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Abstract Background Rhodococcus equi (R. equi) is a Gram-positive zoonotic pathogen that frequently leads to illness and death in young horses (foals). This study presents the complete genome sequence of R. equi strain BJ13, which was isolated from a thoroughbred racehorse breeding farm in Beijing, China. Results The BJ13 genome has a length of 5.30 Mb and consists of a complete chromosome and a plasmid measuring 5.22 Mb and 0.08 Mb, respectively. We predicted 4,929 coding gene open reading frames, along with 52 tRNAs and 12 rRNAs. Through analysis of mobile genetic elements, we identified 6 gene islands and 1 prophage gene. Pathogenic system analysis predicted the presence of 418 virulence factors and 225 drug resistance genes. Secretion system analysis revealed the prediction of 297 secreted proteins and 1,106 transmembrane proteins. BJ13 exhibits genomic features, virulence-associated genes, potential drug resistance, and a virulence plasmid structure that may contribute to the evolution of its pathogenicity. Lastly, the pathogenicity of the isolated strain was assessed through animal experiments, which resulted in inflammatory reactions or damage in the lungs, liver, and spleen of mice. Moreover, by the 7th day post-infection, the mortality rate of the mice reached 50.0%, indicating complex immune regulatory mechanisms, including overexpression of IL-10 and increased production of pro-inflammatory cytokines like TNF-α. These findings validate the strong pathogenicity of the isolated strain and provide insights for studying the pathogenic mechanisms of Rhodococcus equi infection. Conclusions The complete genome sequence of R. equi strain BJ13 provides valuable insights into its genomic characteristics, virulence potential, drug resistance, and secretion systems. The strong pathogenicity observed in animal experiments underscores the need for further investigation into the pathogenic mechanisms of R. equi infection.

Summary: Background: In the EC-CRT-001 phase II study, the combination of toripalimab (an anti-programmed death-1 antibody) and definitive chemoradiotherapy (CRT) has shown promising efficacy in patients with locally advanced oesophageal squamous cell carcinoma (ESCC). Here, we reported the long-term outcomes and post-hoc exploratory analyses. Methods: This single-arm, phase II trial enrolled 42 patients diagnosed with unresectable stage I–IVA ESCC was conducted at Sun Yat-sen University Cancer Center between November 2019 and January 2021. Treatment consisted of chemotherapy (weekly 50 mg/m2 of paclitaxel and 25 mg/m2 of cisplatin for five cycles), concurrent radiotherapy (50.4 Gy in 28 fractions), and toripalimab (240 mg every 3 weeks for up to 1 year). The primary endpoint was clinical complete response (CR) rate at 3 months after CRT completion. The 3-year overall survival (OS) and progression-free survival (PFS) rates were evaluated. Additionally, the exploratory objectives included analysing recurrence patterns, assessing the associations between immune-related adverse events (irAEs) and efficacy, and identifying potential predictors for irAEs. The trial was registered with ClinicalTrials.gov (NCT04005170). Findings: With a median follow-up of 44.3 months (IQR 40.8–46.1), the 3-year OS and PFS rates were 44.8% (95% CI 31.9–62.8) and 35.7% (95% CI 23.8–53.6), respectively. Patients who failed to achieve a clinical complete response (CR) demonstrated significantly worse OS (hazard ratio [HR] = 13.73, 95% CI 4.43–42.54, P

Abstract Power system dynamic security assessment (DSA) has long been essential for protecting the system from the risk of cascading failures and wide‐spread blackouts. The machine learning (ML) based data‐driven strategy is promising due to its real‐time computation speed and knowledge discovery capacity. However, ML algorithms are found to be vulnerable against well‐designed malicious input samples that can lead to wrong outputs. Adversarial attacks are implemented to measure the vulnerability of the trained ML models. Specifically, the targets of attacks are identified by interpretation analysis that the data features with large SHAP values will be assigned with perturbations. The proposed method has the superiority that an instance‐based DSA method is established with interpretation of the ML models, where effective adversarial attacks and its mitigation countermeasure are developed by assigning the perturbations on features with high importance. Later, these generated adversarial examples are employed for adversarial training and mitigation. The simulation results present that the model accuracy and robustness vary with the quantity of adversarial examples used, and there is not necessarily a trade‐off between these two indicators. Furthermore, the rate of successful attacks increases when a greater bound of perturbations is permitted. By this method, the correlation between model accuracy and robustness can be clearly stated, which will provide considerable assistance in decision making.

Abstract The combination of toripalimab (an anti-PD-1 antibody) with definitive chemoradiotherapy (CRT) demonstrated encouraging efficacy against locally advanced esophageal squamous cell carcinoma (ESCC) in the EC-CRT-001 phase II trial (NCT04005170). The primary endpoint of this trial was the clinical complete response rate (cCR), and the secondary endpoints included overall survival (OS), progression-free survival (PFS), duration of response, and quality of life. The exploratory analyses of EC-CRT-001 include exploring the role of circulating tumor DNA (ctDNA) and blood-based tumor mutational burden (bTMB) in predicting the response and survival. In total, 118 blood and 35 tissue samples from 42 enrolled patients were included in the analyses. We found that ctDNA-negative patients achieved a higher cCR compared to those with detectable ctDNA during CRT (83%, 19/23 vs. 39%, 7/18; p = 0.008) or post-CRT (78%, 21/27 vs. 30%, 3/10; p = 0.017). Patients with detectable ctDNA during CRT had shorter PFS (p = 0.014). Similarly, patients with post-CRT detectable ctDNA had a significantly shorter PFS (p = 0.012) and worse OS (p = 0.004). Moreover, patients with high bTMB levels during CRT had prolonged OS (p = 0.027). In conclusion, ctDNA and bTMB have the potential to predict treatment efficacy and survival in ESCC treated with CRT and immunotherapy.

Trichomonas gallinae is a globally distributed protozoan parasite that causes avian trichomoniasis, leading to significant morbidity and mortality in birds. The present study aims to investigate the prevalence, genetic diversity, and phylogenetic relationship of T. gallinae in various bird species in Beijing. A total of 413 oropharyngeal swab samples were collected from domestic pigeons, wild pigeons, and other bird species. The overall prevalence of T. gallinae infection was 32.0% (132/413). The infection was detected in domestic pigeons, wild pigeons, and red-necked turtledoves, but not in other wild birds. Molecular analysis identified two predominant genotypes, A and B, with genotype A found in wild pigeons and genotype B found in domestic pigeons. The present study provides valuable insights on the prevalence and genetic diversity of T. gallinae in Beijing. This can be useful for understanding its pathogen distribution and host range, and the development of strategies for the prevention and control of avian trichomoniasis.

Background: Cardiovascular diseases (CVDs) are the leading age-related disorders worldwide, with their prevalence increasing annually. Cathepsins are protein-degrading enzymes essential for processes such as intracellular protein breakdown, apoptosis, and immune responses. Recent studies suggest a potential link between cathepsins and CVDs, yet the exact causal relationship remains to be elucidated. To address this, we propose using Mendelian randomization (MR) to explore the causal relationships between cathepsins and CVDs.Methods: We obtained single nucleotide polymorphism (SNP) data for cathepsins from the INTERVAL study, a publicly accessible genome-wide association study (GWAS) dataset. Outcome SNP data were sourced from seven distinct GWAS datasets, ensuring a comprehensive analysis across multiple cardiovascular outcomes. For MR analysis, we primarily employed the inverse variance weighted (IVW) method, known for its efficiency when all SNPs are valid instruments. This was supplemented by the weighted median and MR-Egger methods to provide robustness against potential violations of MR assumptions, such as pleiotropy. The IVW method offers precision and efficiency, the weighted median method adds robustness against invalid instruments, and the MR-Egger method helps identify and correct for pleiotropic biases. Cochran’s Q test was utilized to assess heterogeneity, and sensitivity analyses were conducted using MR-PRESSO and the leave-one-out approach.Results: The strength of the associations between exposure and outcome was measured using odds ratios (ORs), and results were presented with 95% confidence intervals (CIs). The cathepsin E increases the risk of myocardial infarction (MI) (OR = 1.053%, 95% CI: 1.007–1.101, p = 0.024) and ischemic stroke (IS) (OR = 1.06%, 95% CI: 1.019–1.103, p = 0.004). Conversely, cathepsin L2 decreases the risk of chronic heart failure (CHF) (OR = 0.922%, 95% CI: 0.859–0.99, p = 0.025) and atrial fibrillation (AF) (OR = 0.956%, 95% CI: 0.918–0.996, p = 0.033). Cathepsin O was associated with an increased risk of IS (OR = 1.054%, 95% CI: 1.008–1.102, p = 0.021) and AF (OR = 1.058%, 95% CI: 1.02–1.098, p = 0.002).Conclusion: Our MR analysis reveals that cathepsin E is a risk factor for MI and IS, cathepsin L2 offers protective effects against CHF and AF, and cathepsin O increases the risk for IS and AF.

Abstract Background Hepatocellular carcinoma (HCC) stands as a prevalent malignancy globally, characterized by significant morbidity and mortality. Despite continuous advancements in the treatment of HCC, the prognosis of patients with this cancer remains unsatisfactory. This study aims at constructing a disulfidoptosis‑related long noncoding RNA (lncRNA) signature to probe the prognosis and personalized treatment of patients with HCC. Methods The data of patients with HCC were extracted from The Cancer Genome Atlas (TCGA) databases. Univariate, multivariate, and least absolute selection operator Cox regression analyses were performed to build a disulfidptosis-related lncRNAs (DRLs) signature. Kaplan–Meier plots were used to evaluate the prognosis of the patients with HCC. Functional enrichment analysis was used to identify key DRLs-associated signaling pathways. Spearman’s rank correlation was used to elucidate the association between the DRLs signature and immune microenvironment. The function of TMCC1-AS1 in HCC was validated in two HCC cell lines (HEP3B and HEPG2). Results We identified 11 prognostic DRLs from the TCGA dataset, three of which were selected to construct the prognostic signature of DRLs. We found that the survival time of low-risk patients was considerably longer than that of high-risk patients. We further observed that the composition and the function of immune cell subpopulations were significantly different between high- and low-risk groups. Additionally, we identified that sorafenib, 5-Fluorouracil, and doxorubicin displayed better responses in the low-score group than those in the high-score group, based on IC50 values. Finally, we confirmed that inhibition of TMCC1-AS1 impeded the proliferation, migration, and invasion of hepatocellular carcinoma cells. Conclusions The DRL signatures have been shown to be a reliable prognostic and treatment response indicator in HCC patients. TMCC1-AS1 showed potential as a novel prognostic biomarker and therapeutic target for HCC.

Abstract Background Gliomas, a prevalent form of primary brain tumors, are linked with a high mortality rate and unfavorable prognoses. Disulfidptosis, an innovative form of programmed cell death, has received scant attention concerning disulfidptosis-related lncRNAs (DRLs). The objective of this investigation was to ascertain a prognostic signature utilizing DRLs to forecast the prognosis and treatment targets of glioma patients. Methods RNA-seq data were procured from The Cancer Genome Atlas database. Disulfidptosis-related genes were compiled from prior research. An analysis of multivariate Cox regression and the least absolute selection operator was used to construct a risk model using six DRLs. The risk signature’s performance was evaluated via Kaplan-Meier survival curves and receiver operating characteristic curves. Additionally, functional analysis was carried out using GO, KEGG, and single-sample GSEA to investigate the biological functions and immune infiltration. The research also evaluated tumor mutational burden, therapeutic drug sensitivity, and consensus cluster analysis. Reverse transcription quantitative PCR was conducted to validate the expression level of DRLs. Results A prognostic signature comprising six DRLs was developed to predict the prognosis of glioma patients. High-risk patients had significantly shorter overall survival than low-risk patients. The robustness of the risk model was validated by receiver operating characteristic curves and subgroup survival analysis. Risk model was used independently as a prognostic indicator for the glioma patients. Notably, the low-risk patients displayed a substantial decrease in the immune checkpoints, the proportion of immune cells, ESTIMATE and immune score. IC50 values from the different risk groups allowed us to discern three drugs for the treatment of glioma patients. Lastly, the potential clinical significance of six DRLs was determined. Conclusions A novel six DRLs signature was developed to predict prognosis and may provide valuable insights for patients with glioma seeking novel immunotherapy and targeted therapy.

Abstract Background Definitive radiotherapy plus concurrent chemotherapy has been a standard treatment for esophagus patients who are unfit to undergo surgery. However, there are a variety of concurrent chemotherapy regimens with varying efficacy. In this phase II prospective study, we compared the efficacy and toxicity of DP (docetaxel and cisplatin) and PF (cisplatin and 5-fluorouracil) regimens with concurrent chemoradiotherapy (CCRT) in patients with esophageal squamous cell carcinoma (ESCC) and analyzed the 5-year overall survival (OS) and progression free survival (PFS). We also summarized the salvage treatments and late toxicities. Methods We enrolled 86 patients with clinical stage II-IVA from the Sun Yat-sen University Cancer Center. The patients were divided into two groups: PF group (41) and DP group (45). Statistics were analyzed using SPSS version 19.0. Results The 5-year OS rates were 62.9% ± 7.6% in PF group, and 52.7% ± 7.5% in DP group (P = 0.131), respectively. The 5-year PFS rates were 43.9% ± 7.8% for PF group, and 40.0% ± 7.3% for DP group (P = 0.398), respectively. Sixteen patients in the DP group and thirteen in the PF group received salvage treatment. For those patients with local residual or local recurrent disease, the median survival time after salvage treatment was 13.5 months and the 1, 2, and 3-year survival rates were 79.0%, 50.3%, and 43.1%, respectively. For all patients, thirteen (15.1%) had Grade 2 late cardiac toxicities. One patient had Grade 2 pleural effusion and required diuretic. Most patients with pneumonia are mild, and only one patient in PF group had Grade 2 pneumonia. One patient in the DP group developed tracheoesophageal fistula. Conclusions The 5-year follow-up confirmed that definitive CCRT with the DP regimen did not improve the treatment response, OS, or PFS in patients with ESCC compared to the PF regimen. The PF regimen remains the standard regimen for definitive CCRT for patients with locally advanced ESCC. Long-term follow-up also suggested that appropriate and active salvage treatment has a survival benefit for some patients, and late cardiopulmonary toxicities should be noticed during follow-up. Trial registration The trial was registered at https://clinicaltrials.gov (ClinicalTrials.gov Identifier: NCT 02969473, October 2010).

Abstract Background This phase I study aimed to assess the safety, dose‐limiting toxicity (DLT), maximum tolerated dose (MTD) and preliminary effect of nanoparticle albumin‐bound (nab)‐paclitaxel in combination with concurrent chemoradiotherapy in patients with locally advanced esophageal squamous cell carcinoma (ESCC). Methods Patients with locally advanced ESCC who were ineligible or refused surgery were enrolled. Nab‐paclitaxel (60 mg/m2, 75 mg/m2, and 90 mg/m2) and cisplatin (25 mg/m2) were administered intravenously weekly on days 1, 8, 15, 22, and 29 on the basis of the 3 + 3 dose escalation method. The total dose of radiation was 50–64 Gy. The primary endpoint was the safety of chemotherapy. Results The study enrolled 12 patients across three dose levels. No treatment‐related deaths occurred. One patient in the 60 mg/m2 dose level occurred dose‐limiting Grade 3 febrile neutropenia. No DLT was found in the 90 mg/m2 dose level thus the MTD was not reached. The phase II study's recommended dose was 75 mg/m2 based on the available preclinical and clinical data including pharmacokinetics, pharmacodynamics, efficacy, and toxicity. The frequent hematologic toxicities were leukocytopenia (Grade 1–2 of 66.7% and Grade 3–4 of 33.3%), neutropenia (Grade 1–2 of 91.7% and Grade 3–4 of 8.3%). Nonhematologic toxicities were mild and manageable. Overall response rate (ORR) of all patients achieved 100%. Conclusions Weekly schedule of cisplatin and nab‐paclitaxel in combination with concurrent radiotherapy showed manageable toxicities and promising antitumor activity in patients with locally advanced ESCC. The recommended dose of nab‐paclitaxel for further studies is 75 mg/m2.

Abstract Background Esophageal squamous cell carcinoma (ESCC) is the most common esophageal malignancy, and RNA methylation has been reported to be involved in the tumorigenesis of ESCC. However, no study has explored methylation modifications in m1A and m7G as prognostic markers for survival prediction in ESCC. Methods Public gene-expression data and clinical annotation of 254 patients obtained from The Cancer Genome Atlas and the Gene Expression Omnibus databases were analyzed to identify potential consensus clusters of m1A and m7G modification-related genes. The RNA-seq of 20 patients in Sun Yat-Sen University Cancer Center was used as the validation set. Following screening for relevant differentially expressed genes (DEGs) and enrichment pathways were elucidated. DEGs were used to construct risk models using the randomForest algorithm, and the prognostic role of the models was assessed by applying Kaplan–Meier analysis. Extent of immune cell infiltration, drug resistance, and response to cancer treatment among different clusters and risk groups were also evaluated. Results Consensus clustering analysis based on m1A and m7G modification patterns revealed three potential clusters. In total, 212 RNA methylation-related DEGs were identified. The methylation-associated signature consisting of 6 genes was then constructed to calculate methylation-related score (MRScore) and patients were dived into MRScore-high and MRScore-low groups. This signature has satisfied prognostic value for survival of ESCC (AUC = 0.66, 0.67, 0.64 for 2-, 3-, 4- year OS), and has satisfied performance in the validation SYSUCC cohort (AUC = 0.66 for 2- and 3-year OS). Significant correlation between m1A and m7G modification-related genes and immune cell infiltration, and drug resistance was also observed. Conclusions Transcriptomic prognostic signatures based on m1A and m7G modification-related genes are closely associated with immune cell infiltration in ESCC patients and have important correlations with the therapeutic sensitivity of multiple chemotherapeutic agents.

Study region: Upper Shiyang River in the eastern Qilian Mountains, China. Study focus: Quantifying the impacts of anthropogenic and climate change on wet and dry hydrological variability was done by improving the Slope Change Ratio of Cumulative Quantities (ISCRCQ) method. New hydrological insights for the region: The scientific method is critical to quantify the driving factors of dry-wet hydrological changes. In this study, the slope change ratio of cumulative quantity (SCRCQ) method was improved to quantify the impacts of human activities and climate change on dry-wet hydrological changes. The results show a hydrological aridification trend at an annual scale from 1961 to 2016 in the upper reaches of the Shiyang River. However, the dry-wet hydrological change trends of the six tributaries differed: the hydrological humidification of the four western tributaries was apparent, while the remaining tributaries showed hydrological aridification. The influences of human activities and climate change on dry-wet hydrological changes were also evidently distinct in the different tributaries. Changing in climate is a vital factor triggering the dry-wet hydrological changes in the western tributaries, while human activities have completely changed the direction of the dry-wet hydrological changes and intensified the hydrological aridification in the eastern tributaries. Human activities have resulted in an increase both in the frequency of droughts and in the risk of socio-economic droughts. Thus, human activities in the region of eastern tributaries should be controlled within reasonable limits.

Background: Heart failure (HF) is a complex and heterogeneous manifestation of multiple cardiovascular diseases that usually occurs in the advanced stages of disease progression. The role of neutrophil extracellular traps (NETs) in the pathogenesis of HF remains to be explored.Methods: Bioinformatics analysis was employed to investigate general and single-cell transcriptome sequencing data downloaded from the GEO datasets. Differentially expressed genes (DEGs) associated with NETs in HF patients and healthy controls were identified using transcriptome sequencing datasets and were subsequently subjected to functional enrichment analysis. To identify potential diagnostic biomarkers, the random forest algorithm (RF) and the least absolute shrinkage and selection operator (LASSO) were applied, followed by the construction of receiver operating characteristic (ROC) curves to assess accuracy. Additionally, single-cell transcriptome sequencing data analysis identified key immune cell subpopulations in TAC (transverse aortic constriction) mice potentially involved in NETs regulation. Cell-cell communication analysis and trajectory analysis was then performed on these key cell subpopulations.Results: We identified thirteen differentially expressed genes (DEGs) associated with NET through differential analysis of transcriptome sequencing data from HF (heart failure) samples. Utilizing the Random Forest and Lasso algorithms, along with experimental validation, we successfully pinpointed four diagnostic markers (CXCR2, FCGR3B, VNN3, and FPR2) capable of predicting HF risk. Furthermore, our analysis of intercellular communication, leveraging single-cell sequencing data, highlighted macrophages and T cells as the immune cell subpopulations with the closest interactions with neutrophils. Pseudo-trajectory analysis sheds light on the differentiation states of distinct neutrophil subpopulations.Conclusion: In this study, we conducted an in-depth investigation into the functions of neutrophil subpopulations that infiltrate cardiac tissue in TAC mice. Additionally, we identified four biomarkers (CXCR2, FCGR3B, VNN3, and FPR2) associated with NETs in HF. Our findings enhance the understanding of immunology in HF.

ABSTRACT Gut microbiota and their secreted metabolites have an influence on the initiation and progression of colon cancer. Probiotics are extensively perceived as a potential microbiota-modulation strategy to promote the health of the host, while the effectiveness of preventing colon cancer based on microbiota therapy has not been confirmed, and antitumor mechanisms influenced by microbiota and their metabolites with the intervention of probiotics remain to be further investigated. In vitro, Lactobacillus (JY300-8 and JMR-01) significantly inhibited the proliferation of CT26, HT29, and HCT116 cells. Moreover, we studied the prevention and therapy efficiency of Lactobacillus and its underlying antitumor mechanism through the alteration of gut microbiota and their metabolites regulated by Lactobacillus in colon cancer models in mice. We demonstrated that the pre-administration of Lactobacillus (JY300-8 and JMR-01) for 20 days before establishing tumor models resulted in an 86.21% reduction in tumor formation rate compared to tumor control group. Subsequently, continuous oral administration of living Lactobacillus significantly suppresses tumor growth, and tumor volumes decrease by 65.2%. Microbiome and metabolome analyses reveal that Lactobacillus suppresses colonic tumorigenesis and progression through the modulation of gut microbiota homeostasis and metabolites, including the down-regulation of secondary bile acids, sphingosine 1-phosphate (S1P), and pyrimidine metabolism, as well as the production of anticarcinogenic compounds in tumor-bearing mice. Additionally, metabolome analyses of Lactobacillus (JY300-8 and JMR-01) indicate that living Lactobacillus could reduce the relative abundance of alanine and L-serine to suppress tumor progression by regulating the tumor microenvironment, including down-regulation of pyrimidine metabolism and S1P signaling in cancer. These findings provide a potential prevention strategy and therapeutic target for colon cancer through the intervention of dietary Lactobacillus. IMPORTANCE The modulation of gut microbiota and metabolites has a significant influence on the progression of colon cancer. Our research indicated that the intervention of probiotics is a potentially feasible strategy for preventing colon cancer. We have also revealed the underlying antitumor mechanism through the alteration of gut microbiota and their metabolites, which could lead to broader biomedical impacts on the prevention and therapy of colon cancer with microbiota-based therapy regulated by probiotics.

While photoelectrochemical water splitting offers a promising means to obtain renewable H2, it is challenging to balance light absorption and carrier transport in semiconductor thin films. Here, authors combine surface doping and bulk gradient doping to decouple these factors to boost performances.

A major challenge for the effective use of Ti-based MXenes in applications with harsh environmental conditions is their poor resistance to oxidation. Here, authors report an air-stable Ti3C2T x composite with extracted bentonite able to endure high-temperature annealing in air by an oxygen adsorption competition mechanism.

Summary: Background: To evaluate the efficacy and safety of toripalimab combined with neoadjuvant chemoradiotherapy (NCRT) for locally advanced esophageal squamous cell carcinoma (ESCC). Methods: In this single arm, phase II trial, 44 ESCC patients were enrolled from December 2019 to July 2021 at Sun Yat-sen University Cancer Center (Guangzhou, China). All patients received concurrent radiotherapy (44 Gy in 20 fractions), chemotherapy (paclitaxel 50 mg/m2 and cisplatin 25 mg/m2 on days 1, 8, 15, and 22), and toripalimab (240 mg on days 1 and 22). Within 6–8 weeks of neoadjuvant treatment, patients underwent surgery. The results of the study patients were compared with those of 86 matched patients between July 2015 and March 2022. The primary endpoint was pathological complete response (pCR) rate, and the secondary endpoints were treatment-related adverse events and R0 rates. This trail was registered with ClinicalTrails.gov, NCT04006041. Findings: All patients received neoadjuvant treatment, and 42 completed esophagectomy. Of the 42 patients, 21 (50%; 95% CI 35–65) achieved pCR and 2 (5%) patients were ypT0N+. The R0 resection rate was 98% (41/42). Nine (20%) of 44 patients had grade 3/4 adverse events. Among the perioperative complications (n = 42), anastomotic leakage occurred in five cases (12%), tracheal fistula in three cases (7%), and postoperative death in one case (2%) due to tracheal fistula. Compared with the control cohort, the pCR rate of the study group was higher but without significant difference (50% vs. 36%, P = 0.19). Interpretation: Toripalimab combined with NCRT failed to show significantly better pCR rate than historical data. Nevertheless, considering the signs of efficacy and acceptable safety of this regimen, further evaluation in phase III randomized trials might be warranted. Funding: National Natural Science Foundation of China.

Background: The molecular mechanisms of esophageal squamous cell carcinoma (ESCC) remain poorly understood. Transmembrane emp24 trafficking protein 3 (TMED3) acts as an oncogene or tumor suppressor gene in different cancers. Our study was to explore the clinicopathological significance and functional roles of TMED3 in ESCC. Methods: Immunohistochemistry, qPCR, and western blotting were used to analyze the expression of TMED3 in ESCC tissues and cells. Statistical analysis was performed to analyze the relationship between TMED3 expression and tumor characteristics in patients with ESCC. The role of TMED3 in vitro and in vivo was investigated by performing functional verification experiments and using a xenograft mouse model. Proteins that are functionally related to TMED3 were recognized by Affymetrix microarray and Ingenuity Pathway Analysis (IPA). Functional verification experiments were performed to analyze the role of FAM60A (a protein functionally related to TMED3) in vitro. Results: We confirmed the overexpression of TMED3 was correlated with poor prognosis in ESCC patients. When TMED3 was knocked down, ESCC cell proliferation, migration, and invasion were inhibited whereas cell apoptosis was promoted in vitro, and tumorigenicity was inhibited in vivo. We further revealed significant changes in gene expression profile in TMED3 knockdown cells. Among these differentially expressed genes, FAM60A was overexpressed in ESCC tissues. Furthermore, knocking down FAM60A significantly weakened the proliferation ability of ESCC cells and reversed TMED3's tumorigenicity of ESCC cells. Conclusion: Our study revealed an oncogenic role of TMED3 in ESCC.

Abstract It is now well known that non-coding RNAs (ncRNAs), rather than protein-coding transcripts, are the preponderant RNA transcripts. NcRNAs, particularly microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are widely appreciated as pervasive regulators of multiple cancer hallmarks such as proliferation, apoptosis, invasion, metastasis, and genomic instability. Despite recent discoveries in cancer therapy, resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy continue to be a major setback. Recent studies have shown that ncRNAs also play a major role in resistance to different cancer therapies by rewiring essential signaling pathways. In this review, we present the intricate mechanisms through which dysregulated ncRNAs control resistance to the four major types of cancer therapies. We will focus on the current clinical implications of ncRNAs as biomarkers to predict treatment response (intrinsic resistance) and to detect resistance to therapy after the start of treatment (acquired resistance). Furthermore, we will present the potential of targeting ncRNA to overcome cancer treatment resistance, and we will discuss the challenges of ncRNA-targeted therapy—especially the development of delivery systems.

Oil and gas exploration near faults in shallow strata is investigated in this study based on an analysis of oil-source faults in reservoir–cap rock combinations without a source rock. The oil-source faults were mapped by superimposition of the distribution area of oil-source faults and the leakage area of cap rocks. This method is applied to the mapping of oil-source faults for two sets of reservoir–cap rock combinations without a source rock in the Banqiao area of the Qikou Sag in the Bohai Bay Basin, eastern China. Combination B is formed by a mudstone cap rock of the middle sub-member of the 1st member of the Shahejie Formation (E3s1M) with its underlying reservoir, while Combination C is formed by a mudstone cap rock of the 2nd member of the Dongying Formation (E3d2) with its underlying reservoir. The results show that the oil-source faults of Combination B are relatively better developed and mainly occur in the northeast and southeast, while those of Combination C are not as well developed and are only distributed at the southeastern edge of the study area with a small proportion in the north. These results are consistent with the fact that oil and gas are mainly distributed near oil-source faults, proving the method proposed is workable in determining the oil-source faults in reservoir–cap rock combinations without a source rock.

The benefit of induction chemotherapy before definitive chemoradiotherapy (CRT) for patients with esophageal cancer is still uncertain. The results of this phase II randomized trial show that the addition of induction chemotherapy to CRT does not improve the response rate or survival of patients with unresectable esophageal squamous cell carcinoma.

Fulvic acid (FA) is a mixture of polyphenolic acid compounds extracted from humus, peat, lignite, and aquatic environments; it is used in traditional medicine to treat digestive tract diseases. The purpose of the present study was to investigate the effect of FA on growth performance, inflammation, intestinal microbiota, and metabolites in Xianju yellow chicken. The 240 Xianju yellow chickens (age, 524 days) included were randomly categorized into 4 treatments with 6 replicates per treatment and 10 birds per replicate. Birds received a basal diet or a diet supplemented with 500, 1,000, or 1,500 mg/kg of FA, for a period of 42 days. Dietary supplementation of FA improved average daily gain (ADG) and feed conversion ratio (FCR) (P > 0.05). Compared with the control group, the serum level of TNF-α in birds supplemented with FA was significantly decreased (P < 0.05), and that of IL-2 was significantly increased after administration of 1,500 mg/kg FA (P < 0.05). Analysis of gut microbiota indicated that FA reduced the relative abundance of genus Mucispirillum, Anaerofustis, and Campylobacter, but enriched genus Lachnoclostridium, Subdoligranulum, Sphaerochaeta, Oscillibacter, and Catenibacillus among others. Untargeted metabolomic analyses revealed that FA increased 7-sulfocholic acid, but reduced the levels of Taurochenodeoxycholate-7-sulfate, LysoPC 20:4 (8Z, 11Z, 14Z, 17Z), LysoPC 18:2, Phosphocholine and other 13 metabolites in the cecum. The results demonstrated that FA may potentially have a significant positive effect on the growth performance and immune function of Xianju yellow chicken through the modulation of the gut microbiota.

Background: Proton pump inhibitors (PPIs) have been shown to regulate the gut microbiome and affect the response to immune checkpoint inhibitors (ICIs). Contradictory results on survival have been observed in patients concomitantly treated with ICIs and PPIs. We performed a systematic review and meta-analysis to determine the association between PPI use and survival outcomes in ICI-treated cancer patients. Methods: EMBASE, MEDLINE/PubMed, Cochrane Library databases, and major oncology conference proceedings were searched. Studies comparing overall survival (OS) and progression-free survival (PFS) between PPI-treated and PPI-free groups of ICI-treated cancer patients were included. Data regarding study and patient characteristics, ICI and PPI treatments, and survival outcomes were extracted. Hazard ratios (HRs) with 95% confidence interval (CI) were pooled using random effects models. Subgroup meta-analyses and meta-regressions were performed to explore possible factors of heterogeneity among the studies. Results: A total of 33 studies were included, comprising 7383 ICI- and PPI-treated patients and 8574 ICI-treated and PPI-free patients. The pooled HR was 1.31 (95% CI, 1.19–1.44; p

The development and evaluation of the transport capacity of oil and gas determine the location of the associated fractures based on the analysis of its ability to transport oil and gas and finding favorable locations in different periods of the faults. This paper also explored the distribution of oil and gas in different positions near the lower generation and upper reservoir faults in the petroliferous basin, while locations of the faults’ convex ridges with stronger oil and gas transporting ability are also determined and evaluated. A set of prediction methods in determining favorable locations for oil and gas transport capacity configured in different periods of fault are established and applied in different periods of the F3 fault in the Daliuquan area, Langgu Sag, Jizhong Depression, Bohai Bay Basin. The results of these two evaluations indicate that the development position of associated fractures of the F3 fault with strong oil and gas transport capacity was distributed primarily in the eastern part of the area. Sections of the convex ridge with stronger oil and gas transport capacity, on the other hand, are mainly distributed in the western, middle, and eastern faults. The favorable location of transporting oil and gas ability configuration of the F3 fault in different periods is distributed mainly in the east of the F3 fault, where oil and gas generated by the source rock of the Sha 4 Member (Es4) migrate and accumulate to the middle and lower sections of the Sha 3 Member (Es31−2) through the developmental position of associated fractures and convex ridges.

Abstract Background The prevalence of myopia and associated risk factors among children in Chongqing has not yet been determined. This study investigated the prevalence of myopia and possible relationships between myopia and several related factors among school children in Chongqing. Methods This cross-sectional study assessed a sample of 997 children (7–13 years of age) attending primary school in Chongqing. Data were obtained from visual acuity and refractive error measurements and a structured questionnaire. Myopia was defined as visual acuity

In this study, the purification of crocin-I from Gardenia yellow by macroporous resin columns in-series was systematically investigated. The in-series macroporous adsorption resins consisting of XAD 4 and XAD 1600N resins were selected on the basis of the evaluation of performance and separation characteristics of 17 kinds of resins, including the adsorption capacities, desorption ratio, and separation degree. According to the analysis results, the optimum conditions were as follows: bed volume ratio of XAD 4 and XAD 1600N resins, sample volume, flow rate, and methanol concentration were 3 : 1, 5 BV, 15 BV/h, and 70%, respectively (BV was the bed volume of XAD 4 resin). After one run treatment, the separation degree of crocin-I at 254 nm and 440 nm decreased from 1.92 to 0.08 (DC−254 nm) and from 0.71 to 0.36 (DC−440 nm), respectively. The results showed that the in-series macroporous resins revealed a high capacity in the purification of crocin-I. Meanwhile, in the animal experiment, the forced swimming tests were regulated by crocin-I and Gardenia yellow, which demonstrated that crocin-I was the main constituent of Gardenia yellow and had potential antidepressant biological activities.

Bulk III-nitride materials MN (M = Al, Ga and In) and their alloys have been widely used in high-power electronic and optoelectronic devices, but stable two-dimensional (2D) III-nitride materials, except h-BN, have not been realized yet. A new kind of 2D III-nitride material M2Si2N4 (M = Al, Ga and In) is predicted by choosing Si as the appropriate passivation element. The stability, electronic and optical properties of 2D M2Si2N4 materials are studied systematically based on first-principles calculations. The results show that Al2Si2N4 and Ga2Si2N4 are found to be indirect bandgap semiconductors, while In2Si2N4 is a direct bandgap semiconductor. Moreover, Al2Si2N4 and In2Si2N4 have good absorption ability in the visible light region, while Ga2Si2N4 is an ultraviolet-light-absorbing material. Furthermore, the carrier lifetimes of Ga2Si2N4 and In2Si2N4 are as large as 157.89 and 103.99 ns, respectively. All these desirable properties of M2Si2N4 materials make them attractive for applications in electronics and photoelectronics.

In October 2021, a wild bird-origin H3N8 influenza virus-A/Chinese pond heron/Jiangxi 5-1/2021 (H3N8)-was isolated from Chinese pond heron in China. Phylogenetic and molecular analyses were performed to characterize the genetic origin of the H3N8 strain. Phylogenetic analysis revealed that eight gene segments of this avian influenza virus H3N8 belong to Eurasian lineages. HA gene clustered with avian influenza viruses is circulating in poultry in southern China. The NA gene possibly originated from wild ducks in South Korea and has the highest homology (99.3%) with A/Wild duck/South Korea/KNU2020-104/2020 (H3N8), while other internal genes have a complex and wide range of origins. The HA cleavage site is PEKQTR↓GLF with one basic amino acid, Q226 and T228 at HA preferentially bind to the alpha-2,3-linked sialic acid receptor, non-deletion of the stalk region in the NA gene and no mutations at E627K and D701N of the PB2 protein, indicating that isolate A/Chinese pond heron/Jiangxi 5-1/2021 (H3N8) was a typical avian influenza with low pathogenicity. However, there are some mutations that may increase pathogenicity and transmission in mammals, such as N30D, T215A of M1 protein, and P42S of NS1 protein. In animal studies, A/Chinese pond heron/Jiangxi 5-1/2021 (H3N8) replicates inefficiently in the mouse lung and does not adapt well to the mammalian host. Overall, A/Chinese pond heron/Jiangxi 5-1/2021 (H3N8) is a novel wild bird-origin H3N8 influenza virus reassortant from influenza viruses of poultry and wild birds. This wild bird-origin avian influenza virus is associated with wild birds along the East Asian-Australasian flyway. Therefore, surveillance of avian influenza viruses in wild birds should be strengthened to assess their mutation and pandemic risk in advance.

Probiotics, as novel functional foods via microbiota-modulation to enhance host health and inhibit tumor carcinogenesis, have been attracted considerable interests. L. casei JY, as a potential probiotic, was irradiated by 12C6+ beams and a new mutant strain JY300-8 was generated through three round selections of transit tolerance in the upper human gastrointestinal tract, adhesion ability to Caco-2 cells and inhibitory pathogenic microorganisms, respectively. Interestingly, JY300-8 presented excellent properties, including the strongest adhesion ability (86.81%) to Caco-2 cells to our knowledge and more excellent antimicrobial properties, which was used for the potential candidate probiotic. Additionally, JY300-8 could significantly inhibit the proliferation of Caco-2, HT29 and HCT116 cells in vitro, respectively. Furthermore, there were better therapeutic effects at an early stage in colon cancer mice, which included the similar survival rates (90%) and stronger inhibitory effect on tumor (83.48%), lower treatment cost and less side effects in comparison to the therapy drug (DFUR) for colon cancer (65.65%), which was attributed to promoting the apoptosis of colon cells and enhancing antitumor response via modulation cancer-induced gut microbiota dysbiosis by oral administration of JY300-8. Therefore, JY300-8 has great potential for bio-prophylactic and bio-therapeutic functional food in colon carcinogenesis. This work provided a promising approach that could improve human health, reduce greatly cancer incidence and mitigate cancer progression via modulation gut microbiota by excellent probiotics intervention.

Dry eye disease (DED) is the most common clinical ocular surface disease. Given its multifactorial etiology, no consensus has been reached on the diagnosis criteria for dry eye disease. Topical drug administration remains the mainstay of treatment but is limited to the rapid clearance from the eye surface. To address these problems, hydrogel-based materials were designed to detect biomarkers or act as drug delivery systems by taking advantage of their good biocompatibility, excellent physical and mechanical properties, and long-term implant stability. Biosensors prepared using biocompatible hydrogels can be sensitive in diagnosing DED, and the designed hydrogels can also improve the drug bioavailability and retention time for more effective and long-term treatment. This review summarizes recent advances in the use of hydrogels for diagnosing and treating dry eye, aiming to provide a novel reference for the eventual clinical translation of hydrogels in the context of dry eye disease.

Tumor-associated macrophages (TAMs), which display a tumor-supportive M2 phenotype, are closely related to tumor growth and metastasis. The reprogramming of TAMs toward a tumoricidal M1 profile has emerged as an attractive strategy for cancer immunotherapy. In this study, we found that the intratumoral injection of PcrV protein, a component of the Pseudomonas aeruginosa type 3 secretion system, suppressed tumor growth and increased apoptosis, inducible nitric oxide synthase (iNOS) expression, and the percentage of M1-polarized TAMs in tumor tissues. Furthermore, the intratumoral injection of PcrV-primed macrophages exerted a similar tumoricidal effect. In vitro analyses revealed that PcrV reeducated TAMs toward an antitumoral M1 phenotype and augmented their nitric oxide (NO)-mediated cytotoxicity against cancer cells. Mechanistically, we found that these effects were dependent on the activation of Toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)-mediated regulation of a PI3K/AKT/mTOR-glycolysis-NO feedback loop via direct interaction with TLR4. Collectively, these results revealed a potential role for PcrV in cancer immunotherapy through the targeting of TAM plasticity.

Scientific understanding of regional wind speed variation characteristics and driving mechanisms is of great practical significance to the management and rational utilization of wind energy resources, ecological protection and governance, and sustainable development of agriculture. Taking the Shiyang River Basin in inland river basin of monsoon marginal zone as the study area, this paper analyzed wind speed changes and influencing factors at different time and space scales. The results showed that, first of all, the annual average wind speed showed a downward trend as a whole in Shiyang River Basin, and the change of spring wind speed and the decreasing frequency of daily max-wind speed above Grade 5 were the main contributors. The turning point of annual average wind speed was consistent with that in spring and autumn (1981) and earlier than that in winter and summer (1982). Secondly, as far as the wind speed change tendency rate is concerned, before the turning point, Yongchang area had the largest decline rate with obvious “2000 m effect”, while after the turning point, Wuwei Basin had the largest rise rate with obvious “basin effect”. Focusing on the downstream desert oasis region, the sand-driving wind speed showed a decreasing trend as a whole, and showed a “cliff-like” decline after 1988. The rising trend of sand-driving wind speed after 2014 will pose greater challenges to ecological governance. Finally, under the background of unbalanced global warming, the wind speed changes in different periods were driven by the circulation system changes. In 1970–1981, the decline of the wind speed was the result of the combined action of Arctic Oscillation and Asia Polar Vortex. However, after 1981, it was affected by North Atlantic Oscillation, Asian Meridional Circulation, Tibet Plateau Circulation, India-Burma Trough, Western Pacific Subtropical High and Northern Hemisphere Subtropical High.

To study the spatial distribution and scale of oil and gas near faults in petroliferous basins, a prediction model is established for the degree of damage that faults in different stages of evolution exert on the sealing ability of mudstone cap rocks by calculating the stages and degree of fault damage to the sealing ability of mudstone cap rocks. This model is applied to the Nanpu 5th Structure and the results show that at survey lines L2 and L8, the F1 Fault destroyed the sealing capacity of mudstone cap rock of the 2nd member of Dongying Formation (E3d2). The undamaged cap rock stage, when the degree of damage was zero, persisted from 23.8 to 16.0 Ma at survey line L2 and from 23.8 to 13.6 Ma at survey line L8. Complete destruction, i.e., where the degree of damage was 100%, at survey lines L2 and L8 occurred from 16.0 to 13.3 Ma and from 13.6 to 13.3 Ma, respectively. The partial destruction stage began 13.3 Ma ago and persists today; the degrees of damage at survey lines L2 and L8 were 89.96% and 82.58%, respectively. This was not conducive to oil and gas accumulation in the reservoir under the mudstone cap rock of E3d2. These results agreed with the current findings of small amounts of oil and gas under the mudstone cap rock of E3d2 at survey line L8 and no oil and gas at survey line L2. This indicates that the model is feasible for predicting the degree of damage to the sealing ability of the mudstone cap rocks by faults at different stages in their evolution.

Atrial fibrillation is the most common form of cardiac arrhythmia. Atrial fibrosis is a significant feature of atrial fibrillation though its mechanism is not well understood. We searched the Gene Expression Omnibus database to compare mRNA expression patterns between atrial fibrillation and sinus rhythm samples; one hundred and forty eight differentially expressed genes were identified. Most of these genes were significantly enriched in the extracellular matrix organization process and collagen-activated tyrosine kinase receptor signaling pathway. To screen hub genes involved in atrial fibrosis, we constructed a protein-protein interaction network and found that three hub genes (SERPINE1/plasminogen activator inhibitor-1/PAI-1, TIMP Metallopeptidase Inhibitor 3/TIMP3 and decorin/DCN) play vital roles in atrial fibrosis, especially plasminogen activator inhibitor-1. Elevated plasminogen activator inhibitor-1 expression was positively correlated with the p53 signaling pathway. Plasminogen activator inhibitor-1 and p53 protein expression levels were verified in patients with sinus rhythm and atrial fibrillation by Western blot analysis. Compared with the sinus rhythm controls, p53 and plasminogen activator inhibitor-1 protein expressions were upregulated in the atrial tissues of patients with atrial fibrillation. p53 was also found to regulate plasminogen activator inhibitor-1 based on the results of cellular and molecular experiments. Thus, the p53/plasminogen activator inhibitor-1 signaling axis may participate in the pathophysiological processes of atrial fibrillation, and plasminogen activator inhibitor-1 may serve as a new therapeutic biomarker in atrial fibrillation.

Background: Non-alcoholic fatty liver disease (NAFLD) is a burgeoning health problem but no drug has been approved for its treatment. Animal experiments and clinical trials have demonstrated the beneficial of saffron on NAFLD. However, the bioactive ingredients and therapeutic targets of saffron on NAFLD are unclear.Purpose: This study aimed to identify the bioactive ingredients of saffron responsible for its effects on NAFLD and explore its therapy targets through network pharmacology combined with experimental tests.Methods: Various network databases were searched to identify bioactive ingredients of saffron and identify NAFLD-related targets. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment were conducted to enrich functions and molecular pathways of common targets and the STRING database was used to establish a protein-protein interaction network (PPI). The effect of crocetin (CCT) on NAFLD was evaluated in a mouse model of NAFLD by measuring the biomarkers of lipid, liver and renal function, oxidative stress, and inflammation. Liver histopathology was performed to evaluate liver injury. Nuclear factor erythroid-related factor (Nrf2) and hemeoxygenase-1 (HO-1) were examined to elucidate underlying mechanism for the protective effect of saffron against NAFLD.Results: A total of nine bioactive ingredients of saffron, including CCT, with 206 common targets showed therapeutic effects on NAFLD. Oxidative stress and diabetes related signaling pathways were identified as the critical signaling pathways mediating the therapeutic effects of the active bioactive ingredients on NAFLD. Treatment with CCT significantly reduced the activities of aspartate aminotransferase (AST), alanine transaminase (ALT), and the levels of total cholesterol (TC), triglyceride (TG), malondialdehyde (MDA), blood urea nitrogen (BUN), creatinine (CR), and uric acid (UA). CCT significantly increased the activities of superoxide dismutase (SOD), and catalase (CAT). Histological analysis showed that CCT suppressed high-fat diet (HFD) induced fat accumulation, steatohepatitis, and renal dysfunctions. Results of ELISA assay showed that CCT decreased the expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), and increased the expression of HO-1 and Nrf2.Conclusion: This study shows that CCT is a potential bioactive ingredient of saffron that treats NAFLD. Its mechanism of action involves suppressing of oxidative stress, mitigating inflammation, and upregulating Nrf2 and HO-1 expression.

Abstract Background The efficient utilization of lignocellulosic biomass for biofuel production has received increasing attention. Previous studies have investigated the pretreatment process of biomass, but the detailed enzymatic hydrolysis process of pretreated biomass remains largely unclear. Thus, this study investigated the pretreatment efficiency of dilute alkali, acid, hydrogen peroxide and its ultimate effects on enzymatic hydrolysis. Furthermore, to better understand the enzymatic digestion process of alkali-pretreated sweet sorghum straw (SSS), multimodal microscopy techniques were used to visualize the enzymatic hydrolysis process. Result After pretreatment with alkali, an enzymatic hydrolysis efficiency of 86.44% was obtained, which increased by 99.54% compared to the untreated straw (43.23%). The FTIR, XRD and SEM characterization revealed a sequence of microstructural changes occurring in plant cell walls after pretreatment, including the destruction of lignin–polysaccharide interactions, the increase of porosity and crystallinity, and reduction of recalcitrance. During the course of hydrolysis, the cellulase dissolved the cell walls in the same manner and the digestion firstly occurred from the middle of cell walls and then toward the cell wall corners. The CLSM coupled with fluorescent labeling demonstrated that the sclerenchyma cells and vascular bundles in natural SSS were highly lignified, which caused the nonproductive bindings of cellulase on lignin. However, the efficient delignification significantly increased the accessibility and digestibility of cellulase to biomass, thereby improving the saccharification efficiency. Conclusion This work will be helpful in investigating the biomass pretreatment and its structural characterization. In addition, the visualization results of the enzymatic hydrolysis process of pretreated lignocellulose could be used for guidance to explore the lignocellulosic biomass processing and large-scale biofuel production.

Abstract Background Small cell carcinoma of the esophagus (SCCE) is characterized by its progressive feature and poor prognosis. There is no consensus on a standard therapeutic modality for SCCE. In this study, we aimed to characterize the outcomes of primary SCCE patients treated by radiation therapy as part of treatment and investigate prognostic factors. Methods We retrospectively analyzed the data of 42 SCCE patients who were treated by RT as part of treatment at the Sun Yat-sen University Cancer Center from 2001 to 2014. The Kaplan-Meier and log-rank method were used to analyze survival. Cox’s hazard regression model was applied to determine prognostic factors. Results Of the 42 enrolled patients, 25 had limited disease (LD) and 17 with extensive disease (ED). The overall response rate (CR + PR) was 60.0% (21/35). The median overall survival time (OS) for whole and LD group were 12.9 and 36.8 months. The 1-, 3- and 5-year OS rates of the whole cohort were 64.9, 31.3, and 13.9%, respectively. OS was significantly longer in patients with ECOG performance score (ECOG PS)

This paper proposes a novel structure extraction approach that is able to achieve high classification accuracy and low computing burden to hyperspectral image (HSI) classification based on total variation (SETV). Specifically, a two-scale decomposition-based relative total variation (TSD-RTV) method is presented for the first time to process the information of different scales, such that the structure can be well extracted. Moreover, a new weighted-average fusion method is introduced, which can reduce the dimensionality and also remove the noise due to hyperspectral sensors. The support vector machine (SVM) is applied to HSI classification as a classifier. The experiments are conducted on three real hyperspectral datasets: Indian Pines, Salinas, and Kennedy Space Center. The experimental results show the outstanding performance of the proposed SETV model in terms of classification accuracy and computational efficiency.

Abstract Background Toxoplasma gondii is an obligate intracellular parasite that infects humans and other warm-blooded animals. Previous quantitative proteomic analyses of infected host cells revealed that the expression of many host proteins is modulated by T. gondii infection. However, at present limited data are available on the differentially expressed miRNAs (DEMs) associated with the pathology and host immune responses induced by acute and chronic infection with T. gondii in pigs in vivo. In this study, high-throughput sequencing was used to investigate expression profiles of spleen miRNAs at 10, 25 and 50 days post-infection (DPI) in pigs infected with Chinese I genotype strain T. gondii isolated from a dead pig. Results When compared to the control group, 34, 6 and 86 DEMs were found in spleens of infected pigs at 10, 25 and 50 DPI, respectively. Gene Ontology (GO) enrichment analysis of the target genes of DEMs showed that no GO terms were enriched at 25 DPI, whereas 28 and 241 GO terms, of which two and 215 were sample-specific, were significantly enriched at 10 and 50 DPI, respectively. The top 20 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of the target genes of DEMs included signal transduction, immune system, metabolism and diseases. miRNA–gene network analysis revealed that the DEMs played important roles in the host immune response to T. gondii infection by modulating expression levels of cellular immunity-related cytokines and immune-related C-type lectins. Conclusion Our results not only showed that host miRNA expression is altered by T. gondii but also revealed differences in the regulation of key biological processes and pathways involved in host responses to acute versus chronic T. gondii infection. This will aid future research into miRNA-target interactions during T. gondii infection in pigs and the development of novel therapies against T. gondii.

Background: Valvular heart disease (VHD) is a major precipitating factor of atrial fibrillation (AF) that contributes to decreased cardiac function, heart failure, and stroke. Stroke induced by VHD combined with atrial fibrillation (AF-VHD) is a much more serious condition in comparison to VHD alone. The aim of this study was to explore the molecular mechanism governing VHD progression and to provide candidate treatment targets for AF-VHD. Methods: Four public mRNA microarray datasets were downloaded and differentially expressed genes (DEGs) screening was performed. Weighted gene correlation network analysis was carried out to detect key modules and explore their relationships and disease status. Candidate hub signature genes were then screened within the key module using machine learning methods. The receiver operating characteristic curve and nomogram model analysis were used to determine the potential clinical significance of the hub genes. Subsequently, target gene protein levels in independent human atrial tissue samples were detected using western blotting. Specific expression analysis of the hub genes in the tissue and cell samples was performed using single-cell sequencing analysis in the Human Protein Atlas tool. Results: A total of 819 common DEGs in combined datasets were screened. Fourteen modules were identified using the cut tree dynamic function. The cyan and purple modules were considered the most clinically significant for AF-VHD. Then, 25 hub genes in the cyan and purple modules were selected for further analysis. The pathways related to dilated cardiomyopathy, hypertrophic cardiomyopathy, and heart contraction were concentrated in the purple and cyan modules of the AF-VHD. Genes of importance (CSRP3, MCOLN3, SLC25A5, and FIBP) were then identified based on machine learning. Of these, CSRP3 had a potential clinical significance and was specifically expressed in the heart tissue. Conclusions: The identified genes may play critical roles in the pathophysiological process of AF-VHD, providing new insights into VHD development to AF and helping to determine potential biomarkers and therapeutic targets for treating AF-VHD.

The Shiyang River Basin is a typical arid watershed in Northwest China. Scientific understanding of the driving mechanism of runoff change is the basis of scientific utilization of water resources and regional sustainable development. In this study, runoff changes at different time scales were analyzed for the period 1960–2018, and the impacts of climate variability and human activities on runoff were investigated in the middle and lower reaches of the Shiyang River Basin (SRB). A combination of mutation analysis and human-designed analysis was adopted to divide the study period into the baseline period and the variation period. The Mann–Kendall test (M−K) and Double Mass Curve method (DMC) were used to detect abrupt changes and quantify the relative effects of climate change and human activities on runoff. The results reveal a significant declining trend in annual runoff on the whole in the middle and lower reaches of the SRB, and there was an obvious recovery trend after the implementation of the Comprehensive Treatment Program of the SRB (CTSRB) in 2007. Abrupt changes occurred in 1976, 1991 and 2007, which divided the study period into the baseline period (1960–1975), the Variation Ⅰ period (1976–1990), the Variation Ⅱ period (1991–2006) and the Variation III period (2007–2018). The contribution of human activities to runoff reduction was 88.72%, whereas the contribution of climate change to runoff reduction was only 11.28%. Furthermore, the contribution of human activities to runoff reduction in the Variation Ⅰ period, Variation Ⅱ period and Variation III period was 89.44%, 93.02% and 83.69%, respectively. Therefore, human activities played the most dominant role in the variation of runoff, followed by climate change and upstream runoff. Further analysis of the impact of human activities on runoff indicated that agricultural irrigation was the dominant factor of runoff reduction. This study can provide detailed information on water resources and a scientific basis for the development and utilization of water resources in the future.

Crocus sativus L. is commonly used as functional food and medicinal herb in traditional Chinese medicine. In this study, the spectrum–effect relationship was established between HPLC fingerprints and in vitro antioxidant activity of saffron to improve the quality evaluation method of saffron. The fingerprints of 21 batches of saffron collected from different regions were assessed, and the data were further analyzed by chemometric methods, including similarity analysis, hierarchical clustering analysis, principal component analysis, and orthogonal partial least squares discriminant analysis. The spectrum–effect relationship between fingerprints and antioxidant effect of saffron was analyzed by grey relational analysis and partial least square methods to figure out the antioxidant component of saffron. Thirteen common peaks of 21 batches of saffron were included in the analysis, and peak 3 (picrocrocin), peak 7 (crocin I), and peak 10 (crocin II) were identified as the main active components responsible for antioxidant efficacy. Besides, a multi-index quality control method was developed for simultaneous determination of these three antioxidant components in saffron. Taken together, this study provided new strategies for the quality control and the development of new bioactive products of saffron in the future.

The mechanisms by which Y chromosome microdeletions cause infertility have been well described; however, the therapeutic targets remain a challenge. Here, we used whole-genome sequencing to explore the mechanism of Y chromosome deletion and potential therapeutic targets in a patient with infertility. There were no abnormalities in the patient’s medical history. Routine semen analysis showed immotile sperm and only two motile spermatozoa were occasionally see after centrifugation, indicating that the direct cause of infertility was an abnormal sperm count and motility. A Y chromosome microdeletion test revealed partial deletion of the AZFc region, including AZFc1 , AZFc2 , AZFc3 , and AZFc4 . Whole-genome sequencing showed that the patient had seven harmful mutations, with only one significant epigenetic mutation, SH3KBP1 . Gene Ontology analysis of these meaningful mutations indicated involvement of cAMP signaling pathways. The patient’s wife became pregnant following in vitro fertilization, and no significant abnormalities were found during prenatal examination. This case suggests that Y chromosome microdeletion and gene mutation may affect the cAMP signaling pathway, leading to reduced sperm quality and male infertility.

Crocetin is one of the major active constituents of saffron (Crocus sativus L.) which has a reputation for facilitating blood circulation and dispersing blood stasis in traditional Chinese medicine. However, there is little evidence showing the relationship between crocetin intake and the risk of gastrointestinal diseases such as colitis. In order to investigate the effect of crocetin on the regulation of intestinal barrier function and intestinal microbiota composition, mice were treated with crocetin after 3% dextran sulfate sodium (DSS) administration for one week. We found that crocetin intake at 10 mg/kg aggravated colitis in mice, showing increased weight loss and more serious histological abnormalities compared with the DSS group. The 16s rDNA sequencing analysis of the feces samples showed that mice treated with 10 mg/kg crocetin had lower species diversity and richness than those treated with DSS. At the genus level, a higher abundance of Akkermansia and Mediterraneibacter, and a lower abundance of Muribaculaceae, Dubosiella, Paramuribaculum, Parasutterella, Allobaculum, Duncaniella, Candidatus Stoquefichus, and Coriobacteriaceae UCG-002 were observed in the crocetin group. Untargeted metabolomic analyses revealed that crocetin reduced the levels of primary and secondary bile acids such as 12-ketodeoxycholic acid, 7-ketodeoxycholic acid, 3-sulfodeoxycholic acid, 6-ethylchenodeoxycholic acid, chenodeoxycholate, glycochenodeoxycholate-7-sulfate, glycocholate, and sulfolithocholic acid in the colon. In conclusion, crocetin intake disturbed intestinal homeostasis and prolonged recovery of colitis by promoting inflammation and altering gut microbiota composition and its metabolic products in mice. Our findings suggest that patients with gastrointestinal diseases such as inflammatory bowel disease should use crocetin with caution.

Pseudomonas aeruginosa biofilms employ a variety of strategies to hijack the host immune defense system to achieve chronic infection. However, the bacterial components that are involved in this process are not yet fully understood. PcrV, a needle tip protein of the P. aeruginosa type III secretion system (T3SS), was downregulated during P. aeruginosa biofilm infection. The impaired expression of the P. aeruginosa pcrV gene is associated with attenuated immune activation and an increased percentage of M2 macrophages following P. aeruginosa biofilm infection. Treatment with exogenous PcrV produced from Escherichia coli elevated tissue inflammation and the percentage of M1 macrophages, resulting in reduction in the biofilm burden. Further analyses demonstrated that the potential of PcrV to induce classically activated M1 macrophages as evidenced by the increased production of proinflammatory cytokines and anti-bacterial mediators, including inducible nitric oxide synthase (iNOS) and reactive oxygen species (ROS), as well as increased phagocytosis of bacteria. Mechanistically, PcrV-mediated promotion of macrophage M1 polarization and phagocytosis occurs through the activation of mitogen-activated protein kinases (MAPKs) and NF-κB signaling pathways. Collectively, these findings reveal a potential role of PcrV in skewing host immune defense to promote P. aeruginosa biofilm infection and provide new insights into the therapeutic strategies for P. aeruginosa biofilm infection.

The reduction of grain production caused by drought is one of the most serious problems caused by natural disasters. The relative soil moisture of farmland is the most important monitoring indicator for agricultural drought. This study investigated the relative soil moisture of farmland data from 38 agrometeorological stations in a continental river basin area in China from 1992 to 2012. Spatial and temporal variations of the relative soil moisture of farmland were studied using geostatistical analysis. The results show that, from 1992 to 2012, the average annual relative soil moisture of farmland in the continental river basin ranged from 62.5 to 86.1%, and the relative soil moisture of farmland was high in the marginal areas of basins and low in the central areas of basins and plateau areas. The relative soil moisture of farmland was high in the Tarim Basin and the Hexi Corridor, which are located in the northern Tianshan Mountains and the southern and northern Qilian Mountains, and was low from the northern Altun Mountains to the south of Lop Nor, the Turpan Depression, and the Tarbagatai Mountains. From 1992 to 2012, the annual average relative soil moisture of farmland in the continental river basins showed an increasing trend, with a growth rate of 0.57% yr−1. The variation tendency of the relative soil moisture of farmland was different in different river basins; the relative soil moisture showed a decreasing trend in the Mongolian Plateau and an increasing trend in other basin areas. The relative soil moisture of farmland increased in summer, spring, and winter, and decreased in autumn. The change in relative soil moisture of farmland was due to a combination of climatic factors, such as precipitation and temperature, as well as topography and glacial meltwater.

As one of the most destructive and costly natural disasters, drought has far-reaching negative effects on agriculture, water resources, the environment, and human life. Scientific understanding of propagation from meteorological to hydrological drought is of great significance for accurate forecasting of hydrological drought and preventing and mitigating drought disasters. The objective of this study is to analyze the spatio-temporal variational characteristics of propagation from meteorological drought to hydrological drought and the associated driving mechanisms in the eastern Qilian Mountains using the standard precipitation index (SPI), standardized runoff index (SRI), and drought propagation intensity index (DPI). The results show that there has been meteorological humidification and hydrological aridification in the upper reaches of the Shiyang River Basin over the last 56 years; especially in the 2000s, the intensity of hydrological drought was the strongest and the intensity of meteorological drought was the weakest, indicating the propagation intensity of meteorological drought to hydrological drought was extremely strong during this period. The changes of meteorological and hydrological dry−wet are different, both on seasonal and monthly scales. The meteorological dry−wet is shown to have had a significant effect both on the current and month-ahead hydrological dry−wet, where the one-month lag effect was most obvious. The relationship between meteorological and hydrological droughts also vary in space: Hydrological aridification in the Huangyang River, and the rivers east of it, was greater than that in the western tributaries. The drought propagation intensities from west to east showed a decreasing trend, excluding the Huangyang River. Climate and land-use changes are the main factors affecting the propagation from meteorological drought to hydrological drought. When the natural vegetation area accounted for between 76.3−78%, the cultivated land area between 0.55−3.6% and the construction area between 0.08−0.22% were a peer-to-peer propagation process from meteorological drought to hydrological drought in the upper reaches of the Shiyang River.

From the 1994 bailout policies to the 2015 Shanghai-Hong Kong Stock Connect, the policy impact on the Chinese stock market has changed over time. By May 2015, global investors can directly invest in a more legalized and normalized Chinese stock market, whereas they are still concerned about the policy-oriented market and its attendant risks. In this study, we employ the family of GARCH models to investigate the structural changes in risks with the implementation of a series of policies. Our results show that although many policies improve or stabilize the stock market, certain policies lead to substantial volatility. Among them, macro-control policies and transaction cost adjustments are a double-edged sword, which should be used with caution. Furthermore, with opening-up policies being launched recently, the Chinese stock market has entered a new stage in which it affects international capital markets. However, the increased risks, which may result in a sharp turnaround, cause worry.