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Abstract Background Although cholesterol metabolism is a common pathway for the development of antitumor drugs, there are no specific targets and drugs for clinical use. Here, based on our previous study of sterol O-acyltransferase 1 (SOAT1) in hepatocelluar carcinoma, we sought to screen an effective targeted drug for precise treatment of hepatocelluar carcinoma and, from the perspective of cholesterol metabolism, clarify the relationship between cholesterol regulation and tumorigenesis and development. Methods In this study, we developed a virtual screening integrated affinity screening technology for target protein drug screening. A series of in vitro and in vivo experiments were used for drug activity verification. Multi-omics analysis and flow cytometry analysis were used to explore antitumor mechanisms. Comparative analysis of proteome and transcriptome combined with survival follow-up information of patients reveals the clinical therapeutic potential of screened drugs. Results We screened three compounds, nilotinib, ABT-737, and evacetrapib, that exhibited optimal binding with SOAT1. In particular, nilotinib displayed a high affinity for SOAT1 protein and significantly inhibited tumor activity both in vitro and in vivo. Multi-omics analysis and flow cytometry analysis indicated that SOAT1-targeting compounds reprogrammed the cholesterol metabolism in tumors and enhanced CD8+ T cells and neutrophils to suppress tumor growth. Conclusions Taken together, we reported several high-affinity SOAT1 ligands and demonstrated their clinical potential in the precision therapy of liver cancer, and also reveal the potential antitumor mechanism of SOAT1-targeting compounds. Graphical Abstract

Abstract Plant phenology regulates the carbon cycle and land‐atmosphere coupling. Currently, climate models often disagree with observations on the seasonal cycle of vegetation growth, partially due to how spring onset is measured and simulated. Here we use both thermal and leaf area index (LAI) based indicators to characterize spring onset in CMIP6 models. Although the historical timing varies considerably across models, most agree that spring has advanced in recent decades and will continue to arrive earlier with future warming. Across the Northern Hemisphere for the periods 1950–2014, 1981–2014, and 2015–2099 in the historical and SSP5‐8.5 simulations, thermal‐based indicators estimate spring advances of −0.7 ± 0.2, −1.4 ± 0.4, and −2.4 ± 0.7 days/decade, while LAI‐based indicators estimate −0.4 ± 0.3, −0.1 ± 0.3, and −1±1.1 days/decade. Thereby, LAI‐based indicators exhibit weaker trends toward earlier onset, leading to uncertainties from different indices being as large or larger than model uncertainty. Reconciling these discrepancies is critical for understanding future changes in spring onset.

Abstract Background Extracellular vesicles (EVs) are emerging mediators of intercellular communication that have been shown to play important roles in tumor progression. YRNA fragments, a type of small non-coding RNA, are dysregulated in non-small cell lung cancer (NSCLC) cell-derived EVs, suggesting that they may be an effective biomarker for cancer diagnosis and treatment strategies. Methods Differentially expressed YRNA hY4 fragments (hY4F) in EVs from NSCLC cells and normal lung fibroblasts were isolated by differential ultra-centrifugation. RNA-binding proteins that interacted with hY4F were identified by screening with an RNA pulldown assay and mass spectrometry. The molecular mechanism of hY4F and the RNA-binding protein Y box binding protein 1 (YBX1) was demonstrated by qRT-PCR, western blot, RNA pulldown, and rescue experiments. Transcriptome sequencing, qRT-PCR validation, bioinformatics analysis and NF-κB pathway inhibitor assays elucidate the mechanism of YBX1 and hY4F inhibiting lung cancer. A peptide pulldown assay was performed to screen and identify a potential methyltransferase for YBX1. The roles of hY4F, YBX1, and SET domain containing 3 in biological functions, such as proliferation, migration, invasion, and apoptosis, in lung cancer cells were also examined by EdU incorporation assay, Transwell assay, flow cytometry, and other methods. Lastly, a mouse xenograft assay was used to assess the clinical relevance of YBX1 and hY4F in vivo. Results Our data demonstrate that hY4 RNA fragments were upregulated in lung cancer- derived EVs, hY4F inhibits tumor progression through downregulating MAPK/NF-κB signaling, and then the selective sorting and secretion of hY4F into lung cancer EVs is regulated by the RNA-binding protein YBX1. Furthermore, we identified lysine K264 within the YBX1 C-terminal domain as the necessary site for its interaction with hY4Fs. K264 is modified by methylation, which affects its binding to hY4F and subsequent selective sorting into EVs in lung cancer cells. Conclusion Our findings demonstrate that hY4F acts as a tumor suppressor and is selectively sorted into lung cancer cell-derived EVs by interacting with methylated YBX1, which in turn promotes lung cancer progression. hY4F is a promising circulating biomarker for non-small cell lung cancer diagnosis and prognosis and an exceptional candidate for further therapeutic exploration.

The quantitative calculation and evaluation of seismic damage play a crucial role in ensuring structural safety, conducting performance-based structural analysis, and implementing seismic strengthening measures. However, there is limited research on the damage performance of blind-bolted T-stub steel connections used extensively in prefabricated buildings. In this study, the tensile sub model of a blind-bolted T-stub steel connection in a beam–column joint is investigated. The influence of the flange and web thickness of the T-stub connector, as well as the shear-loaded connecting bolts on the web of the T-stub, on the tensile performance of the sub model are considered. Four tensile destructive tests are conducted on a T-stub connector connected to a hollow section column using blind bolts. The experimental results, including failure modes, force–displacement curves, and strain development in the hollow section column and T-stub, are discussed and analyzed in this study. The test results reveal three main failure modes for this tensile substructure: the plastic deformation of the hollow section column, the bending fracture of the T-stub flange, and the fracture of the T-stub web bolt holes due to compression. Furthermore, a ductile damage finite element analysis method is employed to simulate the fracture damage process of the substructure, and the corresponding damage index is calculated using the typical Park–Ang damage model for evaluation, showing good agreement with the damage classification levels specified in FEMA.

Change detection of natural lake boundaries is one of the important tasks in remote sensing image interpretation. In an ordinary fully connected network, or CNN, the signal of neurons in each layer can only be propagated to the upper layer, and the processing of samples is independent at each moment. However, for time-series data with transferability, the learned change information needs to be recorded and utilized. To solve the above problems, we propose a lake boundary change prediction model combining U-Net and LSTM. The ensemble of LSTMs helps to improve the overall accuracy and robustness of the model by capturing the spatial and temporal nuances in the data, resulting in more precise predictions. This study selected Lake Urmia as the research area and used the annual panoramic remote sensing images from 1996 to 2014 (Lat: 37°00′ N to 38°15′ N, Lon: 46°10′ E to 44°50′ E) obtained by Google Earth Professional Edition 7.3 software as the research data set. This model uses the U-Net network to extract multi-level change features and analyze the change trend of lake boundaries. The LSTM module is introduced after U-Net to optimize the predictive model using historical data storage and forgetting as well as current input data. This method enables the model to automatically fit the trend of time series data and mine the deep information of lake boundary changes. Through experimental verification, the model’s prediction accuracy for lake boundary changes after training can reach 89.43%. Comparative experiments with the existing U-Net-STN model show that the U-Net-LSTM model used in this study has higher prediction accuracy and lower mean square error.

Text classification has been highlighted as the key process to organize online texts for better communication in the Digital Media Age. Text classification establishes classification rules based on text features, so the accuracy of feature selection is the basis of text classification. Facing fast-increasing Chinese electronic documents in the digital environment, scholars have accumulated quite a few algorithms for the feature selection for the automatic classification of Chinese texts in recent years. However, discussion about how to adapt existing feature selection algorithms for various types of Chinese texts is still inadequate. To address this, this study proposes three improved feature selection algorithms and tests their performance on different types of Chinese texts. These include an enhanced CHI square with mutual information (MI) algorithm, which simultaneously introduces word frequency and term adjustment (CHMI); a term frequency–CHI square (TF–CHI) algorithm, which enhances weight calculation; and a term frequency–inverse document frequency (TF–IDF) algorithm enhanced with the extreme gradient boosting (XGBoost) algorithm, which improves the algorithm’s ability of word filtering (TF–XGBoost). This study randomly chooses 3000 texts from six different categories of the Sogou news corpus to obtain the confusion matrix and evaluate the performance of the new algorithms with precision and the F1-score. Experimental comparisons are conducted on support vector machine (SVM) and naive Bayes (NB) classifiers. The experimental results demonstrate that the feature selection algorithms proposed in this paper improve performance across various news corpora, although the best feature selection schemes for each type of corpus are different. Further studies of the application of the improved feature selection methods in other languages and the improvement in classifiers are suggested.

Abstract Background Compelling evidences demonstrated that gut microbiota dysbiosis plays a critical role in the pathogenesis of inflammatory bowel diseases (IBD). Therapies for targeting the microbiota may provide alternative options for the treatment of IBD, such as probiotics. Here, we aimed to investigate the protective effect of a probiotic strain, Pediococcus pentosaceus (P. pentosaceus) CECT 8330, on dextran sulfate sodium (DSS)-induced colitis in mice. Methods C57BL/6 mice were administered phosphate-buffered saline (PBS) or P. pentosaceus CECT 8330 (5 × 108 CFU/day) once daily by gavage for 5 days prior to or 2 days after colitis induction by DSS. Weight, fecal conditions, colon length and histopathological changes were examined. ELISA and flow cytometry were applied to determine the cytokines and regulatory T cells (Treg) ratio. Western blot was used to examine the tight junction proteins (TJP) in colonic tissues. Fecal short-chain fatty acids (SCFAs) levels and microbiota composition were analyzed by targeted metabolomics and 16S rRNA gene sequencing, respectively. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Cluster of orthologous groups of proteins (COG) pathway analysis were used to predict the microbial functional profiles. Results P. pentosaceus CECT 8330 treatment protected DSS-induced colitis in mice as evidenced by reducing the weight loss, disease activity index (DAI) score, histological damage, and colon length shortening. P. pentosaceus CECT 8330 decreased the serum levels of proinflammatory cytokines (TNF-α, IL-1β, and IL-6), and increased level of IL-10 in DSS treated mice. P. pentosaceus CECT 8330 upregulated the expression of ZO-1, Occludin and the ratio of Treg cells in colon tissue. P. pentosaceus CECT 8330 increased the fecal SCFAs level and relative abundances of several protective bacteria genera, including norank_f_Muribaculaceae, Lactobacillus, Bifidobacterium, and Dubosiella. Furthermore, the increased abundances of bacteria genera were positively correlated with IL-10 and SCFAs levels, and negatively associated with IL-6, IL-1β, and TNF-α, respectively. The KEGG and COG pathway analysis revealed that P. pentosaceus CECT 8330 could partially recover the metabolic pathways altered by DSS. Conclusions P. pentosaceus CECT 8330 administration protects the DSS-induced colitis and modulates the gut microbial composition and function, immunological profiles, and the gut barrier function. Therefore, P. pentosaceus CECT 8330 may serve as a promising probiotic to ameliorate intestinal inflammation.

The loss of biodiversity due to rapid urbanization can be mitigated by urban riparian corridors. As an important component of urban biodiversity, spontaneous herbaceous plants play an essential role in the ecological functions of urban river corridors. Currently, the influence of the landscape structure within corridors on plant diversity has been poorly understood. In this study, we investigated the species and functional diversity, especially the functional traits of origin, pollination, and dispersal, of spontaneous herbaceous plants in the Wenyu River-North Canal riparian corridor in Beijing. The results showed that urban riparian corridors have a positive effect on the spread of alien and invasive plants as well as increasing the native plant diversity. No significant differences in diversity indicators but significant differences in the composition of functional traits between habitat types. Plants with long pollination and dispersal distances tended to be more closely related to the landscape structure indices at larger scales. Invasive plants were more common in patches with significant connectivity, while native plants were positively correlated with water and road connectivity. Anemophilous and anemochores were more common in habitats with sinuous edges. Ant-dispersed plants were closely related to the water bodies. Autochores were positively correlated with the connectivity of habitat patches. Plants dispersed by birds and mammals were weakly correlated with landscape structure. Our study underlines that emphasis should be placed on the support for plant pollination and dispersal, together with the prevention and control of invasive plants in the construction and management of future urban ecological corridors.

Background. Arising from T progenitor cells, T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignant tumor, accounting for 15% of childhood ALL and 25% of adult ALL. Composing of putative enhancers in close genomic proximity, super enhancer (SE) is critical for cell identity and the pathogenesis of multiple cancers. Belonging to the cytosolute linker protein group, FYB1 is essential for TCR signaling and extensively studied in terms of tumor pathogenesis and metastasis. Dissecting the role of FYN binding protein 1 (FYB1) in T-ALL holds the potential to improve the treatment outcome and prognosis of T-ALL. Methods. In this study, SEs were explored using public H3K27ac ChIP-seq data derived from T-ALL cell lines, AML cell lines and hematopoietic stem and progenitor cells (HSPCs). Downstream target of FYB1 gene was identified by RNA-seq. Effects of shRNA-mediated downregulation of FYB1 and immunoglobulin lambda-like polypeptide 1 (IGLL1) on self-renewal of T-ALL cells were evaluated in vitro and/or in vivo. Results. As an SE-driven gene, overexpression of FYB1 was observed in T-ALL, according to the Cancer Cell Line Encyclopedia database. In vitro, knocking down FYB1 led to comprised growth and enhanced apoptosis of T-ALL cells. In vivo, downregulation of FYB1 significantly decreased the disease burden by suppressing tumor growth and improved survival rate. Knocking down FYB1 resulted in significantly decreased expression of IGLL1 that was also an SE-driven gene in T-ALL. As a downstream target of FYB1, IGLL1 exerted similar role as FYB1 in inhibiting growth of T-ALL cells. Conclusion. Our results suggested that FYB1 gene played important role in regulating self-renewal of T-ALL cells by activating IGLL1, representing a promising therapeutic target for T-ALL patients.

Fatigue life is a crucial design factor which dictates the safe operation of the wind turbines, but it is influenced by uncertain factors such as environmental loads, analytical models, material properties, and manufacturing methods. In this study, a 1.5 MW wind turbine was monitored in operation to understand the fatigue mechanism and enhance wind turbine design. The influence of different operating conditions on fatigue damage was analyzed by correlating strain monitoring data with supervisory control and data acquisition (SCADA) data. Furthermore, a fatigue evaluation method based on measured strain data was proposed. Fatigue damage increases with the increase of wind and rotation speed. More than 50% of the damage occurred at the rated rotation speed state, the corresponding wind speed was greater than the rated wind speed and the pitch control system was active. The findings of this study provide insights for investigating the real fatigue state of similar wind turbine towers and improving the return on investment by closely estimating their service life.

ObjectiveSympathetic remodeling after myocardial infarction (MI) is the primary cause of ventricular arrhythmias (VAs), leading to sudden cardiac death (SCD). M1-type macrophages are closely associated with inflammation and sympathetic remodeling after MI. Long noncoding RNAs (lncRNAs) are critical for the regulation of cardiovascular disease development. Therefore, this study aimed to identify the lncRNAs involved in MI and reveal a possible regulatory mechanism.Methods and resultsM0- and M1-type macrophages were selected for sequencing and screened for differentially expressed lncRNAs. The data revealed that lncRNA LOC100911717 was upregulated in M1-type macrophages but not in M0-type macrophages. In addition, the lncRNA LOC100911717 was upregulated in heart tissues after MI. Furthermore, an RNA pull-down assay revealed that lncRNA LOC100911717 could interact with growth-associated protein 43 (GAP43). Essentially, immunofluorescence assays and programmed electrical stimulation demonstrated that GAP43 expression was suppressed and VA incidence was reduced after lncRNA LOC100911717 knockdown in rat hearts using an adeno-associated virus.ConclusionsWe observed a novel relationship between lncRNA LOC100911717 and GAP43. After MI, lncRNA LOC100911717 was upregulated and GAP43 expression was enhanced, thus increasing the extent of sympathetic remodeling and the frequency of VA events. Consequently, silencing lncRNA LOC100911717 could reduce sympathetic remodeling and VAs.

Methanol has been studied to solve the problems of insufficient combustion and unstable operation of natural gas engines. To explore the influence of methanol addition on natural gas/air mixture, the laminar combustion characteristics of stoichiometric methane/methanol/air mixture with methanol volume fractions of 0–100% are measured in a constant volume combustion chamber under the initial pressures of 1–4 bar and initial temperatures of 353–393 K. The experimental results show that the laminar combustion characteristics are linearly enhanced by methanol addition. When the methanol volume fraction varies from 0% to 100% at 393 K and 4 bar, the change rates are 11.7%, 120.4%, - 28.1% and 61.7% for combustion peak pressure, maximum pressure rise rate, combustion duration and laminar burning velocity (LBV) respectively. At high pressure, the influence of methanol addition is enhanced. Chemical kinetics analysis shows that CH2OH, the intermediate product of methanol oxidation, generates HO2 through R134: CH2OH + O2CH2O + HO2, which contributes from 14% to 56% to the generation of HO2, so that HO2 replaces part of the O2 to participate the reaction with H, resulting in the transformation of part of R1: H + O2OH + O to R10: HO2+H2OH, thereby generating more OH and promoting the reaction.

Abstract Background Actinomycosis is a rare infectious disease caused by Actinomyces, especially in children. Here, we present a case of musculoskeletal actinomycosis in a 5-year-old girl from China. Case presentation A 5-year-old girl presented with recurrent episodes of fever, pain, erythema, swelling, and festering sores on the right lower extremity, and pus was discharged from a sinus in the right foot. Magnetic resonance imaging (MRI) suggested subcutaneous soft tissue infection and osteomyelitis of the right crus. A bacterial culture of pus extracted from a festering sore on the right popliteal fossa detected the growth of Actinomycetes europaeus. The patient was cured with 7 weeks of treatment with intravenous ampicillin-sulbactam, followed by 6 weeks of treatment with oral amoxicillin-clavulanate with surgical debridement and drainage. There were no symptoms of recurrence during the 15-month period of follow-up. Conclusions Pediatric actinomycosis is a rare and challenging infectious disease. Early accurate diagnosis and optimal surgical debridement are important for the management of pediatric actinomycosis.

Aminoacyl-tRNA synthetases (ARSs) are widely found in organisms, which can activate amino acids and make them bind to tRNA through ester bond to form the corresponding aminoyl-tRNA. The classic function of ARS is to provide raw materials for protein biosynthesis. Recently, emerging evidence demonstrates that ARSs play critical roles in controlling inflammation, immune responses, and tumorigenesis as well as other important physiological and pathological processes. With the recent development of genome and exon sequencing technology, as well as the discovery of new clinical cases, ARSs have been reported to be closely associated with a variety of cardiovascular diseases (CVDs), particularly angiogenesis and cardiomyopathy. Intriguingly, aminoacylation was newly identified and reported to modify substrate proteins, thereby regulating protein activity and functions. Sensing the availability of intracellular amino acids is closely related to the regulation of a variety of cell physiology. In this review, we summarize the research progress on the mechanism of CVDs caused by abnormal ARS function and introduce the clinical phenotypes and characteristics of CVDs related to ARS dysfunction. We also highlight the potential roles of aminoacylation in CVDs. Finally, we discuss some of the limitations and challenges of present research. The current findings suggest the significant roles of ARSs involved in the progress of CVDs, which present the potential clinical values as novel diagnostic and therapeutic targets in CVD treatment.

Malaria still threatens global health seriously today. While the current discoveries of antimalarials are almost totally focused on single mode-of-action inhibitors, multi-targeting inhibitors are highly desired to overcome the increasingly serious drug resistance. Here, we performed a structure-based drug design on mitochondrial respiratory chain of Plasmodium falciparum and identified an extremely potent molecule, RYL-581, which binds to multiple protein binding sites of P. falciparum simultaneously (allosteric site of type II NADH dehydrogenase, Qo and Qi sites of cytochrome bc1). Antimalarials with such multiple targeting mechanism of action have never been reported before. RYL-581 kills various drug-resistant strains in vitro and shows good solubility as well as in vivo activity. This structure-based strategy for designing RYL-581 from starting compound may be helpful for other medicinal chemistry projects in the future, especially for drug discovery on membrane-associated targets.

Detecting changes in land cover is a critical task in remote sensing image interpretation, with particular significance placed on accurately determining the boundaries of lakes. Lake boundaries are closely tied to land resources, and any alterations can have substantial implications for the surrounding environment and ecosystem. This paper introduces an innovative end-to-end model that combines U-Net and spatial transformation network (STN) to predict changes in lake boundaries and investigate the evolution of the Lake Urmia boundary. The proposed approach involves pre-processing annual panoramic remote sensing images of Lake Urmia, obtained from 1996 to 2014 through Google Earth Pro Version 7.3 software, using image segmentation and grayscale filling techniques. The results of the experiments demonstrate the model’s ability to accurately forecast the evolution of lake boundaries in remote sensing images. Additionally, the model exhibits a high degree of adaptability, effectively learning and adjusting to changing patterns over time. The study also evaluates the influence of varying time series lengths on prediction accuracy and reveals that longer time series provide a larger number of samples, resulting in more precise predictions. The maximum achieved accuracy reaches 89.3%. The findings and methodologies presented in this study offer valuable insights into the utilization of deep learning techniques for investigating and managing lake boundary changes, thereby contributing to the effective management and conservation of this significant ecosystem.

Facing fast-increasing electronic documents in the Digital Media Age, the need to extract textual features of online texts for better communication is growing. Sentiment classification might be the key method to catch emotions of online communication, and developing corpora with annotation of emotions is the first step to achieving sentiment classification. However, the labour-intensive and costly manual annotation has resulted in the lack of corpora for emotional words. Furthermore, single-label semantic corpora could hardly meet the requirement of modern analysis of complicated user’s emotions, but tagging emotional words with multiple labels is even more difficult than usual. Improvement of the methods of automatic emotion tagging with multiple emotion labels to construct new semantic corpora is urgently needed. Taking Twitter short texts as the case, this study proposes a new semi-automatic method to annotate Internet short texts with multiple labels and form a multi-labelled corpus for further algorithm training. Each sentence is tagged with both the emotional tendency and polarity, and each tweet, which generally contains several sentences, is tagged with the first two major emotional tendencies. The semi-automatic multi-labelled annotation is achieved through the process of selecting the base corpus and emotional tags, data preprocessing, automatic annotation through word matching and weight calculation, and manual correction in case of multiple emotional tendencies are found. The experiments on the Sentiment140 published Twitter corpus demonstrate the effectiveness of the proposed approach and show consistency between the results of semi-automatic annotation and manual annotation. By applying this method, this study summarises the annotation specification and constructs a multi-labelled emotion corpus with 6500 tweets for further algorithm training.

Natural extracellular vesicles (EVs) play important roles in many life processes such as in the intermolecular transfer of substances and genetic information exchanges. Investigating the origins and working mechanisms of natural EVs may provide an understanding of life activities, especially regarding the occurrence and development of diseases. Additionally, due to their vesicular structure, EVs (in small molecules, nucleic acids, proteins, etc.) could act as efficient drug-delivery carriers. Herein, we describe the sources and biological functions of various EVs, summarize the roles of EVs in disease diagnosis and treatment, and review the application of EVs as drug-delivery carriers. We also assess the challenges and perspectives of EVs in biomedical applications.

Background: Recent evidence suggests that the changes in gut microbiota and its metabolites could predict the clinical response of anti-tumor necrosis factor (TNF) agents, such as infliximab (IFX). However, whether manipulation of the gut microbiota can enhance the efficacy of anti-TNF agents remains unclear. Here, we aim to evaluate the effect of a probiotic strain, Bifidobacterium longum (B. longum) CECT 7894, on IFX efficacy for dextran sulfate sodium (DSS)-induced colitis in mice and attempt to explore the potential involved mechanisms.Methods: C57BL/6 mice were treated with phosphate-buffered saline (PBS) or B. longum CECT 7894 (5 × 108 CFU/day) once daily by gavage for 5 days and subsequently induced acute colitis by 3% (w/v) DSS in drinking water. The efficacies of IFX combined with or without B. longum CECT 7894 were assessed by weight loss, fecal consistency, colon length, and histopathological changes. Immunohistochemistry (IHC) was used to examine the expression of tight junction proteins (TJPs) in colonic tissues. The microbiota composition was characterized through 16 S rRNA gene sequencing. Fecal bile acids (BAs) levels were analyzed by targeted metabolomics.Results:B. longum CECT 7894 improved the efficacy of IFX for DSS-induced colitis as evidenced by decreased weight loss, disease activity index (DAI) scores, colon length shortening, histological damage, increased ZO-1, and Occludin expressions as compared with mice that received IFX only. B. longum CECT 7894 modified the composition and structure of the gut microbiota community in DSS-induced colitis mice. B. longum CECT 7894 increased the relative abundances of genera Bifidobacterium, Blautia, Butyricicoccus, Clostridium, Coprococcus, Gemmiger, and Parabacterioides, and reduced the relative abundances of bacteria genera Enterococcus and Pseudomonas. Furthermore, B. longum CECT 7894 changed the BAs metabolism by increasing the abundance of secondary BAs, such as a-MCA, ß-MCA, LCA, CDCA, UDCA, HCA, isoLCA, isoalloLCA. The covariance analysis revealed the upregulated secondary BAs were positively associated with the increased abundance of bacteria that contained bile salt hydrolases (BSH) and 7α-dehydroxylases genes.Conclusion:B. longum CECT 7894 improved the efficacy of IFX for DSS-induced colitis via regulating the gut microbiota composition and bile acid metabolism. Probiotics supplementation may provide a possibility to improve the clinical response of anti-TNF agents in IBD management.

Summary: Background: Alveolar echinococcosis (AE), which is caused by larval Echinococcus multilocularis, is one of the world's most dangerous neglected diseases. Currently, no fully effective treatments are available to cure this disease. Methods: In vitro protoscolicidal assay along with in vivo murine models was applied in repurposing drugs against AE. Genome-wide identification and homology-based modeling were used for predicting drug targets. RNAi, enzyme assay, and RNA-Seq analyses were utilized for investigating the roles in parasite survival and validations for the drug target. Findings: We identified nelfinavir as the most effective HIV protease inhibitor against larval E. multilocularis. Once-daily oral administration of nelfinavir for 28 days resulted in a remarkable reduction in parasite infection in either immune-competent or immunocompromised mice. E. multilocularis DNA damage-inducible 1 protein (EmuDdi1) is predicted as a target candidate for nelfinavir. We proved that EmuDdi1 is essential for parasite survival and protein excretion and acts as a functionally active protease for this helminth. We found nelfinavir is able to inhibit the proteolytic activity of recombinant EmuDdi1 and block the EmuDdi1-related pathways for protein export. With other evidence of drug efficacy comparison, our results suggest that inhibition of EmuDdi1 is a mechanism by which this HIV proteinase inhibitor mediates its antiparasitic action on echinococcosis. Interpretation: This study demonstrates that nelfinavir is a promising candidate for treating echinococcosis. This drug repurposing study proves that the widely prescribed drug for AIDS treatment is potent in combating E. multilocularis infection and thus provides valuable insights into the development of single-drug therapy for highly prevalent co-infection between HIV and helminth diseases. Funding: This work was supported by the National Natural Science Foundation of China (31802179), the Natural Science Foundation of Gansu Province, China (No. 21JR7RA027), and the State Key Laboratory of Veterinary Etiological Biology (No. SKLVEB2021YQRC01).

ABSTRACT: Background: Clostridiodes difficile infection (CDI) is one of the most common causes of antibiotic-associated diarrhea in children. Conventional antibiotics and emerging fecal microbiota transplantation (FMT) are used to treat CDI. Methods: Children with CDI admitted to the Shanghai Children's Hospital, from September 2014 to September 2020, were retrospectively included to this observational study. Pediatric patients were assigned as initial CDI and recurrent CDI (RCDI), and symptoms, comorbidities, imaging findings, laboratory tests, and treatments were systematically recorded and analyzed. Results: Of 109 pediatric patients with CDI, 58 were boys (53.2%), and the median age was 5 years (range, 2-9 years). The main clinical symptoms of CDI children were diarrhea (109/109, 100%), hematochezia (55/109, 50.46%), abdominal pain (40/109, 36.70%); fever, pseudomembrane, vomit, and bloating were observed in 39 (35.78%), 33 (30.28%), and 24 (22.02%) patients, respectively. For the primary therapy with conventional antibiotics, 68 patients received metronidazole, and 41 patients received vancomycin. RCDI occurred in 48.53% (33/68) of those initially treated with metronidazole compared with 46.33% (19/41) of those initially treated with vancomycin (p=0.825). The total resolution rate of FMT for RCDI children was significantly higher than with vancomycin treatment (28/29, 96.55% vs 11/23, 47.83%, p < 0.001). There were no serious adverse events (SAEs) reported after two months of FMT. Conclusions: The major manifestations of children with CDI were diarrhea, hematochezia, and abdominal pain. The cure rate of FMT for pediatric RCDI is superior to vancomycin treatment.

Acute myeloid leukemia (AML) represents an aggressive hematopoietic malignancy with a prognosis inferior to that of other leukemias. Recent targeted therapies offer new opportunities to achieve better treatment outcomes. However, due to the complex heterogeneity of AML, its prognosis remains dismal. In this study, we first identified the correlation between high expression of BRD4 and overall survival of patients with AML. Targeted degradation of BRD2, BRD3, and BRD4 proteins by dBET1, a proteolysis-targeting chimera (PROTAC) against the bromodomain and extra-terminal domain (BET) family members, showed cytotoxic effects on Kasumi (AML1-ETO), NB4 (PML-RARa), THP-1 (MLL-AF9), and MV4-11 (MLL-AF4) AML cell lines representing different molecular subtypes of AML. Furthermore, we determined that dBET1 treatment arrested cell cycling and enhanced apoptosis and c-MYC was identified as the downstream target. Collectively, our results indicated that dBET1 had broad anti-cancer effects on AML cell lines with different molecular lesions and provided more benefits to patients with AML.

Abstract Background T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease with a high risk of induction failure and poor outcomes, with relapse due to drug resistance. Recent studies show that bromodomains and extra-terminal (BET) protein inhibitors are promising anti-cancer agents. ARV-825, comprising a BET inhibitor conjugated with cereblon ligand, was recently developed to attenuate the growth of multiple tumors in vitro and in vivo. However, the functional and molecular mechanisms of ARV-825 in T-ALL remain unclear. This study aimed to investigate the therapeutic efficacy and potential mechanism of ARV-825 in T-ALL. Methods Expression of the BRD4 were determined in pediatric T-ALL samples and differential gene expression after ARV-825 treatment was explored by RNA-seq and quantitative reverse transcription-polymerase chain reaction. T-ALL cell viability was measured by CCK8 assay after ARV-825 administration. Cell cycle was analyzed by propidium iodide (PI) staining and apoptosis was assessed by Annexin V/PI staining. BRD4, BRD3 and BRD2 proteins were detected by western blot in cells treated with ARV-825. The effect of ARV-825 on T-ALL cells was analyzed in vivo. The functional and molecular pathways involved in ARV-825 treatment of T-ALL were verified by western blot and chromatin immunoprecipitation (ChIP). Results BRD4 expression was higher in pediatric T-ALL samples compared with T-cells from healthy donors. High BRD4 expression indicated a poor outcome. ARV-825 suppressed cell proliferation in vitro by arresting the cell cycle and inducing apoptosis, with elevated poly-ADP ribose polymerase and cleaved caspase 3. BRD4, BRD3, and BRD2 were degraded in line with reduced cereblon expression in T-ALL cells. ARV-825 had a lower IC50 in T-ALL cells compared with JQ1, dBET1 and OTX015. ARV-825 perturbed the H3K27Ac-Myc pathway and reduced c-Myc protein levels in T-ALL cells according to RNA-seq and ChIP. In the T-ALL xenograft model, ARV-825 significantly reduced tumor growth and led to the dysregulation of Ki67 and cleaved caspase 3. Moreover, ARV-825 inhibited cell proliferation by depleting BET and c-Myc proteins in vitro and in vivo. Conclusions BRD4 indicates a poor prognosis in T-ALL. The BRD4 degrader ARV-825 can effectively suppress the proliferation and promote apoptosis of T-ALL cells via BET protein depletion and c-Myc inhibition, thus providing a new strategy for the treatment of T-ALL.

Food polysaccharides are well acclaimed in the field of delivery systems due to their natural safety, biocompatibility with the human body, and capability of incorporating/releasing various bioactive compounds. Electrospinning, a straightforward atomization technique that has been attracting researchers worldwide, is also versatile for coupling food polysaccharides and bioactive compounds. In this review, several popular food polysaccharides including starch, cyclodextrin, chitosan, alginate, and hyaluronic acid are selected to discuss their basic characteristics, electrospinning conditions, bioactive compound release characteristics, and more. Data revealed that the selected polysaccharides are capable of releasing bioactive compounds from as rapidly as 5 s to as prolonged as 15 days. In addition, a series of frequently studied physical/chemical/biomedical applications utilizing electrospun food polysaccharides with bioactive compounds are also selected and discussed. These promising applications include but are not limited to active packaging with 4-log reduction against E. coli, L. innocua, and S. aureus; removal of 95% of particulate matter (PM) 2.5 and volatile organic compounds (VOCs); heavy metal ion removal; increasing enzyme heat/pH stability; wound healing acceleration and enhanced blood coagulation, etc. The broad potentials of electrospun food polysaccharides loaded with bioactive compounds are demonstrated in this review.

Understory vegetation affects the richness and stability of urban forest ecosystems. To investigate the influence of soil physicochemical properties on the diversity of understory plants in urban forests, this study used 30 urban forest communities in the Beijing Plain area as the research object and analyzed the correlation between understory plant diversity and soil factors by correlation analysis. Furthermore, pH, soil bulk density (SBD), total soil porosity (TSP), soil water content (SWC), soil organic carbon (SOC), soil organic matter (SOM), total nitrogen (TN), total phosphorus (TP), effective phosphorous (AP), and effective potassium (AK) were determined in this study. The Shannon diversity index (H’), Pielou evenness index (E), Simpson dominance index (C), and Margalef richness index (DMG) of understory plants were calculated. The soil nutrient contents and the understory plant diversity indices of the different community types showed significant differences. There was a strong correlation between soil properties and the diversity index of understory vegetation. SOM and SOC were the main factors affecting the Shannon-Wiener index, Pielou index, Simpson index, and Margalef richness index of the understory plants. We conclude that soil properties were one of the primary drivers of the formation of understory vegetation diversity. The results of the study can provide scientific guidance for the management of urban forests.

Abstract Background Efficient utilization of all available carbons from lignocellulosic biomass is critical for economic efficiency of a bioconversion process to produce renewable bioproducts. However, the metabolic responses that enable Pseudomonas putida to utilize mixed carbon sources to generate reducing power and polyhydroxyalkanoate (PHA) remain unclear. Previous research has mainly focused on different fermentation strategies, including the sequential feeding of xylose as the growth stage substrate and octanoic acid as the PHA-producing substrate, feeding glycerol as the sole carbon substrate, and co-feeding of lignin and glucose. This study developed a new strategy—co-feeding glycerol and lignin derivatives such as benzoate, vanillin, and vanillic acid in Pseudomonas putida KT2440—for the first time, which simultaneously improved both cell biomass and PHA production. Results Co-feeding lignin derivatives (i.e. benzoate, vanillin, and vanillic acid) and glycerol to P. putida KT2440 was shown for the first time to simultaneously increase cell dry weight (CDW) by 9.4–16.1% and PHA content by 29.0–63.2%, respectively, compared with feeding glycerol alone. GC–MS results revealed that the addition of lignin derivatives to glycerol decreased the distribution of long-chain monomers (C10 and C12) by 0.4–4.4% and increased the distribution of short-chain monomers (C6 and C8) by 0.8–3.5%. The 1H–13C HMBC, 1H–13C HSQC, and 1H–1H COSY NMR analysis confirmed that the PHA monomers (C6–C14) were produced when glycerol was fed to the bacteria alone or together with lignin derivatives. Moreover, investigation of the glycerol/benzoate/nitrogen ratios showed that benzoate acted as an independent factor in PHA synthesis. Furthermore, 1H, 13C and 31P NMR metabolite analysis and mass spectrometry-based quantitative proteomics measurements suggested that the addition of benzoate stimulated oxidative-stress responses, enhanced glycerol consumption, and altered the intracellular NAD+/NADH and NADPH/NADP+ ratios by up-regulating the proteins involved in energy generation and storage processes, including the Entner–Doudoroff (ED) pathway, the reductive TCA route, trehalose degradation, fatty acid β-oxidation, and PHA biosynthesis. Conclusions This work demonstrated an effective co-carbon feeding strategy to improve PHA content/yield and convert lignin derivatives into value-added products in P. putida KT2440. Co-feeding lignin break-down products with other carbon sources, such as glycerol, has been demonstrated as an efficient way to utilize biomass to increase PHA production in P. putida KT2440. Moreover, the involvement of aromatic degradation favours further lignin utilization, and the combination of proteomics and metabolomics with NMR sheds light on the metabolic and regulatory mechanisms for cellular redox balance and potential genetic targets for a higher biomass carbon conversion efficiency.

Abstract Background Vesicular stomatitis (VS) is an acute, highly contagious and economically important zoonotic disease caused by the vesicular stomatitis virus (VSV). There is a need for effective and safe stable recombinant vaccine for the control of the disease. The human type 5 replication-defective adenovirus expression vector is a good way to construct recombinant vaccines. Results Three recombinant adenoviruses (rAd) were successfully constructed that expressed the VSV Indiana serotype glycoprotein (VSV-IN-G), VSV New Jersey serotype glycoprotein (VSV-NJ-G), and the G fusion protein (both serotypes of G [VSV-IN-G-NJ-G]) with potentiality to induce protective immunity. G proteins were successfully expressed with good immunogenicity. The rAds could induce the production of VSV antibodies in mice, and VSV neutralizing antibodies in goats, respectively. The neutralizing antibody titers could reach 1:32 in mice and 1:64 in goats. The rAds induced strong lymphocyte proliferation in mice and goats, which was significantly higher compared to the negative control groups. Conclusions The three rAds constructed in the study expressed VSV-G proteins and induced both humoral and cellular immune responses in mice and goats. These results lay the foundation for further studies on the use of rAds in vaccines expressing VSV-G.

Vulnerability assessment plays a crucial role in the management of complex and large-scale urban rail transit networks (URTNs). Even a temporary disruption may paralyze an entire public transportation network under a cascading failure. In the terms of vulnerability of the URTN, most studies have focused on changes in URTN topological characteristics and travel costs under disturbances, thereby neglecting the impact of alternative public transportation modes on passenger flow redistribution within the URTN. Therefore, in this study, considering the impact of changes in travel costs and modes on passenger flow redistribution, a novel model is proposed to analyze the cascading failure of weighted URTNs. Furthermore, adopting the estimated operation interruption time of the station (EOITS) to characterize the system disturbance intensity, the dynamic vulnerability of the URTN is simulated and analyzed. The results show that the EOITS exerts a major impact on the vulnerability of URTNs. With increasing of EOITS, the travel behavior of passengers becomes more diverse, and the process of cascading failure in URTNs also becomes more challenging to control. This research has implications for managers in terms of implementing of protective measures to mitigate the cascading failure risk and avert extreme catastrophes.

A man in his early 40s developed palpitations brought on by swallowing and was found to have short runs of atrial tachycardia induced by swallowing solid food. Atrial tachycardia during swallowing was documented on electrocardiography and 24-hour Holter monitoring. No structural heart disease or esophageal disorders were found by echocardiography. The patient then underwent an electrophysiological study and catheter ablation. We mapped the left atrium with a multipolar mapping catheter while the patient swallowed bread and found that the earliest endocardial breakthrough was on the left anterior superior atrium, where the left superior ganglionated plexus was located. We successfully eliminated the paroxysmal atrial tachycardia at this site. Interestingly, in the process of ablation, atrioventricular node reentrant tachycardia was triggered. After the slow-pathway ablation procedure, no further tachycardia was induced.

Microbial communities are an important component of aquatic ecosystems. They play active roles in the biogeochemical cycles of organic matter and nutrients to maintain the health and stability of aquatic ecosystems. In the present study, the shifts in microbial communities in overlying water of 15 shallow lakes with different trophic states in Hubei Province (China) were assessed using Illumina MiSeq sequencing technology. The results revealed that the proteobacteria to be the most abundant phylum in lakes with different trophic states. Mesotrophic lakes were found to be similar to moderately eutrophic lakes in terms of the microbial community composition, the interrelation between microbial communities, and expression level of metabolic pathways. In mesotrophic and moderately eutrophic lakes, Bacillus and Pseudomonas were the dominant genera in overlying water. In lakes with less eutrophication, the microbial diversity tended to be higher. Lightly eutrophic lakes had the most microbial species; however, the interaction between microorganisms was the weakest in these lakes and the internal steady-state balance of the lakes was most susceptible to being broken. These results indicate that lightly eutrophication may be one of the most unstable transition states in the eutrophication process. Particulate organic matter, chlorophyll-a, and ammonium nitrogen were the main drivers affecting the distribution of microbial communities in the overlying water of lakes with different trophic states. In addition, the correlation between microbial communities and lake trophic states was analyzed based on the bacterial eutrophic index (BEI). An obvious positive correlation was noted between BEI and the trophic level index (TLI), indicating that microbial communities could play a role as biological factors in the evaluation of lake trophic states along with other known physicochemical indicators.

Abstract Background To investigate the diagnostic value of arterial spin labeling (ASL) and intravoxel incoherent motion (IVIM) imaging in distinguishing nasopharyngeal carcinoma (NPC) in T1 stage from healthy controls (HC). Methods Forty-five newly diagnosed NPC patients in the T1 stage and thirty-one healthy volunteers who underwent MR examinations for both 3D pseudo-continuous ASL (pCASL) and IVIM were enrolled in this study. The Mann-Whitney test was used to compare the mean values of blood flow (BF) derived from pCASL and IVIM derived parameters, including apparent diffusion coefficient (ADC), pure molecular diffusion (D), pseudo-diffusion coefficient (D*) and perfusion fraction (f) between NPC tumor and benign nasopharyngeal mucosa of HC. Receiver Operating Characteristic (ROC) was performed to determine diagnostic cutoff and efficiency. The correlation coefficients among parameters were investigated using Spearman’s test. Results The NPC in the T1 stage showed higher mean BF, lower ADC, D, and f compared to benign nasopharyngeal mucosa (P < 0.001) with the area under curve of ROC of 0.742–0.996 (highest by BF). BF cutoff was set at > 36 mL/100 g/min; the corresponding sensitivity, specificity, and accuracy in differentiating NPC stage T1 from benign nasopharyngeal mucosa were 95.56% (43/45), 100% (31/31) and 97.37% (74/76), respectively. BF demonstrated moderate negative correlation with D* on HC (ρ [Spearman correlation coefficients] = − 0.426, P = 0.017). Conclusions ASL and IVIM could reflect the difference in perfusion and diffusion between tumor and benign nasopharyngeal mucosa, indicating a potential for accessing early diagnosis of NPC. Notably, BF, with a specificity of 100%, demonstrated better performance compared to IVIM in distinguishing malignant lesions from healthy tissue.

Abstract Background This study aimed to understand the association between socioeconomic status (SES) and Health Related Quality of Life (HRQoL) and the contribution of SES to health inequality among Tibetans of agricultural and pastoral areas (APA) in Tibet, China. Methods The data were from Health Survey of Tibetans in APA conducted in 2014. A total of 816 respondents were enrolled for the analysis Multiple linear regression was employed to examine the relationship between SES and HRQoL. Concentration index (CI) was used to measure the degree of health inequality and a Wagstaff-type CI decomposition method was applied to measure the contribution of SES to inequality. Results SES had significant association with HRQoL among the Tibetans in APA. The high SES group was more likely to have a higher Eq-5d index (0.77 vs. 0.67, P

Abstract Background Beckwith-Wiedemann syndrome (BWS) is a genetic overgrowth disorder with variable clinical features and cancer predisposition. In this study, we aim to characterize the clinical features and molecular defects of BWS patients in China. Methods Thirty-one patients with clinical suspicion of BWS were retrospectively recruited to the study from Shanghai Children’s Hospital between January 2014 and December 2017. Clinical data, including demographics, clinical features, and molecular testing results were extracted and systematically analyzed. Results Twenty-one patients with a BWS score ≥ 4 (6, IQR 4, 7) were clinically diagnosed with BWS, and 10 children with a BWS score ≥ 2 and

Vulnerability analysis is the premise of operational risk management and control for the large-scale and complex urban rail transit network (URTN) under the operation interruption of important stations. The temporary operation interruption of one station in an emergency may lead to the cascading failure and the paralysis of the whole URTN due to the load of other stations exceeding the limited capacity. The priority of important stations is proposed by combining its location and function in URTN. In addition, focusing on the analysis of the travel behaviour of passengers and the synergy of public transport networks, a novel cascading failure evolution model is established to simulate the cascading failure process of URTN under different attack scenarios. The vulnerability indicators are constructed to dynamically evaluate the vulnerability of URTN considering cascading failure evolution, which are different from the traditional vulnerability indicators based on complex network theory. Taking the Beijing urban rail transit network as an example, the dynamic simulation results show that the cascading failure of URTN is closely related to the temporal-spatial distribution of passenger flows and malicious attacks are more destructive than random attacks. Compared with the important stations with the largest betweenness or degree, the interrupted stations with largest intensity have a greater impact on the operational stability of URTN. Moreover, increasing the capacity coefficient of the station can reduce the vulnerability of URTN.

Background. AML (acute myeloid leukemia) is a common hematological malignancy in children with poor treatment effects and poor prognosis. Recent studies have shown that as a novel BRD4 (bromodomain containing 4) PROTACs (proteolysis targeting chimeras) degrader, GNE-987 can slow down the growth of various tumors and increase apoptosis, with promising clinical prospects. However, the function and molecular mechanism of GNE-987 in AML remain unclear. This study is aimed at investigating the therapeutic effect of GNE-987 on AML and its underlying mechanism. Methods. The association between BRD4 and AML was assessed by studying public databases. After GNE-987 was added to AML cells, cell proliferation slowed down, the cycle was disturbed, and apoptosis increased. Western blotting was used to detect BRD2 (bromodomain containing 2), BRD3 (bromodomain containing 3), BRD4, and PARP (poly ADP-ribose polymerase) proteins. The effect of GNE-987 on AML cells was analyzed in vivo. RNA-seq (RNA sequencing) and ChIP-seq (chromatin immunoprecipitation sequencing) validated the function and molecular pathways of GNE-987 in processing AML. Results. BRD4 expression was significantly elevated in pediatric AML samples compared with healthy donors. GNE-987 inhibited AML cell proliferation by inhibiting the cell cycle and inducing apoptosis. BRD2, BRD3, and BRD4 were consistent with decreased VHL (Von Hippel Lindau) expression in AML cells. In an AML xenograft model, GNE-987 significantly reduced the hepatosplenic infiltration of leukemia cells and increased the mouse survival time. Based on analysis of RNA-seq and ChIP-seq analyses, GNE-987 could target multiple SE- (super-enhancer-) related genes, including LYL1 (lymphoblastic leukemia 1), to inhibit AML. Conclusions. GNE-987 had strong antitumor activity in AML. GNE-987 could effectively inhibit the expression of SE-related oncogenes including LYL1 in AML. Our results suggested that GNE-987 had broad prospects in the treatment of AML.

In order to investigate the influence of typical hypervelocity gas effects on the gas lubrication performance of compliant foil face gas seal (CFFGS) end surfaces, the gas–elastic coupling lubrication theory model of CFFGS is modified by considering the choked flow and inertia effect, and the lubrication performance is solved using the finite difference method. Based on the choking effect, the effect of hypervelocity choked flow on the pressure field and velocity field of the seal is analyzed, and the influence of operating parameters on the choked flow and the mechanism of choked flow on the change in dynamic lubrication and sealing performance are explored. Furthermore, based on the inertia effect, the effect of gas inertia force on the flow field, and the correlation law between the pressure field and velocity field under the influence of operating parameters are studied. Then, the relationship between the inertia effect and sealing performance are analyzed. The results show that choked flow increases sealing outlet pressure significantly, from 0.1 MPa to a maximum of 14.25 MPa, and the sealing outlet flow velocity decreases by up to 50 times. The increase in medium pressure and balance film thickness aggravate the choking effect, resulting in a 20% maximum increase in opening force and a 99.6% maximum decrease in leakage rate. In addition, the inertia effect causes obvious centrifugal movement of the gas flow. As result, the radial flow velocity reduces by up to 50%, and the pressure distribution varies widely. Especially under high rotational speed and high medium pressure, the inertia effect is enhanced to clearly reduce the opening force (max. decrement of 3.5%) and leakage rate (max. decrement of 23%).

The mechanical properties of sandy soil depend on both the confining pressure and the state of compactness. Therefore, both the buried depth of the tunnel and the relative density of the sand are key factors that affect the ground deformation induced by the tunneling of a super-large-diameter shield. In this study, the parameters of the SANISAND constitutive model are first calibrated based on triaxial test data for Foshan silty fine sand. Then, based on the actual project, a two-dimensional finite-element analysis model is established to investigate the ground deformation induced by the tunneling of a super-large-diameter shield. The width and maximum value of the settlement trough, the volume loss ratio, and the deformation characteristics of the soil are summarized and analyzed for 13 cases. The results show that as the ratio of the buried depth to the diameter and the relative density of sand increases, the anti-disturbance ability of the sand layer to the tunnel construction increases and the volume loss ratio of the stratum reduces correspondingly. The denser the sand and the smaller the confining pressure of the soil around the tunnel, the more significant the shear-induced expansion of the sand at the tunnel haunch; this expansion partially makes up the volume loss caused by the tunnel excavation and reduces the loss ratio of the stratum at the arch crown.

Thiol-based post-translational modifications (PTMs) play a key role in redox-dependent regulation and signaling. Functional cysteine (Cys) sites serve as redox switches, regulated through multiple types of PTMs. Herein, we aim to characterize the complexity of thiol PTMs at the proteome level through the establishment of a direct detection workflow. The LC-MS/MS based workflow allows for simultaneous quantification of protein abundances and multiple types of thiol PTMs. To demonstrate its utility, the workflow was applied to mouse pancreatic β-cells (β-TC-6) treated with thapsigargin to induce endoplasmic reticulum (ER) stress. This resulted in the quantification of >9000 proteins and multiple types of thiol PTMs, including intra-peptide disulfide (S–S), S-glutathionylation (SSG), S-sulfinylation (SO2H), S-sulfonylation (SO3H), S-persulfidation (SSH), and S-trisulfidation (SSSH). Proteins with significant changes in abundance were observed to be involved in canonical pathways such as autophagy, unfolded protein response, protein ubiquitination pathway, and EIF2 signaling. Moreover, ~500 Cys sites were observed with one or multiple types of PTMs with SSH and S–S as the predominant types of modifications. In many cases, significant changes in the levels of different PTMs were observed on various enzymes and their active sites, while their protein abundance exhibited little change. These results provide evidence of independent translational and post-translational regulation of enzyme activity. The observed complexity of thiol modifications on the same Cys residues illustrates the challenge in the characterization and interpretation of protein thiol modifications and their functional regulation.

ObjectiveSuppression of bromodomain and extra terminal (BET) proteins has a bright prospect to treat MYC-driven tumors. Bromodomain containing 4 (BRD4) is one of the BET proteins. ARV-825, consisting of a BRD4 inhibitor conjugated with a cereblon ligand using proteolysis-targeting chimera (PROTAC) technology, was proven to decrease the tumor growth effectively and continuously. Nevertheless, the efficacy and mechanisms of ARV-825 in gastric cancer are still poorly understood.MethodsCell counting kit 8 assay, lentivirus infection, Western blotting analysis, Annexin V/propidium iodide (PI) staining, RNA sequencing, a xenograft model, and immunohistochemistry were used to assess the efficacy of ARV-825 in cell level and animal model.ResultsThe messenger RNA (mRNA) expression of BRD4 in gastric cancer raised significantly than those in normal tissues, which suggested poor outcome of patients with gastric cancer. ARV-825 displayed higher anticancer efficiency in gastric cancer cells than OTX015 and JQ1. ARV-825 could inhibit cell growth, inducing cell cycle block and apoptosis in vitro. ARV-825 induced degradation of BRD4, BRD2, BRD3, c-MYC, and polo-like kinase 1 (PLK1) proteins in four gastric cancer cell lines. In addition, cleavage of caspase 3 and poly-ADP-ribose polymerase (PARP) was elevated. Knockdown or overexpression CRBN could increase or decrease, respectively, the ARV-825 IC50 of gastric cancer cells. ARV-825 reduced MYC and PLK1 expression in gastric cancer cells. ARV-825 treatment significantly reduced tumor growth without toxic side effects and downregulated the expression of BRD4 in vivo.ConclusionsHigh mRNA expression of BRD4 in gastric cancer indicated poor prognosis. ARV-825, a BRD4 inhibitor, could effectively suppress the growth and elevate the apoptosis of gastric cancer cells via transcription downregulation of c-MYC and PLK1. These results implied that ARV-825 could be a good therapeutic strategy to treat gastric cancer.

Protein S-glutathionylation (SSG) is a reversible post-translational modification (PTM) featuring the conjugation of glutathione to a protein cysteine thiol. SSG can alter protein structure, activity, subcellular localization, and interaction with small molecules and other proteins. Thus, it plays a critical role in redox signaling and regulation in various physiological activities and pathological events. In this review, we summarize current biochemical and analytical approaches for characterizing SSG at both the proteome level and at individual protein levels. To illustrate the mechanism underlying SSG-mediated redox regulation, we highlight recent examples of functional and structural consequences of SSG modifications. Finally, we discuss the analytical challenges in characterizing SSG and the thiol PTM landscape, future directions for understanding of the role of SSG in redox signaling and regulation and its interplay with other PTMs, and the potential role of computational approaches to accelerate functional discovery.

The Joule heating behavior of the carbon fiber/epoxy composite (CF/EP) was studied in this work, as well as their influence on the in-situ mechanical properties of the composites and their de-icing performance. The equilibrium temperature of the CF/EP composite could be conveniently adjusted by tuning the current according to the Joule’s law. Dynamic mechanical analysis (DMA) tests indicated that the rigidity and stiffness of the fiber-reinforced composite decreased with increasing temperature, and the glass transition temperature (Tg) of the composites was around 104 °C. It was found that the flexural properties of the composites in situ, measured under the electric-current loading, depended on the current value in the range of room temperature to Tg. With increasing the loading current, either the flexural modulus or strength of CF/EP decreased gradually. Such results could be explained that the higher current loading, the larger Joule heat, led to the higher operating temperature of the composite samples and the evolution of their mechanical properties accordingly. Vickers hardness tests indicated that the micro-hardness of the composite decreased with the increase of the operating temperature, which coincided with the evolution of its flexural properties with the electric-current loading. The dependence of the failure behaviors of the CF/EP on the loading current was revealed by the analysis of their fractured surface, where micro-buckling, kinking, fiber pull-out and breakage were involved. A preliminary study indicated that less energy was consumed for the deicing of the same amount of the ice with the CF/EP composite in the case of less electric-current loading. The research on the Joule heating effect of CF/EP and their corresponding mechanical properties benefits the design and direct application of the composites under the electric-current loading.

In this work, the effect of a hydrothermal environment on mechanical properties and the electrical response behavior of continuous carbon fiber/epoxy (CFRE) composite produced by the pultrusion method were investigated. Due to the relatively uniform distribution of fibers and lack of resin-rich interlayer area, this effect for the pultruded CFRE composite plates is different from the common CFRE laminated composites. Firstly, its hygroscopicity behavior was studied. The absorption ratio increases rapidly to 1.02% within 3 days before reaching a relatively stable state. A three-point bending test, a Vickers hardness test, a thermogravimetric analysis (TGA), and a scanning electron microscope (SEM) analysis were performed to investigate the effect of the hydrothermal environment on the mechanical properties and thermal stability of the CFRE composite. The results indicated that the bending strength decreased quickly within 3 days of hydrothermal treatment, followed by a stable trend, which coincided with that of the hygroscopicity behavior of the composites. The fracture surface analysis indicated that the interfacial properties of carbon fibers in the epoxy matrix were decreased after the hydrothermal treatment, and more carbon fibers could be pulled out from the CFRE in the hygroscopic state. After the hydrothermal treatment, the micro-hardness of the composites was reduced by 25%. TGA confirmed the decreased thermal stability of the CFRE composites after the hydrothermal treatment as well. Moreover, the hydrothermally treated CFRE composites could a reach stable resistance response more readily. The revealing of the effect of moisture and hot environment on the mechanical properties and electrical response behavior of pultruded CFRE composites prepares the ground for their design and practical application in the corresponding environment.

Concrete is the main material in building. Since its poor structural integrity may cause accidents, it is significant to detect defects in concrete. However, it is a challenging topic as the unevenness of concrete would lead to the complex dynamics with uncertainties in the ultrasonic diagnosis of defects. Note that the detection results mainly depend on the direct parameters, e.g., the time of travel through the concrete. The current diagnosis accuracy and intelligence level are difficult to meet the design requirement for automatic and increasingly high-performance demands. To solve the mentioned problems, our contribution of this paper can be summarized as establishing a diagnosis model based on the GA-BPNN method and ultrasonic information extracted that helps engineers identify concrete defects. Potentially, the application of this model helps to improve the working efficiency, diagnostic accuracy and automation level of ultrasonic testing instruments. In particular, we propose a simple and effective signal recognition method for small-size concrete hole defects. This method can be divided into two parts: (1) signal effective information extraction based on wavelet packet transform (WPT), where mean value, standard deviation, kurtosis coefficient, skewness coefficient and energy ratio are utilized as features to characterize the detection signals based on the analysis of the main frequency node of the signals, and (2) defect signal recognition based on GA optimized back propagation neural network (GA-BPNN), where the cross-validation method has been used for the stochastic division of the signal dataset and it leads to the BPNN recognition model with small bias. Finally, we implement this method on 150 detection signal data which are obtained by the ultrasonic testing system with 50 kHz working frequency. The experimental test block is a C30 class concrete block with 5, 7, and 9 mm penetrating holes. The information of the experimental environment, algorithmic parameters setting and signal processing procedure are described in detail. The average recognition accuracy is 91.33% for the identification of small size concrete defects according to experimental results, which verifies the feasibility and efficiency.

Owing to its broad-spectrum antivirus activities, interferon (IFN) is an important alternative agent for use in the treatment of hepatitis B virus (HBV)-infected patients; however, the mechanism involved in the inhibition of HBV infection and replication by IFN remains unclear. We previously reported that the induction of TRIM5γ is important in the IFN treatment of HBV patients as it promotes the degradation of the HBx protein, while the manner in which TRIM5γ is induced by IFN and how TRIM5γ interacts with HBx remain unestablished until date. Our present findings confirmed the TRIM5γ-HBx-DDB1 interactions in the HBV-infected Primary human hepatocytes (PHH), and we further found that STAT3, and not STAT1, was responsible for the induction of TRIM5γ upon IFN stimulation and that the zinc binding site His123 on the BBOX domain was a decisive site in the interaction between TRIM5γ BBOX and HBx. In addition, based on the BBOX domain, we detected a 7-amino acid peptide with the potential of promoting HBx degradation and inhibiting HBV replication. On the other hand, we noted that the TRIM5γ expression was inhibited by HBV in chronically HBV infected patients. Thus, our study identified the crucial role of STAT3 in the induction of TRIM5γ, as well as proposed a 7-amino acid, small peptide as a potential candidate for the development of therapeutic agents targeting HBx.

BackgroundEEF1E1 has been reported to play a role in ovarian cancer, breast cancer, non-small cell lung cancer and other cancers, but its role and mechanism in hepatocellular carcinoma (HCC) are still unknown.MethodsEEF1E1 expression in human HCC was analyzed via the GTEx and TCGA database. Logistic regression analysis was used to analyze the clinicopathological correlation of EEF1E1 expression. The correlation between EEF1E1 expression and patients’ prognosis was analyzed in HCC, shown by forest plots, nomogram and Kaplan–Meier curves. Hazard ratio (HR) with 95% confidence intervals and log-rank p-value were calculated via multivariate/univariate survival analyses. Moreover, the correlation between EEF1E1 and tumor immune infiltration was analyzed using the gsva package with the ssgsea algorithm. Pearson correlation was used to investigate the correlation between EEF1E1 expression and p53 pathway genes expression. Two third-party databases were used to validate the content of EEF1E1 protein and mRNA expression patterns and prognosis analysis. The immunohistochemistry and multiplex immunohistochemistry was used to verify the bio-informatics results.ResultsEEF1E1 mRNA and protein expression in tumor was statistically higher than normal (EEF1E1 mRNA: p < 0.001; EEF1E1 protein: p < 0.01). Results from paired t-test (cancer and adjacent tissues) exhibited consistent trend (t = 7.572, p < 0.001). Immunohistochemistry showed that EEF1E1 is highly expressed in cancer. The expression of EEF1E1 was positively correlated with body weight, BMI, tumor status, vascular invasion, AFP, logistic grade, T stage and pathological stage. The univariate Cox model revealed that high EEF1E1 expression was strongly associated with worse OS (HR=2.581; 95% CI: 1.782-3.739; p < 0.001), as was T stage, pathologic stage, Histologic grade. High EEF1E1 expression was the only independent prognostic factor associated with OS (HR=2.57; 95% CI: 1.715-3.851; p < 0.001) in the multivariate analysis. EEF1E1 was significantly correlated with various immune cells, including cytotoxic cells, DC, macrophages, neutrophils, NK cd56bright, TFH, Tgd, Th17, Th2, Treg. Multiplex immunohistochemistry showed that the EEF1E1 protein level is positively correlated to the CD3, CD4, PD1 and is negatively correlated to the CD8. The expression level of EEF1E1 in HCC was significantly correlated with the key genes involved in the p53 pathway. The expression of EEF1E1, ATM, p53 and CASPASE3 in HCC tissues was significantly higher than that in adjacent tissues.ConclusionEEF1E1 is highly expressed in cancer tissues in HCC. EEF1E1’s high expression is significantly correlated with worse prognosis and immune cell infiltration of HCC. EEF1E1 may be participating in EEF1E1/ATM/p53 signaling pathway in HCC.

Although vaccine resources are being distributed worldwide, insufficient vaccine production remains a major obstacle to herd immunity. In such an environment, the cases of re-positive occurred frequently, and there is a big controversy regarding the cause of re-positive episodes and the infectivity of re-positive cases. In this case-control study, we tracked 39 patients diagnosed with COVID-19 from the Jiaodong Peninsula area of China, of which 7 patients tested re-positive. We compared the sex distribution, age, comorbidities, and clinical laboratory results between normal patients and re-positive patients, and analysed the correlation between the significantly different indicators and the re-positive. Re-positive patients displayed a lower level of serum creatinine (63.38 ± 4.94 U/L vs. 86.82 ± 16.98 U/L; P =0.014) and lower albumin (34.70 ± 5.46 g/L vs. 41.24 ± 5.44 g/L, P =0.039) at the time of initial diagnosis. In addition, two positive phases and the middle negative phase in re-positive patients with significantly different eosinophil counts (0.005 ± 0.005 × 109/L; 0.103 ± 0.033 × 109/L; 0.007 ± 0.115 × 109/L; Normal range: 0.02-0.52 × 109/L). The level of eosinophils in peripheral blood can be used as a marker to predict re-positive in patients who once had COVID-19.

This paper proposes a novel gas journal bearing in which orifices are different in diameter and distribute unevenly. Finite Difference Method (FDM) combined with Linear Perturbation Method (LPM) is used to solve the unsteady-state Reynolds equation of the flow field in the bearing clearance. Moreover, four types of bearing structures are used to discuss the effects of orifices different in diameter and uneven distribution on the bearing performance. The results demonstrate that the new bearing has better static and dynamic performances compared with those of traditional bearing in which orifices are equal in diameter and distribute evenly. Moreover, thin gas film thickness, high supply pressure, and large eccentricity ratio are hopeful for improving load capacity of the new bearing. Furthermore, the stability of the novel bearing is improved if eccentricity ratio is 0.25–0.3.

Abstract Background Molecular characteristics of CpG island methylator phenotype (CIMP) in colorectal cancer (CRC) have been well documented in Western, but not in Chinese, populations. Methods We investigated the incidence of CIMP, BRAF/KRAS mutation, and microsatellite instability (MSI) in a Chinese population with CRC (n = 401) and analysed associations between CIMP status and clinicopathological and molecular features. Results A total of 41 cases, 310 cases, and 40 cases were classified as CIMP-high, CIMP-low, and CIMP-negative, respectively. We detected a significantly low incidence of BRAF mutation in adenomas (2%) and CRC (0.7%), and a relatively low incidence of KRAS mutation (24.9%) compared with that in other populations. We also detected a relatively low incidence of CIMP-high (10.2%), which was significantly associated with younger age (≤49 years of age), female sex, and proximal tumour location. Conclusions This study revealed unique characteristics of CIMP in a Chinese population with colorectal cancer. Developing specific CIMP markers based on unique populations or ethnic groups will further help to fully elucidate CIMP pathogenesis.