in PCD, including caspase 3/7 activities in apoptosis, Beclin 1, LC3, and some autophagy-related proteins in autophagy, glutathione peroxidase 4 (GPX4) and nuclear receptor coactivator 4 (NCOA4) in ferroptosis, and receptor-interacting protein kinase 1-receptor-interacting protein kinase 3-mixed lineage kinase domain-like protein (RIPK1-RIPK3-MLKL) in necroptosis. Our study summarizes the regulatory relationship between DNMT1 and different types of PCD in various diseases and discusses the potential of DNMT1 as a common regulatory hub in multiple types of PCD, offering a perspective for therapeutic approaches in disease.

Abstract Recovery of skin function remains a significant clinical challenge for deep burns owing to the severe scar formation and poor appendage regeneration, and stem cell therapy has shown great potential for injured tissue regeneration. Here, a cell‐free therapy system for deep burn skin was explored using mesenchymal stem cell paracrine proteins (MSC‐PP) and polyethylene glycol (PEG) temperature‐sensitive hydrogels. A three‐dimensional (3D) dynamic culture system for MSCs' large‐scale expansion was established using a porous gelatin microcarrier crosslinked with hyaluronic acid (PGM‐HA), and the purified MSC‐PP from culture supernatant was characterized by mass spectrometric analysis. The results showed the 3D dynamic culture system regulated MSCs cell cycle, reduced apoptosis, and decreased lactic acid content, and the MSC‐PP produced in 3D group can promote cell proliferation, migration, and adhesion. The MSC‐PP + PEG system maintained stable release in 28 days of observation in vitro. The in vivo therapeutic efficacy was investigated in the rabbit's third‐degree burn model, and saline, PEG, MSC‐PP, and MSC‐PP + PEG treatments groups were set. The in vivo results showed that the MSC‐PP + PEG group significantly improved wound healing, inhibited scar formation, and facilitated skin appendage regeneration. In conclusion, the MSC‐PP + PEG sustained‐release system provides a potentially effective treatment for deep burn skin healing.

Temperature is an important factor in the growth, development, survival, and reproduction of organisms. The high-temperature resistance mechanism of insects may be significant for use in the prevention and control of insect pests. The silkworm, Bombyx mori, is an important Lepidoptera model species for studies on pest control in agriculture and forestry. We identified a gene in B. mori, the B. mori singed (Bmsn) gene, which is involved in the high-temperature resistance of silkworms. Sn proteins are highly conserved among species in many taxonomic groups. The overexpression of the Bmsn gene promoted the proliferation of silkworm cells, reduced oxidation, and reduced the accumulation of reactive oxygen species under stress. Interfering with the Bmsn gene had the opposite result. We constructed a transgenic B. mori strain that overexpressed the Bmsn gene. The physiological traits of the transgenic strain were significantly improved, and it had stronger high-temperature resistance. The Bmsn gene is involved in the process by which fat bodies respond to high-temperature stress. These findings provide insights into the mechanism of high-temperature resistance of insects and offer a new perspective on agricultural and forestry pest control.

The challenge of precise dynamic positioning for mobile robots is addressed through the development of a multi-inertial navigation system (M-INSs). The inherent cumulative sensor errors prevalent in traditional single inertial navigation systems (INSs) under dynamic conditions are mitigated by a novel algorithm, integrating multiple INS units in a predefined planar configuration, utilizing fixed distances between the units as invariant constraints. An extended Kalman filter (EKF) is employed to significantly enhance the positioning accuracy. Dynamic experimental validation of the proposed 3INS EKF algorithm reveals a marked improvement over individual INS units, with the positioning errors reduced and stability increased, resulting in an average accuracy enhancement rate exceeding 60%. This advancement is particularly critical for mobile robot applications that demand high precision, such as autonomous driving and disaster search and rescue. The findings from this study not only demonstrate the potential of M-INSs to improve dynamic positioning accuracy but also to provide a new research direction for future advancements in robotic navigation systems.