Search

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with a low 5-year survival rate. Treatment options for PDAC patients are limited. Recent studies have shown promising results with MRTX1133, a KRASG12D inhibitor that demonstrated potent antitumor activity in various types of tumors with KRASG12D mutation. Resistance to KRAS inhibitors is frequently occurred and one of the main reasons for treatment failure. Understanding resistance mechanisms to novel KRAS inhibitors is crucial to ensure sustained and durable remissions. Methods Two KRASG12D inhibitor MRTX1133-resistant PDAC cell lines were established in vitro. The resistance mechanisms to KRASG12D inhibitor MRTX1133 against PDAC in vitro and in vivo were characterized by RNA sequencing, reverse transcript polymerase chain reaction, cytotoxicity test, plasmid transfection, lentivirus transfection, lipid peroxidation detection, malondialdehyde levels detection, glutathione levels detection, western blot, immunofluorescence, nude mice tumorigenesis experiment and immunohistochemistry. Results The bioinformatics analysis and transcriptome sequencing showed that ferroptosis was involved in the resistant effect of the KRASG12D inhibitor treatment, and MGST1 was the key molecule against MRTX1133-induced ferroptosis. Increased expression of MGST1 weakened the cytotoxicity of MRTX1133 by inhibiting lipid peroxidation-induced ferroptosis in KRASG12D inhibitor-resistant PDAC cells. Knockdown or overexpression of MGST1 conferred sensitivity or resistance to KRASG12D inhibitor MRTX1133, respectively. Mechanismly, increased nuclear localization and higher levels of active β-catenin were observed in MRTX1133-resistant PDAC cells, which contributed to higher MGST1 expression. Knockdown of CTNNB1 or TCF4 can decreased MGST1 expression. Additionally, we found that PKF-118-310, an antagonist of β-catenin/Tcf4 complex, repressed MGST1 expression. In both in vitro and in vivo models, a synergistic effect was observed when combining MRTX1133 and PKF-118-310 in KRASG12D inhibitor MRTX1133-resistant PDAC cells and tumors. Conclusion Our data showed that KRASG12D inhibitor MRTX1133 combined with PKF-118-310 could enhance the effectiveness of MRTX1133 treatment response through induction of ferroptosis via inhibiting MGST1 expression in MRTX1133-resistant PDAC cells and tumors. This evidence may provide a promising strategy to overcome KRASG12D inhibitor MRTX1133 resistance in PDAC patients with KRASG12D mutations. Graphical Abstract

Abstract As a basic component of the versatile semiconductor devices, metal oxides play a critical role in modern electronic information industry. However, ultra-high precision nanopatterning of metal oxides often involves multi-step lithography and transfer process, which is time-consuming and costly. Here, we report a strategy, using metal-organic compounds as solid precursor photoresist for multi-photon lithography and post-sintering, to realize ultra-high precision additive manufacturing of metal oxides. As a result, we gain metal oxides including ZnO, CuO and ZrO2 with a critical dimension of 35 nm, which sets a benchmark for additive manufacturing of metal oxides. Besides, atomic doping can be easily accomplished by including the target element in precursor photoresist, and heterogeneous structures can also be created by multiple multi-photon lithography, allowing this strategy to accommodate the requirements of various semiconductor devices. For instance, we fabricate an ZnO photodetector by the proposed strategy.

Abstract Background Although recent studies have increasingly focused on examining the potential benefits of creatine supplementation to improve performance in swimming events, the impact of creatine supplementation on swimming performance remains a topic of debate and controversy. A comprehensive meta-analytical review was undertaken to evaluate the effects of creatine supplementation on the performance, physiological response, and body composition among swimmers. Methods The research methodology adhered strictly to the guidelines outlined by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A comprehensive search was conducted across six databases (Cochrane Library, Web of Science, Scopus, Embase, PubMed, and SPORTDiscus) until March 23, 2024. Eligible studies that investigated the impact of creatine supplementation on swimming time, physiological parameters, and body composition in swimmers were included. For the meta-analysis, a random-effects model was employed to determine the collective effect and assess variations across distinct subgroups defined by swimming time, physiological metrics, and body composition. Meta-regression analysis was conducted on datasets comprising ten or more studies. Standardized mean differences (SMD) along with their corresponding 95% confidence intervals (CI) were calculated. To evaluate the methodological rigor of the included studies, the Physiotherapy Evidence Database (PEDro) scale was utilized. Results The systematic review included seventeen studies with a total of 361 subjects. No significant differences were observed in the overall effect during single sprint swimming (SMD: -0.05, 95% CI: -0.26, 0.15; p = 0.61), repeated interval swimming (SMD: -0.11; 95% CI: -0.46, 0.25; p = 0.56), physiological response (SMD: 0.04, 95% CI: -0.16, 0.23; p = 0.71), and body composition (SMD: 0.18; 95% CI: -0.05, 0.41; p = 0.12) between creatine and placebo groups. Conclusions Creatine supplementation exhibited ineffectiveness in enhancing the performance, physiological response, and body composition among swimmers.

Abstract Background and Objective Adult-onset Still’s disease (AOSD) is a recognized autoinflammatory disorder of unknown etiology. The standard initial management for AOSD includes conventional corticosteroids and disease-modifying antirheumatic drugs. In cases that are resistant to these treatments, additional therapeutic options such as immunosuppressants, biologics, and other alternative treatments may be considered. Yet, a significant proportion of patients remain unresponsive to these therapeutic interventions. Herein, a case is reported involving a patient with AOSD who had persistent pruritic lesions that did not respond to conventional therapy, but were alleviated with Janus kinase inhibitors (JAKi), namely baricitinib and upadacitinib. The objective is to expand the number of refractory AOSD cases treated with JAKi in clinical practice. Another aim is to offer potentially effective therapeutic options for AOSD patients who experience persistent pruritus. Methods A case was reported involving AOSD characterized by persistent pruritic lesions that failed to respond to conventional treatment, but showed favorable outcomes with JAKi therapy. An analysis of the PubMed literature was performed to assess the medication’s efficacy and explore possible mechanisms. Results The present case study is one of the few documented instances exploring the use of JAKi for treating AOSD, aligning with previously published research. After initiating JAKi therapy, the patient exhibited significant improvement in symptoms, most notably a reduction in persistent pruritus. Additionally, there was a substantial decrease in the patient’s glucocorticoid dosage. Aside from minor renal function anomalies, no adverse reactions were observed. Conclusions The present case illustrates that JAKi can provide rapid and sustained clinical improvement in patients with AOSD, especially those who have not responded to conventional treatment, and they have the ability to alleviate persistent itching. Further investigation is needed to ascertain the precise mechanism.

Abstract Liver metastasis remains the primary cause of mortality in patients with colon cancer. Identifying specific driver gene mutations that contribute to metastasis may offer viable therapeutic targets. To explore clonal evolution and genetic heterogeneity within the metastasis, we conducted single-cell exome sequencing on 150 single cells isolated from the primary tumor, liver metastasis, and lymphatic metastasis from a stage IV colon cancer patient. The genetic landscape of the tumor samples revealed that both lymphatic and liver metastases originated from the same region of the primary tumor. Notably, the liver metastasis was derived directly from the primary tumor, bypassing the lymph nodes. Comparative analysis of the sequencing data for individual cell pairs within different tumors demonstrated that the genetic heterogeneity of both liver and lymphatic metastases was also greater than that of the primary tumor. This finding indicates that liver and lymphatic metastases arose from clusters of circulating tumor cell (CTC) of a polyclonal origin, rather than from a single cell from the primary tumor. Single-cell transcriptome analysis suggested that higher EMT score and CNV scores were associated with more polyclonal metastasis. Additionally, a mutation in the TRPS1 (Transcriptional repressor GATA binding 1) gene, TRPS1 R544Q, was enriched in the single cells from the liver metastasis. The mutation significantly increased CRC invasion and migration both in vitro and in vivo through the TRPS1R544Q/ZEB1 axis. Further TRPS1 mutations were detected in additional colon cancer cases, correlating with advanced-stage disease and inferior prognosis. These results reveal polyclonal seeding and TRPS1 mutation as potential mechanisms driving the development of liver metastases in colon cancer.

Abstract Background Alterations in epigenetic factors are recognized as key contributors to the emergence of human cancer. The active and reversible alteration of N6‐methyladenosine (m6A) RNA is crucial for controlling gene activity and determining cellular destiny. Even with these insights, the triggering of KIAA1429 (also called VIRMA) and its role in lung adenocarcinoma (LUAD) is mostly unclear. As a result, the objective of this study was to elucidate how KIAA1429 contributes to cancer development in LUAD. Methods This study utilized multiple methods for investigation, encompassing the in vitro functional examination of KIAA1429 in lung adenocarcinoma cells, transcriptome sequencing, methylation RNA immunoprecipitation sequencing (MeRIP‐seq), as well as RNA stability tests to ascertain the half‐life and stability of the target genes. Results The results indicated that modifying the expression of KIAA1429 regulated the proliferation and metastasis of LUAD. By employing transcriptome sequencing alongside MeRIP‐seq analysis, the research pinpointed genes affected by m6A alterations triggered by KIAA1429. In a more detailed manner, it was discovered that KIAA1429 plays a regulatory role in the expression of ARHGAP30. Suppressing KIAA1429 results in reduced m6A levels in the mRNA of the target gene ARHGAP30, boosting its stability and expression, thus inhibiting tumor proliferation and metastasis. Conclusion This study revealed the activation mechanism and pivotal function of KIAA1429 in LUAD tumor development, paving the way for molecular‐based interventions for LUAD.

Abstract The buried interface between the electron transport layer (ETL) and the perovskite layer plays a crucial role in enhancing the power conversion efficiency (PCE) and stability of n–i–p type perovskite solar cells (PSCs). In this study, the interface between the chemical bath deposited (CBD) titanium oxide (TiO2) ETL and the perovskite layer using multi‐functional potassium trifluoromethyl sulfonate (SK) is modified. Structural and elemental analyses reveal that the trifluoromethyl sulfonate serves as a crosslinker between the TiO2 and the perovskite layer, thus improving the adhesion of the perovskite to the TiO2 ETL through strong bonding of the ─CF3 and ─SO3− terminal groups. Furthermore, the multi‐functional modifiers reduced interface defects and suppressed carrier recombination in the PSCs. Consequently, devices with a champion PCE of 25.22% and a fill factor (FF) close to 85% is achieved, marking the highest PCE and FF observed for PSCs based on CBD TiO2. The unencapsulated device maintained 81.3% of its initial PCE after operating for 1000 h.

Abstract Accurate presurgical prediction of pathological complete response (pCR) can guide treatment decisions, potentially avoiding unnecessary surgeries and improving the quality of life for cancer patients. We developed a minimal residual disease (MRD) profiling approach with enhanced sensitivity and specificity for detecting minimal tumor DNA from cell-free DNA (cfDNA). The approach was validated in two independent esophageal squamous cell carcinoma (ESCC) cohorts. In a cohort undergoing neoadjuvant, surgical, and adjuvant therapy (NAT cohort), presurgical MRD status precisely predicted pCR. All MRD-negative cases (10/10) were confirmed as pCR by pathological evaluation on the resected tissues. In contrast, MRD-positive cases included all the 27 non-pCR cases and only one pCR case (10/10 vs 1/28, P < 0.0001, Fisher’s exact test). In a definitive radiotherapy cohort (dRT cohort), post-dRT MRD status was closely correlated with patient prognosis. All MRD-negative patients (25/25) remained progression-free during the follow-up period, while 23 of the 26 MRD-positive patients experienced disease progression (25/25 vs 3/26, P < 0.0001, Fisher’s exact test; progression-free survival, P < 0.0001, log-rank test). The MRD profiling approach effectively predicted the ESCC patients who would achieve pCR with surgery and those likely to remain progression-free without surgery. This suggests that the cancer cells in these MRD-negative patients have been effectively eliminated and they could be suitable candidates for a watch-and-wait strategy, potentially avoiding unnecessary surgery.

Abstract Tertiary lymphoid structures (TLSs) have been associated with favorable immunotherapy responses and prognosis in various cancers. Despite their significance, their quantification using multiplex immunohistochemistry (mIHC) staining of T and B lymphocytes remains labor-intensive, limiting its clinical utility. To address this challenge, we curated a dataset from matched mIHC and H&E whole-slide images (WSIs) and developed a deep learning model for automated segmentation of TLSs. The model achieved Dice coefficients of 0.91 on the internal test set and 0.866 on the external validation set, along with intersection over union (IoU) scores of 0.819 and 0.787, respectively. The TLS ratio, defined as the segmented TLS area over the total tissue area, correlated with B lymphocyte levels and the expression of CXCL13, a chemokine associated with TLS formation, in 6140 patients spanning 16 tumor types from The Cancer Genome Atlas (TCGA). The prognostic models for overall survival indicated that the inclusion of the TLS ratio with TNM staging significantly enhanced the models’ discriminative ability, outperforming the traditional models that solely incorporated TNM staging, in 10 out of 15 TCGA tumor types. Furthermore, when applied to biopsied treatment-naïve tumor samples, higher TLS ratios predicted a positive immunotherapy response across multiple cohorts, including specific therapies for esophageal squamous cell carcinoma, non-small cell lung cancer, and stomach adenocarcinoma. In conclusion, our deep learning-based approach offers an automated and reproducible method for TLS segmentation and quantification, highlighting its potential in predicting immunotherapy response and informing cancer prognosis.

Abstract Mask-free multi-photon lithography enables the fabrication of arbitrary nanostructures low cost and more accessible than conventional lithography. A major challenge for multi-photon lithography is to achieve ultra-high precision and desirable lateral resolution due to the inevitable optical diffraction barrier and proximity effect. Here, we show a strategy, light and matter co-confined multi-photon lithography, to overcome the issues via combining photo-inhibition and chemical quenchers. We deeply explore the quenching mechanism and photoinhibition mechanism for light and matter co-confined multiphoton lithography. Besides, mathematical modeling helps us better understand that the synergy of quencher and photo-inhibition can gain a narrowest distribution of free radicals. By using light and matter co-confined multiphoton lithography, we gain a 30 nm critical dimension and 100 nm lateral resolution, which further decrease the gap with conventional lithography.

In cold climatic areas, bridge expansion joint concrete is susceptible to damage from freeze-thaw (F-T) cycles and chloride-salt erosion. This paper investigates the differences between the surface layer of concrete (C-S) and the interior of concrete (C-I) under various curing conditions, focusing on pore structure characteristics. The salt freeze-thaw (sF-T) resistance of the C-S and C-I was analyzed using the surface scaling, mass growth rate, and apparent chloride diffusion coefficient after one-sided sF-T cycles (Dapp′). The results indicate that the pore structure of the C-S was more intricate than that of the C-I. However, the paste structure of the C-I was denser. The fractal dimension (DF) of the C-I was lower than that of the C-S under different curing conditions, with a reduction of approximately 10 %. Additionally, it was observed that the C-I exhibited significantly higher sF-T resistance than the C-S. To obtain a more precise evaluation of the concrete's sF-T resistance, it is recommended to remove 2 mm from the edges of the specimen. Furthermore, the Dapp′ is a more reliable indicator of concrete's sF-T resistance when the F-T medium is a chloride-salt solution. The Dapp′ of the C-I decreased by 26.8 %, 33.2 %, and 49.9 % under the curing conditions of 20℃-95 %RH, 5℃-70 %RH, and 0℃-50 %RH, respectively, when using concrete specimens with 2 mm of edges removed, compared to the C-S. The study results can serve as a fundamental basis for designing and constructing of concrete for bridge expansion joints in cold climatic areas.

ABSTRACT Current microbiome signatures for chronic diseases such as diabetic kidney disease (DKD) are mainly based on low-resolution taxa such as genus or phyla and are often inconsistent among studies. In microbial ecosystems, bacterial functions are strain specific, and taxonomically different bacteria tend to form co-abundance functional groups called guilds. Here, we identified guild-level signatures for DKD by performing in-depth metagenomic sequencing and conducting genome-centric and guild-based analysis on fecal samples from 116 DKD patients and 91 healthy subjects. Redundancy analysis on 1,543 high-quality metagenome-assembled genomes (HQMAGs) identified 54 HQMAGs that were differentially distributed among the young healthy control group, elderly healthy control group, early-stage DKD patients (EDG), and late-stage DKD patients (LDG). Co-abundance network analysis classified the 54 HQMAGs into two guilds. Compared to guild 2, guild 1 contained more short-chain fatty acid biosynthesis genes and fewer genes encoding uremic toxin indole biosynthesis, antibiotic resistance, and virulence factors. Guild indices, derived from the total abundance of guild members and their diversity, delineated DKD patients from healthy subjects and between different severities of DKD. Age-adjusted partial Spearman correlation analysis showed that the guild indices were correlated with DKD disease progression and with risk indicators of poor prognosis. We further validated that the random forest classification model established with the 54 HQMAGs was also applicable for classifying patients with end-stage renal disease and healthy subjects in an independent data set. Therefore, this genome-level, guild-based microbial analysis strategy may identify DKD patients with different severity at an earlier stage to guide clinical interventions.IMPORTANCETraditionally, microbiome research has been constrained by the reliance on taxonomic classifications that may not reflect the functional dynamics or the ecological interactions within microbial communities. By transcending these limitations with a genome-centric and guild-based analysis, our study sheds light on the intricate and specific interactions between microbial strains and diabetic kidney disease (DKD). We have unveiled two distinct microbial guilds with opposite influences on host health, which may redefine our understanding of microbial contributions to disease progression. The implications of our findings extend beyond mere association, providing potential pathways for intervention and opening new avenues for patient stratification in clinical settings. This work paves the way for a paradigm shift in microbiome research in DKD and potentially other chronic kidney diseases, from a focus on taxonomy to a more nuanced view of microbial ecology and function that is more closely aligned with clinical outcomes.

The presence of clay in aggregate is frequently associated with the deterioration of concrete properties. The objective of this study was to investigate the effects of varying clay contents on the mechanical properties, freeze-thaw resistance, permeability and water absorption behavior of concrete. Additionally, the differences in the permeability, and water absorption behavior of the surface layer and interior of concrete were comparatively analyzed using self-designed tests. The results indicate that the presence of a minimal quantity of clay did not diminish the compressive strength and static compressive modulus of elasticity of concrete. However, it did result in a reduction in the tensile properties and durability of concrete. Furthermore, the mechanical properties, freeze-thaw resistance, and anti-permeability of concrete were significantly diminished when the clay content reached 1.6%. Furthermore, this study proposed an innovative evaluation method for dividing the water absorption behavior of concrete into three stages, which more accurately reflected the trend of water absorption behavior in concrete. It was found that the sorptivity and permeable porosity of concrete in the three stages exhibited a strong correlation. The presence of clay increased the sorptivity and permeable porosity of concrete, with the most pronounced effect observed in the initial water absorption stage. Moreover, the permeable porosity of the interior of concrete was found to be reduced in comparison to that of the surface layer of concrete at all ages with varying clay contents, with the reduction ranging from 10.7% to 14.7%. In practical engineering construction, it is recommended that the clay content be kept within reasonable limits, and the effect of the clay content on the properties of the surface layer of concrete be given greater attention.

Introducing Holstein cows on Qinghai-Tibetan Plateau is a potential solution to enhance local milk production. However, the relationship between milk quality and altitude in China remains unknown. Therefore, the components and plasmin (PL) system of raw milk from different altitudes (sea level, 1600, 2700, and 3800 m) were investigated. The daily milk production of Holstein cows and PL activity decreased as the altitude increased. However, the components content of raw milk, plasminogen (PLG)/PL ratio, activities of PLG and plasmin activator (PA) increased with altitude. The pasteurization resulted a significant decrease in PA activity of all milk and a significant increase in PL activity in milk collected at higher altitudes (2700 and 3800 m), suggesting the pasteurization was unsuitable for preserving milk at higher altitudes. This study offered references for the production and storage of milk after introducing Holstein cows on Qinghai-Tibetan Plateau.

Pyran- and furanocoumarins are key representatives of tetrahydropyrans and tetrahydrofurans, respectively, exhibiting diverse physiological and medical bioactivities. However, the biosynthetic mechanisms for their core structures remain poorly understood. Here we combined multiomics analyses of biosynthetic enzymes in Peucedanum praeruptorum and in vitro functional verification and identified two types of key enzymes critical for pyran and furan ring biosynthesis in plants. These included three distinct P. praeruptorum prenyltransferases (PpPT1–3) responsible for the prenylation of the simple coumarin skeleton 7 into linear or angular precursors, and two novel CYP450 cyclases (PpDC and PpOC) crucial for the cyclization of the linear/angular precursors into either tetrahydropyran or tetrahydrofuran scaffolds. Biochemical analyses of cyclases indicated that acid/base-assisted epoxide ring opening contributed to the enzyme-catalyzed tetrahydropyran and tetrahydrofuran ring refactoring. The possible acid/base-assisted catalytic mechanisms of the identified cyclases were theoretically investigated and assessed using site-specific mutagenesis. We identified two possible acidic amino acids Glu303 in PpDC and Asp301 in PpOC as vital in the catalytic process. This study provides new enzymatic tools in the epoxide formation/epoxide-opening mediated cascade reaction and exemplifies how plants become chemically diverse in terms of enzyme function and catalytic process.

The drill-blasting method is a commonly used mining technique in open-pit mines, and the peak particle velocity (PPV) caused by blasting vibrations is an important indicator for evaluating the rationality of blasting mining design parameters. To develop an effective PPV prediction model, a parameter self-optimizing RUN-XGBoost prediction model is implemented using the Runge-Kutta optimization algorithm (RUN) combined with extreme gradient boosting (XGBoost). The factors affecting the prediction of PPV, including maximum explosive (ME), total explosive (TE), blast center distance (BCD), blast hole depth (BHD), and height difference between the measurement location and the blast location (DH), are selected as the influencing indicators. 188 pieces of blasting operation data were measured at the RK open pit copper-cobalt mine. Then, the RUN-XGBoost prediction model for PPV is studied and compared with the Sadovsky empirical formula, traditional XGBoost model, PSO-XGBoost model, and some traditional machine learning models (Ridge, LASSO, SVM, and SVR) using R2, RMSE, VAF, MAE, and MBE as evaluation indicators for model prediction results. Finally, the Shapley Additive Explanations (SHAP) method is used to evaluate the contribution of different influencing indicators to the PPV prediction results. The results show that the RUN-XGBoost prediction model is significantly better than other machine learning models and the Sadovsky empirical formula in the prediction of PPV, further demonstrating that the RUN-XGBoost prediction model can handle the nonlinear features of multiple factors and provide a reliable, simple, and effective PPV prediction model, forming a rapid prediction and evaluation method for blasting vibrations in open-pit mining.

Recent developments on the electron optics simulator (EOS) are reported in this paper. The EOS is a finite element two-dimensional (2D) and three-dimensional (3D) electrostatic particle steady-state trajectory code that has been widely used for beam optics modeling of vacuum electronic devices. To extend the application scope and improve the computation efficiency, four significant advances have been made and are presented in this paper. First, the code is reprogrammed to consider physical models that contain dielectrics and to support charge excitation. Second, more primary particle emission models are added in EOS to meet the needs for simulating electron and ion optics devices for diverse applications. For the precise simulation of the secondary electron emission, the Vaughan model is improved, and the Furman model is newly added in EOS. Finally, the algebraic multigrid algorithm has been embedded in EOS, which can significantly improve the computation efficiency for problems with large-scale matrices. For these developments, the necessary principles and corresponding performance are shown in detail in this paper.

Electron beam welding of GH4169 and Ni is required in the manufacture of the regenerative cooling system of the liquid rocket motor. The thermoelectric effect is observed during the welding of dissimilar metals; however, there has been a lack of investigation into the influence of this effect on electron beam welding joint formation and its dependence on test plate thickness. The thermoelectric effect of electron beam welding between GH4169 and Ni with varying thicknesses, as well as the influence of induced magnetic fields on electron beam trajectories, are investigated through the establishment of a numerical model incorporating thermal-electric-magnetic coupling.The results show that when the test plate increases from 2.5 mm to 10 mm the peak current density increases from 5.1 × 106 A/m2 to 7.6 × 106 A/m2, and the maximum magnetic flux density increases from 1.49× 10−2 T to 1.77 × 10−2 T. The increase in magnetic flux density results in a greater displacement of the electron beam spot away from the interface between the two materials, thereby causing incomplete fusion defects in the joints. This study elucidates the fundamental physical principles underlying the occurrence of incomplete fusion defects in electron beam welding joints, thereby furnishing essential theoretical underpinnings for enhancing the quality of dissimilar metal electron beam weld joints.

Abstract Basal cell carcinoma (BCC) is the most common cancer with a rising incidence among white-skinned individuals. A number of epidemiological studies have suggested that obesity and serum 25-hydroxy-vitamin D (25(OH)D) levels may affect the arising of BCC. To address this, we selected 443 and 96 single nucleotide polymorphisms (SNPs) associated with body mass index (BMI) and serum level of 25(OH)D from large-scale genome-wide association studies (GWAS), respectively. The univariable and multivariable two-sample Mendelian randomization (MR) analyses were conducted with a series of sensitivity analyses to ensure the results were reliable and reproducible. The results of univariable two-sample MR analysis showed that higher BMI was related to lower risk for BCC (Odds ratio(OR) = 0.90; 95% confidence interval (CI),[0.81,0.99]; p = 0.02). In addition, this causal effect of BMI on BCC still remained (OR = 0.88; 95%CI,[− 0.22, − 0.03], p-value = 0.008) after adjusting for 25(OH)D level in the multivariable MR analysis. However, the results suggested that 25(OH)D level was not associated with BCC(OR = 1.02; 95%CI, [0.94,1.09], p-value = 0.67). In conclusion, similar to the conclusions of retrospective observational studies, the MR results indicate that high BMI is an independent protective factor for BCC. Meanwhile, vitamin D levels may not be causally associated with the risk of basal cell carcinoma and increasing vitamin D supplementation is unlikely to reduce the risk.

Backward erosion piping, a soil erosion phenomenon induced by seepage, compromises the stability of water-retaining structures such as dikes. During floods, the seepage in the dike body increases due to high water levels, which directly affects the progression of the piping channel. The formation of the piping channel then impacts the stability of the dike. In this paper, an improved piping model that considers the impact of seepage in the dike body is proposed based on Wewer’s model. Specifically, we added a seepage field of the dike body to the original model to account for the impact of dike-body seepage on the evolution of piping. The seepage field of the dike body is solved using Darcy’s law and the continuity equation for unsaturated porous media. In addition, this approach also incorporates the coupling effect of seepage stress. The accuracy of the model was verified through comparing the calculated results with the IJkdijk experiment and Wewer’s results. The effects of BEP on dike stability were investigated using the proposed improved piping model. The two major conclusions of the study are that (1) the incorporation of unsaturated seepage enhanced the performance of the piping model, allowing it to more accurately simulate the development of pipe length and the changing of pore pressure; and (2) the formation of the pipe impacted dike stability, leading to a substantial reduction in the safety factor of the dike slope.

Immunoglobulin G (IgG) N-glycosylation plays a crucial role in the development of inflammatory diseases. This study aimed to evaluate the diagnostic performance of IgG for gastrointestinal (GI) cancer subtypes. A total of 749 GI cancer patients were enrolled from the Cancer Hospital, Chinese Academy of Medical Sciences, including esophageal cancer (EC), gastric cancer (GC), colorectal cancer (CRC), and pancreatic cancer (PC) patients. Hydrophilic interaction liquid chromatography using ultra-performance liquid chromatography (HILIC-UPLC) was employed to analyze the composition of the plasma IgG N-glycome. The levels of circulating inflammatory cytokines were detected by means of a Bio-Plex Pro Human Th17 Cytokine Assay. Canonical correlation analysis (CCA) was used to explore the correlation between IgG N-glycosylation patterns and inflammatory cytokines. A Lasso algorithm, accompanied by a logistic regression model, was used to develop a glycan-based model for differentiating GI cancer patients from healthy individuals. The levels of sialylation and galactosylation were significantly decreased among EC, GC, CRC, and PC patients, whereas the abundance of glycans with bisecting N-acetylglucosamine (GlcNAc) was increased in GI cancer patients in comparison with the healthy controls. Moreover, only PC patients had a decreased level of fucosylation. The levels of interleukin 1β (IL-1β), IL-31, and soluble CD40 ligand (sCD40L) were significantly higher in GI cancer patients than in the controls. In addition, the composition of IgG N-glycans was correlated with that of inflammatory cytokines (r = 0.556). The glycan-based models for diagnosing GI cancers exhibited an excellent performance, with areas under the receiver operating characteristic curves (AUCs) of 0.972 for EC, 0.871 for GC, 0.867 for CRC, and 0.907 for PC. Our findings demonstrate that IgG N-glycosylation plays an important role in modulating the pathogenesis of GI cancers. Serological IgG N-glycosylation is thus a potential candidate for noninvasively assisting in the clinical diagnosis of GI cancer subtypes.

Lysine is an essential amino acid that cannot be synthesized in humans. Rice is a global staple food for humans but has a rather low lysine content. Identification of the quantitative trait nucleotides (QTNs) and genes underlying lysine content is crucial to increase lysine accumulation. In this study, five grain and three leaf lysine content datasets and 4,630,367 single nucleotide polymorphisms (SNPs) of 387 rice accessions were used to perform a genome-wide association study (GWAS) by ten statistical models. A total of 248 and 71 common QTNs associated with grain/leaf lysine content were identified. The accuracy of genomic selection/prediction RR-BLUP models was up to 0.85, and the significant correlation between the number of favorable alleles per accession and lysine content was up to 0.71, which validated the reliability and additive effects of these QTNs. Several key genes were uncovered for fine-tuning lysine accumulation. Additionally, 20 and 30 QTN-by-environment interactions (QEIs) were detected in grains/leaves. The QEI-sf0111954416 candidate gene LOC_Os01g21380 putatively accounted for gene-by-environment interaction was identified in grains. These findings suggested the application of multi-model GWAS facilitates a better understanding of lysine accumulation in rice. The identified QTNs and genes hold the potential for lysine-rich rice with a normal phenotype.

The wide range and high intensity of landslides in the mining area pose a great threat to the safety of human life and property. It is particularly important to identify and monitor them. However, due to the serious surface damage, small landslide scale, complex background and other factors in the mining area, it is impossible to accurately identify and detect the landslide in the mining area. It is necessary to select an efficient detection model to detect it. In this paper, aiming at the problem of landslide identification in mining area, the remote sensing image of mining area is obtained by unmanned aerial vehicle (UAV), and the landslide data set of mining area is constructed by data enhancement method. An improved YOLOv8 algorithm is proposed. By adding a mixed attention mechanism in the channel and spatial dimensions, the detection accuracy of the model for mining landslide is improved, and the monitoring of landslide changes in the mining area is successfully completed. At the same time, an algorithm for locating the landslide position is proposed. Through this algorithm, the detected landslide pixel coordinates can be converted into geodetic coordinates. The results show that the improved YOLOv8 algorithm proposed in this paper has a recognition accuracy of 93.10% for mining area landslides. Compared with the mAP@0.5 of the original YOLOv8 algorithm and YOLOv5 algorithm, the improved YOLOv8 algorithm has an increase of 4.2% and 5.1%. This study has realized the monitoring and positioning of the landslide in the mining area, which can provide the necessary data support for the ecological restoration on mining area.

With the introduction of tertiary oil recovery technology, polymer oil drive technology has effectively improved the recovery rate of crude oil, but the resulting oilfield wastewater-containing polyacrylamide (PAM) is viscous and complex in composition, which brings difficulties to wastewater treatment. The treatment of this kind of wastewater has become an urgent problem to be solved, and the removal of PAM is the key. In this paper, a dielectric barrier discharge (DBD) co-catalyst was used to treat PAM-containing solutions to investigate the effect of different catalytic reaction systems on the degradation of PAM. The morphological changes of the PAM solution before and after the reaction were also studied by the environmental electron microscope scanner (ESEM), and the information of the functional groups in the solution before and after the reaction was studied by infrared spectroscopy analysis of the PAM solution. The degradation rate rose by 26.3% in comparison to that without discharge when AC/Mn + TiO2 and Al2O3 were combined and catalyzed at a mass ratio of 2:1 and a discharge period of 300 min. The degradation rate rose by 19.3 and 6.8%, respectively, in comparison to AC/Mn + TiO2 and Al2O3-catalyzed alone. It demonstrates that this catalytic system has the optimum catalytic effect. HIGHLIGHT In this paper, the feasibility of low-temperature plasma generated by dielectric barrier discharge (DBD) to degrade poly-containing wastewater was studied. From the perspective of improving the degradation efficiency, a double glass DBD reactor with a water-cooling function was designed, and the effect of low-temperature plasma on the degradation rate of PAM solution under different catalyst combinations conditions was studied.;

Abstract Background Metastasis is a significant factor that affects the survival of patients with non-small cell lung cancer (NSCLC). Nevertheless, the molecular regulatory mechanism underlying the metastasis is currently not fully understood. This study aims to identify the important role of miR-124-3p in metastasis of NSCLC, thereby providing a potential therapeutic intervention. Methods Exosome secretion was determined by Nanoparticle Tracking Analysis (NTA) and the uptake was measured by fluorescence inverted microscope. The binding mechanism between miR-124-3p and its upstream or downstream target genes was validated experimentally by Luciferase reporter. Cells migration was evaluated by transwell assays. Transcriptome sequencing on A549 was carried out to verify the potential signaling pathway underlying miR-124-3p regulation. Western blotting analysis was used to assess the level of AKT, p-AKT, PI3K, and p-PI3K protein expression in NSCLC cell lines. The role of miR-124-3p to suppress the tumor metastasis was verified in NSCLC xenograft model. Results Exosomes were more abundant in serum from patients with advanced lung cancer (n = 24 patients) than in these from patients with early-stage lung cancer (n = 30 patients), which suggested the potential correlation between amount of exosome secretion and the metastasis of NSCLC. Interestingly, the exosome release, uptake and the migration of NSCLC cells were notably inhibited by miR-124-3p. LINC00511 suppressed the expression of miR-124-3p to facilitate exosome transport due to its role as the competitive endogenous RNA for miR-124-3p. The miR-124-3p could directly target the 3′-UTR of Rab27a in NSCLC cells to inhibit exosome secretion and thereby prevent cell migration and invasion. Aside from the inhibition of exosome transport, miR-124-3p inhibited the activation of PI3K/AKT signaling in the intracellular environment. Finally, by measuring subcutaneous tumor weight and volume and lung metastasis, we also demonstrated that miR-124-3p inhibited tumor growth in vivo. Conclusion In NSCLC, miR-124-3p significantly suppressed metastasis through extracellular exosome transport and intracellular PI3K/AKT signaling. These findings provide new insights toward a better understanding of the NSCLC metastasis and suggest a potential treatment biomarker for NSCLC.

Abstract Background Photodynamic therapy (PDT) has become an ideal and promising therapeutic method for fighting cancer, but its common application in clinical practice is prevented by the limitations of expensive devices in light sources and phototoxicity in photosensitizers. The aim of this study was to explore the antitumor efficiency of the novel 450-nm blue laser (BL) combined with sinoporphyrin sodium (DVDMS)-mediated PDT against human gastric cancer (GC) in vitro and in vivo, focusing on autophagy pathway. Methods Cell viability was detected by Cell Counting Kit-8 and colony formation assays in HGC27, MGC803, AGS, and GES-1 cells. Cell apoptosis was measured by flow cytometry and western blotting. The production of reactive oxygen species (ROS) was measured by fluorescence microscopy and flow cytometry. Autophagy was determined by transmission electron microscopy and western blotting. The antitumor effect of BL-PDT in vivo was detected by a subcutaneous tumor model in nude mice. Results The novel 450-nm laser-mediated DVDMS-based PDT caused remarkable growth inhibition and apoptosis induction in GC cells in vitro by the production of excessive ROS. Autophagy flux was induced by BL-PDT in GC cells, as determined by LC3 conversion assay, LC3 turnover assay, and mRFP-GFP-LC3 puncta assay. Furthermore, autophagy induction was demonstrated to positively contribute to BL-PDT-induced apoptotic effects on GC cells. Mechanically, ROS/PI3K/Akt/mTOR pathway was identified to involve in the regulation of BL-PDT-induced autophagy as determined by transcriptomic analysis and functional studies. Consistently, xenograft studies confirmed the significant antitumor effect of BL-PDT and its favorable safety in vivo. Conclusions The novel 450-nm laser-mediated DVDMS-based PDT may be a safe and effective approach against GC. Our results thus provide compelling evidence for the therapeutic application of BL-PDT in human GC.

It is widely acknowledged that the operating parameters of fuel cell stack have significant influences on the output performances. However, there is still a lack of relevant research on the parameter sensitivity test for high-power vehicular stacks. In the study, the orthogonal test method is adopted for a 65 kW fuel cell stack. Effects of operating temperature, relative humidity, stoichiometric ratio, and inlet pressure are quantitatively investigated. It is found that the stack voltage increases significantly when the operating temperature rises from 60 °C to 70 °C while no remarkable performance differences are observed when the temperature further rises from 75 °C to 80 °C. With the increase of reactant relative humidity, the change of voltage change ratio is more obvious in the low current density regions. It is also inferred that the stack performance enhancement caused by better hydration level will be less effective once the inlet relative humidity reaches a certain degree. Increasing the inlet reactant pressure promotes the mass transfer capacity. Besides, the performance is improved more significantly in the high current density regions, which may be attributed to the improvement of concentration polarization. When the stoichiometric ratio increases, the stack output voltage does not increase significantly at lower current regions, but there exists significant performance optimization at higher current regions. The paper contributes to the deeper understanding of transport phenomena as well as better performance enhancement suggestions for vehicular fuel cell stacks.

Energy consumption is essential for evaluating the competitiveness of fuel cell electric vehicles. A critical step in energy consumption measurement is measuring hydrogen consumption, including the mass method, the P/T method, and the flowmeter method. The flowmeter method has always been a research focus because of its simple operation, low cost, and solid real-time performance. Current research has shown the accuracy of the flowmeter method under specific conditions. However, many factors in the real scenario will influence the test result, such as unintended vibration, environment temperature, and onboard hydrogen capacity calibration. On the other hand, the short-cut method is also researched to replace the run-out method to improve test efficiency. To evaluate whether the flowmeter method basing on the short-cut method can genuinely reflect the hydrogen consumption of an actual vehicle, we research and test for New European Driving Cycle (NEDC) and China Light-Duty Vehicle Test Cycle (CLTC) using the same vehicle. The results show that the short-cut method can save at least 50% of the test time compared with the run-out method. The error of the short-cut method based on the flowmeter for the NEDC working condition is less than 0.1%, and for the CLTC working conditions is 8.12%. After adding a throttle valve and a 4L buffer tank, the error is reduced to 4.76% from 8.12%. The test results show that hydrogen consumption measurement based on the flowmeter and short-cut method should adopt corresponding solutions according to the scenarios.

In order to select pioneer plants suitable for ecological restoration of high and steep rock slopes in North China, two high-and-steep slope ecological restoration test sites were established in the limestone area of Jinan by using the technology of landscape reconstruction. The sites planted a total of 14 kinds of deciduous plants, evergreens and lianas, whose survival rate and growth status were monitored for a long period of time. The data collected was analyzed by the plant suitability evaluation model and the result is displayed in the form of the comprehensive evaluation index. According to the result, in the group of evergreens, Platycladus orientalis, juniper and fufangteng are the preferred pioneer plants; in the group of deciduous plants, Robinia pseudoacacia, Cotinus japonicus and Forsythia suspensa are the preferred ones; the vine creeper has a high survival rate and fast growth rate which can effectively cover high-and-steep rock walls in a short time. It is the preferred pioneer plant in the group of lianas.

Abstract Aims Previous prediction studies for 30 day readmission in patients with heart failure were built mainly based on electronic medical records and rarely involved patient‐reported outcomes. This study aims to develop and validate a nomogram including patient‐reported outcomes to predict the possibility of 30 day all‐cause readmission in older patients with heart failure and to explore the value of patient‐reported outcomes in prediction model. Methods and results This was a prospective cohort study. The nomogram was developed and internally validated by Logistic regression analysis based on 381 patients in training group from March to December 2019. The nomogram was externally validated based on 170 patients from July to October 2020. Receiver operating characteristic curves, calibration plots and decision‐curve analysis were used to evaluate the performance of the nomogram. A total of 381 patients' complete data were analysed in the training group and 170 patients were enrolled in the external validation group. In the training group, 14.4% (n = 55) patients were readmitted to hospitals within 30 days of discharge and 15.9% (n = 27) patients were readmitted in the external validation group. The nomogram included six factors: history of surgery, changing the type of medicine by oneself, information acquisition ability, subjective support, depression level, quality of life, all of which were significantly associated with 30 day readmission in older patients with heart failure. The areas under the receiver operating characteristic curves of nomogram were 0.949 (95% CI: 0.925, 0.973, sensitivity: 0.873, specificity: 0.883) and 0.804 (95% CI: 0.691, 0.917, sensitivity: 0.778, specificity: 0.832) respectively in the training and external validation groups, which indicated that the nomogram had better discrimination ability. The calibration plots demonstrated favourable coordination between predictive probability of 30 day readmission and observed probability. Decision‐curve analysis showed that the net benefit of the nomogram was better between threshold probabilities of 0–85%. Conclusions A novel and easy‐to‐use nomogram is constructed and demonstrated which emphasizes the important role of patient‐reported outcomes in predicting studies. The performance of the nomogram drops in the external validation cohort and the nomogram must be validated in a wide prospective cohort of HF patients before its clinical relevance can be demonstrated. All these findings in this study can assist professionals in identifying the needs of HF patients so as to reduce 30 day readmission.

The genome of Aechmea fasciata , a common house plant and popular bromelioid provides insights into its evolution.

Aluminum-ion batteries (AIBs) have become a research hotspot in the field of energy storage due to their high energy density, safety, environmental friendliness, and low cost. However, the actual capacity of AIBs is much lower than the theoretical specific capacity, and their cycling stability is poor. The exploration of energy storage mechanisms may help in the design of stable electrode materials, thereby contributing to improving performance. In this work, molybdenum disulfide (MoS2) was selected as the host material for AIBs, and carbon nanofibers (CNFs) were used as the substrate to prepare a molybdenum disulfide/carbon nanofibers (MoS2/CNFs) electrode, exhibiting a residual reversible capacity of 53 mAh g−1 at 100 mA g−1 after 260 cycles. The energy storage mechanism was understood through a combination of electrochemical characterization and first-principles calculations. The purpose of this study is to investigate the diffusion behavior of ions in different channels in the host material and its potential energy storage mechanism. The computational analysis and experimental results indicate that the electrochemical behavior of the battery is determined by the ion transport mechanism between MoS2 layers. The insertion of ions leads to lattice distortion in the host material, significantly impacting its initial stability. CNFs, serving as a support material, not only reduce the agglomeration of MoS2 grown on its surface, but also effectively alleviate the volume expansion caused by the host material during charging and discharging cycles.

Objectives: This study aimed to explore the role of CD4+ T cells in the mechanisms of COVID-19 related diarrhea. Methods: We analyzed lymphocyte subsets in patients with COVID-19 and the expression of angiotensin-converting enzyme 2 (ACE2), the transmembrane protease serine 2, and CD4+ T cell-related indicators in the colon were compared between patients with and without diarrhea. Correlation analyses were performed for ACE2 and other indicators to identify the relationship between SARS-CoV-2 infection and CD4+ mediated inflammation. The expression and distribution of CD4+ T cell-associated chemokines and their receptors were detected to determine the possibility of migration of CD4+ T cells to inflammation sites. Results: The CD4+ T cell counts and percentages and CD4/CD8 ratio showed the most significant differences between the 2 groups. The diarrhea group expressed higher levels of ACE2, T-box expressed in T cells (Tbet), and tumor necrosis factor-alpha (TNFα) at both the mRNA and protein levels, with no difference from the nondiarrhea group for the percentage of ACE2+TNFα+ cells, indicating an indirect association between ACE2 and TNFα. The mRNA expression of CXCL10, CXCL11, and CXCR3 and the number of CD4+CXCR3+T cells were increased in the diarrhea group. Conclusions: CD4+ T cell-mediated inflammation may contribute to COVID-19 related diarrhea. CXCR3+ mediated migration of CD4+ T cells into the gut may perpetuate inflammation.

Abstract Background Non-invasive, especially the urine-based diagnosis of prostate cancer (PCa) remains challenging. Although prostate cancer antigen (PSA) is widely used in prostate cancer screening, the false positives may result in unnecessary invasive procedures. PSA elevated patients are triaged to further evaluation of free/total PSA ratio (f/t PSA), to find out potential clinically significant PCa before undergoing invasive procedures. Genomic instability, especially chromosomal copy number variations (CNVs) were proved much more tumor specific. Here we performed a prospective study to evaluate the diagnostic value of CNV via urine-exfoliated cell DNA analysis in PCa. Methods We enrolled 28 PSA elevated patients (≥ 4 ng/ml), including 16 PCa, 9 benign prostate hypertrophy (BPH) and 3 prostatic intraepithelial neoplasia (PIN). Fresh initial portion urine was collected after hospital admission. Urine exfoliated cell DNA was analyzed by low coverage Whole Genome Sequencing, followed by CNV genotyping by the prostate cancer chromosomal aneuploidy detector (ProCAD). CNVs were quantified in absolute z-score (|Z|). Serum free/total PSA ratio (f/t PSA) was reported altogether. Results In patients with PCa, the most frequent CNV events were chr3q gain (n = 2), chr8q gain (n = 2), chr2q loss (n = 4), and chr18q loss (n = 3). CNVs were found in 81.2% (95% Confidence Interval (CI) 53.7–95.0%) PCa. No CNV was identified in BPH patients. A diagnosis model was established by incorporating all CNVs. At the optimal cutoff of |Z|≥ 2.50, the model reached an AUC of 0.91 (95% CI 0.83–0.99), a sensitivity of 81.2% and a specificity of 100%. The CNV approach significantly outperformed f/t PSA (AUC = 0.62, P = 0.012). Further analyses showed that the CNV positive rate was significantly correlated with tumor grade. CNVs were found in 90.9% (95% CI 57.1–99.5%) high grade tumors and 60.0% (95% CI 17.0–92.7%) low grade tumors. No statistical significance was found for patient age, BMI, disease history and family history. Conclusions Urine exfoliated cells harbor enriched CNV features in PCa patients. Urine detection of CNV might be a biomarker for PCa diagnosis, especially in terms of the clinically significant high-grade tumors.

Periodontitis is an inflammatory disease that is characterized by progressive destruction of the periodontium and causes tooth loss in adults. Periodontitis is known to be associated with dysbiosis of the oral microflora, which is often linked to various diseases. However, the complexity of plaque microbial communities of periodontitis, antibiotic resistance, and enhanced virulence make this disease difficult to treat. In this study, using metagenomic shotgun sequencing, we investigated the etiology, antibiotic resistance genes (ARGs), and virulence genes (VirGs) of periodontitis. We revealed a significant shift in the composition of oral microbiota as well as several functional pathways that were represented significantly more abundantly in periodontitis patients than in controls. In addition, we observed several positively selected ARGs and VirGs with the Ka/Ks ratio > 1 by analyzing our data and a previous periodontitis dataset, indicating that ARGs and VirGs in oral microbiota may be subjected to positive selection. Moreover, 5 of 12 positively selected ARGs and VirGs in periodontitis patients were found in the genomes of respiratory tract pathogens. Of note, 91.8% of the background VirGs with at least one non-synonymous single-nucleotide polymorphism for natural selection were also from respiratory tract pathogens. These observations suggest a potential association between periodontitis and respiratory infection at the gene level. Our study enriches the knowledge of pathogens and functional pathways as well as the positive selection of antibiotic resistance and pathogen virulence in periodontitis patients, and provides evidence at the gene level for an association between periodontitis and respiratory infection.

To research serious nonlinear coupling problems among aerodynamics, flight mechanics, and flight control during high maneuvers, a virtual flight testing platform has been developed for a large-scale, high-speed wind tunnel, based on the real physical environment, and it can significantly mitigate risks and reduce the costs of subsequent flight tests. The platform of virtual flight testing is composed of three-degrees-of-freedom model support, measuring devices for aerodynamic and motion parameters, a virtual flight control system, and a test model. It provides the ability to realistically simulate real maneuvers, investigate the coupling characteristics of unsteady aerodynamics and nonlinear flight dynamics, evaluate flight performance, and verify the flight control law. The typical test results of a pitch maneuver with open-loop and closed-loop control are presented, including a one-degree-of-freedom pitch motion and a two-degrees-of-freedom pitch and roll motion. The serious pitch and roll-coupled motion during a pitch maneuver at a high angle of attack is revealed, and the flight control law for decoupled control is successfully verified. The comparison of the test results and the flight data of a real pitch maneuver proves the reliability and capability of virtual flight testing.

Background: Non-alcoholic fatty liver disease (NAFLD) is a popular chronic liver disorder with high morbidity and with no approved therapeutic drugs. Fibrosis is a crucial drug efficacy indicator for NAFLD. Thus, investigating the mechanisms of NAFLD-associated fibrosis and exploring effective therapeutic targets is imperative. Methods: Gerbil NAFLD-associated fibrosis model was constructed by feeding a high-fat and high-cholesterol diet. The hematoxylin and eosin staining and the alanine transaminase (ALT) and aspartate transaminase (AST) assays were used to determine liver tissue injury. Masson staining and hydroxyproline (Hyp) level determination were used to assess liver fibrosis. High-throughput mRNA sequencing was used to screen differentially expressed genes in the NAFLD-associated fibrosis model. Cell Counting Kit-8 was utilized to test cell viability. Results: Liver injury and fibrosis were observed in the gerbil NAFLD-associated fibrosis model with increased ALT, AST, and Hyp levels. The screened differentially expressed genes were mainly enriched in “negative regulation of hemopoiesis”, “response to interleukin-1”, and “granulocyte migration”. Zinc Finger and BTB Domain Containing 14 (Zbtb14) was upregulated in liver tissues of the gerbil NAFLD-associated fibrosis model, patients with liver fibrosis, and hepatic stellate cells (HSCs). Additionally, Zbtb14 regulated primary HSCs activation via the β-catenin pathway. Conclusions: Zbtb14 regulated NAFLD-associated fibrosis via the β-catenin pathway, for the first time, and it serves as the probable target for NAFLD therapy.

Pogostemon cablin is an important aromatic medicinal herb widely used in the pharmaceutical and perfume industries. However, our understanding of the phytochemical compounds and metabolites within P. cablin remains limited. To our knowledge, no integrated studies have hitherto been conducted on the metabolites of the aerial parts of P. cablin. In this study, twenty-three volatile compounds from the aerial parts of P. cablin were identified by GC-MS, predominantly sesquiterpenes. Quantitative analysis showed the highest level of patchouli alcohol in leaves (24.89 mg/g), which was 9.12 and 6.69-fold higher than in stems and flowers. UHPLC-QTOFMS was used to analyze the non-volatile compounds of leaf, stem and flower tissues. The differences in metabolites between flower and leaf tissues were the largest. Based on 112, 77 and 83 differential metabolites between flower-leaf, flower-stem and leaf-stem, three tissue-specific biomarkers of metabolites were identified, and the differential metabolites were enriched in several KEGG pathways. Furthermore, labeling differential metabolites in the primary and secondary metabolic pathways showed that flowers accumulated more lipids and amino acids, including proline, lysine and tryptophan; the leaves accumulated higher levels of terpenoids, vitamins and flavonoids, and stems contained higher levels of carbohydrate compounds. Based on the role of acetyl coenzyme A, the distribution and possible exchange mechanism of metabolites in leaves, stems and flowers of P. cablin were mapped for the first time, laying the groundwork for future research on the metabolites in P. cablin and their regulatory role.

Although microorganisms and silicon are well documented as factors that mitigate salt stress, their effect mitigating saline-alkaline stress in plants remains unknown. In this study, wheat plant seeds were treated with silicon, Enterobacter sp. FN0603 alone and in combination of both. Wheat seeds were soaked in silicon and bacterial solutions and sown in pots containing artificial saline-alkaline soils to compare the effects among all treatments. The results showed that the treatments with silicon and FN0603 alone significantly changed plant morphology, enhanced the rhizosphere soil nutrient content and enzyme activities, improved some important antioxidant enzyme activities (e.g., superoxide dismutase) and the contents of small molecules (e.g., proline) that affected osmotic conditions in the top second leaves. However, treatment with silicon and FN0603 in combination significantly further increased these stress tolerance indexes and eventually promoted the plant growth dramatically compared to the treatments with silicon or FN0603 alone (p

Sarcoma is a malignant tumor derived from interstitial tissues and requires comprehensive treatment including chemotherapy. Paclitaxel (PTX) is an active agent against sarcoma, but its effect is not sufficiently acceptable and needs to be improved. Low-frequency ultrasound (LFU) has been documented to improve the efficacy of drugs by inducing reversible changes in membrane permeability; however, the effects of the combined use of LFU and PTX for sarcoma tumors remain unclear and warrant further investigation. We investigated the effects of 30 kHz LFU treatment combined with PTX on sarcoma cells A-204 and HT-1080 by analyzing in vitro apoptosis and cell growth inhibition rates, and determined their antitumor effects by examining tumor weights with or without LFU in the S180 sarcoma xenograft model. Drug concentrations in the subcutaneous tumors were measured using high performance liquid chromatography (HPLC). LFU combined with PTX significantly induced cell apoptosis, and blocked the cell cycle of sarcoma cells in G2/M phase, and furthermore, inhibited the activation of JAK2/STAT3 signaling pathway. Meanwhile, LFU combined with PTX inhibited the expression of PD-L1 in vitro, suggesting the potential of enhanced antitumor immunity by this treatment. LFU combined with PTX significantly inhibited the growth of S180 tumors transplanted subcutaneously in Institute of Cancer Research (ICR) mice, and its enhanced effect may be associated with increased local concentrations of PTX in tumor tissues in vivo, with no significant adverse subsequences on body weight observed. We conclude that the combination of LFU and PTX has synergistic antitumor effects and is a candidate for subcutaneous treatment of sarcoma by further increasing the intracellular concentration of PTX.

Objective: Immune checkpoint inhibitors have revolutionized cancer therapy for multiple types of solid tumors, but as expected, a large percentage of patients do not show durable responses. Biomarkers that can predict clinical responses to immunotherapies at diagnosis are therefore urgently needed. Herein, we determined the associations between baseline gut commensal microbes and the clinical treatment efficiencies of patients with thoracic neoplasms during anti-programmed death protein 1 (PD-1) therapy. Methods: Forty-two patients with advanced thoracic carcinoma who received anti-PD-1 treatment were enrolled in the study. Baseline and time-serial stool samples were analyzed using 16S ribosomal RNA gene sequencing. Tumor responses, patient progression-free survival, and overall survival were used to measure clinical outcomes. Results: The diversities of the baseline gut microbiota were similar between responders (n = 23) and nonresponders (n = 19). The relative abundances of the Akkermansiaceae, Enterococcaceae, Enterobacteriaceae, Carnobacteriaceae and Clostridiales Family XI bacterial families were significantly higher in the responder group. These 5 bacterial families acted as a commensal consortium and better stratified patients according to clinical responses (P = 0.014). Patients with a higher abundance of commensal microbes had prolonged PFS (P = 0.00016). Using multivariable analysis, the abundance of the commensal consortium was identified as an independent predictor of anti-PD-1 immunotherapy in thoracic neoplasms (hazard ratio: 0.17; 95% confidence interval: 0.05–0.55; P = 0.003). Conclusions: Baseline gut microbiota may have a critical impact on anti-PD-1 treatment in thoracic neoplasms. The abundance of gut commensal microbes at diagnosis might be useful for the early prediction of anti-PD-1 immunotherapy responses.

Efficient CO2 photoreduction in pure water remains challenging. Here, the authors propose to use van der Waals gaps-rich BiOCl atomic layers with low exciton binding energy and abundant surface oxygen vacancies for CO2 to CO conversion.

Subjective well-being is a global health issue exacerbated by the COVID-19 pandemic. Social support has a positive impact on subjective well-being, however, the level of impact and the regulatory mechanism of social support on subjective well-being with reference to economic and cultural differences is unknown. Based on the Gallup survey data, a panel fixed effect model is constructed to examine the heterogeneity and regulatory mechanisms of social support on subjective well-being according to country-based economic and cultural matrix. Our findings show that, first, economic differences cause heterogeneous influence of social support on subjective well-being. Specifically, high-income countries have positive impact of social support on subjective well-being; whereas the lower ones have no significant influence. Secondly, cultural differences also cause heterogeneous impact, i.e. generosity of cultural characteristics regardless of high or low level in countries has a significant positive impact on subjective well-being, however, the degree of impact varies and is associated with level of generosity. Thirdly, a cross examination of heterogeneous moderating effect shows that democracy and freedom have a significant positive adjustment effect in both high and low generosity culture-characterized countries. These findings are significant to shape the conception of economic dominated social support for well-being, with significant implication for balancing (or shifting) social and public health policy with economic support towards building generosity and democratic societies.

To study the aerodynamic characteristics of the convex structure of a surface-monitoring device on a high-speed train and to evaluate its impact on the aerodynamic performance of the high-speed train, numerical simulation research was conducted on three different layouts of the monitoring device. The computational fluid dynamics (CFD) method was used for the simulation study, and the unsteady compressible NS equation was used as the control equation. Hexagonal grid technology was used to reduce the demand for the grid quantity. The rationality of the grid size and layout was verified through grid independence research. To increase the accuracy of the numerical simulation, the γ-Reθ transition model and improved delayed detached eddy simulation (IDDES) method were coupled for the simulation research. The aerodynamic characteristics of the different operation directions and configurations were compared and analyzed. The research results showed that the windward side of the single pantograph detection device experienced positive pressure, and the sideline and leeward sides experienced negative pressure. Increasing the fillet radius of the sideline could appropriately reduce the aerodynamic resistance. When the speed was about 110 m/s, the drag force coefficient of the detection device was 210~410 N, and the lateral force was small, which means that it had little impact on the overall aerodynamic force of the train. According to the results of the unsteady analysis of the layout with a large space, the resistance during forward travel was greater than that during negative travel. The streamlined upwind surface was conducive to reducing the scope of the leeward separation zone and the amplitude of the pressure fluctuation in the leeward zone, and it thus reduced the resistance. For the running trains, a vortex was formed on their leeward surface. The pressure monitoring results showed that the separated airflow had no dominant frequency or energy peak. The possibility of the following train top and other components experiencing resonance damage is low.

Abstract Aims Cardiac autonomic neuropathy (CAN) is a serious complication of diabetes and is associated with adipokines. The C1q tumor necrosis factor‐related protein 9 (CTRP9) is a newly discovered adipokine. This study aimed to evaluate the association of serum CTRP9 levels with the prevalence and severity of CAN in patients with type 2 diabetes mellitus. Materials and Methods We enrolled 262 patients (aged ≥18 years) with type 2 diabetes mellitus into this study. Standard cardiovascular autonomic reflex tests (CARTs) were used to assess CAN and patients were divided into three groups accordingly: a non‐CAN group, an early CAN group, and a definite CAN group. Serum CTRP9 levels were measured by enzyme‐linked immunosorbent assay, and the tertiles were calculated. Results Serum CTRP9 levels decreased significantly in the early CAN and definite CAN groups (P

Abstract Aflatoxin exposure is a crucial factor in promoting the development of primary hepatocellular carcinoma (HCC) in individuals infected with the hepatitis virus. However, the molecular pathways leading to its bioactivation and subsequent toxicity in hepatocytes have not been well-defined. Here, we carried out a genome-wide CRISPR-Cas9 genetic screen to identify aflatoxin B1 (AFB1) targets. Among the most significant hits was the aryl hydrocarbon receptor (AHR), a ligand-binding transcription factor regulating cell metabolism, differentiation, and immunity. AHR-deficient cells tolerated high concentrations of AFB1, in which AFB1 adduct formation was significantly decreased. AFB1 triggered AHR nuclear translocation by directly binding to its N-terminus. Furthermore, AHR mediated the expression of P450 induced by AFB1. AHR expression was also elevated in primary tumor sections obtained from AFB1-HCC patients, which paralleled the upregulation of PD-L1, a clinically relevant immune regulator. Finally, anti-PD-L1 therapy exhibited greater efficacy in HCC xenografts derived from cells with ectopic expression of AHR. These results demonstrated that AHR was required for the AFB1 toxicity associated with HCC, and implicate the immunosuppressive regimen of anti-PD-L1 as a therapeutic option for the treatment of AFB1-associated HCCs.

Abstract With the aim for a low-aspect-ratio flying wing configuration, this study explores the influence of wall temperature gradient on the laminar and turbulent boundary layers of aircraft surface and determines the effect on the transition Reynolds number and wall friction drag. A four-equation turbulence model with transition mode is used to numerically simulate the flow around the model. The variation of wall friction coefficient, transition Reynolds number, and turbulent boundary layer flow with wall temperature are emphatically investigated. Results show that when the wall temperature increases from 288 to 500 K, the boundary layer transition Reynolds number for the wing section increased by approximately 28% and the surface friction drags decreases by approximately 10.7%. The hot wall enhances the viscous effects of the laminar temperature boundary layer, reduces the Reynolds shear stress and turbulent kinetic energy, and increases the flow stability. However, the velocity gradient and shear stress in the bottom of the turbulent boundary layer decreases, which leads to reduced friction shear stress on the wall surface. Therefore, for the low-aspect-ratio flying wing model, the hot wall can delay the boundary layer transition and reduce the friction drag coefficient in the turbulent region.