FOXA3 regulates cholesterol metabolism to compensate for low uptake during the progression of lung adenocarcinoma.

Cholesterol metabolism is vital for multiple cancer progression, while how cholesterol affects lung, a low-cholesterol tissue, for cancer metastasis and the underlying mechanism remain unclear. In this study, we found that metastatic lung adenocarcinoma cells acquire cellular dehydrocholesterol and cholesterol by endogenous cholesterol biosynthesis, instead of uptake upon cholesterol treatment. Besides, we demonstrated that exogenous cholesterol functions as signaling molecule to induce FOXA3, a key transcription factor for lipid metabolism via GLI2. Subsequently, ChIP-seq analysis and molecular studies revealed that FOXA3 transcriptionally activated Hmgcs1, an essential enzyme of cholesterol biosynthesis, to induce endogenous dehydrocholesterol and cholesterol level for membrane composition change and cell migration. Conversely, FOXA3 knockdown or knockout blocked cholesterol biosynthesis and lung adenocarcinoma metastasis in mice. In addition, the potent FOXA3 inhibitor magnolol suppressed metastatic gene programs in lung adenocarcinoma patient-derived organoids (PDOs). Altogether, our findings shed light onto unique cholesterol metabolism and FOXA3 contribution to lung adenocarcinoma metastasis.

Obesity Paradox in Patients with Acute Coronary Syndrome: Is Malnutrition the Answer?

BACKGROUND: Obesity paradox has been reported in patients with cardiovascular disease, showing an inverse association between obesity as defined by BMI (in kg/m2) and prognosis. Nutritional status is associated with systemic inflammatory response and affects cardiovascular disease outcomes. OBJECTIVES: This study sought to examine the influence of obesity and malnutrition on the prognosis of patients with acute coronary syndrome (ACS). METHODS: This study included consecutive patients diagnosed with ACS and underwent coronary angiogram between January 2009 and February 2023. At baseline, patients were categorized according to their BMI as follows: underweight (<18), normal weight (18-24.9), overweight (25.0-29.9), and obese (>30.0). We assessed the nutritional status by Prognostic Nutritional Index (PNI). Malnutrition was defined as a PNI value of <38. RESULTS: Of the 21,651 patients with ACS, 582 (2.7%) deaths from any cause were observed over 28.7 months. Compared with the patient's state of normal weight, overweight, and obesity were associated with decreased risk of all-cause mortality. Malnutrition was independently associated with poor survival (hazards ratio: 2.64; 95% CI: 2.24, 3.12; P < 0.001). In malnourished patients, overweight and obesity showed a 39% and 72% reduction in the incidence of all-cause mortality, respectively. However, in nourished patients, no significant reduction in the incidence of all-cause mortality was observed (all P > 0.05). CONCLUSIONS: Obesity paradox appears to occur in patients with ACS. Malnutrition may be a significant independent risk factor for prognosis in patients with ACS. The obesity paradox is influenced by the status of malnutrition.

Chromatin remodeler Znhit1 controls bone morphogenetic protein signaling in embryonic lung tissue branching.

Branching morphogenesis is a key process essential for lung and other organ development in which cellular and tissue architecture branch out to maximize surface area. While this process is known to be regulated by differential gene expression of ligands and receptors, how chromatin remodeling regulates this process remains unclear. Znhit1 (zinc finger HIT-type containing 1), acting as a chromatin remodeler, has previously been shown to control the deposition of the histone variant H2A.Z. Here, we demonstrate that Znhit1 also plays an important role in regulating lung branching. Using Znhit1 conditional KO mice, we show that Znhit1 deficiency in the embryonic lung epithelium leads to failure of branching morphogenesis and neonatal lethality, which is accompanied by reduced cell proliferation and increased cell apoptosis of the epithelium. The results from the transcriptome and the chromatin immunoprecipitation assay reveal that this is partially regulated by the derepression of Bmp4, encoding bone morphogenetic protein (BMP) 4, which is a direct target of H2A.Z. Furthermore, we show that inhibition of BMP signaling by the protein inhibitor Noggin rescues the lung branching defects of Znhit1 mutants ex vivo. Taken together, our study identifies the critical role of Znhit1/H2A.Z in embryonic lung morphogenesis via the regulation of BMP signaling.

Chemotherapy-induced exosomal circBACH1 promotes breast cancer resistance and stemness via miR-217/G3BP2 signaling pathway.

BACKGROUND: Chemoresistance involves metastasis and aggressiveness of breast cancer (BC). Chemotherapy-elicited exosomes have been reported to be associated with drug resistance and pro-metastatic capacity of BC cells. Non-coding RNAs (ncRNAs) are enriched in exosomes, which participated in generation, progression, and resistance of BC. However, the mechanism underlying the chemoresistance and metastasis in BC cells mediated by the BC-derived exosomal ncRNAs remained to be elucidated. METHODS: The effects of PTX-induced exosomal circBACH1 on BC cell function were assessed using RNA Binding Protein Immunoprecipitation (RIP), dual luciferase reporter gene, tube formation, CCK-8, and Western Blot assays. The circBACH1 and miR-217 expression levels were detected using quantitative real-time PCR (RT-qPCR) and Immunohistochemistry (IHC) assays in BC tissues and precancerous tissues of BC patients. RESULTS: CircBACH1 expression was increased in paclitaxel-treated BC-derived exosomes (PTX-EXO) and BC tissue. PTX-EXO was shown to promote PTX-resistance and angiogenesis through upregulation circBACH1. Downregulation of circBACH1 improved PTX-sensitiveness by suppressing the cell viability, stemness, migration, and angiogenesis of BC cells. Moreover, we found that miR-217 interacted with circBACH1 and targeted GTPase-activating SH3 domain-binding protein 2 (G3BP2) in BC cells. CircBACH1 combined miR-217 cotransfection suppressed the expression of G3BP2 proteins compared with circBACH1 treatment in MCF-7 cells. In addition, downregulation of G3BP2 suppressed BC cell migration. CONCLUSIONS: These results demonstrated that PTX-induced exosomal circBACH1 promoted stemness and migration of BC cells by sponging miR-217 to upregulate the expression of G3BP2, which provided a new therapeutic target for PTX-resistance and progression of BC via circBACH1/miR-217/G3BP2 axis.

γδT17 cells promote the accumulation and expansion of myeloid-derived suppressor cells in human colorectal cancer.

Development of cancer has been linked to chronic inflammation, particularly via interleukin-23 (IL-23) and IL-17 signaling pathways. However, the cellular source of IL-17 and underlying mechanisms by which IL-17-producing cells promote human colorectal cancer (CRC) remain poorly defined. Here, we demonstrate that innate γδT (γδT17) cells are the major cellular source of IL-17 in human CRC. Microbial products elicited by tumorous epithelial barrier disruption correlated with inflammatory dendritic cell (inf-DC) accumulation and γδT17 polarization in human tumors. Activated inf-DCs induced γδT17 cells to secrete IL-8, tumor necrosis factor alpha, and GM-CSF with a concomitant accumulation of immunosuppressive PMN-MDSCs in the tumor. Importantly, γδT17 cell infiltration positively correlated with tumor stages and other clinicopathological features. Our study uncovers an inf-DC-γδT17-PMN-MDSC regulatory axis in human CRC that correlates MDSC-meditated immunosuppression with tumor-elicited inflammation. These findings suggest that γδT17 cells might be key players in human CRC progression and have the potential for treatment or prognosis prediction.

Protective Roles of Xijiao Dihuang Tang on Coronary Artery Injury in Kawasaki Disease.

PURPOSE: Xijiao Dihuang Tang (XJDHT) is a classical formula of traditional Chinese medicine constituted of Cornu Bubali, Rehmannia glutinosa (Gaertn.) DC., Paeonia lactiflora Pall., and Paeonia suffruticosa Andrews. It was first mentioned in the medical classic "Beiji Qianjin Yaofang" written by Simiao Sun in Tang Dynasty. It shows very strong antipyretic and anticoagulant effects and has been clinically applied to treat various type of blood loss, purple and black spots, heat stroke, and glossitis. Kawasaki disease (KD) is considered as a kind of acute febrile illness in children with systemic vasculitis as the main lesions. The aim of this research is to clarify whether XJDHT can play a protective role in KD. METHODS: A mouse model of Candida albicans water-soluble fraction (CAWS)-induced coronary arteritis and a KD cell model with tumor necrosis factor (TNF)-α induction were employed to investigate the potential effect and mechanism of XJDHT on coronary artery injury in KD. RESULTS: Data showed that XJDHT remarkably alleviated the coronary artery injury of KD mice, as evidenced by reduced inflammation and downregulated expression of pro-inflammatory cytokines interleukin (IL)-1ß and TNF-α. In vitro investigation showed that XJDHT could promote cell proliferation, inhibit cell apoptosis, and improve mitochondrial functions. Subsequent studies demonstrated that XJDHT rescued endothelial cell injury by PI3K/Akt-NFκB signaling pathway. Component analysis of XJDHT detected thirty-eight chemically active ingredients, including paeoniflorin, albiflorin, and paeoniflorigenone, which in in vitro experiments exhibited significant rescue effects on TNF-α-mediated endothelial cell injury. CONCLUSION: Our findings demonstrated that XJDHT mitigated coronary artery injury of KD through suppressing endothelial cell damage via PI3K/Akt-NFκB signaling.

Optimized protocol for double vaccine immunization against classical swine fever and porcine reproductive and respiratory syndrome.

BACKGROUND: Classical swine fever and porcine reproductive and respiratory syndrome have seriously affected the development of the swine breeding industry in China. Vaccine immunization remains the main way to prevent these infections. The aim of this study was to establish an optimized protocol for vaccine immunization against classical swine fever virus (CSFV) and porcine reproductive and respiratory syndrome virus (PRRSV). METHODS: Blood samples were collected from the anterior vena cava of pigs after immunization, and blood indices, secreted levels of specific antibodies and neutralizing antibodies associated with humoral immunity, the proliferation capacity of T lymphocytes as a measure of cellular immunity, and secreted levels of IFN-γ and TNF-α were determined. RESULTS: The results showed that simultaneous immunization against CSFV and PRRSV infections induced strong and specific humoral and T-cellular immune responses, high levels of cytokine IFN-γ secretion and delayed secretion of cytokine TNF-α. Moreover, significantly higher lymphocyte percentages and red blood cell and leukocyte counts were found in the group simultaneously immunized against CSFV and PRRSV. However, no statistically significant differences were observed in hemoglobin values, neutrophil counts, and median cell percentages among the S + PRRS, PRRS-S, and S-PRRS groups. CONCLUSION: This study demonstrated that simultaneous immunization against CSFV and PRRSV had the advantages of inducing a rapid, enhanced, and long-lasting immune response. These findings provide a theoretical basis for the establishment of a reasonable and optimized vaccine immunization protocol against CSFV and PRRSV in combination with a variety of other vaccine inoculations.

Optimization of Tungsten Heavy Alloy Cutting Parameters Based on RSM and Reinforcement Dung Beetle Algorithm.

Tungsten heavy alloys (WHAs) are an extremely hard-to-machine material extensively used in demanding applications such as missile liners, aerospace, and optical molds. However, the machining of WHAs remains a challenging task as a result of their high density and elastic stiffness which lead to the deterioration of the machined surface roughness. This paper proposes a brand-new multi-objective dung beetle algorithm. It does not take the cutting parameters (i.e., cutting speed, feed rate, and depth of cut) as the optimization objects but directly optimizes cutting forces and vibration signals monitored using a multi-sensor (i.e., dynamometer and accelerometer). The cutting parameters in the WHA turning process are analyzed through the use of the response surface method (RSM) and the improved dung beetle optimization algorithm. Experimental verification shows that the algorithm has better convergence speed and optimization ability compared with similar algorithms. The optimized forces and vibration are reduced by 9.7% and 46.47%, respectively, and the surface roughness Ra of the machined surface is reduced by 18.2%. The proposed modeling and optimization algorithms are anticipated to be powerful to provide the basis for the parameter optimization in the cutting of WHAs.

MMST: A Multi-Modal Ground-Based Cloud Image Classification Method.

In recent years, convolutional neural networks have been in the leading position for ground-based cloud image classification tasks. However, this approach introduces too much inductive bias, fails to perform global modeling, and gradually tends to saturate the performance effect of convolutional neural network models as the amount of data increases. In this paper, we propose a novel method for ground-based cloud image recognition based on the multi-modal Swin Transformer (MMST), which discards the idea of using convolution to extract visual features and mainly consists of an attention mechanism module and linear layers. The Swin Transformer, the visual backbone network of MMST, enables the model to achieve better performance in downstream tasks through pre-trained weights obtained from the large-scale dataset ImageNet and can significantly shorten the transfer learning time. At the same time, the multi-modal information fusion network uses multiple linear layers and a residual structure to thoroughly learn multi-modal features, further improving the model's performance. MMST is evaluated on the multi-modal ground-based cloud public data set MGCD. Compared with the state-of-art methods, the classification accuracy rate reaches 91.30%, which verifies its validity in ground-based cloud image classification and proves that in ground-based cloud image recognition, models based on the Transformer architecture can also achieve better results.

Wideband Filtering Slot Antenna Design with Stable Gain Using Characteristic Mode Analysis.

A filtering slot antenna with a simple structure combination using characteristic mode analysis (CMA) is proposed. To realize filtering characteristics, characteristic magnetic currents of line and ring slots are analyzed and designed. Then, the folding-line slot and double-ring slot are selected to realize radiation null separately and combined to construct the basic slot antenna. By properly exciting the selected characteristic modes, a wide filtering bandwidth and a stable gain are obtained. To validate the design process, a prototype antenna with a finite ground plane of about 1.1 λ × 1.1 λ is designed and fabricated. Simulated and measured results agree well, which both show a sharping roll rate in the lower and higher frequency and a flat gain realization in the pass band. The filtering bandwidth is 32.7%, the out-of-band suppression level at the higher frequency is over 20 dB, and the gain in the working frequency varies from 3.9 to 5.2 dB.

Auto-Modal: Air-Quality Index Forecasting with Modal Decomposition Attention.

The air-quality index (AQI) is an important comprehensive evaluation index to measure the quality of air, with its value reflecting the degree of air pollution. However, it is difficult to predict the AQI accurately by the commonly used WRF-CMAQ model due to the uncertainty of the simulated meteorological field and emission inventory. In this paper, a novel Auto-Modal network with Attention Mechanism (AMAM) has been proposed to predict the hourly AQI with a structure of dual input path. The first path is based on bidirectional encoder representation from the transformer to predict the AQI with the historical measured meteorological data and pollutants. The other path is a baseline to improve the generalization ability based on predicting the AQI by the WRF-CMAQ model. Several experiments were undertaken to evaluate the performance of the proposed model, with the results showing that the auto-modal network achieves a superior performance for all prediction lengths compared to some state-of-the-art models.

Drosophila decapping protein 2 modulates the formation of cortical F-actin for germ plasm assembly.

In Drosophila, the deposition of the germ plasm at the posterior pole of the oocyte is essential for the abdomen and germ cell formation during embryogenesis. To assemble the germ plasm, oskar (osk) mRNA, produced by nurse cells, should be localized and anchored on the posterior cortex of the oocyte. Processing bodies (P-bodies) are cytoplasmic RNA granules responsible for the 5'-3' mRNA degradation. Evidence suggests that the components of P-bodies, such as Drosophila decapping protein 1 and Ge-1, are involved in the posterior localization of osk. However, whether the decapping core enzyme, Drosophila decapping protein 2 (dDcp2), is also involved remains unclear. Herein, we generated a dDcp2 null allele and showed that dDcp2 was required for the posterior localization of germ plasm components including osk. dDcp2 was distributed on the oocyte cortex and was localized posterior to the osk. In the posterior pole of dDcp2 mutant oocytes, osk was mislocalized and colocalized with F-actin detached from the cortex; moreover, considerably fewer F-actin projections were observed. Using the F-actin cosedimentation assay, we proved that dDcp2 interacted with F-actin through its middle region. In conclusion, our findings explored a novel function of dDcp2 in assisting osk localization by modulating the formation of F-actin projections on the posterior cortex.

RETRACTED: lncRNA RMST Enhances DNMT3 Expression through Interaction with HuR

Large bodies of studies have shown that the CRISPR/Cas9-based library screening is a very powerful tool for the identification of gene functions. However, most of these studies have focused on protein-coding genes, and, furthermore, very few studies have used gene reporters for screening. In the present study, we generated DNA methyltransferase 3B (DNMT3B) reporter and screened a CRISPR/Cas9 synergistic activation mediator (SAM) library against a focused group of lncRNAs. With this screening approach, we identified Rhabdomyosarcoma 2-Associated Transcript (RMST) as a positive regulator for DNMT3B. This was confirmed by activation of the endogenous RMST by SAM or ectopic expression of RMST. Moreover, RMST knockout (KO) suppresses DNMT3, while rescue with RMST in the KO cells restores the DNMT3 level. Finally, RMST KO suppresses global DNA methylation, leading to the upregulation of methylation-regulated genes. Mechanistically, RMST promotes the interaction between the RNA-binding protein HuR and DNMT3B 3' UTR, increasing the DNMT3B stability. Together, these results not only provide the feasibility of a reporter system for CRISPR library screening but also demonstrate the previously uncharacterized factor RMST as an important player in the modulation of DNA methylation.

Using esophagus organoid to explore the role of c-Myc in esophageal cancer initiation.

C-Myc gene is aberrantly highly expressed and participates in cancer initiation and development in various malignant tumors including esophageal cancer, while the underlying mechanism(s) still remains unclear. In order to explore the role of c-Myc in the occurrence of esophageal cancer, we successfully established the esophageal organoids (EOs) as the research model. By constructing a lentivirus overexpressing c-Myc and developing more effective infection method, EOs with stable overexpression of c-Myc were efficiently obtained. The morphologies of EOs with or without overexpressing c-Myc were first analyzed with ImageJ, which showed no difference between two groups during continuous subculture. Subsequently, we applied immunofluorescence and CCK8 assays to evaluate the cell proliferation, and the results showed no change in the c-Myc-overexpressed group as compared to control EOs. Furthermore, qPCR was used to detect the expression of genes that are related to cell cycle, cell metabolism as well as esophageal cancer. The results indicated the expression of these genes was not significantly increased in the c-Myc overexpressing EOs. In conclude, we discovered that overexpression of c-Myc gene alone in the esophagus organoid is not sufficient to induce carcinogenesis in esophageal carcinoma. In this study, we successfully established an esophagus organoid culture system and together with efficient lentivirus-infection method for investigation on the effects of overexpressing c-Myc in esophageal cancer. Our work demonstrated a promising research model for the study of esophagus development and esophageal cancer.

Defect Detection of Industry Wood Veneer Based on NAS and Multi-Channel Mask R-CNN.

Wood veneer defect detection plays a vital role in the wood veneer production industry. Studies on wood veneer defect detection usually focused on detection accuracy for industrial applications but ignored algorithm execution speed; thus, their methods do not meet the required speed of online detection. In this paper, a new detection method is proposed that achieves high accuracy and a suitable speed for online production. Firstly, 2838 wood veneer images were collected using data collection equipment developed in the laboratory and labeled by experienced workers from a wood company. Then, an integrated model, glance multiple channel mask region convolution neural network (R-CNN), was constructed to detect wood veneer defects, which included a glance network and a multiple channel mask R-CNN. Neural network architect search technology was used to automatically construct the glance network with the lowest number of floating-point operations to pick out potential defect images out of numerous original wood veneer images. A genetic algorithm was used to merge the intermediate features extracted by the glance network. Multi-Channel Mask R-CNN was then used to classify and locate the defects. The experimental results show that the proposed method achieves a 98.70% overall classification accuracy and a 95.31% mean average precision, and only 2.5 s was needed to detect a batch of 50 standard images and 50 defective images. Compared with other wood veneer defect detection methods, the proposed method is more accurate and faster.

Prognostic Value and Clinicopathologic Features of Platelet Distribution Width in Cancer: A Meta-Analysis.

BACKGROUND The association between platelet distribution width (PDW) and cancer has been evaluated by a few studies, but the influence of PDW on cancer prognosis is unclear. Therefore, we conducted the present meta-analysis. MATERIAL AND METHODS We identified relevant research using identical search strategies. The influence of PDW level on cancer prognosis, as well as clinical characteristics, was analyzed. RESULTS A total of 11 studies comprising 2625 cancer patients were included in our meta-analysis. The results suggested that high PDW level was obviously related to poor OS (HR=1.54, 95%CI 1.18-2.00), especially for breast cancer (HR=1.21, 95%CI 1.07-1.36) and pharyngolaryngeal cancer (HR=3.06, 95%CI 1.68-5.57). Furthermore, high PDW was obviously related to poor OS both in older and younger subgroups, with combined HR estimates of 1.58 (95%CI 1.15-2.16) and 1.64 (95%CI 1.19-2.26), respectively. High PDW level was notably related to poor OS in the cut-off value ³16% subgroup (HR=1.84, 95%CI 1.01-3.40). Moreover, high PDW level was obviously associated with lymph node metastasis (OR=1.43, 95%CI 1.04-1.99). CONCLUSIONS The findings of this study suggest that PDW is an effective and convenient indicator of cancer prognosis. Furthermore, high PDW level is obviously associated with lymph node metastasis.