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Abstract Background Insulin like growth factor II mRNA binding protein 3 (IGF2BP3) has been implicated in numerous inflammatory and cancerous conditions. However, its precise molecular mechanisms in endometriosis (EMs) remains unclear. The aim of this study is to examine the influence of IGF2BP3 on the occurrence and progression of EMs and to elucidate its underlying molecular mechanism. Methods Efects of IGF2BP3 on endometriosis were confrmed in vitro and in vivo. Based on bioinformatics analysis, RNA immunoprecipitation (RIP), RNA pull-down assays and Fluorescent in situ hybridization (FISH) were used to show the association between IGF2BP3 and UCA1. Single-cell spatial transcriptomics analysis shows the expression distribution of glutaminase 1 (GLS1) mRNA in EMs. Study the effect on glutamine metabolism after ectopic endometriotic stromal cells (eESCs) were transfected with Sh-IGF2BP3 and Sh-UCA1 lentivirus. Results Immunohistochemical staining have revealed that IGF2BP3 was upregulated in ectopic endometriotic lesions (EC) compared to normal endometrial tissues (EN). The proliferation and migration ability of eESCs were greatly reduced by downregulating IGF2BP3. Additionally, IGF2BP3 has been observed to interact with urothelial carcinoma associated 1 (UCA1), leading to increased stability of GLS1 mRNA and subsequently enhancing glutamine metabolism. Results also demonstrated that IGF2BP3 directly interacts with the 3’ UTR region of GLS1 mRNA, influencing its expression and stability. Furthermore, UCA1 was able to bind with c-MYC protein, stabilizing c-MYC mRNA and consequently enhancing GLS1 expression through transcriptional promotion. Conclusion These discoveries underscored the critical involvement of IGF2BP3 in the elevation and stability of GLS1 mRNA in the context of glutamine metabolism by interacting with UCA1 in EMs. The implications of our study extended to the identification of possible therapeutic targets for individuals with EMs.

In aquaculture, quantifying the real-time feeding behaviour of fish is essential for making feeding decisions. However, most existing methods for assessing fish appetite are inefficient and subjective. To address these issues, this study proposes an improved tilapia feeding level classification model with ResNet34. First, we introduce the attention module CBAM into the ResNet34 model to adjust the attention of the model according to the importance of different channel features and enhance the effective extraction of important features. We then used migration learning to transfer the knowledge learned from the source data (ImageNet dataset) to the tilapia ingestion image dataset, which allowed us to train the tilapia ingestion behaviour classification model faster while retaining the pre-trained model. Experimental results showed that the improved ResNet34 model in this study achieved an accuracy of 99.72%, an improvement of 7.84 percentage points over the original model. In addition, the model outperformed models such as MobileNetV2, AlexNet, VGG11, ShuffleNet_v2_x0_5 and ResNet18 in terms of accuracy, precision, recall and F1 scores.These results suggest that the proposed method can accurately identify feeding behavior of fish and provide a scientific basis for determining feeding amounts.

Although exercise training has been shown to enhance neurological function, there is a shortage of research on how exercise training affects the temporal-spatial synchronization properties of functional networks, which are crucial to the neurological system. This study recruited 23 professional and 24 amateur dragon boat racers to perform simulated paddling on ergometers while recording EEG. The spatiotemporal dynamics of the brain were analyzed using microstates and omega complexity. Temporal dynamics results showed that microstate D, which is associated with attentional networks, appeared significantly altered, with significantly higher duration, occurrence, and coverage in the professional group than in the amateur group. The transition probabilities of microstate D exhibited a similar pattern. The spatial dynamics results showed the professional group had lower brain complexity than the amateur group, with a significant decrease in omega complexity in the α (8–12 Hz) and β (13–30 Hz) bands. Dragon boat training may strengthen the attentive network and reduce the complexity of the brain. This study provides evidence that dragon boat exercise improves the efficiency of the cerebral functional networks on a spatiotemporal scale.

Objectives: This study aimed to develop and validate a radiomics nomogram based on multiparameter MRI for preoperative differentiation of type II and type I endometrial carcinoma (EC). Methods: A total of 403 EC patients from two centers were retrospectively recruited (training cohort, 70 %; validation cohort, 30 %). Radiomics features were extracted from T2-weighted imaging, dynamic contrast-enhanced T1-weighted imaging at delayed phase(DCE4), and apparent diffusion coefficient (ADC) maps. Following dimensionality reduction, radiomics models were developed by logistic regression (LR), random forest (RF), bootstrap aggregating (Bagging), support vector machine (SVM), artificial neural network (ANN), and naive bayes (NB) algorithms. The diagnostic performance of each radiomics model was evaluated using the ROC curve. A nomogram was constructed by incorporating the optimal radiomics signatures with significant clinical-radiological features and immunohistochemistry (IHC) markers obtained from preoperative curettage specimens. The diagnostic performance and clinical value of the nomogram were evaluated using ROC curves, calibration curves, and decision curve analysis (DCA). Results: Among the radiomics models, the NB model, developed from 12 radiomics features derived from ADC and DCE4 sequences, exhibited strong performance in both training and validation sets, with the AUC values of 0.927 and 0.869, respectively. The nomogram, incorporating the radiomics model with significant clinical-radiological features and IHC markers, demonstrated superior performance in both the training (AUC = 0.951) and the validation sets (AUC = 0.915). Additionally, it exhibited excellent calibration and clinical utility. Conclusions: The radiomics nomogram has great potential to differentiate type II from type I EC, which may be an effective tool to guide clinical decision-making for EC patients.

Abstract In this study, we investigated the effect of Hippophae rhamnoides L. (HRP) on the activity of CYP2D6 via the CAMP/PKA/NF-κB pathway in rats with Bacille Calmette–Guerin (BCG)-induced immunological liver injury. BCG (125 mg/kg) was injected to establish the rat model of liver injury. HRP was administered intragastrically for one week as the intervention drug. Proteomics techniques were used to analyze protein expression levels, obtaining a comprehensive understanding of the liver injury process. ELISA or western blotting was used to detect specific protein levels. Dextromethorphan was detected using high-performance liquid chromatography to reflect the metabolic activity of CYP2D6. BCG downregulated the expression of CYP2D6, cAMP, PKA, IκB, and P-CREB and upregulated that of NF-κB, IL-1β, TNF-α, and CREB in the liver; HRP administration reversed these effects. Therefore, HRP may restore the metabolic function of the liver by reversing the downregulation of CYP2D6 through inhibition of NF-κB signal transduction and regulation of the cAMP/PKA/CREB/CYP2D6 pathway. These findings highlight the role of HRP as an alternative clinical drug for treating hepatitis B and other immune-related liver diseases.

Abstract Endometriosis is a gynecological inflammatory disease that is linked with immune cells, specifically macrophages. IL-33 secreted from macrophages is known to accelerate the progression of endometriosis. The periodic and repeated bleeding that occurs in women with endometriosis leads to excess iron in the microenvironment that is conducive to ferroptosis, a process related to intracellular ROS production, lipid peroxidation and mitochondrial damage. It is suggested that eESCs may specifically be able to inhibit ferroptosis. However, it is currently unclear whether IL-33 directly regulates ferroptosis to influence the disease course in endometriosis. In this study, eESCs co-cultured with macrophages or stimulated with IL-33/ST2 were observed to have increased cell viability and migration. Additionally, IL-33/ST2 decreased intracellular iron levels and lipid peroxidation in eESCs exposed to erastin treatment. Furthermore, IL-33/ST2 treatment resulted in a notable upregulation in SLC7A11 expression in eESCs due to the downregulation of negative transcription factor ATF3, thereby suppressing ferroptosis. The P38/JNK pathway activated by IL-33/ST2 was also found to inhibit the transcription factor ATF3. Therefore, we concluded that IL-33/ST2 inhibits the ATF3-mediated reduction in SLC7A11 transcript levels via the P38/JNK pathway. The findings reveal that macrophage-derived IL-33 upregulates SLC7A11 in eESCs through the p38/JNK/ATF3 pathway, ultimately resulting in protection against ferroptosis in eESCs. Moreover, we conducted an experiment using endometriosis model mice that showed that a combination of IL-33-Ab and erastin treatment alleviated the disease, showing the promise of combining immunotherapy and ferroptosis therapy.

Abstract Background There are few studies on acute-on-chronic liver failure (ACLF) in patients with recompensated cirrhosis. This study was aimed to investigate the clinical features of ACLF patients with recompensated cirrhosis. Methods A total of 461 ACLF patients were enrolled and divided into three groups: compensated, recompensated, and decompensated cirrhosis with ACLF. The baseline clinical data and 1-year survival rates were compared among the three groups. Results Compared with the decompensated group, in the recompensated group, the levels of hemoglobin, albumin, and serum sodium were significantly higher and the white blood cell count, international normalized ratio, and incidence of respiratory failure were significantly lower; there were no evident differences in other organ failures. The proportion of patients with ACLF grade 3 and 1-year survival rates significantly differed between the two groups. Conversely, compared with the compensated group, in the recompensated group, the platelet and total bilirubin levels were significantly lower and the proportion of patients with ACLF grade 1 was significantly higher. However, other clinical indicators or 1-year survival rates did not significantly differ between the two groups. Conclusions Compared with patients who developed ACLF with decompensated cirrhosis, those who developed ACLF with recompensated cirrhosis had a less severe condition, lower incidence of respiratory failure, and better 1-year prognosis. However, the baseline clinical features and prognosis were similar between ACLF patients with recompensated and compensated cirrhosis. Trial registration Chinese clinical trials registry: ChiCTR1900021539.

Heme biosynthesis is a highly conserved pathway from bacteria to higher animals. Heme, which serves as a prosthetic group for various enzymes involved in multiple biochemical processes, is essential in almost all species, making heme homeostasis vital for life. However, studies on the biological functions of heme in filamentous fungi are scarce. In this study, we investigated the role of heme in Fusarium graminearum. A mutant lacking the rate-limiting enzymes in heme synthesis, coproporphyrinogen III oxidase (Cpo) or ferrochelatase (Fc), was constructed using a homologous recombination strategy. The results showed that the absence of these enzymes was lethal to F. graminearum, but the growth defect could be rescued by the addition of hemin, so we carried out further studies with the help of hemin. The results demonstrated that heme was required for the activity of FgCyp51, and its absence increased the sensitivity to tebuconazole and led to the upregulation of FgCYP51 in F. graminearum. Additionally, heme plays an indispensable role in the life cycle of F. graminearum, which is essential for vegetative growth, conidiation, external stress response (especially oxidative stress), lipid accumulation, fatty acid β-oxidation, autophagy, and virulence.

Cold chain logistics are crucial for reducing agricultural product loss, yet the environmental impact of energy and packaging consumption, among others, demands attention, making the search for eco-friendly development modes essential. Based on data from 30 provinces in China from 2015 to 2021, this study analyzes the basic correlation between the development of cold chain logistics of fresh agricultural products (CCLFAP) and the ecological environment (EE) by using a random forest regression model in comparison with the XGBoost model. Correlation heatmaps were used to analyze the relationships between the cold chain logistics of fresh agricultural products and various factors of the ecological environment. The generalized additive model was then used to establish the connection between cold chain logistics and the ecological environment, identifying significant factors impacting EE. The results demonstrate that a higher development level of cold chain logistics corresponds to a better development trend of EE. The economic efficiency and technical aspects of cold chain logistics for fresh agricultural products are closely related to ecological pressures and responses. The number of employees in the logistics industry, the trading volume of fresh agricultural products, the number of refrigerated vehicles, and the capacity of the cold room have significant positive correlations with the ecological environment, while the per capita consumption of fresh agricultural products, the number of cold chain logistics patent applications, and the road density had significant negative correlations with the ecological environment. The effects of the number of cold chain logistics enterprises and the freight turnover of agricultural products transported by the cold chain on the ecological environment fluctuated. These findings contribute to reducing climate and environmental emergencies throughout the life cycle, offering sustainable development solutions for the fresh agricultural product cold chain logistics industry.

Leucine-rich repeat receptor-like proteins (LRR-RLPs), a major group of receptor-like proteins in plants, have diverse functions in plant physiology, including growth, development, signal transduction, and stress responses. Despite their importance, the specific roles of kiwifruit LRR-RLPs in response to biotic and abiotic stresses remain poorly understood. In this study, we performed family identification, characterization, transcriptome data analysis, and differential gene expression analysis of kiwifruit LRR-RLPs. We identified totals of 101, 164, and 105 LRR-RLPs in Actinidia chinensis ‘Hongyang’, Actinidia eriantha ‘Huate’, and Actinidia chinensis ‘Red5’, respectively. Synteny analysis revealed that the expansion of kiwifruit LRR-RLPs was primarily attributed to segmental duplication events. Based on RNA-seq data from pathogen-infected kiwifruits, we identified specific LRR-RLP genes potentially involved in different stages of pathogen infection. Additionally, we observed the potential involvement of kiwifruit LRR-RLPs in abiotic stress responses, with upstream transcription factors possibly regulating their expression. Furthermore, protein interaction network analysis unveiled the participation of kiwifruit LRR-RLP in the regulatory network of abiotic stress responses. These findings highlight the crucial roles of LRR-RLPs in mediating both biotic and abiotic stress responses in kiwifruit, offering valuable insights for the breeding of stress-resistant kiwifruit varieties.

Rapid detection of heparin-binding protein (HBP) is essential for timely intervention in sepsis cases. Current detection techniques are usually antibody-based immunological methods, which have certain problems, such as complexity and slow detection, and fall short in meeting the urgency of clinical needs. The application of an aptamer can address these concerns well. In this study, HBP-specific DNA aptamers were screened first. Among which, Apt-01, Apt−02, and Apt−13 had a high affinity for HBP, exhibiting impressive KD values of 3.42, 1.44, and 1.04 nmol/L, respectively. Then, the aptamer of HBP and its partially complementary primer probe were combined to form double-stranded DNA (dsDNA) and synthesize a circular DNA template. The template is complementary to the primer probe, but due to the presence of dsDNA, ExoIII cleaves C2-13 as an RCA primer probe, rendering the template unable to recognize the primer probe and preventing the RCA reaction from proceeding. When the target is present, it competes with the adapter for recognition and releases C2-13, exposing its 3′ end. After initiating the RCA at room temperature and reacting with SYBR GreenII at 37 °C for 20 min, fluorescence changes can be observed and quantitatively analyzed at a 530 nm wavelength, achieving quantitative biological analysis. Apt-01 was used to develop a fluorescent biosensor for HBP detection, which exhibited a good linear range (0.01 nmol/L to 10 nmol/L) and detection limit (0.0056 nmol/L). This advancement holds the potential to lay a solid groundwork for pioneering sensitive and specific methods for HBP detection and to significantly enhance the diagnostic processes for sepsis.

In order to reduce the environmental pressure caused by petroleum based packaging materials, the development of natural and environmentally friendly soybean protein based food packaging film has become a hot research topic. This paper searched research papers on soy protein based food packaging films from 1990 to 2021 in the Web of Science (WOS), visualized 1318 related articles by using scientific knowledge mapping tool CiteSpace5.8.R3, deeply discussed and analyzed the research hotspots and development trends of soybean protein based food packaging film combined with the method of literature and quantitative analysis. The results showed that the research process of soybean protein based food packaging film could be divided into three stages: Initial, steady and accelerated development, and now it was in the accelerated development stage. China ranked first in the number of publications, reflecting its huge development potential in this field. The betweenness value of the United States was 0.59, indicating that it had a strong scientific research strength. Food Hydrocolloids was a leading journal in this field. The modification of soybean protein based food packaging film and its application in food packaging are the promising research topics, and it tends to develop green food packaging film with natural bioactive compounds in the future.

Abstract Identifying patients that are likely to respond to cancer immunotherapy is an important, yet highly challenging clinical need. Using 3139 patients across 17 different cancer types, we comprehensively studied the ability of two common copy-number alteration (CNA) scores—the tumor aneuploidy score (AS) and the fraction of genome single nucleotide polymorphism encompassed by copy-number alterations (FGA)—to predict survival following immunotherapy in both pan-cancer and individual cancer types. First, we show that choice of cutoff during CNA calling significantly influences the predictive power of AS and FGA for patient survival following immunotherapy. Remarkably, by using proper cutoff during CNA calling, AS and FGA can predict pan-cancer survival following immunotherapy for both high-TMB and low-TMB patients. However, at the individual cancer level, our data suggest that the use of AS and FGA for predicting immunotherapy response is currently limited to only a few cancer types. Therefore, larger sample sizes are needed to evaluate the clinical utility of these measures for patient stratification in other cancer types. Finally, we propose a simple, non-parameterized, elbow-point-based method to help determine the cutoff used for calling CNAs.

PurposesA meta-analysis was conducted to examine the differences in heart rate variability (HRV) between depressed patients and healthy individuals, with the purpose of providing a theoretical basis for the diagnosis of depression and the prevention of cardiovascular diseases.MethodsTo search China National Knowledge Infrastructure (CNKI), WanFang, VIP, PubMed, Web of Science, Science Direct, and Cochrane Library databases to collect case–control studies on HRV in depressed patients, the retrieval date is from the establishment of the database to December 2022. Effective Public Health Practice Project (EPHPP) scale was used to evaluate literature quality, and Stata14.0 software was used for meta-analysis.ResultsThis study comprised of 43 papers, 22 written in Chinese and 21 in English, that included 2,359 subjects in the depression group and 3,547 in the healthy control group. Meta-analysis results showed that compared with the healthy control group, patients with depression had lower SDNN [Hedges’ g = −0.87, 95% CI (−1.14, −0.60), Z = −6.254, p

The extent of immune-mediated hepatic damage (such as in viral hepatitis) is characterised by the downregulation of cytochrome P450s (CYPs), a class of drug-metabolising enzymes. However, whether this downregulation aids liver cells in maintaining their homeostasis or whether the damage is aggravated remains largely unexplored. Herein, we evaluated the effects of phosphorylation mediated by the protein kinase C (PKC)/cAMP-response element binding protein (CREB) and nitration mediated by inducible nitric oxide synthase (iNOS) on the downregulation of CYP2E1 during immune-mediated liver injury. Additionally, we investigated the regulatory mechanism mediated by the nuclear factor κB (NF-κB). The rat model of immune-mediated liver injury was replicated by administering a single i.v. injection of Bacillus Calmette–Guerin (BCG, 125 mg/kg) vaccine and three i.p. injections of ammonium pyrrolidine dithiocarbamate (25, 50, 100 mg/kg/d, days 11, 12, and 13); blood was then collected on day 14. Subsequently, the livers were extracted to identify the different pharmacokinetic and biochemical indicators involved in the process. Our study reports new findings on the dependence between PKC-mediated CREB phosphorylation in the anti-inflammatory pathway and nitration emergency induced by iNOS in pro-inflammatory pathways in the NF-κB pathway. The interaction of these two pathways leads to the downregulation and recovery of CYP2E1, thus alleviating inflammation and nitration stress. Our results confirm that BCG-mediated downregulation of CYP2E1 is linked to iNOS-induced nitration and PKC/NF-κB-mediated CREB phosphorylation, and that NF-κB is an important molecular target in this process. These findings suggest that the downregulation of CYP2E1 may be an autonomous process characteristic of liver cells, helping them adapt to environmental changes, alleviate further hypoxia in inflamed tissues, and minimise exposure to toxic and harmful metabolites.

Abstract Background Early detection of pancreatic ductal adenocarcinoma (PDAC) may improve the prognosis of patients. This study was to identify metabolic features of PDAC and to discover early detection biomarkers for PDAC by tissue and serum metabolomics analysis. Methods We conducted nontargeted metabolomics analysis in tissue samples of 51 PDAC tumors, 40 noncancerous pancreatic tissues (NT), and 14 benign pancreatic neoplasms (BP) as well as serum samples from 80 patients with PDAC, 36 with BP, and 48 healthy controls (Ctr). The candidate metabolites identified from the initial analysis were further quantified using targeted analysis in serum samples of an independent cohort of 22 early stage PDAC, 27 BP, and 27 Ctr subjects. Unconditional binary logistic regression analysis was used to construct the optimal model for PDAC diagnosis. Results Upregulated levels of fatty acids and lipids and downregulated amino acids were observed in tissue and serum samples of PDAC patients. Proline, creatine, and palmitic acid were identified as a panel of potential biomarkers to distinguish PDAC from BP and Ctr (odds ratio = 2.17, [95% confidence interval 1.34–3.53]). The three markers showed area under the receiver‐operating characteristic curves (AUCs) of 0.854 and 0.865, respectively, for the comparison of PDAC versus Ctr and PDAC versus BP. The AUCs were 0.830 and 0.852 in the validation set and were improved to 0.949 and 0.909 when serum carbohydrate antigen 19‐9 (CA19‐9) was added to the model. Conclusion The novel metabolite biomarker panel identified in this study exhibited promising performance in distinguishing PDAC from BP or Ctr, especially in combination with CA19‐9.

Abstract We developed a continuous learning system (CLS) based on deep learning and optimization and ensemble approach, and conducted a retrospective data simulated prospective study using ultrasound images of breast masses for precise diagnoses. We extracted 629 breast masses and 2235 images from 561 cases in the institution to train the model in six stages to diagnose benign and malignant tumors, pathological types, and diseases. We randomly selected 180 out of 3098 cases from two external institutions. The CLS was tested with seven independent datasets and compared with 21 physicians, and the system’s diagnostic ability exceeded 20 physicians by training stage six. The optimal integrated method we developed is expected accurately diagnose breast masses. This method can also be extended to the intelligent diagnosis of masses in other organs. Overall, our findings have potential value in further promoting the application of AI diagnosis in precision medicine.

In intensive aquaculture systems, accurate water temperature prediction is crucial for aquaculture efficiency. Traditional prediction models often have limitations in dealing with strongly coupled, nonlinear, and time-varying water temperature data. A novel hybrid model for temperature prediction is proposed to improve prediction generalization ability and robustness. The model integrates advanced data processing and prediction techniques. Firstly, the VMD method is utilized to achieve effective data decomposition and noise reduction. Secondly, the CNN algorithm is applied to achieve feature extraction of the data. Finally, the bi-directional LSTM and self-concerned combination are used to obtain the final prediction results. The experimental results show that the MAE, RMSE, MSE, MAPE, and R2 of the VMD-CNN-BILSTM-SA combination prediction model proposed in this paper are 0.016, 0.143, 0.020, 0.035, and 0.978, respectively. Compared with other deep learning models, the BiLSTM model presented in this paper improves the R2 by 13.2% compared with LSTM and 13.7% over the GRU model. This study can be applied in fishery farming, which can reduce the risk of farming and promote the modernization of fishery.

Dissolved oxygen content is a key indicator of water quality in aquaculture environment. Because of its nonlinearity, dynamics, and complexity, which makes traditional methods face challenges in the accuracy and speed of dissolved oxygen content prediction. As a solution to these issues, this study introduces a hybrid model consisting of the Light Gradient Boosting Machine (LightGBM) and the Bidirectional Simple Recurrent Unit (BiSRU). Firstly, Linear interpolation and smoothing were used to identify significant parameters. LightGBM algorithm then determines the significance of dissolved oxygen by eliminating irrelevant variables and predicting dissolved oxygen in intensive aquaculture. Finally, the attention method was implemented to map the weighting and learning parameter matrices, so enabling the BiSRU’s hidden states to be assigned different weights. The findings shown that the presented prediction model can accurately anticipate the fluctuating trend of dissolved oxygen over a 10-day period in just 122 seconds, and the accuracy rate reached 96.28%. Comparing the model effects of LightGBM-BiSRU, LightGBM - GRU, LightGBM-LSTM, and BiSRU - Attention takes the least time. Its higher prediction accuracy can provide an essential reference for intensive aquaculture water quality regulation.

Sucrose non-fermenting–1-related protein kinase–1 (SnRK1) is a highly conserved serine–threonine kinase complex regulating plants’ energy metabolisms and resistance to various types of stresses. However, the downstream genes regulated by SnRK1 in these plant physiological processes still need to be explored. In this study, we found that the knockout of OsSnRK1a resulted in no obvious defects in rice growth but notably decreased the seed setting rate. The ossnrk1a mutants were more sensitive to blast fungus (Magnaporthe oryzae) infection and showed compromised immune responses. Transcriptome analyses revealed that SnRK1a was an important intermediate in the energy metabolism and response to biotic stress. Further investigation confirmed that the transcription levels of OsNADH-GOGAT2, which positively controls rice yield, and the defense-related gene pathogenesis-related protein 1b (OsPR1b) were remarkably decreased in the ossnrk1a mutant. Moreover, we found that OsSnRK1a directly interacted with the regulatory subunits OsSnRK1β1 and OsSnRK1β3, which responded specifically to blast fungus infection and starvation stresses, respectively. Taken together, our findings provide an insight into the mechanism of OsSnRK1a, which forms a complex with specific β subunits, contributing to rice seed set and resistance by regulating the transcription of related genes.

Graphical user interfaces (GUIs) hold an irreplaceable position in modern software and applications. Users can interact through them. Due to different terminal devices, there are sometimes display errors, such as component occlusion, image loss, text overlap, and empty values during software rendering. To address the aforementioned common four GUI display errors, a target detection algorithm based on the improved Faster R-CNN is proposed. Specifically, ResNet-50 is used instead of the traditional VGG-16 as the feature extraction network. The feature pyramid network (FPN) and the enhanced multi-scale attention (EMA) algorithm are introduced to improve accuracy. ROI-Align is used instead of ROI-Pooling to enhance the generalization capability of the network. Since training models require a large number of labeled screenshots of errors, there is currently no publicly available dataset with GUI display problems. Therefore, a training data generation algorithm has been developed, which can automatically generate screenshots with GUI display problems based on the Rico dataset. Experimental results show that the improved Faster R-CNN achieves a detection accuracy of 87.3% in the generated GUI problem dataset, which is a 7% improvement compared to the previous version.

Background: Pancreatic ductal adenocarcinoma (PDAC) develops rapidly and has a poor prognosis. It has been demonstrated that pancreatic ductal adenocarcinoma and chronic pancreatitis (CP) have a close connection. However, the underlying mechanisms for chronic pancreatitis transforming into pancreatic ductal adenocarcinoma are still unclear. The purpose of this study was to identify real hub genes in the development of chronic pancreatitis and pancreatic ductal adenocarcinoma.Methods: RNA-seq data of chronic pancreatitis and pancreatic ductal adenocarcinoma were downloaded from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was performed to construct a gene co-expression network between chronic pancreatitis and pancreatic ductal adenocarcinoma. GEO2R and a Venn diagram were used to identify differentially expressed genes. Then visualized networks were constructed with ClueGO, and modules of PPI network were calculated by MCODE plugin. Further validation of the results was carried out in two additional cohorts. Analyses of CEL-coexpressed genes and regulators including miRNAs and transcription factors were performed by using the corresponding online web tool. Finally, the influence of CEL in the tumor immune microenvironment (TIME) was assessed by immune contextual analysis.Results: With the help of WGCNA and GEO2R, four co-expression modules and six hub genes were identified, respectively. ClueGO enrichment analysis and MCODE cluster analysis revealed that the dysfunctional transport of nutrients and trace elements might contribute to chronic pancreatitis and pancreatic ductal adenocarcinoma development. The real hub gene CEL was identified with a markedly low expression in pancreatic ductal adenocarcinoma in external validation sets. According to the miRNA-gene network construction, hsa-miR-198 may be the key miRNA. A strong correlation exists between CEL and TIME after an evaluation of the influence of CEL in TIME.Conclusion: Our study revealed the dysfunctional transport of nutrients and trace elements may be common pathogenesis of pancreatic ductal adenocarcinoma and chronic pancreatitis. Examination on these common pathways and real hub genes may shed light on the underlying mechanism.

Amphotericin B (AmB) is a widely used antifungal agent especially for the therapy of systemic fungal infections. However, the severe side effects of AmB often leads to the premature termination of the treatment. So it is imperative to find the drugs that can both reduce the dosage and enhance the antifungal efficacy of AmB. Here we demonstrated that Nicotinamide (NAM), a cheap and safe vitamin, could enhance the antifungal activities of AmB. We demonstrated the synergistic interaction of NAM and AmB against Candida albicans as well as other Candida spp. and Cryptococcus neoformans. Moreover, NAM could enhance of the activity of AmB against biofilm. This enhancement was also observed in disseminated candidiasis in vivo. Our further study revealed that AmB could induce oxidative damage through the modification of histone acetylation. AmB could inhibit the expression of HST3, an H3K56 deacetylase in C. albicans. The immunoblotting test revealed excessive H3K56ac in AmB-treated fungal cells. Consistantly, the hst3Δ mutant displayed high sensitivity to AmB, while addition of NAM, an H3K56 deacetylation inhibitor, resulted in an even severe inhibition in the growth of this strain. These results indicated that AmB could execute antifungal activity via boosting H3K56ac which was mediated by HST3, and the mechanism for the synergistic interaction of NAM and AmB was based on exacerbating this process, which led to even excessive H3K56ac and oxidative damage. This finding provided theoretical basis for better understanding the antifungal mechanisms of AmB and clinical application of this drug.

The tree shrew (Tupaia belangeri) is currently placed in the order Scandentia. Owing to their unique characteristics, such as small body size, high brain-to-body mass ratio, short reproductive cycle and life span, and low maintenance costs in laboratory conditions, tree shrews have been proposed as alternative experimental animals to primates in biomedical research. In this study, we determined the complete mitochondrial genome of the subspecies Tupaia belangeri yaoshanensis (T.b. yaoshanensis). The mitochondrial DNA (mtDNA) is 16,777 bp long and contains 13 protein-coding genes (PCGs), two ribosomal RNA genes (12S and 16S), and 22 transfer RNA (tRNA) genes. The base composition of the mitogenome was A (32.28%), T (26.82%), G (14.79%), and C (26.11%). For the 13 PCGs, 1405 variable sites were found between T.b. yaoshanensis and T.b. chinensis (JN800724), of which 916 were synonymous and 489 were nonsynonymous. The frequency of mutations significantly varied among the different genes, with the highest value in the mt-NAD5 gene of tree shrews. Phylogenetic analysis based on the amino acid sequences of 13 PCGs revealed a closer relationship between the species of Scandentia and Lagomorpha. To the best of our knowledge, this is the first study to report the complete mitochondrial genome sequence of T.b. yaoshanensis.

Abstract Background Endometriosis (EMs) is a common benign gynecological disease that affects approximately 10% of females of reproductive age. Endometriosis ectopic lesions could recruit macrophages, which in turn facilitates endometriosis progression. Several studies have indicated that CCL20 derived from macrophages activates the expression of CCR6 in several cells and induces cell proliferation and migration. However, the function of the CCL20/CCR6 axis in the interactions between macrophages and endometriotic stromal cells (ESCs) in EMs has yet to be elucidated. Methods Ectopic and normal endometrial tissues were collected from 35 ovarian endometriosis patients and 21 control participants for immunohistochemical staining. It was confirmed that macrophages secreted CCL20 to promote CCR6 activation of ESCs during co-culture by ELISA, qRT-PCR and western blot analysis. CCK8 and Edu assays were used to detect cell proliferation, and wound healing and Transwell assay were used to detect cell migration. Autophagic flux was detected by measuring the protein expression levels of LC3 and P62by western blot and analyzing the red/yellow puncta after ESCs were transfected with mRFP-GFP-LC3 double fluorescence adenovirus (Ad‐LC3). Lysosomal function was tested by quantifying the fluorescent intensities of Lyso-tracker and Gal3 and activity of acid phosphatase. In addition, co-IP experiments verified the binding relationship between CCR6 and TFEB. Finally, the suppressive effect of CCL20-NAb on endometriosis lesions in vivo was demonstrated in mice models. Results We demonstrated that macrophages secreted CCL20 to promote CCR6 activation of ESCs during co-culture, which further induced the proliferation and migration of ESCs. We observed that the CCL20/CCR6 axis impaired lysosomal function and then blocked the autolysosome degradation process of autophagic flux in ESCs. The combination of CCR6 and TFEB to inhibit TFEB nuclear translocation mediates the role of the CCL20/CCR6 axis in the above process. We also found that co-culture with ESCs upregulated the production and secretion of CCL20 by macrophages. The suppression effect of CCL20-NAb on endometriosis lesions in vivo was demonstrated in mice models. Conclusions Our data indicate that macrophages block TFEB-mediated autolysosome degradation process of autophagic flux in ESCs via the CCL20/CCR6 axis, thereby promoting ESC proliferation and migration.

PurposesDragon boat is a traditional sport in China, but the brain function characteristics of dragon boat athletes are still unclear. Our purpose is to explore the changing characteristics of brain function of dragon boat athletes at different levels before and after exercise by monitoring the changes of EEG power spectrum and microstate of athletes before and after rowing.MethodsTwenty-four expert dragon boat athletes and 25 novice dragon boat athletes were selected as test subjects to perform the 1,000 m all-out paddling exercise on a dragon boat dynamometer. Their resting EEG data was collected pre- and post-exercise, and the EEG data was pre-processed and then analyzed using power spectrum and microstate based on Matlab software.ResultsPost-Exercise, the Heart Rate peak (HR peak), Percentage of Heart Rate max (HR max), Rating of Perceived Exertion (RPE), and Exercise duration of the novice group were significantly higher than expert group (p

Objective: Intraductal papillary mucinous neoplasm (IPMN) is a rare pancreatic lesion. The identification of malignancy is critical for the establishment of treatment strategies. Main pancreatic duct (MPD) diameter is one critical feature for malignant IPMNs. However, the threshold of 1.0 cm is challenged. In this study, we explored independent risk factors and further calculated the threshold of MPD in identifying malignant IPMNs. Method: A total of 151 IPMN patients were included in this retrospective study. Demographic information, clinicopathological features, laboratory testing, and preoperative radiological characteristics by magnetic resonance imaging were collected. The receiver operating characteristic (ROC) curves were performed to determine the MPD diameter's cutoff levels and evaluate the predicted factors' diagnostic ability. Results: A cutoff value of 0.77 cm MPD (an area under the curve (AUC) = 0.746) in all IPMNs and 0.82 cm (AUC = 0.742) in the main duct involved IPMNs was obtained. MPD diameter (odds ratio (OR), 12.67; 95% confidence interval (CI), 4.80–33.48) and the mural nodule (OR, 12.98; 95% CI, 3.18–52.97) were the independent associated factors with high-risk IPMNs. The combined model with MPD and mural nodule showed a better predictive performance than mural nodule or MPD diameter alone (AUC = 0.803 vs 0.619, 0.746). A nomogram was developed and showed good performance (C index = 0.803). Conclusion: Our data show that mural nodule and MPD diameter are independent risk factors in identifying malignant intraductal papillary mucinous neoplasms. A cutoff value of 0.77 cm of MPD diameter may be a threshold value in identifying malignant intraductal papillary mucinous neoplasms or undergoing surgical resection.

Acute liver injury is a serious clinical syndrome with multiple causes and unclear pathological process. Here, CCl4‐ and D‐galactosamine/lipopolysaccharide (D‐gal/LPS)‐induced acute liver injury was established to explore the cell death patterns and determine whether or not liver regeneration occurred. In CCl4‐induced hepatic injury, three phases, including the early, progressive, and recovery phase, were considered based on alterations of serum transaminases and liver morphology. Moreover, in this model, cytokines exhibited double‐peak fluctuations; apoptosis and pyroptosis persisted throughout all phases; autophagy occurred in the early and the progressive phases; and sufficient and timely hepatocyte regeneration was observed only during the recovery phase. All of these phenomena contribute to mild liver injury and subsequent regeneration. Strikingly, only the early and progressive phases were observed in the D‐gal/LPS model. Slight pyroptosis occurred in the early phase but diminished in the progressive phase, while apoptosis, reduced autophagy, and slight but subsequently diminished regeneration occurred only during the progressive phase, accompanied by a strong cytokine storm, resulting in severe liver injury with high mortality. Taken together, our work reveals variable modes and dynamics of cell death and regeneration, which lead to different consequences for mild and severe acute liver injury, providing a helpful reference for clinical therapy and prognosis.

Abstract Endometriosis is a chronic disorder characterized by the implantation of endometrial glands and stroma outside the uterus. However, the pathogenesis of endometriosis is still unclear. To date, there is no fully effective treatment without trauma because of various side effects. Recent data suggest that ferroptosis is a novel recognized form of nonapoptosis-regulated cell death characterized by iron-dependent and lethal lipid peroxidation accumulation, showing great promise in the treatment of many diseases. In the present study, we verified that erastin induced ferroptosis in ectopic endometrial stromal cells (EESCs). Furthermore, we found that the expression of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was decreased during erastin-induced ferroptosis. Knockdown of MALAT1 significantly aggravated the inhibition of cell viability and increased intracellular iron, Liperfluo, and MDA levels in EESCs upon erastin treatment. Mechanistically, we demonstrated that MALAT1 served as a competing endogenous RNA of miR-145-5p to regulate the expression of MUC1, a suppressor of ferroptosis. MALAT1 knockdown-mediated ferroptotic cell death and MUC1 downregulation could be abrogated by inhibition of miR-145-5p. In addition, miR-145-5p inhibition-mediated ferroptotic cell death could be abolished by MUC1 knockdown. Furthermore, erastin-induced ferroptosis shrunk endometriotic lesions via the MALAT1/miR-145-5p/MUC1 axis in vivo. Taken together, our data indicate that knockdown of MALAT1 facilitates ferroptosis upon erastin treatment via miR-145-5p/MUC1 signaling. The synergistic effect of MALAT1 knockdown and erastin induction in ferroptosis may be a new therapeutic strategy for endometriosis.

Current commercialized production processes of glyphosate are generally associated with manufacturing hazards and toxic wastes. Here, to address the problems, the authors report the bioproduction of aminomethylphosphonate (AMP) and a chemical process for the conversion of AMP to glyphosate.

Background Although most patients with newly diagnosed high-risk neuroblastoma (NB) achieve remission after initial therapy, more than 50% experience late relapses caused by minimal residual disease (MRD) and succumb to their cancer. Therapeutic strategies to target MRD may benefit these children. We developed a new chimeric antigen receptor (CAR) targeting glypican-2 (GPC2) and conducted iterative preclinical engineering of the CAR structure to maximize its anti-tumor efficacy before clinical translation.Methods We evaluated different GPC2-CAR constructs by measuring the CAR activity in vitro. NOD-SCID mice engrafted orthotopically with human NB cell lines or patient-derived xenografts and treated with human CAR T cells served as in vivo models. Mechanistic studies were performed using single-cell RNA-sequencing.Results Applying stringent in vitro assays and orthotopic in vivo NB models, we demonstrated that our single-chain variable fragment, CT3, integrated into a CAR vector with a CD28 hinge, CD28 transmembrane, and 4-1BB co-stimulatory domain (CT3.28H.BBζ) elicits the best preclinical anti-NB activity compared with other tested CAR constructs. This enhanced activity was associated with an enrichment of CD8+ effector T cells in the tumor-microenvironment and upregulation of several effector molecules such as GNLY, GZMB, ZNF683, and HMGN2. Finally, we also showed that the CT3.28H.BBζ CAR we developed was more potent than a recently clinically tested GD2-targeted CAR to control NB growth in vivo.Conclusion Given the robust preclinical activity of CT3.28H.BBζ, these results form a promising basis for further clinical testing in children with NB.

The feeding amount of bass farming is closely related to the number of bass. It is of great significance to master the number of bass to achieve accurate feeding and improve the economic benefits of the farm. In view of the interference caused by the problems of multiple targets and target occlusion in bass data for bass detection, this paper proposes a bass target detection model based on improved YOLOV5 in circulating water system. Firstly, acquiring by HD cameras, Mosaic-8, a data augmentation method, is utilized to expand datasets and improve the generalization ability of the model. And K-means clustering algorithm is applied to generate suitable coordinates of prior boxes to improve training efficiency. Secondly, Coordinate Attention mechanism (CA) is introduced into backbone feature extraction network and neck feature fusion network to enhance attention to targets of interest. Finally, Soft-NMS algorithm replaces Non-Maximum Suppression algorithm (NMS) to re-screen prediction boxes and keep targets with higher overlap, which effectively solves the problems of missed detection and false detection. The experiments show that the proposed model can reach 98.09% in detection accuracy and detection speed reaches 13.4ms. The proposed model can help bass farmers under the circulating water system to accurately grasp the number of bass, which has important application value to realize accurate feeding and water conservation.

Abstract Background The manifestations and prognoses of acute-on-chronic liver failure (ACLF) with different precipitating events remain heterogeneous. We aimed to investigate the characteristics and prognosis of patients with hepatotropic viral insult (HVI)-induced hepatitis B-related ACLF (HBV-ACLF). Methods 452 patients with confirmed diagnosis of ACLF were screened in three medical centers in China, and 203 HBV-ACLF patients with definite acute precipitating events were retrospectively analyzed. According to the precipitating events, HBV-ACLF patients induced by HBV reactivation and super-infection with HAV were classified as the hepatotropic viral insult group and those induced by other factors, as the non-virus insult (NVI) group. The clinical characteristics, predictive scoring model, and prognosis of the two groups were compared. Results Hepatitis B virus reactivation accounted for the largest proportion (39.9%) among all precipitating events. Exacerbation time frame of the HVI group was significantly longer than that of the NVI group (20 days vs. 10 days, P

The incidence of fungal infections has increased continuously in recent years. Caspofungin (CAS) is one of the first-line drugs for the treatment of systemic fungal infection. However, the emerging CAS-resistant clinical isolates and high economic cost for CAS administration hamper the wide application of this drug. Thus, the combined administration of CAS with other compounds that can enhance the antifungal activity and reduce the dose of CAS has gained more and more attention. In this study, we investigated the effect of mangiferin (MG) on the antifungal activities of CAS. Our results showed that MG acted synergistically with CAS against various Candida spp., including CAS-resistant C. albicans. Moreover, MG could enhance the activity of CAS against biofilm. The in vivo synergism of MG and CAS was further confirmed in a mouse model of disseminated candidiasis. To explore the mechanisms, we found that SPE1-mediated polyamine biosynthesis pathway was involved in the fungal cell stress to caspofungin. Treatment of CAS alone could stimulate SPE1 expression and accumulation of polyamines, while combined treatment of MG and CAS inhibited SPE1 expression and destroyed polyamine accumulation, which might contribute to increased oxidative damage and cell death. These results provided a promising strategy for high efficient antifungal therapies and revealed novel mechanisms for CAS resistance.

Unlike bulk materials, nanomaterials have unique properties that make them suitable for biosensor applications. Nanomaterial-based biosensors have a series of advantages that can help realize high throughput and ultrasensitive detection. In recent years, considerable research has been performed on integrating nanomaterials and single-molecule immunosensors. This review provides an overview on the various types of nanomaterials used for signal amplification in single-molecule immunosensors, with a focus on the development of optics-based immunosensors using precious plasmonic noble metals (e.g., gold, silver), magnetic beads, quantum dots, upconversion nanoparticles, and nanocomposites. In particular, an approach is presented of using single-molecule immunosensors to detect and quantify biomolecular interactions (e.g., antibody–antigen). Integrating supersensitive bio-devices and nanomaterials is expected to offer significant advantages for trace element diagnosis and early diagnosis.

A process for extraction of artemisinin (Ars) from Artemisia annua L. based on aqueous solution of cyclodextrin derivative under ultrasonic irradiation was proposed. Among the test additives, the system containing edible hydroxypropyl-β-cyclodextrin (HPBCD) was shown to be efficient for this extraction. The optimal extraction conditions were predicted by artificial neural network, under which the extraction amount of Ars could reach 8.66 mg per gram of the leaves, much higher than the value in water (1.70 mg g-1). Kinetics study indicated that HPBCD enhanced the equilibrium amount of Ars in water, and ultrasonic irradiation accelerated extraction rate and reduced the activation energy. Mechanism study showed that the formation of Ars-HPBCD complex during extraction enhanced the water solubility of Ars and facilitated the extraction, and the configuration of Ars-HPBCD complex was modeled by molecular docking, which was further verified by characterizations. This work provides a convenient way to fabricate the traditional tea-based medicament of natural drugs to make production of this famous antimalarial medicine cheaper.

BackgroundAbrupt change in the caliber of the main pancreatic duct (MPD) with distal pancreatic atrophy (PA) was considered as one of worrisome features in the International Association of Pancreatology guideline and American College of Gastroenterology guideline for the management of intraductal papillary mucinous neoplasms (IPMNs). However, this feature was not included in other guidelines. Moreover, the association between PA alone and malignancy in IPMNs has not been fully evaluated. In the present study, we investigated the role of image-based PA in identifying malignant IPMNs or invasive carcinoma.MethodsA total of 186 patients with IPMNs were included for analysis. The tumor size, location, MPD diameter, presence of a mural nodule (MN), and PA were evaluated using magnetic resonance imaging. Demographic information and serum carbohydrate antigen 19-9 and carcinoembryonic antigen (CEA) levels were also collected. IPMNs with high-grade dysplasia and associated invasive carcinoma were regarded as malignant IPMNs.ResultsPA was observed in 34 cases (18.3%). The occurrence of malignant IPMNs or invasive carcinoma in patients with PA were significantly higher than in those without PA (52.9% vs. 22.3%; 44.1% vs. 8.9%, all P < 0.01). Multivariate logistic regression analysis showed that PA was an independently associated factor for malignant IPMNs [odds ratio (OR) = 2.69, 95% confidence interval (CI): 1.07-6.78] or invasive carcinoma (OR = 7.78, 95%CI: 2.62-23.10) after modified with confounders. Subgroup analysis in MPD-involved IPMNs also indicated that PA was an independently associated factor for invasive carcinoma (OR = 9.72, 95%CI: 2.43-38.88). PA had a similar performance with MPD plus MN [the area under the curve (AUC) was both 0.71] in identifying malignancy. PA had a higher performance in identifying invasive carcinoma in MPD-involved IPMNs than MN (AUC = 0.71 vs. 0.65, P = 0.02).ConclusionOur data showed that imaging-based PA was associated with malignancy or invasive carcinoma regardless of abrupt change in the caliber of MPD in IPMNs. PA had an acceptable performance in identifying malignant IPMNs.

The function of the autoinducer-2 exporters (AI-2E) family transporter protein of Lactobacillus acidophilus is still unclear. The phylogenetic analysis was used to analyze the relationship between the AI-2E protein of the L. acidophilus CICC 6074 strain and other AI-2E family members. Escherichia coli KNabc strain was used to verify whether the protein has Na+ (Li+)/H+ antiporter activity. The AI-2E protein overexpression strain was constructed by using the pMG36e expression vector, and the overexpression efficiency was determined by real-time quantitative PCR. The vitality and AI-2 activity of L. acidophilus CICC 6074 strains were determined. The results showed that the AI-2E protein of Lactobacillus formed a single branch on the phylogenetic tree and was closer to the AI-2E family members whose function was AI-2 exporter group I. The expression of AI-2E protein in the E. coli KNabc strain did not recover the resistance of the bacteria to the saline environment. Overexpression of AI-2E protein in L. acidophilus CICC 6074 could promote the AI-2 secretion of L. acidophilus CICC 6074 strain and enhance their survival ability in intestinal juice.

Abstract Background Associations between trajectories of systolic blood pressure (SBP) during pregnancy and pregnant outcomes remain unclear and disparate. Methods Data of 20,353 mothers without chronic hypertension and who delivered live singletons between January, 2014 and November, 2019, was extracted from Taicang register-based cohort. Based on SBP measured during 10 to 40 weeks of gestation, SBP trajectories were explored using latent class growth mixture model, and their associations with maternal and neonatal outcomes were assessed by logistic regression analyses. Results Six heterogeneous SBP trajectories were identified: low delayed-increasing (7.47%), low reverse-increasing (21.88%), low-stable (19.13%), medium-stable (21.64%), medium reverse-increasing (16.47%), and high stable (13.41%) trajectories. The high-stable trajectory had SBP around 125 mmHg in the 10th gestational week, and increased slightly onwards. When compared with the low-stable trajectory, the high-stable trajectory had maximally adjusted odds ratio (95% confidence interval) of 5.28 (2.76–10.10), 1.30 (1.13–1.50), 1.53 (1.12–2.08), 1.32 (1.06–1.65) and 1.64 (1.08–2.48) for gestational hypertension (GH), early-term delivery (ETD), preterm delivery (PTD), small for gestational age and low birth weight (LBW), respectively. Besides, the medium reverse-increasing trajectory showed significantly increased risk of GH and ETD, while the medium-stable trajectory had significantly elevated risk of ETD and PTD. Notably, SBP trajectories slightly but significantly improved risk discrimination of GH, ETD and LBW, over traditional risk factors. Conclusion Women with different SBP trajectories were at varied risk of adverse maternal and fetal outcomes. Meanwhile, our study suggested that BP monitoring during pregnancy is necessary, especially for women with high SBP in early pregnancy or upward trajectory.

Abstract Studies have shown that tumor microenvironment (TME) might affect drug sensitivity and the classification of colorectal cancer (CRC). Using TME-specific gene signature to identify CRC subtypes with distinctive clinical relevance has not yet been tested. A total of 18 “bulk” RNA-seq datasets (total n = 2269) and four single-cell RNA-seq datasets were included in this study. We constructed a “Signature associated with FOLFIRI resistant and Microenvironment” (SFM) that could discriminate both TME and drug sensitivity. Further, SFM subtypes were identified using K-means clustering and verified in three independent cohorts. Nearest template prediction algorithm was used to predict drug response. TME estimation was performed by CIBERSORT and microenvironment cell populations-counter (MCP-counter) methods. We identified six SFM subtypes based on SFM signature that discriminated both TME and drug sensitivity. The SFM subtypes were associated with distinct clinicopathological, molecular and phenotypic characteristics, specific enrichments of gene signatures, signaling pathways, prognosis, gut microbiome patterns, and tumor lymphocytes infiltration. Among them, SFM-C and -F were immune suppressive. SFM-F had higher stromal fraction with epithelial-to-mesenchymal transition phenotype, while SFM-C was characterized as microsatellite instability phenotype which was responsive to immunotherapy. SFM-D, -E, and -F were sensitive to FOLFIRI and FOLFOX, while SFM-A, -B, and -C were responsive to EGFR inhibitors. Finally, SFM subtypes had strong prognostic value in which SFM-E and -F had worse survival than other subtypes. SFM subtypes enable the stratification of CRC with potential chemotherapy response thereby providing more precise therapeutic options for these patients.

Abstract Acute-on-chronic liver failure (ACLF) is a dynamic syndrome, and sequential assessments can reflect its prognosis more accurately. Our aim was to build and validate a new scoring system to predict short-term prognosis using baseline and dynamic data in ACLF. We conducted a retrospective cohort analysis of patients with ACLF from three different hospitals in China. To construct the model, we analyzed a training set of 541 patients from two hospitals. The model’s performance was evaluated in a validation set of 130 patients from another center. In the training set, multivariate Cox regression analysis revealed that age, WGO type, basic etiology, total bilirubin, creatinine, prothrombin activity, and hepatic encephalopathy stage were all independent prognostic factors in ACLF. We designed a dynamic trend score table based on the changing trends of these indicators. Furthermore, a logistic prediction model (DP-ACLF) was constructed by combining the sum of dynamic trend scores and baseline prognostic parameters. All prognostic scores were calculated based on the clinical data of patients at the third day, first week, and second week after admission, respectively, and were correlated with the 90-day prognosis by ROC analysis. Comparative analysis showed that the AUC value for DP-ACLF was higher than for other prognostic scores, including Child–Turcotte–Pugh, MELD, MELD-Na, CLIF-SOFA, CLIF-C ACLF, and COSSH-ACLF. The new scoring model, which combined baseline characteristics and dynamic changes in clinical indicators to predict the course of ACLF, showed a better prognostic ability than current scoring systems. Prospective studies are needed to validate these results.

Effects of two high pressure processing treatments and various levels of konjac glucomannan (KGM) and sodium caseinate (SC) on texture properties, water-holding capacity, and ultra-structure of gels of rabbit myosin protein were investigated. The two high pressure processing treatments were as follows: (1) mean pressure (200 MPa), low temperature (37 °C), and holding for a short time (5 min) followed heating (80 °C for 40 min) (gel LP + H), and (2) high pressure (500 MPa), high temperature (60 °C), and holding for a long time (30 min) (gel HP). Gel LP + H have better gel properties (increased hardness, springiness, gumminess, adhesiveness, cohesiveness, and water binding capacity) than gels HP. Above all, gels myosin + SC:KGM (2:1) have best gel properties. KGM and SC both significantly improved the gel texture properties and water binding capacity.

Abstract Background RNA-Seq, the high-throughput sequencing (HT-Seq) of mRNAs, has become an essential tool for characterizing gene expression differences between different cell types and conditions. Gene expression is regulated by several mechanisms, including epigenetically by post-translational histone modifications which can be assessed by ChIP-Seq (Chromatin Immuno-Precipitation Sequencing). As more and more biological samples are analyzed by the combination of ChIP-Seq and RNA-Seq, the integrated analysis of the corresponding data sets becomes, theoretically, a unique option to study gene regulation. However, technically such analyses are still in their infancy. Results Here we introduce intePareto, a computational tool for the integrative analysis of RNA-Seq and ChIP-Seq data. With intePareto we match RNA-Seq and ChIP-Seq data at the level of genes, perform differential expression analysis between biological conditions, and prioritize genes with consistent changes in RNA-Seq and ChIP-Seq data using Pareto optimization. Conclusion intePareto facilitates comprehensive understanding of high dimensional transcriptomic and epigenomic data. Its superiority to a naive differential gene expression analysis with RNA-Seq and available integrative approach is demonstrated by analyzing a public dataset.

Background & ObjectivesPancreatic ductal adenocarcinoma remains an extremely malignant tumor having a poor prognosis. The 5-year survival rate of PDAC is related to its stage (about 80% for stage I vs 20% for other stages). However, detection of PDAC in an early stage is difficult due to the lack of effective screening methods. In this study, we aimed to construct a novel metabolic model for stage-I PDAC detection, using both serum and tissue samples.MethodsWe employed an untargeted technique, UHPLC-Q-TOF-MS, to identify the potential metabolite, and then used a targeted technique, GC-TOF-MS, to quantitatively validate. Multivariate and univariate statistics were performed to analyze the metabolomic profiles between stage-I PDAC and healthy controls, including 90 serum and 53 tissue samples. 28 patients with stage-I PDAC and 62 healthy controls were included in this study.ResultsA total of 10 potential metabolites presented the same expression levels both in serum and in tissue. Among them, a 2-metabolites-model (isoleucine and adrenic acid) for stage-I PDAC was constructed. The area under the curve (AUC) value was 0.93 in the discovery set and 0.90 in the independent validation set. Especially, the serum metabolite model had a better diagnostic performance than CA19-9 (AUC = 0.79). Pathway analysis revealed 11 altered pathways in both serum and tissue of stage-I PDAC.ConclusionsThis study developed a novel serum metabolites model that could early separate stage-I PDAC from healthy controls.

Abstract Background Epigenetic alterations are involved in various aspects of colorectal carcinogenesis. N 6-methyladenosine (m6A) modifications of RNAs are emerging as a new layer of epigenetic regulation. As the most abundant chemical modification of eukaryotic mRNA, m6A is essential for the regulation of mRNA stability, splicing, and translation. Alterations of m6A regulatory genes play important roles in the pathogenesis of a variety of human diseases. However, whether this mRNA modification participates in the glucose metabolism of colorectal cancer (CRC) remains uncharacterized. Methods Transcriptome-sequencing and liquid chromatography-tandem mass spectrometry (LC-MS) were performed to evaluate the correlation between m6A modifications and glucose metabolism in CRC. Mass spectrometric metabolomics analysis, in vitro and in vivo experiments were conducted to investigate the effects of METTL3 on CRC glycolysis and tumorigenesis. RNA MeRIP-sequencing, immunoprecipitation and RNA stability assay were used to explore the molecular mechanism of METTL3 in CRC. Results A strong correlation between METTL3 and 18F-FDG uptake was observed in CRC patients from Xuzhou Central Hospital. METTL3 induced-CRC tumorigenesis depends on cell glycolysis in multiple CRC models. Mechanistically, METTL3 directly interacted with the 5′/3’UTR regions of HK2, and the 3’UTR region of SLC2A1 (GLUT1), then further stabilized these two genes and activated the glycolysis pathway. M6A-mediated HK2 and SLC2A1 (GLUT1) stabilization relied on the m6A reader IGF2BP2 or IGF2BP2/3, respectively. Conclusions METTL3 is a functional and clinical oncogene in CRC. METTL3 stabilizes HK2 and SLC2A1 (GLUT1) expression in CRC through an m6A-IGF2BP2/3- dependent mechanism. Targeting METTL3 and its pathway offer alternative rational therapeutic targets in CRC patients with high glucose metabolism.

Background and Aims: Acute-on-chronic liver failure (ACLF) is an acute deterioration of chronic liver disease with high short-term mortality. The inclusion or exclusion of previously decompensated cirrhosis (DC) in the diagnostic criteria of ACLF defined by the Asian Pacific Association for the Study of the Liver (APASL-ACLF) has not been conclusive. We aimed to evaluate the prognostic impact of decompensated cirrhosis in ACLF.Methods: We retrospectively collected a cohort of patients with a diagnosis of APASL-ACLF (with or without DC) hospitalized from 2012 to 2020 at three liver units in tertiary hospitals. Baseline characteristics and survival data at 28, 90, 180, 360, 540, and 720 days were collected.Results: Of the patients assessed using APASL-ACLF criteria without the diagnostic indicator of chronic liver disease, 689 patients were diagnosed with ACLF, of whom 435 had no decompensated cirrhosis (non-DC-ACLF) and 254 had previously decompensated cirrhosis (DC-ACLF). The 28-, 90-, 180-, 360-, 540-, and 720-day mortality were 24.8, 42.9, 48.7, 57.3, 63.4, and 68.1%, respectively, in DC-ACLF patients, which were significantly higher than in non-DC-ACLF patients (p < 0.05). DC was independently associated with long-term (180/360/540/720 days) but not short-term (28/90 days) mortality in patients with ACLF. Age, total bilirubin, international normalized ratio, and hepatic encephalopathy were independent risk factors for short- and long-term mortality risk in ACLF patients (p < 0.05).Conclusions: Patients with DC-ACLF have a higher mortality rate, especially long-term mortality, compared to non-DC-ACLF patients. Therefore, DC should be included in the diagnostic criteria of APASL-ACLF and treated according to the ACLF management process.

Purpose: This study aimed to detect differences in post-exercise brain activity between the left and right paddlers due to exercise by analyzing the resting-state electroencephalogram (EEG) power spectrum before and after exercise. Methods: Twenty-one right paddlers and twenty-two left paddlers completed a 1 km all-out test on a dragon boat ergometer, and their heart rate and exercise time were recorded. EEG signals were collected from superficial brain layers before and after exercise; then, the EEG power spectrum was extracted and compared in different frequency bands. In addition, the degree of lateralization in each brain region was assessed by the asymmetry index. Results: There was no significant difference in the power spectrum values and asymmetry indices between the left and right paddlers before rowing (p ˃ 0.05). However, after rowing, the left-paddlers group had significantly higher spectral power values in θ and α bands than the right-paddlers group (p < 0.05), and brain lateralization in both groups of athletes occurred mainly in the ipsilateral hemisphere of the frontal and central regions. Conclusion: The 1 km of rowing induced more brain activation in the left paddlers, and both left and right paddlers showed functional aggregation of hemispheric lateralization.

Grapevine (Vitisvinifera L.) fruit ripening is a complex biological process involving a phase transition from immature to mature. Understanding the molecular mechanism of fruit ripening is critical for grapevine fruit storage and quality improvement. However, the regulatory mechanism for the critical phase transition of fruit ripening from immature to mature in grapevine remains poorly understood. In this work, to identify the key molecular events controlling the critical phase transition of grapevine fruit ripening, we performed an integrated dynamic network analysis on time-series transcriptomic data of grapevine berry development and ripening. As a result, we identified the third time point as a critical transition point in grapevine fruit ripening, which is consistent with the onset of veraison reported in previous studies. In addition, we detected 68 genes as being key regulators involved in controlling fruit ripening. The GO (Gene Ontology) analysis showed that some of these genes participate in fruit development and seed development. This study provided dynamic network biomarkers for marking the initial transcriptional events that characterizes the transition process of fruit ripening, as well as new insights into fruit development and ripening.

BackgroundThe pathogenesis of COVID-19 emerges as complex, with multiple factors leading to injury of different organs. Some of the studies on aspects of SARS-CoV-2 cell entry and innate immunity have produced seemingly contradictory claims. In this situation, a comprehensive comparative analysis of a large number of related datasets from several studies could bring more clarity, which is imperative for therapy development.MethodsWe therefore performed a comprehensive comparative study, analyzing RNA-Seq data of infections with SARS-CoV-2, SARS-CoV and MERS-CoV, including data from different types of cells as well as COVID-19 patients. Using these data, we investigated viral entry routes and innate immune responses.Results and ConclusionFirst, our analyses support the existence of cell entry mechanisms for SARS and SARS-CoV-2 other than the ACE2 route with evidence of inefficient infection of cells without expression of ACE2; expression of TMPRSS2/TPMRSS4 is unnecessary for efficient SARS-CoV-2 infection with evidence of efficient infection of A549 cells transduced with a vector expressing human ACE2. Second, we find that innate immune responses in terms of interferons and interferon simulated genes are strong in relevant cells, for example Calu3 cells, but vary markedly with cell type, virus dose, and virus type.