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The genetic basis of colorectal cancer (CRC) and its clinical associations remain poorly understood due to limited samples or targeted genes in current studies. Here, we perform ultradeep whole-exome sequencing on 1015 patients with CRC as part of the ChangKang Project. We identify 46 high-confident significantly mutated genes, 8 of which mutate in 14.9% of patients: LYST , DAPK1 , CR2 , KIF16B , NPIPB15 , SYTL2 , ZNF91 , and KIAA0586 . With an unsupervised clustering algorithm, we propose a subtyping strategy that classisfies CRC patients into four genomic subtypes with distinct clinical characteristics, including hypermutated, chromosome instability with high risk, chromosome instability with low risk, and genome stability. Analysis of immunogenicity uncover the association of immunogenicity reduction with genomic subtypes and poor prognosis in CRC. Moreover, we find that mitochondrial DNA copy number is an independent factor for predicting the survival outcome of CRCs. Overall, our results provide CRC-related molecular features for clinical practice and a valuable resource for translational research. The ChangKang (Heathy Bowel) project was established to collect molecular and clinical information of a thousand Chinese colorectal cancer patients. Here, the authors present the genomic landscape of the ChangKang cohort and find a subgroup of patients defined by abnormal mitochondrial copy numbers.

We employ optical pump-terahertz probe spectroscopy to investigate the composition-dependent photoconductivity in ternary CdSxSel_x nanobelts. The observed carrier dynamics of CdS nanobelts display much shorter lifetime than those of ternary CdSKSel_K nanobelts. This indicates the implementation of CdS nanobelts as ultrafast switching devices with a switching speed potentially up to 46.7 GHz. Surprisingly, ternary CdS,-Sel_x nanobelts are found to exhibit much higher photoconductivity than binary CdS and CdSe. This is attributed to the higher photocarrier densities in ternary compounds. In addition, the presence of Se in samples resulted in prominent CdSe-like transverse optical （TO） phonon modes due to electron-phonon interactions. The strength of this mode shows a large drop upon photoexcitation but recovers gradually with time. These results demonstrated that growth of ternary nanostructures can be utilized to alleviate the high surface defect density in nanostructures and improve their photoconductivity.

Background The co-culture strategy which mimics natural ecology by constructing an artificial microbial community is a useful tool to activate the biosynthetic gene clusters to generate new metabolites. However, the conventional method to study the co-culture is to isolate and purify compounds separated by HPLC, which is inefficient and time-consuming. Furthermore, the overall changes in the metabolite profile cannot be well characterized. Results A new approach which integrates computational programs, MS-DIAL, MS-FINDER and web-based tools including GNPS and MetaboAnalyst, was developed to analyze and identify the metabolites of the co-culture of Aspergillus sydowii and Bacillus subtilis . A total of 25 newly biosynthesized metabolites were detected only in co-culture. The structures of the newly synthesized metabolites were elucidated, four of which were identified as novel compounds by the new approach. The accuracy of the new approach was confirmed by purification and NMR data analysis of 7 newly biosynthesized metabolites. The bioassay of newly synthesized metabolites showed that four of the compounds exhibited different degrees of PTP1b inhibitory activity, and compound N2 had the strongest inhibition activity with an IC 50 value of 7.967 μM. Conclusions Co-culture led to global changes of the metabolite profile and is an effective way to induce the biosynthesis of novel natural products. The new approach in this study is one of the effective and relatively accurate methods to characterize the changes of metabolite profiles and to identify novel compounds in co-culture systems.

The proper regulation of transcription is essential for maintaining genome integrity and executing other downstream cellular functions 1 , 2 . Here we identify a stable association between the genome-stability regulator sensor of single-stranded DNA (SOSS) 3 and the transcription regulator Integrator-PP2A (INTAC) 4 , 5 – 6 . Through SSB1-mediated recognition of single-stranded DNA, SOSS–INTAC stimulates promoter-proximal termination of transcription and attenuates R-loops associated with paused RNA polymerase II to prevent R-loop-induced genome instability. SOSS–INTAC-dependent attenuation of R-loops is enhanced by the ability of SSB1 to form liquid-like condensates. Deletion of NABP2 (encoding SSB1) or introduction of cancer-associated mutations into its intrinsically disordered region leads to a pervasive accumulation of R-loops, highlighting a genome surveillance function of SOSS–INTAC that enables timely termination of transcription at promoters to constrain R-loop accumulation and ensure genome stability. SOSS–INTAC stimulates promoter-proximal termination of transcription and attenuates R-loops associated with paused RNA polymerase II to prevent R-loop-induced genome instability.

Licochalcone A (LCA), a flavonoid isolated from the famous Chinese medicinal herb Glycyrrhiza uralensis Fisch, presents obvious anti-cancer effects. In this study, the anti-cancer effects and potential mechanisms of LCA in non-small cell lung cancer (NSCLC) cells were studied. LCA decreased cell viability, increased lactate dehydrogenase release and induced apoptosis in a concentration-dependent manner in NSCLC cells while not in human embryonic lung fibroblast cells. The expression of phosphatidylethanolamine-modified microtubule-associated protein light-chain 3 (LC3-II) and formation of GFP-LC3 punta, two autophagic markers, were increased after treatment with LCA. LCA-induced LC3-II expression was increased when combined with chloroquine (CQ), while knock-down of autophagy related protein (ATG) 7 or ATG5 reversed LCA-induced LC3-II expression and GFP-LC3 punta formation, suggesting that LCA induced autophagy in NSCLC cells. Inhibition of autophagy could not reverse the LCA-induced cell viability decrease and apoptosis. In addition, LCA increased the expression of endoplasmic reticulum stress related proteins, such as binding immunoglobulin protein and C/EBP homologous protein (CHOP). Knock-down of CHOP reversed LCA-induced cell viability decrease, apoptosis and autophagy. Taken together, LCA-induced autophagic effect is an accompanied phenomenon in NSCLC cells and CHOP is critical for LCA-induced cell viability decrease, apoptosis and autophagy.

Adhesion-regulating molecule 1 (ADRM1) has been implicated in tumor development, yet its specific role in bladder cancer (BC) remains undefined. This study aimed to elucidate the function of ADRM1 in BC through a combination of bioinformatics analysis and immunohistochemical analysis (IHC). Utilizing R version 3.6.3 and relevant packages, we analyzed online database data. Validation was conducted through IHC data, approved by the Institutional Ethics Committee (Approval No. K20220830). In both paired and unpaired comparisons, ADRM1 expression was significantly elevated in BC tissues compared to adjacent tissues, as evidenced by the results of TCGA dataset and IHC data. Patients with high ADRM1 expression had statistically worse overall survival than those with low ADRM1 expression in TCGA dataset, GSE32548 dataset, GSE32894 dataset, and IHC data. Functional analysis unveiled enrichment in immune-related pathways, and a robust positive correlation emerged between ADRM1 expression and pivotal immune checkpoints, including CD274, PDCD1, and PDCD1LG2. In tumor microenvironment, samples with the high ADRM1 expression contained statistical higher proportion of CD8 + T cells and Macrophage infiltration. Meanwhile, these high ADRM1-expressing samples displayed elevated tumor mutation burden scores and stemness indices, implying potential benefits from immunotherapy. Patients with low ADRM1 expression were sensitive to cisplatin, docetaxel, vinblastine, mitomycin C, and methotrexate. According to the findings from bioinformatics and IHC analyses, ADRM1 demonstrates prognostic significance for BC patients and holds predictive potential for both immunotherapy and chemotherapy responses. This underscores its role as a biomarker and therapeutic target in BC.

ObjectivesTo determine and validate alanine aminotransferase (ALT)-adapted dual cut-offs of liver stiffness measurements (LSMs) for assessing liver fibrosis with two-dimensional shear wave elastography (2D-SWE) in patients with chronic hepatitis B (CHB) infection.MethodsPatients with CHB infection who underwent liver biopsy to assess liver fibrosis were consecutively included. 2D-SWE confirmation thresholds with a positive likelihood ratio ≥10 and 2D-SWE exclusion thresholds with a negative likelihood ratio ≤0.1 were identified to rule in or rule out significant fibrosis and cirrhosis, respectively.ResultsThe first 515 patients (index cohort) and the next 421 patients (validation cohort) were included in the final analysis. The low and high cut-offs to rule out and rule in patients with significant fibrosis (≥ F2) were 5.4 kPa and 9.0 kPa, respectively, in patients with ALT levels ≤ 2 × the upper limit of normal (ULN) and 7.1 kPa and 11.2 kPa in patients with ALT levels > 2 × ULN. For cirrhosis (F4), the corresponding values were 8.1 kPa and 12.3 kPa in patients with ALT levels ≤ 2 × ULN and 11.9 kPa and 24.7 kPa in patients with ALT levels > 2 × ULN. The dual cut-off values showed an overall accuracy of more than 90% for diagnosis of the presence or absence of significant fibrosis and cirrhosis in the index and validation cohorts. There were no significant differences in the accuracy values between the cohorts (all p>0.05).ConclusionThe ALT-adapted dual cut-offs of LSMs showed high accuracy for diagnosis of the presence or absence of significant fibrosis and cirrhosis in patients with CHB infection.Key Points• The ALT-adapted dual cut-off values of LSMs showed high accuracy for diagnosis of the presence or absence of significant fibrosis and cirrhosis.• ALT levels did not influence the overall diagnostic accuracy for predicting significant fibrosis and cirrhosis.• The ALT-adapted dual cut-offs in patients with ALT levels > 2 × ULN were markedly higher than those in patients with ALT levels ≤ 2 × ULN.

Background Antineutrophil cytoplasmic antibody (ANCA)‐associated vasculitis (AAV) is an autoimmune disease often accompanied by rapidly progressive renal failure, and the genetic background is still unknown. Our study was performed to test whether autophagy‐related 16 like 1 (ATG16L1) rs4663402 and rs4663396 single nucleotide polymorphisms (SNPs) were associated with AAV in the Chinese Guangxi population. Methods One hundred seventy seven unrelated AAV patients and 216 healthy controls were included in this case–control study. Multiplex polymerase chain reaction combined with high‐throughput sequencing was used for typing, and SNPStats and SHEsis were used for association analysis, pairwise linkage disequilibrium, and haplotype analysis. Results rs4663402 and rs4663396 were in Hardy–Weinberg equilibrium in AAV and control groups. The frequencies of rs4663402 AA, AT, and TT genotypes were 82.5%, 16.9%, and 0.6%, respectively, in patients with AAV, and 83.5%, 16.2%, and 0.5%, respectively, in controls. The frequencies of rs4663396 CC, CT, and TT genotypes were 63.8%, 33.9%, and 2.3%, respectively, in patients with AAV, and 69.2%, 26.6%, and 4.2%, respectively, in controls. Haplotype analysis revealed two SNPs in a single haplotype block (D′ = 1.0). Our logistic regression adjusted for sex and age showed no association between rs4663402 and rs4663396 and the risk for AAV in genetic models (p > 0.05). However, ATG16L1 rs4663396 CC and CT + TT genotypes exhibited statistically significant differences in the incidence of arthralgia (p = 0.03). Conclusions Our results indicated that ATG16L1 rs4663402 and rs4663396 polymorphisms were not associated with AAV in the Chinese Guangxi population. ATG16L1 rs4663396 CT + TT genotype may be associated with arthralgia. Overview of the autophagy pathway in ANCA‐Associated Vasculitis Under certain conditions, neutrophils are activated and intracellular autoantigens (MPO and PR3) migrate to the cell membrane. The interaction between exposed autoantigens and ANCAs antibodies triggers the autophagy mechanism of neutrophils and carries out activities such as membrane nucleation, autophagosome prolongation, lysosome fusion, and degranulation. The neutrophils adhering to endothelial cells release cytokines, reactive oxygen species (ROS), and lyases, and form neutrophil extracellular traps (NETs) at the same time, resulting in vascular endothelial cell injury. The continuous production of ANCAs antibodies leads to a vicious circle of excessive neutrophil activation, inflammatory activity, and vasculitis. Among them, the prolongation of autophagosomes is regulated by ATG5‐ATG12‐ATG16L1 complex, while the formation of defective ATG5‐ATG12‐ATG16L1 complex will affect the prolongation of autophagosomes, inhibit autophagy, and block the lysis of intracellular chromatin, resulting in impaired NETs formation. Both autophagy and ROS have independent effects on the formation of NET; therefore, we can regulate the formation of NETs against autophagy and retain the production of ROS to maintain innate immune defense.

Background and aims Salt is a critical environmental factor that profoundly impacts plant growth and development. However, the investigation into how plants regulate carbon and nitrogen metabolism in response to different levels of salinity has been limited. Methods In this study, we investigated the impact of fluctuating salinity on Avicennia marina , a typical pioneer mangrove plant. We measured physiological indicators like photosynthesis to understand these effects. To gain deeper insights, we conducted an integrated analysis of genes and metabolites associated with carbohydrate and nitrogen compound metabolic pathways using transcriptomics and metabolomics. Results Our findings showed that low salinity treatment increased the leaf C/N ratio compared to the control group without salt treatment. Low salinity improved chlorophyll content and up-regulated PsbB gene expression in A. marina leaves, enhancing light absorption capacity. It also reduced leaf specific area, improving photosystem II utilization efficiency and minimizing heat dissipation. Furthermore, low salinity up-regulated genes encoding large subunit of RubisCO ( RBCL ) involved in Calvin cycle within A. marina leaves, leading to improved photosynthetic capacity, resulting in an increased C/N ratio. Under high salinity, A. marina leaves enhanced glycolysis and the TCA cycle for energy production while activating N metabolic pathway to accumulate amino acids and lipids. The balance between carbon and nitrogen metabolism was restored by returning the C/N ratio to control levels under high salinity. Conclusions These findings highlight the distinct response strategies of leaf carbon and nitrogen metabolism in A. marina when adapting to fluctuating salt environments in intertidal zones.

The African swine fever virus (ASFV) has the ability to infect pigs and cause a highly contagious acute fever that can result in a mortality rate as high as 100%. Due to the viral epidemic, the pig industry worldwide has suffered significant financial setbacks. The absence of a proven vaccine for ASFV necessitates the development of a sensitive and reliable serological diagnostic method, enabling laboratories to effectively and expeditiously detect ASFV infection. In this study, four strains of monoclonal antibodies (mAbs) against p72, namely, 5A1, 4C4, 8A9, and 5E10, were generated through recombinant expression of p72, the main capsid protein of ASFV, and immunized mice with it. Epitope localization was performed by truncated overlapping polypeptides. The results indicate that 5A1 and 4C4 recognized the amino acid 20–39 aa, 8A9 and 5E10 are recognized at 263–282 aa, which is consistent with the reported 265–280 aa epitopes. Conserved analysis revealed 20–39 aa is a high conservation of the epitopes in the ASFV genotypes. Moreover, a blocking ELISA assay for detection ASFV antibody based on 4C4 monoclonal antibody was developed and assessed. The receiver-operating characteristic (ROC) was performed to identify the best threshold value using 87 negative and 67 positive samples. The established test exhibited an area under the curve (AUC) of 0.9997, with a 95% confidence interval ranging from 99.87 to 100%. Furthermore, the test achieved a diagnostic sensitivity of 100% (with a 95% confidence interval of 95.72 to 100%) and a specificity of 98.51% (with a 95% confidence interval of 92.02 to 99.92%) when the threshold was set at 41.97%. The inter- and intra-batch coefficient of variation were below 10%, demonstrating the exceptional repeatability of the method. This method can detect the positive standard serum at a dilution as high as 1:512. Subsequently, an exceptional blocking ELISA assay was established with high diagnostic sensitivity and specificity, providing a novel tool for detecting ASFV antibodies. Key points • Four strains of ASFV monoclonal antibodies against p72 were prepared and their epitopes were identified. • Blocking ELISA method was established based on monoclonal antibody 4C4 with an identified conservative epitope. • The established blocking ELISA method has a good effect on the detection of ASFV antibody.