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Abstract Background Congenital diarrheas and enteropathies (CODEs) caused by diacylglycerol transferase 1 (DGAT1) mutations often cause disease within 2 weeks after birth. If not treated properly, the disease can be life-threatening; therefore, early diagnosis and rational treatment strategies are essential. This study was conducted to improve the understanding of congenital diarrhea caused by DGAT1 deficiency. Methods Clinical data from five congenital diarrhea infant cases caused by DGAT1 deficiency were analyzed. Infants were prospectively provided with a nutritional intervention with a low-fat amino acid formula for special medical purposes (FSMP). Their gastrointestinal symptoms and nutritional complications before and after interventions were compared. Results Due to poor weight gain and gastrointestinal symptoms after birth, infants were treated by our clinical nutritionist. Genetic testing confirmed a compound heterozygous mutation in DGAT1. Neither hydrolyzed nor high-medium chain triglyceride (MCT) formula significantly alleviated diarrheal symptoms; however, a low-fat amino acid diet rapidly relieved symptoms and significantly improved nutritional status, with infants showing better tolerance to dietary fat content with age. Conclusions Infants with DGAT1 deficiency can be diagnosed by genetic testing. A low-fat amino acid FSMP formula and diet can quickly relieve diarrhea, vomiting, and other symptoms, and also improve infant growth and development. Trial registration Ethical approval was obtained from the Medical Ethics Committee of the Children’s Hospital of Fudan University (reference code: No.(2022)405).

Abstract Background Current evidence underlines the active role of neural infiltration and axonogenesis within the tumor microenvironment (TME), with implications for tumor progression. Infiltrating nerves stimulate tumor growth and dissemination by secreting neurotransmitters, whereas tumor cells influence nerve growth and differentiation through complex interactions, promoting tumor progression. However, the role of neural infiltration in the progression of non-small cell lung cancer (NSCLC) remains unclear. Methods This study employs the techniques of immunohistochemistry, immunofluorescence, RNA sequencing, molecular biology experiments, and a murine orthotopic lung cancer model to deeply analyze the specific mechanisms behind the differential efficacy of NSCLC immunotherapy from the perspectives of neuro-tumor signal transduction, tumor metabolism, and tumor immunity. Results This study demonstrates that nerve growth factor (NGF) drives neural infiltration in NSCLC, and 5-hydroxytryptamine (5-HT), which is secreted by nerves, is significantly elevated in tumors with extensive neural infiltration. Transcriptome sequencing revealed that 5-HT enhanced glycolysis in NSCLC cells. Pathway analysis indicated that 5-HT activated the PI3K/Akt/mTOR pathway, promoting tumor metabolic reprogramming. This reprogramming exacerbated immunosuppression in the TME. Neutralizing 5-HT-mediated metabolic reprogramming in tumor immunity enhanced the efficacy of PD-1 monoclonal antibody treatment in mice. Conclusions The findings of this study provide a novel perspective on the crosstalk between nerves and lung cancer cells and provide insights into further investigations into the role of nerve infiltration in NSCLC progression.

Abstract DNA polymerase ζ (Pol ζ) plays an essential role in replicating damaged DNA templates but contributes to mutagenesis due to its low fidelity. Therefore, ensuring tight control of Pol ζ’s activity is critical for continuous and accurate DNA replication, yet the specific mechanisms remain unclear. This study reveals a regulation mechanism of Pol ζ activity in human cells. Under normal conditions, an autoinhibition mechanism keeps the catalytic subunit, REV3L, inactive. Upon encountering replication stress, however, ATR-mediated phosphorylation of REV3L’s S279 cluster activates REV3L and triggers its degradation via a caspase-mediated pathway. This regulation confines the activity of Pol ζ, balancing its essential role against its mutations causing potential during replication stress. Overall, our findings elucidate a control scheme that fine tunes the low-fidelity polymerase activity of Pol ζ under challenging replication scenarios.

Background Patent foramen ovale (PFO)‐associated stroke has a complex and diverse pathogenesis. It mainly results from a paradoxical embolism caused by venous thrombosis. However, few studies have investigated the presence of an in situ thrombus in the right atrium. Transesophageal echocardiography can effectively detect right atrial septal in situ microthrombus. Therefore, we aimed to explore the relationship between a right atrial septal in situ microthrombus and PFO‐associated stroke and further dissect the pathophysiological basis of microthrombus formation. Methods and Results Between April 2022 and October 2023, we prospectively investigated 466 patients who visited our hospital for transesophageal echocardiography with a high clinical suspicion of PFO. Right atrial septal in situ microthrombus was detected in 34 patients (7%), and 23 of them were examined. The microthrombus disappeared in 13 patients and decreased in 7; PFO recanalization and anatomical variations were observed in 2 and 1 patient, respectively. The incidence of index stroke was higher in the microthrombus group than in the nonmicrothrombus group (76.47% versus 61.11%). Univariate and multivariable (adjusted) analyses revealed PFO as an independent risk factor for right atrial septal in situ microthrombus formation (odds ratio, 3.29 [95% CI, 1.49–7.26]; P=0.003). Conclusions Transesophageal echocardiography effectively detects right atrial septal in situ microthrombus. A PFO may promote the formation of right atrial septal in situ microthrombus. Right atrial septal in situ microthrombus significantly increases the risk of PFO‐associated stroke. This finding may be crucial in disease management strategies for patients with PFO.

Fluorotelomer sulfonates (FTSs) are widely used as novel substitutes for perfluorooctane sulfonate, inevitably leading to FTSs accumulation in various environmental media and subsequent exposure to humans. This accumulation eventually poses environmental hazards and health risks. However, their toxicity mechanisms remain unclear. Herein, the mechanisms of two FTSs (6:2 and 8:2 FTS) induced toxicity in human hepatocellular carcinoma cells were investigated via non-targeted metabolomics and lipidomics based on liquid chromatography–high resolution mass spectrometry. Our results revealed that amino acid, purine, acylcarnitine and lipid levels were significantly perturbed by 6:2 and 8:2 FTS exposure. The effects of 8:2 FTS exposure were largely characterized by up-regulation of pyruvate metabolism pathway and down-regulation of purine metabolism pathway, whereas the opposite trends were induced by 6:2 FTS exposure. The opposite trends were confirmed by the mRNA expression levels of four key genes (glyoxalase 1, adenylosuccinate lyase, inosine monophosphate dehydrogenase 1 (IMPDH1) and IMPDH2) determined by real-time PCR. Common lipid perturbations included significantly increased ceramide/sphingomyelin ratios, and obvious accumulation of hexosylceramides and lysoglycerophospholipids. 6:2 FTS exposure induced sharp accumulation of glycerides, including monoglycerides, diglycerides and triglycerides. 8:2 FTS exposure induced decreased levels of acylcarnitines and fatty acids. Both of 6:2 and 8:2 FTS exposure induced increased levels of intracellular reactive oxygen species, an imbalance in energy metabolism homeostasis, and mitochondrial dysfunction. The results of integrated omics analysis are expected to serve as valuable information for the health risk assessment of 6:2 FTS and 8:2 FTS.

This work presents an advanced automated monolithic C18 pipette-tip solid-phase extraction (PT-SPE) method seamlessly integrated with liquid chromatography-tandem mass spectrometry (LC-MS/MS) for precise therapeutic drug monitoring of eleven tyrosine kinase inhibitors (TKIs) in biological samples. Commercially available MonoTip C18 columns facilitate superior extraction efficiency and selectivity from complex biological matrices owing to their large surface areas and enhanced mass transfer capabilities. The sample preparation process, conducted by aspirating and dispensing solutions using a pipettor, completes the overall extraction process within 3 min. The method validation demonstrated excellent linearity within the range of 0.2/0.5/0.8 to 200 ng/mL, with detection limits ranging from 0.049 to 0.206 ng/mL. The method exhibited outstanding accuracy and precision, with intraday relative recovery rates ranging from 96.3 % to 115.0 % and interday recovery rates ranging from 95.0 % to 115.7 %, with coefficient of variation values consistently below 13.8 %. The proposed method is distinguished by its exceptional efficiency, reduced solvent use, enhanced environmental sustainability, and streamlined automation—key advantages in the realm of clinical therapeutic drug monitoring of TKIs. Overall, the MonoTip C18 PT-SPE technique, coupled with LC-MS/MS, offers a formidable, eco-friendly, and effective strategy for the TDM of TKIs, marking a significant advancement in the field.

Objectives Occupational stress is a common complaint in nurses, who perceived more sense of effort-reward imbalance (ERI). Suboptimal health status (SHS) is a state between health and disease. However, the correlation between ERI and SHS is unclear. Therefore, the aim of this study was to examine the prevalence of SHS and ERI and evaluate the relationship between ERI and SHS in clinical nurses by a cross-sectional study. Material and Methods The current cross-sectional study was conducted through an online survey at Dongping People’s Hospital in China. A total of 633 completed surveys were received. Effort-reward imbalance was measured by subscales of the ERI questionnaire. SHS was measured by the Suboptimal Health Status Questionnaire – 25 (SHSQ-25). The relationship between ERI and SHS in nurses was subsequently assessed by Spearman’s correlation coefficient and logistic regression model. Results The mean age of the optimal health status (OHS) group (M±SD 26.3±7.3 years) was younger than the SHS group (M±SD 30.3±6.9 years). The prevalence of SHS was 54.5% (345/633). Female nurses aged ≥30 years, a junior college or university graduate educational level, smokers, and nurses without regular exercise were at a higher risk of SHS. In Spearman’s correlation analysis, ERI reflected by the effort-reward ratio was correlated with SHSQ-25 score (r = 0.662, p < 0.001). In logistic regression, ERI was strongly associated with SHS after potential confounding factors adjusting (OR 27.924, 95% CI 22.845–34.132). Conclusions The prevalence of SHS was significantly high in clinical nurses. Administrators should pay more attention to health status of female nurses aged ≥30 years, with a junior college or bachelor’s degree, smoking, and without regular exercise to reduce the SHS and ERI. Int J Occup Med Environ Health. 2024;37(2):166–75

KRAS mutations are associated with poor prognosis in colorectal cancer (CRC). Although the association between the gut microbiota and CRC has been extensively documented, it is unclear whether KRAS mutations can regulate the gut microbiota. Metagenomics has identified changes in the diversity of the gut microbiota in CRC due to KRAS mutations. Specifically, KRAS mutations positively correlate with the abundance of the bacteroides. Understanding how to regulate the classic carcinogenic bacterium within the bacteroides, such as enterotoxigenic bacteroides fragilis (ETBF), to enhance treatment efficacy of tumors is a key focus of research. Mechanistically, we found that the reduction of miR3655 is indispensable for KRAS mutation-promoted proliferation of CRC and the abundance of ETBF. miR3655 targets SURF6 to inhibit its transcription. Further transcriptomic sequencing revealed that SURF6 promotes intratumoral colonization of ETBF in CRC by inhibiting the nuclear translocation and transcription levels of the IRF7, affecting the activation of the IFNβ promoter. Regulating miR3655 and SURF6 can promote IFNβ secretion in CRC, directly killing ETBF. These data indicate that KRAS mutations affect the intratumoral colonization of ETBF in CRC through the miR3655/SURF6/IRF7/IFNβ axis. This provides new potential strategies for treating CRC associated with KRAS mutations or high levels of ETBF.

Carnitines, essential for human metabolism and fatty acid transport, are primarily obtained from the diet. Inadequate synthesis or intake can lead to serious metabolic disorders, which may result in fatal outcomes. Therefore, the accurate determination of carnitines in both food and biological samples is of high importance. However, these samples are inherently complex and require meticulous preparation procedures before determination. This step is critical for enhancing the sensitivity and precision of the detection process. Moreover, the selection of an appropriate detection method is crucial and must match the analytes’ characteristics. For example, since carnitines lack chromophores for spectroscopic detection, they require derivatization to become spectroscopically visible. Among the various methods available for carnitine determination, chromatography and mass spectrometry are the most prominent, owing to their superior selectivity and sensitivity. Nonetheless, there seems to be a lack of comprehensive reviews on this subject. Consequently, this article aims to compile the latest advancements in analytical methodologies for carnitines over the past decade (2013–2023), with a particular emphasis on the crucial contributions of chromatography and mass spectrometry techniques. This review provides crucial insights for metabolic research, underpinning advances in understanding carnitine's metabolic roles. It aims to highlight current innovations in carnitine analysis and inspire future breakthroughs impacting nutrition, diagnostics, and therapy.

Background: Lung cancer stands as the foremost cause of cancer-related fatalities globally. The presence of cancer stem cells (CSCs) poses a challenge, rendering current targeted tumor therapies ineffective. This study endeavors to investigate a novel therapeutic approach focusing on ferroptosis and delves into the expression of ferroptosis-related genes within lung CSCs. Methods: We systematically examined RNA-seq datasets derived from lung tumor cells (LTCs) and lung cancer stem cells (LSCs), as previously investigated in our research. Our focus was on analyzing differentially expressed genes (DEGs) related to ferroptosis. Utilizing the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO), we conducted functional analysis of these ferroptosis-related DEGs. Additionally, we employed protein‒protein interaction networks to identify hub genes. LC‒MS/MS analysis of LTCs and LSCs was conducted to pinpoint the crucial ferroptosis-related gene–thioredoxin-interacting protein (TXNIP).Further, we delved into the immune cell infiltration landscape of LTCs and LSCs, examining the correlation between TXNIP and lung adenocarcinoma (LUAD) using data from The Cancer Genome Atlas (TCGA) database. To complement these findings, we measured the expression levels of TXNIP, glutathione peroxidase 4(GPX4), nuclear receptor coactivator 4 (NCOA4) in LUAD tissues through immunohistochemistry (IHC) staining. Results: A total of 651 DEGs were identified, with 17 of them being ferroptosis-related DEGs. These seventeen genes were categorized into four groups: driver genes, suppressor genes, unclassified genes, and inducer genes. Enrichment analysis revealed significant associations with oxidative stress, cell differentiation, tissue development, and cell death processes. The RNA-seq analysis demonstrated consistent gene expression patterns with protein expression, as evidenced by mass spectrometry analysis. Among the identified genes, SFN and TXNIP were singled out as hub genes, with TXNIP showing particularly noteworthy expression. The expression of the ferroptosis-related gene TXNIP exhibited correlations with the presence of an immunosuppressive microenvironment, TNM stages, and the degree of histological differentiation.Also, the ferroptosis-markers GPX4 and NCOA4 displayed correlations with LUAD. This comprehensive analysis underscores the significance of TXNIP in the context of ferroptosis-related processes and their potential implications in cancer development and progression. Conclusion: The investigation conducted in this study systematically delved into the role of the ferroptosis-related gene TXNIP in Lung CSCs. The identification of TXNIP as a potentially valuable biomarker in this context could have significant implications for refining prognostic assessments and optimizing therapeutic strategies for advanced lung cancer.

Abstract Background In adults with non-Hodgkin's lymphoma, renal enlargement and acute kidney injury occur infrequently at first presentation, especially in T lymphocytic lymphomas. Case presentation We report three cases of non-Hodgkin’s lymphoma with acute renal injury and bilateral renal enlargement. At diagnosis, one patient presented with an adrenal mass, one patient's lymph node biopsy was consistent with a renal biopsy, and one patient had primary renal lymphoma with no extrarenal disease. Assessment of renal pathology in Case 2 and Case 3 showed interstitial lymphocyte infiltration; the pathological types were non-Hodgkin's diffuse large B lymphoma originating from activated B cells outside germinal centers and non-Hodgkin's T-lymphoblastic lymphoma/leukemia, respectively. Case 1 did not receive anti-lymphoma therapy and died from infection and multiple organ failure within 1 month of hospitalization. Case 2 received eight courses of R-CHOP; her lymphoma recurred 2 years after diagnosis and she died from severe pulmonary infection 3 years after diagnosis. Case 3 received hyper-CVAD regularly and achieved stable renal function; this patient remains under follow-up. Conclusions Renal lymphoma may have diverse manifestations, especially primary renal lymphoma without extrarenal involvement. Nephrologists should pay careful attention to these manifestations to ensure accurate diagnosis.

ABSTRACTThe mammalian Sterile 20-like kinase 1/2 (MST1/2) belongs to the serine/threonine (GC) protein kinase superfamily. Collective studies confirm the vital role MST1/2 in inflammation and immunity. MST1/2 is closely related to the progress of inflammation. Generally, MST1/2 aggravates the inflammatory injury through MST1-JNK, MST1-mROS, MST1-Foxo3, and NF-κB pathways, as well as several regulatory factors such as tumor necrosis factor-α (TNF-α), mitochondrial extension factor 1 (MIEF1), and lipopolysaccharide (LPS). Moreover, MST1/2 is also involved in the regulation of immunity to balance immune activation and tolerance by regulating MST1/2-Rac, MST1-Akt1/c-myc, MST1-Foxos, MST1-STAT, Btk pathways, and lymphocyte function-related antigen 1 (LFA-1), which subsequently prevents immunodeficiency syndrome and autoimmune diseases. This article reviews the effects of MST1/2 on inflammation and immunity.

Background Persistent infection with high-risk human papillomavirus (HPV) is closely related to cervical cancer. The epidemiologic characteristics of cervical HPV have regional differences. Therefore, it is necessary to develop the most favorable policies according to the actual situation of each region to prevent and reduce the prevalence of cervical cancer. This retrospective cross-sectional study investigated the prevalence, gene subtypes, and temporal trends of HPV in women undergoing physical examination in Wenzhou, to provide a decision-making basis for further prevention and control of HPV. Methods A total of 31 131 cervical exfoliated cell specimens obtained from physical examinations in Wenzhou, a coastal city of China, from 2015 to 2020 were collected. The age distribution was analyzed using the chi-squared test, and the time change trend was analyzed using the Mann–Kendall trend test. On this basis, the distribution characteristics of the HPV subtypes were analyzed. Results The total prevalence rate was 9.55%, and the prevalence rate in different age groups ranged from 7.77% to 14.16%. The prevalence rate in different years was 8.84%-11.83%. The prevalence rate was bimodal; it was highest in the group 25 years old, followed by the group >61 years old. The top five high-risk gene subtypes were HPV52, HPV58, HPV53, HPV16, and HPV39, whereas the low-risk subtypes were HPV61, HPV81, HPV44, HPV43, and HPV55. Of all the positive samples, 76.03% were infected with a high-risk subtype. Conclusion Most female HPV patients in Wenzhou are infected with high-risk gene subtypes. Therefore, physical examination and screening for HPV should be further strengthened, and the corresponding vaccination policy should focus on high-risk gene subtypes.

Abstract Background Uncut Roux-en-Y (URY) effectively alleviates the prevalent complexities connected with RY, such as Roux-en-Y stasis syndrome (RSS). Nevertheless, for gastric cancer (GC) patients, it is still controversial whether URY has an impact on long-term prognosis and whether it has fewer afferent loop recanalization. Therefore, compare whether URY and RY have differences in prognosis and long-term complications of GC patients undergoing totally laparoscopic gastrectomy (TLG). Methods We analyzed the data of patients who underwent TLG combined with digestive tract reconstruction from dual-center between 2016 and 2022. Only patients undergoing URY and RY were selected for analysis. Relapse-free survival (RFS) and overall survival (OS) were estimated. Bias between the groups was reduced by propensity score matching (PSM). The Cox proportional hazard regression model was used to further analyze the influence of URY on prognosis. Results Two hundred forty two GC patients were enrolled. The URY had significantly shorter operation time, liquid food intake time, and in-hospital stays than the RY (P

Abstract Background Increasing evidence indicates that radiotherapy (RT) has synergistic inhibitory efficiency with immunotherapy agents in multiple cancers and enhances abscopal effects by regulating the innate immune response, which was further investigated in this study. Neutrophils are recruited in radiated tumors. Therefore, neutrophil membrane-coated nanoparticles potentially deliver R837 (Toll-like receptor 7 agonist) to radiated tumors. Methods A novel nanoparticle R837@PLGA@Neu was prepared by initially assembling PLGA (poly (lactic-co-glycolic acid)) with R837 (TLR7 agonist) into R837@PLGA followed by coating with neutrophil membrane. Characterizations of R837@PLGA@Neu were performed. Tumor targeting efficiency was evaluated by in vivo fluorescent imaging of CT26-bearing mice. Treatments of R837@PLGA@Neu combined with RT were carried out in unilateral and bilateral CRC tumor-bearing mice, followed by validations of immune cells in tumors by flow cytometry. Results The characteristics of R837@PLGA@Neu were well identified, and it was confirmed to have high uptake ability and low cytotoxicity in colorectal cancer (CRC) cells in vitro, as well as its strong tumor-targeting efficiency in vivo in CRC tumor-bearing mice. The exciting findings were that R837@PLGA@Neu combined with RT exerted prominent tumor inhibition not only in radiated tumors, but also in distant tumors without RT, suggesting its enhancement of the efficacy and abscopal effect of RT. The possible underlying mechanisms were remodeling of the tumor microenvironment by triggering mature dendritic cells and CD8+ T cells. Conclusion In summary, our findings suggested that neutrophil membrane-derived nanoparticle R837@PLGA@Neu with high uptake ability and low cytotoxicity showed strong tumor-targeting efficiency, and combination with RT had a promising effect in CT26-bearing mice via immune cell regulation. Our results provide a probable combination strategy for CRC treatment.

Polycyclic aromatic hydrocarbons are considered to be potentially genotoxic and carcinogenic to humans. For non-smoking populations, food is the main source of polycyclic aromatic hydrocarbons exposure. Due to their lipophilic nature, oils and fats rank among the food items with the highest polycyclic aromatic hydrocarbon content. Consequently, the detection of polycyclic aromatic hydrocarbons in edible oils is critical for the promotion of human health. This paper reviews sample pretreatment methods, such as liquid-phase-based extraction methods, adsorbent-based extraction methods, and the QuEChERS (quick, easy, cheap, effective, rugged, and safe) method, combined with detection techniques like mass spectrometry and chromatography-based techniques for accurate quantification of polycyclic aromatic hydrocarbons in edible oils since 2010. An overview on the advances of the methods discussed herein, along with a commentary addition of current challenges and prospects, will guide researchers to focus on developing more effective detection methods and control measures to reduce the potential risks and hazards posed by polycyclic aromatic hydrocarbons.

CeO2 is widely used in the field of chemical–mechanical polishing for integrated circuits. Morphology, particle size, crystallinity, and Ce3+ concentration are crucial factors that affect polishing performance. In this study, we successfully synthesized two novel triangular CeO2 abrasives with similar particle sizes (600 nm) but different morphologies and Ce3+ concentrations using a microwave-assisted hydrothermal method with high-concentration raw materials, and no surfactants or template agents were added. It is generally believed that CeO2 with a higher Ce3+ concentration leads to better polishing performance. However, the results of polishing indicate that CeO2 synthesized at 200 °C, despite its lower Ce3+ concentration, demonstrates outstanding polishing performance, achieving a polishing rate of 324 nm/min, and the Sa of Si wafers decreased by 3.6% after polishing. This suggests that, under similar particle size conditions, the morphology of CeO2 plays a dominant role in the mechanical effects during the polishing process. Additionally, compared to commercial polishing slurries, the synthesized samples demonstrated better polishing performance. This indicates that, in CMP, the pursuit of smaller spherical abrasives may not be necessary. Instead, the appropriate shape and particle size can better balance the material removal rate and surface roughness.

This paper investigates a method for precise mapping of human arm movements using sEMG signals. A multi-channel approach captures the sEMG signals, which, combined with the accurately calculated joint angles from an Inertial Measurement Unit, allows for action recognition and mapping through deep learning algorithms. Firstly, signal acquisition and processing were carried out, which involved acquiring data from various movements (hand gestures, single-degree-of-freedom joint movements, and continuous joint actions) and sensor placement. Then, interference signals were filtered out through filters, and the signals were preprocessed using normalization and moving averages to obtain sEMG signals with obvious features. Additionally, this paper constructs a hybrid network model, combining Convolutional Neural Networks and Artificial Neural Networks, and employs a multi-feature fusion algorithm to enhance the accuracy of gesture recognition. Furthermore, a nonlinear fitting between sEMG signals and joint angles was established based on a backpropagation neural network, incorporating momentum term and adaptive learning rate adjustments. Finally, based on the gesture recognition and joint angle prediction model, prosthetic arm control experiments were conducted, achieving highly accurate arm movement prediction and execution. This paper not only validates the potential application of sEMG signals in the precise control of robotic arms but also lays a solid foundation for the development of more intuitive and responsive prostheses and assistive devices.

Abstract Objective Targeting deubiquitinases (DUBs) has emerged as a promising avenue for anticancer drug development. However, the effect and mechanism of pan-DUB inhibitor EOAI on non-small cell lung cancer (NSCLC) remains to be studied. Materials and methods The expression of ubiquitin-specific peptidase 5 (USP5) in NSCLC was evaluated by immunohistochemistry. The effect of the USP5 inhibitor, EOAI, on NSCLC cell growth and cell cycle was evaluated by CCK-8 and PI staining. Apoptosis was detected by Annexin V-FITC/PI double staining. Autophagy was examined by LC3 immunofluorescence. Comet assay and γ-H2AX immunofluorescence staining were used to detect DNA damage, and Western blotting was used to detect the expression of apoptosis, cycle, autophagy and DNA damage-related proteins. In vivo experiments demonstrated the effect of EOAI on NSCLC. Results We also found that USP5 was significantly upregulated in NSCLC tissues in this study. In addition, we show that EOAI can cause DNA damage in NSCLC cells while modulating the transcriptional activity of P53, thereby inducing cell cycle arrest in NSCLC cells, autophagy and apoptosis. In vivo experiments have shown that EOAI can inhibit tumors and synergistically enhance the anti-tumor effect of cisplatin. Conclusion USP5-mediated epigenetic regulation of oncogenes promotes the occurrence of NSCLC, which provides ideas for developing potential targeted therapy.

Abstract Background Sorafenib resistance is a key impediment to successful treatment of patients with advanced hepatocellular carcinoma (HCC) and recent studies have reported reversal of drug resistance by targeting ferroptosis. The present study aimed to explore the association of fatty acid synthase (FASN) with sorafenib resistance via regulation of ferroptosis and provide a novel treatment strategy to overcome the sorafenib resistance of HCC patients. Methods Intracellular levels of lipid peroxides, glutathione, malondialdehyde, and Fe2+ were measured as indicators of ferroptosis status. Biological information analyses, immunofluorescence assays, western blot assays, and co-immunoprecipitation analyses were conducted to elucidate the functions of FASN in HCC. Both in vitro and in vivo studies were conducted to examine the antitumor effects of the combination of orlistat and sorafenib and CalcuSyn software was used to calculate the combination index. Results Solute carrier family 7 member 11 (SLC7A11) was found to play an important role in mediating sorafenib resistance. The up-regulation of FASN antagonize of SLC7A11-mediated ferroptosis and thereby promoted sorafenib resistance. Mechanistically, FASN enhanced sorafenib-induced ferroptosis resistance by binding to hypoxia-inducible factor 1-alpha (HIF1α), promoting HIF1α nuclear translocation, inhibiting ubiquitination and proteasomal degradation of HIF1α, and subsequently enhancing transcription of SLC7A11. Orlistat, an inhibitor of FASN, with sorafenib had significant synergistic antitumor effects and reversed sorafenib resistance both in vitro and in vivo. Conclusion Targeting the FASN/HIF1α/SLC7A11 pathway resensitized HCC cells to sorafenib. The combination of orlistat and sorafenib had superior synergistic antitumor effects in sorafenib-resistant HCC cells.

Background Prediction of delivery is important for assessing due dates, providing adequate prenatal care, and suggesting appropriate interventions in preterm and post-term pregnancies. Recent metabolomic findings suggested that the temporal abundance information of metabolome can be used to predict delivery timing with high accuracy in a cohort of healthy women. However, a targeted and quantitative assay is required to further validate the clinical performance and utility of this group of metabolomic candidates in delivery prediction with a larger and independent cohort.Method LC-MS/MS quantitative assays were applied to determine the plasma concentrations of four steroid metabolites, including oestriol-16-glucuronide (E3-16-Gluc), 17-alpha-hydroxyprogesterone (17-OHP), tetrahydrodeoxycorticosterone (THDOC), and androstane-3,17-diol (A-3,17-Diol) in asymptomatic women of singleton pregnancies (≥30th gestational weeks). Subsequent statistical analysis was conducted to assess the performance of the above candidates in delivery prediction.Result Using LC-MS/MS, four steroids were separated and quantified in 5.5 min. The coefficients of variation (CVs) of the four analytes at the lower limit of quantification ranged from 7.9% to 14.6%, with the R2 values greater than 0.990 in the calibration curves. Of the 585 recruited pregnant women who ended up with spontaneous delivery, 17.1% and 82.9% of the subjects delivered within and after 7 days since plasma collection, respectively. In the receiver operator curve analysis, the gestational age-adjusted area under the curve of the combined measurements of E3-16-Gluc and 17-OHP was 0.69 (95% CI: 0.60–0.76), with the sensitivity of 87.0% (95% CI: 78.8%–92.9%) and specificity of 60.2% (95% CI: 55.7%–64.6%). Moreover, the positive and the negative predictive values were 28.3%–34.0% and 93.1%–97.4% respectively for this combined panel.Conclusion We performed analytical and clinical validation of a quantitation LC-MS/MS panel for the four steroids in the plasma of pregnant women. The steroid metabolites panel of E3-16-Gluc and 17-OHP was potentially useful for predicting delivery within one week in asymptomatic women of singleton pregnancies. Key messagesA quantitative LC-MS/MS assay for determining the plasma levels of 17-OHP, THDOC, A-3,17-Diol and E3-16-Gluc was developed and validated, in order to evaluate their predictive performance in asymptomatic delivery of singleton pregnancy. The levels of E3-16-Gluc and 17-OHP were found to be significantly elevated at the time of sampling in women that delivered within one week and their combinational testing may be potentially useful in delivery prediction.

Abstract The deubiquitinating enzyme USP1 (ubiquitin-specific protease 1) plays a role in the progression of various tumors, emerging as a potential therapeutic target. This study aimed to determine the role of USP1 as a therapeutic target in hepatocellular carcinoma (HCC). We detected USP1 expression in the tumor and adjacent tissues of patients with HCC using immunohistochemical staining. We evaluated the effect of the USP1 inhibitor ML-323 on HCC cell proliferation and cell cycle using a CCK-8 cell-counting kit and plate cloning assays, and propidium iodide, respectively. Apoptosis was detected by annexin V-FITC/Propidium Iodide (PI) staining and caspase 3 (casp3) activity. Transmission electron microscopy and LC3B immunofluorescence were used to detect autophagy. Western blotting was used to detect the accumulation of ubiquitinated proteins, the expression of endoplasmic reticulum (ER) stress-related proteins, and the AMPK-ULK1/ATG13 signaling pathway. We demonstrated that ML-323 inhibits the growth of HCC cells and induces G1 phase cell cycle arrest by regulating cyclin expression. ML-323 treatment resulted in the accumulation of ubiquitinated proteins, induced ER stress, and triggered Noxa-dependent apoptosis, which was regulated by the Activating Transcription Factor 4(ATF4). Moreover, active ER stress induces protective autophagy by increasing AMPK phosphorylation; therefore, we inhibited ER stress using 4-Phenylbutyric acid (4-PBA), which resulted in ER stress reduction, apoptosis, and autophagy in ML-323-treated HCC cells. In addition, blocking autophagy using the AMPK inhibitor compound C (CC), chloroquine (CQ), or bafilomycin A1 (BafA1) enhanced the cytotoxic effect of ML-323. Our findings revealed that targeting USP1 may be a potential strategy for the treatment of HCC.

Purpose: Emerging evidences have demonstrated that annexin A13 (ANXA13) is closely related to the occurrence and development of malignant tumors. However, the functions and underlying molecular mechanisms of ANXA13 in Clear cell renal cell carcinoma (ccRCC) have not been defined. Therefore, this study aimed to clarify the potential role of ANXA13 in regulating the proliferation, migration, invasion, cell cycle, and apoptosis of ccRCC cells. Patients and methods: The quantitative real-time PCR (qRT-PCR) and western blotting was performed for detecting the ANXA13 expression in ccRCC tissues at the mRNA and protein levels, respectively. The GEPIA2 databases were used to derive data for analyzing the ANXA13 expression in pan-cancer and ccRCC clinical features. Cell Counting and colony formation assays, as well as flow cytometry, were used to detect cell proliferation, apoptosis, or cell cycle. The wound healing assay was used to evaluate the migration ability of cells, and the Trans-well assay was conducted to determine the cell invasiveness. Results: ANXA13 was upregulated in ccRCC cells and human ccRCC tissues. Furthermore, siANXA13 inhibited ccRCC cell proliferation, migration, invasion and induced cell apoptosis. Conclusion: ANXA13 was upregulated in ccRCC. ANXA13 promotes tumorigenic traits of ccRCC cell lines in vitro. ANXA13 is a potential novel biomarker and a potential therapeutic target in ccRCC.

Background: The mortality rate of colorectal cancer (CRC) ranks second worldwide. Previous research had indicated that licochalcone A (LA) was a flavonoid in licorice with diverse anticancer effects. We explored the underlying mechanisms of LA-triggered anticancer activity in CRC. Methods: Thiazolyl Blue (MTT) experiment and EdU staining were utilized to evaluate cell proliferation. Meanwhile, cells were stained by Annexin V/PI to investigate apoptosis through flow cytometry assay. Moreover, expressions of proteins were detected by immunoblotting, and the level of related mRNA was investigated using real-time quantitative PCR. Results: LA selectively suppressed the proliferation and triggered apoptosis of CRC cells. Strikingly, LA induced cytoprotective autophagic activities since the suppression of autophagy significantly strengthened LA-induced cytotoxicity and FLICE inhibitory protein (c-FLIPL) degradation, meanwhile reversing LA-mediated heat shock protein 70 (Hsp70) upregulation. Moreover, autophagy-mediated Hsp70 upregulation resisted LA-induced anticancer effects since the suppression of Hsp70 strengthened LA-triggered cytotoxicity and c-FLIPL degradation. Furthermore, LA greatly activated extracellular signal-regulated protein kinases (ERK) and p38. However, blocking of ERK, but not p38, significantly boosted LA-triggered cell death and c-FLIPL downregulation. Suppression of ERK also reversed LA-mediated autophagic induction. Conclusions: LA increased Hsp70 expression depending on ERK-mediated autophagy, which protected CRC cells from LA-induced anticancer activities.

Abstract Significant variability of raindrop size distributions (DSDs) has been observed in the “21·7” Henan extremely heavy rainfall event (the “21·7” Henan EHR event), while the capability of model to reproduce such complicated heavy rainfall DSDs is yet unclear. This study primarily evaluates the simulated DSDs of multiple microphysics schemes by comparing with the observations from a network of 50 disdrometers. Constrained DSD variability is identified in most schemes that the simulated raindrop mean sizes are gradually restricted around specific values as the growth of heavy rainfall intensity. The schemes are also incapable of reproducing the different raindrop mean sizes from deep convection and shallow convection. Moreover, simulations show unrealistic evolutions of raindrop mean size standard deviations as height declines. By investigating the empirical formula and performing sensitivity experiment, the constrained DSD variability in heavy rainfall is largely blamed on the insufficient parameterizations of the self‐collection (breakup) processes.

Abstract Background Different dialysis treatments may affect the composition and structure of the intestinal flora of dialysis-treated chronic kidney disease (CKD) patients. This study aimed to analyze the correlations between the different flora and the nutritional indexes and further explore the potential metabolic pathways in patients with CKD in end-stage renal disease (ESRD). Methods Altogether, 102 patients with ESRD were recruited and categorized into the hemodialysis (HD) group (N = 49) and the peritoneal dialysis (PD) group (N = 53). Their biochemical indexes, anthropometric indicators, and inflammatory markers were determined. The total genomic DNA was extracted for 16S ribosomal DNA sequencing. Furthermore, bioinformatics analysis was employed for functional analysis. Results Anthropometric indicators, including handgrip strength, mid-upper arm circumference, mid-upper arm muscle circumference, and body mass index, in the HD and PD groups showed a positive correlation with butyric acid-producing bacteria (Rosella and Phascolarctobacterium) and a negative correlation with conditional pathogens (Escherichia spp.). Meanwhile, the inflammatory markers, including high-sensitivity C-reactive protein and interleukin-6, were significantly higher in the PD-protein–energy wasting (PEW) group than in the PD-non-protein–energy wasting (NPEW) group; although they showed an increasing trend in the HD-PEW group, no significant difference was noted. Rosella was considerably scarce in the HD-PEW group than in the HD-NPEW group, whereas Escherichia was substantially more abundant in the PD-PEW group than in the PD-NPEW group. Compared with the HD group, the essential amino acid synthesis pathway, amino acid metabolism-related enzyme pathways, and aminoacyl-transfer RNA biosynthesis pathways were weakened in the PD group. Most carbohydrate metabolic pathways were weakened, although the tricarboxylic acid cycle was slightly enhanced. Concurrently, the fatty acid metabolism was enhanced, whereas fatty acid synthesis was weakened; the metabolic pathways of B vitamins were also weakened. These potential metabolic pathways of the various compounds released by intestinal flora showed a significant correlation with blood biochemical indexes, anthropometric indicators, and inflammatory markers. Conclusion In patients with ESRD, different dialysis treatments affected the abundance of butyric acid-producing bacteria (Rosella and Phascolarctobacterium) and conditional pathogens (Escherichia spp.). Butyric acid-producing bacteria showed a positive correlation with PEW and showed a negative correlation with Escherichia. Improving the intestinal diversity and increasing the amount of butyric acid-producing bacteria, such as Blautella, Faecococcus, and Phascolarctobacterium, are potential therapeutic approaches to enhance protein–energy consumption in patients with ESRD.

Pentraxin 3 (PTX3) is an inflammatory molecule that is closely related to the proliferation, invasion, and metastasis of cancer. In order to explore the role of PTX3 in the occurrence and development of esophageal carcinoma (ESCA), we modified the PTX3 gene in ESCA cell lines to obtain the model of gene knockout and overexpression and studied cell proliferation, cycle, apoptosis, migration ability, energy metabolism, and sensitivity to chemotherapy and radiotherapy. We observed the increase in cell proliferation, cycle, apoptosis, migration ability, and sensitivity to chemotherapy and radiotherapy in the PTX3 knockout model, while in the PTX3 overexpression model, these phenomena were significantly reduced. Knockout of the PTX3 also resulted in decreased cell glycolysis and increased oxidative phosphorylation, which is consistent with other findings that PTX3 affects the tumorigenic ability of cells and their sensitivity to docetaxel. In ESCA, SOX9 directly regulates the expression of PTX3, while human leukocyte antigen (HLA)-system-related genes are significantly up-regulated when lacking PTX3. These results indicate that SOX9 may play a crucial role in regulating PTX3 and affecting the HLA system in ESCA.

Abstract Background Inflorescence architecture and floral development in flowering plants are determined by genetic control of meristem identity, determinacy, and maintenance. The ear inflorescence meristem in maize (Zea mays) initiates short branch meristems called spikelet pair meristems, thus unlike the tassel inflorescence, the ears lack long branches. Maize growth-regulating factor (GRF)-interacting factor1 (GIF1) regulates branching and size of meristems in the tassel inflorescence by binding to Unbranched3. However, the regulatory pathway of gif1 in ear meristems is relatively unknown. Result In this study, we found that loss-of-function gif1 mutants had highly branched ears, and these extra branches repeatedly produce more branches and florets with unfused carpels and an indeterminate floral apex. In addition, GIF1 interacted in vivo with nine GRFs, subunits of the SWI/SNF chromatin-remodeling complex, and hormone biosynthesis-related proteins. Furthermore, key meristem-determinacy gene RAMOSA2 (RA2) and CLAVATA signaling-related gene CLV3/ENDOSPERM SURROUNDING REGION (ESR) 4a (CLE4a) were directly bound and regulated by GIF1 in the ear inflorescence. Conclusions Our findings suggest that GIF1 working together with GRFs recruits SWI/SNF chromatin-remodeling ATPases to influence DNA accessibility in the regions that contain genes involved in hormone biosynthesis, meristem identity and determinacy, thus driving the fate of axillary meristems and floral organ primordia in the ear-inflorescence of maize.

Abstract Background Percutaneous pedicle screw fixation (PPSF) is the primary approach for single-segment thoracolumbar burst fractures (TLBF). The healing angle at the thoracolumbar junction is one of the most significant criteria for evaluating the efficacy of PPSF. Therefore, the purpose of this study was to analyze the predictors associated with the poor postoperative alignment of the thoracolumbar region from routine variables using a support vector machine (SVM) model. Methods We retrospectively analyzed patients with TLBF operated at our academic institute between March 1, 2014 and December 31, 2019. Stepwise logistic regression analysis was performed to assess potential statistical differences between all clinical and radiological variables and the adverse events. Based on multivariate logistic results, a series of independent risk factors were fed into the SVM model. Meanwhile, the feature importance of radiologic outcome for each parameter was explored. The predictive performance of the SVM classifier was evaluated using the area under the receiver operating characteristic curve (AUC), accuracy (ACC) and confusion matrices with 10-fold cross-validation, respectively. Results In the recruited 150 TLBFs, unfavorable radiological outcomes were observed in 53 patients (35.33%). The relationship between osteoporosis (p = 0.036), preoperative Cobb angle (p = 0.001), immediate postoperative Cobb angle (p = 0.029), surgically corrected Cobb angle (p = 0.001), intervertebral disc injury (Score 2 p = 0.001, Score 3 p = 0.001), interpedicular distance (IPD) (p = 0.001), vertebral body compression rate (VBCR) (p = 0.010) and adverse events was confirmed by univariate regression. Thereafter, independent risk factors including preoperative Cobb angle, the disc status and IPD and independent protective factors surgical correction angle were identified by multivariable logistic regression. The established SVM classifier demonstrated favorable predictive performance with the best AUC = 0.93, average AUC = 0.88, and average ACC = 0.87. The variables associated with radiological outcomes, in order of correlation strength, were intervertebral disc injury (42%), surgically corrected Cobb angle (25%), preoperative Cobb angle (18%), and IPD (15%). The confusion matrix reveals the classification results of the discriminant analysis. Conclusions Critical radiographic indicators and surgical purposes were confirmed to be associated with an unfavorable radiographic outcome of TLBF. This SVM model demonstrated good predictive ability for endpoints in terms of adverse events in patients after PPSF surgery.

Introduction: Colorectal cancer (CRC) is the fourth most common cancer worldwide, with high morbidity and mortality rates. In recent years, high-fat diet has been shown to increase CRC morbidity, highlighting the possibility of the application of hypolipidemic drugs for CRC treatment. In this study, we preliminarily evaluated the effects and mechnisms of ezetimibe against CRC through the blockage of lipid absorption in small intesine.Methods: In this study, CRC cell proliferation, invasion, apoptosis, and autophagy were evaluated using cellular and molecular assays. Fluorescent microscopy, and a flow cytometric assay were used to assess mitochondrial activity in vitro. A subcutaneous xenograft mouse model was used to evaluate the effects of ezetimibe in vivo.Results: We found that ezetimibe inhibited CRC cell proliferation, and migration, and facilitated autophage-associated apoptosis in HCT116 and Caco2 cells. Ezetimibe-induced mitochondrial dysfunction in CRC cells was found to be correlated with mTOR signaling activity.Discussion: Ezetimibe exhibits effects against CRC through the promotion of cancer cell death via mTOR signaling-dependent mitochondrial dysfunction, highlighting its potential value in CRC therapy.

Gastric cancer (GC) is one of the most common malignancies. Immunotherapy becomes an indispensable part of GC. This study conducts bibliometric analysis of immunotherapy for GC to clarify the research status and identify potential new research directions. VOS viewer and CiteSpace visualization software were used to demonstrate collaborations and correlations. A total of 1141 English publications from 2012 to 2022 were included. The number of publications increased year by year. The publications were mainly from China (n = 579, 50.70%), followed by the United States. Fudan University published the most publications (n = 48, 4.21%). Frontiers in Oncology and Journal of Clinical Oncology ranked first in cited and co-cited journals, respectively. Kim Kyoung-Mee published the most publications on immunotherapy for GC (n = 14). The clustering of timeline view and co-cited references show the hotspot transformation on immunotherapy for GC. Initially, the hot topic was “cytokine-induced killer cells” and “myeloid-derived suppressor cells.” In recent years, the focus has turned to “targeted therapy.” “CAR-T” has become the hottest topic, and GC has entered precision therapy phase. Screening patients who can benefit from immunotherapy is key to improving prognosis. The combination of immunotherapy with other treatment options, such as chemotherapy and targeted therapy, is currently the focus of research. Chimeric antigen receptor T cell will be further studied in the future.

BackgroundLaparoscopic total gastrectomy (LTG) with Roux-en-Y (RY) is often accompanied by a series of complications. Uncut RY (URY) can effectively reduce Roux stasis syndrome (RSS) in laparoscopic distal gastrectomy. To determine whether totally LTG (TLTG) with URY for gastric cancer (GC) can replace RY in short-term and long-term prognosis.MethodsThis comparative retrospective study selected GC patients from 2016 to 2022. The patients were divided into URY group and RY group. Cox multivariate proportional hazard regression analysis was used to explore the independent prognostic factors. Propensity score matching (PSM) was used to reduce bias.ResultsA total of 100 GC patients met the inclusion criteria. Compared to RY group, URY group showed significant advantages in operation time and length of hospital stay. In addition, URY group can significantly reduce short-term and long-term complications, especially RSS. The 1-, 3- and 5-year progression free survival (PFS) of URY group and RY group were 90.4% vs. 67.8% (P=0.005), 76.6% vs. 52.6% (P=0.009) and 76.6% vs. 32.8% (P

Objectives Understanding the prevalence and genotype distribution of human papillomavirus (HPV) is critical for managing HPV vaccination programmes. Using a retrospective cross-sectional study, we examined long-term trends of HPV prevalence in Wenzhou, a coastal city in China.Setting and participants Cervical exfoliated cells were collected from 127 938 women who underwent cervical cancer screening at the gynaecology outpatient clinic of Wenzhou People’s Hospital from January 2011 to December 2020. HPV infections and genotypes were determined. The HPV genotypes were 16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 6, 11, 42, 43, 44 and 81. From 2011 to 2014, we used PCR and inflow hybridisation for typing assays. In 2015–2020, HPV genotyping was performed on the collected specimens using PCR and flow fluorescence hybridisation.Results The overall prevalence of HPV infection was 17.8%. Across age groups, the prevalence fluctuated between 15.9% and 37.4%, with two peaks in the ≤20 and ≥51 year groups. The annual prevalence varied between 12.2% and 28.8%, with a significant decrease in 2011–2018 and a flat trend in 2018–2020. The five most common HPV genotypes were HPV52 (3.6%), 16 (3.0%), 58 (2.5%), 53 (1.9%) and 81 (1.3%). The prevalence of high-risk gene subtypes HPV56, 59 and the low-risk subtype HPV44 increased. Single HPV infection was the most common.Conclusion The prevalence of HPV in Wenzhou is low to mid-range; however, the high-risk genetic subtypes HPV56 and 59 have increased in recent years. We need to promote HPV vaccination and increase education regarding safer sex.

A Mach-Zehnder interference fiber-optic sensor for simultaneous measurement of temperature and refractive index (RI) is proposed and fabricated. In the sensing structure, no-core fiber (NCF) is cascaded with fiber Bragg grating (FBG), two enlarged tapers between NCF and the single-mode fiber serve as the light coupler, and the shrinked taper between two NCFs is used to enhance the interference effect. The different diameter influence of the shrinked taper on the sensing performance of RI and temperature has been evaluated, and the optimum diameter has been obtained. By monitoring the wavelength shift of FBG and the interference dip in the transmission spectra, the simultaneous measurement of temperature and RI is achieved. The maximum sensitivities of the attenuation peak to RI and temperature are 201.7157 nm/RIU and 87.4 pm/°C, respectively. The sensitivities of FBG to RI and temperature are 80.6 pm/RIU and 13.5 pm/°C, respectively. The transformation matrix has also been given. Own to the simple fabrication and high sensitivity, the sensor has the potential application in simultaneous measurement of multiple parameters.

Abstract Background Asthma is a heterogeneous disease that can be divided into four inflammatory phenotypes: eosinophilic asthma (EA), neutrophilic asthma (NA), mixed granulocytic asthma (MGA), and paucigranulocytic asthma (PGA). While research has mainly focused on EA and NA, the understanding of PGA is limited. In this study, we aimed to identify underlying mechanisms and hub genes of PGA. Methods Based on the dataset from Gene Expression Omnibus(GEO), weighted gene coexpression network analysis (WGCNA), differentially expressed genes (DEGs) analysis and protein–protein interaction (PPI) network analysis were conducted to construct a gene network and to identify key gene modules and hub genes. Functional enrichment analyses were performed to investigate the biological process, pathways and immune status of PGA. The hub genes were validated in a separate dataset. Results Compared to non-PGA, PGA had a different gene expression pattern, in which 449 genes were differentially expressed. One gene module significantly associated with PGA was identified. Intersection between the differentially expressed genes (DEGs) and the genes from the module that were most relevant to PGA were mainly enriched in inflammation and immune response regulation. The single sample Gene Set Enrichment Analysis (ssGSEA) suggested a decreased immune infiltration and function in PGA. Finally six hub genes of PGA were identified, including ADCY2, CXCL1, FPRL1, GPR109B, GPR109A and ADCY3, which were validated in a separate dataset of GSE137268. Conclusions Our study characterized distinct gene expression patterns, biological processes and immune status of PGA and identified hub genes, which may improve the understanding of underlying mechanism and provide potential therapeutic targets for PGA.

Abstract UNESCO Global Geoparks should be of international geological significance in terms of their scientific quality, rarity, aesthetic appeal and tourism value. At least nine Cenozoic volcanic fields are developed in the western Saudi Arabia, with a total area of 180,000 km2. In this paper, the geological and geomorphological features of these volcanic fields induced by the expansion of the Red Sea are interpreted and displayed using multi-source satellite images, such as Landsat-8 OLI (Operational Land Imager) and Gaofen-2 data. Our results show that the Al-Medina volcanic field (AMVF) has great prospects as the aspiring volcanic Geopark in Saudi Arabia. This study indicates that: (1) AMVF has international geoscientific significance and rare natural attribute because the volcanic fields are induced by the rising mantle plume and rare examples of white volcanoes comprised mainly from felsic rock; (2) AMVF has abundant volcanic landscapes, including completely preserved cones and craters and multi-phase lava flows from different eruption stages, which have great aesthetic appreciation and tourism values to attract the general public; (3) AMVF is close to the second holy city of Islam-Medina, which has convenient transportation and is suitable to develop tourism to promote the development of the local economy; (4) AMVF had erupted repeatedly (the latest eruption was in 1256 AD), establishment of the UNESCO Global Geopark Project can not only prevent potential geological hazard risks to the people living in Medina city from future volcanic eruption events, but also provide better protection and conservation to geoheritage sites being damaged by human activities, for example setting protected boundaries of AMVF to avoid the destruction of volcanic landscape integrity caused by urban expansion.

Abstract Competitive endogenous RNA (ceRNA) is a transcript that can be mutually regulated at the post-transcriptional level by competing shared miRNAs. The ceRNA network connects the function of protein-encoded mRNA with the function of non-coding RNA, such as microRNA (miRNA), long non-coding RNA (lncRNA), and circular RNA (circRNA). However, compared with the ceRNA, the identification and combined analysis of lncRNAs, mRNAs, miRNAs, and circRNAs in the cashmere fineness have not been completed. Using RNA-seq technology, we first identified the miRNAs presented in Liaoning Cashmere Goat (LCG) skin, and then analyzed the mRNAs, lncRNAs, circRNAs expressed in LCG and Inner Mongolia cashmere goat (MCG) skin. As a result, 464 known and 45 new miRNAs were identified in LCG skin. In LCG and MCG skin, 1222 differentially expressed mRNAs were identified, 170 differentially expressed lncRNAs and 32 differentially expressed circRNAs were obtained. Then, qRT-PCR was used to confirm further the representative lncRNAs, mRNAs, circRNAs and miRNAs. In addition, miRanda predicted the relationships of ceRNA regulatory network among lncRNAs, circRNAs, miRNAs and mRNAs, the potential regulatory effects were investigated by Go and KEGG analysis. Through the screening and analysis of the results, the ceRNA network regulating cashmere fineness was constructed. LncRNA MSTRG14109.1 and circRNA452 were competed with miRNA-2330 to regulated the expression of TCHH, KRT35 and JUNB, which may provide a potential basis for further research on the process of regulating the cashmere fineness.

Abstract Due to the complex structure and function of central nervous system (CNS), human CNS in vitro modeling is still a great challenge. Neurotoxicity testing of environmental chemicals mainly depends on the traditional animal models, which have various limitations such as species differences, expensive and time-consuming. Meanwhile, in vitro two-dimensional (2D) cultured cells or three-dimensional (3D) cultured neurospheres cannot fully simulate complex 3D structure of neural tissues. Recent advancements in neural organoid systems provides excellent models for the testing of environmental chemicals that affect the development of human CNS. Neural organoids derived from hPSCs not only can simulate the process of CNS development, including early stage neural tube formation, neuroepithelium differentiation and regional specification, but also its 3D structure, thus can be used to evaluate the effect of chemicals on differentiation and morphogenesis. Here, we provide a review of recent progress in the methods of culturing neural organoids and their applications in neurotoxicity testing of environmental chemicals. We conclude by highlighting challenge and future directions in neurotoxicity testing based on neural organoids.

This study aims to decipher the impact and downstream mechanisms of the bioinformatically identified circ_0038138 delivered by cancer-derived exosomes in gastric adenocarcinoma (GAC). Expression of circ_0038138 in clinical GAC tissues and exosomes (Exos) from clinical plasma samples (plasma-Exos) was predicted by bioinformatics analysis and validated by RT-qPCR. The binding affinity between circ_0038138, miR-198 and EZH2 was identified using luciferase activity, RIP, and RNA pull-down assays. GAC cells (AGS) were co-cultured with Exos isolated from GAC cell supernatant (GC9811-P). After co-culture, the behaviors of GAC cells including proliferation and glycolysis were assessed to identify the biological effect of exosomal circ_0038138. Also, in vivo effects of exosomal circ_0038138 on the tumorigenesis and lung metastasis of GAC cells were evaluated by developing nude mouse xenograft and metastatic models. circ_0038138 upregulation was detected in GAC tissues and plasma-Exos. Exos delivered circ_0038138 to GAC cells and potentiated the proliferative, migratory, invasive, and glycolytic potentials of GAC cells. Mechanistically, circ_0038138 competitively bound to miR-198, which in turn targeted EZH2 by binding to its 3′-UTR. Silencing of EZH2 promoted CXXC4 expression and inhibited Wnt/β-catenin pathway activation, thus repressing the malignancy and glycolysis of GAC cells. In vivo assay confirmed that exosomal circ_0038138 induced tumorigenesis and lung metastasis by regulating the miR-198/EZH2 axis. Collectively, our work suggests that the Exo-mediated transfer of circ_0038138 potentially facilitates the glycolysis, growth and metastasis of GAC cells via miR-198/EZH2 axis, which offers a potential prognostic marker and a therapeutic target for GAC.

In the Taihang Mountain areas, known as the “esophageal cancer zone” in China, the incidence of esophageal cancer (ESCA) ranks the first in the country and shows a familial and regional clustering trend. Taihang Mountain areas are located in a mountainous area, with inconvenient transportation, limited living conditions, unbalanced diet, and poor nutrition. Ninety percent of the pathological types of ESCA in Taihang Mountain areas are squamous cell carcinoma, among which the risk factors have not been well understood. These areas are usually remote villages and mountains with low population mobility, large family members, similar environmental factors, and a clear and stable genetic background. Therefore, according to the current situation, second-generation sequencing and multigroup analysis technology are used to analyze the familial ESCA patients; disease-related genetic variation are located; and then disease-related susceptibility genes associated with ESCA are screened and analyzed. Health education, tobacco control, endoscopic screening, and other health management projects for suspected and high-risk patients in areas with a high incidence of ESCA can be carried out for screening and early diagnosis, and the incidence of ESCA in Taihang Mountain areas can be reduced. A comprehensive continuous care pattern based on traditional medical nursing to track, monitor, evaluate, and intervene with patients diagnosed with ESCA to facilitate them with medications guidance, dietary guidance, and timely health problem-solving is established. Furthermore, statistical analysis of epidemiology, gene sequencing, and family genetics information can be performed on patients with ESCA in the Taihang Mountains areas to clarify the relationship between genetic phenotype and genotype during the occurrence of ESCA.

BackgroundReliable biomarkers are needed to improve preeclampsia (PE) prediction accuracy. With the investigational tool of peptidomics, we aimed to identify and validate potential serum peptide biomarkers in cohorts suspected for PE development in middle or late pregnancy.MethodsTotally 195 serum samples were prospectively collected from pregnant women with PE-related syndromes who were followed up for PE development until delivery. Serum peptidomic analysis was performed in the discovery cohort of 115 samples using matrix-assisted laser desorption ionization-time of flight coupled with Linear Trap Quadropole Orbitrap mass spectrometry. The candidate biomarkers were further validated using an in-house developed liquid chromatography tandem mass spectrometry (LC-MS/MS) method in an independent validation cohort of 80 serum samples.ResultsWe identified 8 peptides that were differentially expressed and originated from fibrinogen alpha chain (FGA), inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4) and complement component 3. In the subsequent LC-MS/MS quantitation analysis, the levels of the three peptides (FGA-1033.4, ITIH4-2026.9, ITIH4-2051.1) exhibited a significant difference between the PE-positive and PE-negative groups. Further, the three-peptide panel yielded an area under the ROC curve (AUC) of 0.985 [95% confidence interval (CI) 0.965–1.000] and 0.923 (95% CI 0.845–1.000) in the discovery and validation cohorts respectively, with negative predictive values of 98.1–98.8% and positive predictive values of 73.1–85.3% that were much improved when compared with that of soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio.ConclusionsWe have discovered and validated a novel three-peptide biomarker panel predictive for the occurrence PE in pregnant women.

H-enhanced slip planarity is generally explained in terms of H-reducing stacking fault energy in fcc systems. Here, we showed that H-decreasing dislocation line energies can enhance the tendency toward slip planarity in bcc Fe through systematically studying the interaction between H and 1/2 {110} dislocations using the EAM potential for Fe-H systems. It was found that the binding energy of H, the excess H in the atmosphere, and the interaction energy of H increased with edge components, leading to larger decrements in the line energies of the edge and increased mixed dislocations than those of a screw dislocation. The consequence of such interaction patterns is an increment in the energy change in the system when the edge and mixed dislocations are converted to screw dislocations as compared to the H-free cases. The cross-slip in bcc Fe is thus suppressed by H, increasing the tendency toward slip planarity.

One way to assess the validity of elasticity is with the method of atomic simulations. Molecular statics (MS) simulations are performed to study the interactions between H and edge dislocations in bcc iron using embedded-atom-method potential for a Fe-H system. The nature of H-dislocation interactions can be investigated and the validity of elasticity can be examined. We show that the sites with strong binding energy are found at the dislocation core, as well as in the slip plane, suggesting high H concentrations can form along the slip plane. It is found that the interstitial H not only interacts with hydrostatic stress, but also with the shear stresses generated by the dislocation, especially on the slip plane. When the dislocation stresses are represented using anisotropic elasticity, the validity of elasticity is at H-dislocation distance larger than ~19 Å, i.e., the same as the isotropic predictions. When H lies closer to the dislocation, good agreement with simulations is obtained if considering all strains induced by H at the octahedral sites and using anisotropic elasticity.

Objective To explore the correlation of polymorphisms of endoplasmic reticulum aminopeptidase-1 (ERAP-1) gene in Chinese women with preeclampsia. Method In this case–control study, 51 severely preeclamptic and 48 healthy pregnant women were retrospectively involved in Beijing Obstetrics and Gynecology Hospital from October 2017 to October 2019. The venous blood and umbilical cord blood were collected to analyze different single nucleotide polymorphisms (SNPs) in ERAP-1 gene in both groups. Result We firstly screened nine SNPs that were significantly different between two groups (P

Abstract Primary liver cancer (PLC) is a common malignancy with high morbidity and mortality. Poor prognosis and easy recurrence on PLC patients calls for optimizations of the current conventional treatments and the exploration of novel therapeutic strategies. For most malignancies, including PLC, immune cells play crucial roles in regulating tumor microenvironments and specifically recognizing tumor cells. Therefore, cellular based immunotherapy has its instinctive advantages in PLC therapy as a novel therapeutic strategy. From the active and passive immune perspectives, we introduced the cellular based immunotherapies for PLC in this review, covering both the lymphoid and myeloid cells. Then we briefly review the combined cellular immunotherapeutic approaches and the existing obstacles for PLC treatment.

Abstract Background Hepatocyte growth factor (HGF) binds to the c-mesenchymal-epithelial transition (C-MET) receptor and activates downstream signaling pathways, playing an essential role in the development of various cancers. Given the role of this signaling pathway, the primary therapeutic direction focuses on identifying and designing HGF inhibitors, antagonists and other molecules to block the binding of HGF to C-MET, thereby limiting the abnormal state of other downstream genes. Methods This study focuses on the analysis of immune-related genes and corresponding immune functions that are significantly associated with the HGF/c-MET pathway using transcriptome data from 11 solid tumors. Results We systematically analyzed 11 different cancers, including expression correlation, immune infiltration, tumor diagnosis and survival prognosis from HGF/c-MET pathway and immune regulation, two biological mechanisms having received extensive attention in cancer analysis. Conclusion We found that the HGF/c-MET pathway affected the tumor microenvironment mainly by interfering with expression levels of other genes. Immune infiltration is another critical factor involved in changes to the tumor microenvironment. The downstream immune-related genes activated by the HGF/c-MET pathway regulate immune-related pathways, which in turn affect the degree of infiltration of immune cells. Immune infiltration is significantly associated with cancer development and prognosis.

Abstract Western blotting (WB) is one of the most widely used techniques to identify proteins as well as post translational modifications of proteins. The selection of electroblotted membrane is one of the key factors affecting the detection sensitivity of the protein which is transferred from gel to membrane in WB. The most common used membranes are polyvinylidene fluoride (PVDF) and nitrocellulose (NC) membranes. Which membrane of these two is more suitable for WB has not been reported so far. Here, by incubating proteins which were transferred to PVDF or NC membranes with a series of antibodies and different types of lectins, we investigated the relationship between the binding ability of these two membranes to proteins or glycoproteins and the molecular weight of the target protein. The antibody re-probed ability of the two membranes was also explored. Moreover, we verified the above results by directly incubating proteins having different molecular weights onto PVDF or NC membranes. Bound proteins were stained with direct blue-71, and the staining intensity was quantitated by scanning and densitometry.

Abstract Flexible pressure sensors play significant roles in wearable devices, electronic skins, and human‐machine interface (HMI). However, it remains challenging to develop flexible piezoresistive sensors with outstanding comprehensive performances, especially with excellent long‐term durability. Herein, a facile “interfacial locking strategy” has been developed to fabricate metal aerogel‐based pressure sensors with excellent sensitivity and prominent stability. The strategy broke the bottleneck of the intrinsically poor mechanical properties of metal aerogels by grafting them on highly elastic melamine sponge with the help of a thin polydimethylsiloxane (PDMS) layer as the interface‐reinforcing media. The hierarchically porous conductive structure of the ensemble offered the as‐prepared flexible piezoresistive sensor with a sensitivity as high as 12 kPa−1, a response time as fast as 85 ms, and a prominent durability over 23 000 compression cycles. The excellent comprehensive performance enables the successful application of the flexible piezoresistive sensor as two‐dimensional (2D) array device as well as three‐dimensional (3D) force‐detecting device for real‐time monitoring of HMI activities.

Research on Artificial Intelligence in Education (AIED) has rapidly progressed in recent years, and understanding the research trends and development is essential for technological innovations and implementations in education. Using a bibliometric analysis of 6843 publications from Web of Science and Scopus, we found that China, US, India, Spain, and Germany led the research profuctivity. AIED research is concerned more with higher education compared to K-12 education. Fifteen research trends emerged from the analysis, such as Educational Robots and Large Data Mining. Research has primarily leveraged technologies of machine learning, decision trees, deep learning, speech recognition, and computer vision in AIED. The major implementations of AI include educational robots, automated grading, recommender systems, learning analytics, and intelligent tutoring systems. Among the implementations, a majority of AIED research was conducted in seven major subject domains, chief among them being science, technology, engineering and mathematics (STEM) and language disciplines, with a focus on computer science and English education.

Abstract Esophageal cancer (EC) is one of the most common malignant tumors of the digestive system with high incidence and mortality rate worldwide. Therefore, exploring the pathogenesis of EC and searching for new targeted therapies are the current research hotspot for EC treatment. Long non‐coding RNAs (lncRNAs) are endogenous RNAs with more than 200 nucleotides, but without protein‐coding function. In recent years, lncRNAs have gradually become the focuses in the field of non‐coding RNA. Some lncRNAs have been proved to be closely related to the pathogenesis of EC. Many lncRNAs are abnormally expressed in EC and participate in many biological processes including cell proliferation, apoptosis, and metastasis by inhibiting or promoting target gene expression. LncRNAs can also regulate the progression of EC through epithelial‐mesenchymal transformation (EMT), which is closely related to the occurrence, development, and prognosis of EC. In this article, we review and discuss the involvement of lncRNAs in the progression of EC.