Microbial tryptophan catabolism as an actionable target via diet-microbiome interactions.

In recent years, the role of microbial tryptophan (Trp) catabolism in host-microbiota crosstalk has become a major area of scientific interest. Microbiota-derived Trp catabolites positively contribute to intestinal and systemic homeostasis by acting as ligands of aryl hydrocarbon receptor and pregnane X receptor, and as signaling molecules in microbial communities. Accumulating evidence suggests that microbial Trp catabolism could be therapeutic targets in treating human diseases. A number of bacteria and metabolic pathways have been identified to be responsible for the conversion of Trp in the intestine. Interestingly, many Trp-degrading bacteria can benefit from the supplementation of specific dietary fibers and polyphenols, which in turn increase the microbial production of beneficial Trp catabolites. Thus, this review aims to highlight the emerging role of diets and food components, i.e., food matrix, fiber, and polyphenol, in modulating the microbial catabolism of Trp and discuss the opportunities for potential therapeutic interventions via specifically designed diets targeting the Trp-microbiome axis.

CRISPR/Pepper-tDeg: A Live Imaging System Enables Non-Repetitive Genomic Locus Analysis with One Single-Guide RNA.

CRISPR-based genomic-imaging systems have been utilized for spatiotemporal imaging of the repetitive genomic loci in living cells, but they are still challenged by limited signal-to-noise ratio (SNR) at a non-repetitive genomic locus. Here, an efficient genomic-imaging system is proposed, termed CRISPR/Pepper-tDeg, by engineering the CRISPR sgRNA scaffolds with the degron-binding Pepper aptamers for binding fluorogenic proteins fused with Tat peptide derived degron domain (tDeg). The target-dependent stability switches of both sgRNA and fluorogenic protein allow this system to image repetitive telomeres sensitively with a 5-fold higher SNR than conventional CRISPR/MS2-MCP system using "always-on" fluorescent protein tag. Subsequently, CRISPR/Pepper-tDeg is applied to simultaneously label and track two different genomic loci, telomeres and centromeres, in living cells by combining two systems. Given a further improved SNR by the split fluorescent protein design, CRISPR/Pepper-tDeg system is extended to non-repetitive sequence imaging using only one sgRNA with two aptamer insertions. Neither complex sgRNA design nor difficult plasmid construction is required, greatly reducing the technical barriers to define spatiotemporal organization and dynamics of both repetitive and non-repetitive genomic loci in living cells, and thus demonstrating the large application potential of this genomic-imaging system in biological research, clinical diagnosis and therapy.

Therapeutic Inhibition of LincRNA-p21 Protects Against Cardiac Hypertrophy.

BACKGROUND: Cardiac hypertrophy is an adaptive response to pressure overload aimed at maintaining cardiac function. However, prolonged hypertrophy significantly increases the risk of maladaptive cardiac remodeling and heart failure. Recent studies have implicated long noncoding RNAs in cardiac hypertrophy and cardiomyopathy, but their significance and mechanism(s) of action are not well understood. METHODS: We measured lincRNA-p21 RNA and H3K27ac levels in the hearts of dilated cardiomyopathy patients. We assessed the functional role of lincRNA-p21 in basal and surgical pressure-overload conditions using loss-of-function mice. Genome-wide transcriptome analysis revealed dysregulated genes and pathways. We labeled proteins in proximity to full-length lincRNA-p21 using a novel BioID2-based system. We immunoprecipitated lincRNA-p21-interacting proteins and performed cell fractionation, ChIP-seq (chromatin immunoprecipitation followed by sequencing), and co-immunoprecipitation to investigate molecular interactions and underlying mechanisms. We used GapmeR antisense oligonucleotides to evaluate the therapeutic potential of lincRNA-p21 inhibition in cardiac hypertrophy and associated heart failure. RESULTS: lincRNA-p21 was induced in mice and humans with cardiomyopathy. Global and cardiac-specific lincRNA-p21 knockout significantly suppressed pressure overload-induced ventricular wall thickening, stress marker elevation, and deterioration of cardiac function. Genome-wide transcriptome analysis and transcriptional network analysis revealed that lincRNA-p21 acts in trans to stimulate the NFAT/MEF2 pathway. Mechanistically, lincRNA-p21 is bound to the scaffold protein KAP1. lincRNA-p21 cardiac-specific knockout suppressed stress-induced nuclear accumulation of KAP1, and KAP1 knockdown attenuated cardiac hypertrophy and NFAT activation. KAP1 positively regulates pathological hypertrophy by physically interacting with NFATC4 to promote the overactive status of NFAT/MEF2 signaling. GapmeR antisense oligonucleotide depletion of lincRNA-p21 similarly inhibited cardiac hypertrophy and adverse remodeling, highlighting the therapeutic potential of inhibiting lincRNA-p21. CONCLUSIONS: These findings advance our understanding of the functional significance of stress-induced long noncoding RNA in cardiac hypertrophy and demonstrate the potential of lincRNA-p21 as a novel therapeutic target for cardiac hypertrophy and subsequent heart failure.

Genome-wide identification of SAMS gene family in Cucurbitaceae and the role of ClSAMS1 in watermelon tolerance to abiotic stress.

S-Adenosyl-L-methionine (SAM) is widely involved in plant growth, development, and abiotic stress response. SAM synthetase (SAMS) is the key enzyme that catalyzes the synthesis of SAM from methionine and ATP. However, the SAMS gene family has not been identified and their functions have not been characterized in most Cucurbitaceae plants. Here, a total of 30 SAMS genes were identified in nine Cucurbitaceae species and they were categorized into 3 subfamilies. Physicochemical properties and gene structure analysis showed that the SAMS protein members are tightly conserved. Further analysis of the cis-regulatory elements (CREs) of SAMS genes' promoter implied their potential roles in stress tolerance. To further understand the molecular functions of SAMS genes, watermelon SAMSs (ClSAMSs) were chosen to analyze the expression patterns in different tissues and under various abiotic stress and hormone responses. Among the investigated genes, ClSAMS1 expression was observed in all tissues and found to be up-regulated by abiotic stresses including salt, cold and drought treatments as well as exogenous hormone treatments including ETH, SA, MeJA and ABA. Furthermore, knockdown of ClSAMS1 via virus-induced gene silencing (VIGS) decreased SAM contents in watermelon seedings. The pTRSV2-ClSAMS1 plants showed reduced susceptibility to drought, cold and NaCl stress, indicating a positive role of ClSAMS1 in abiotic stresses tolerance. Those results provided candidate SAMS genes to regulate plant resistance against abiotic stresses in Cucurbitaceae plants.

The long noncoding RNA CARDINAL attenuates cardiac hypertrophy by modulating protein translation.

One of the features of pathological cardiac hypertrophy is enhanced translation and protein synthesis. Translational inhibition has been shown to be an effective means of treating cardiac hypertrophy, although system-wide side effects are common. Regulators of translation, such as cardiac-specific long noncoding RNAs (lncRNAs), could provide new, more targeted therapeutic approaches to inhibit cardiac hypertrophy. Therefore, we generated mice lacking a previously identified lncRNA named CARDINAL to examine its cardiac function. We demonstrate that CARDINAL is a cardiac-specific, ribosome-associated lncRNA and show that its expression was induced in the heart upon pathological cardiac hypertrophy and that its deletion in mice exacerbated stress-induced cardiac hypertrophy and augmented protein translation. In contrast, overexpression of CARDINAL attenuated cardiac hypertrophy in vivo and in vitro and suppressed hypertrophy-induced protein translation. Mechanistically, CARDINAL interacted with developmentally regulated GTP-binding protein 1 (DRG1) and blocked its interaction with DRG family regulatory protein 1 (DFRP1); as a result, DRG1 was downregulated, thereby modulating the rate of protein translation in the heart in response to stress. This study provides evidence for the therapeutic potential of targeting cardiac-specific lncRNAs to suppress disease-induced translational changes and to treat cardiac hypertrophy and heart failure.

Tank-mix adjuvants improved spray performance and biological efficacy in rice insecticide application with unmanned aerial vehicle sprayer.

BACKGROUND: The use of unmanned aerial vehicles (UAVs) for the application of plant protection products (PPPs) in paddy fields is becoming increasingly prevalent worldwide. Despite its growing usage, UAV spraying for rice pest control faces practical challenges, including limited canopy penetration, uneven deposition, and significant spray drift. This study investigated the impact of two tank-mix adjuvants, Wonderful Rosin (Adjuvant-1) and Tiandun (Adjuvant-2), at six volume concentrations, on the spray liquid's physicochemical properties, spray drift, plant deposition, and the biological efficacy of rice insecticides using a quadrotor UAV sprayer. RESULTS: The physicochemical characteristics of the spray liquid influenced spray performance and biological efficacy. Incorporating Adjuvant-1 and Adjuvant-2 led to a decrease in surface tension and contact angle while increasing the viscosity of the spray solution. These alterations in surface tension and viscosity contributed to an optimized droplet size distribution, reduced spray drift, enhanced deposition uniformity and penetration, and improved control efficacy against the rice planthopper in UAV applications. The highest control efficacy was observed at a concentration of 0.5%, showing an improvement of 35.12% (Adjuvant-1) and 20.23% (Adjuvant-2) over applications without tank-mix adjuvant 7 days after treatment. CONCLUSION: The judicious selection of tank-mix adjuvants for UAV PPP applications can significantly enhance spray performance and biological efficacy in controlling rice insects. This study's findings offer valuable insights for integrating tank-mix adjuvants into UAV spraying applications. © 2024 Society of Chemical Industry.

Remodeling the tumor-immune microenvironment by anti-CTLA4 blockade enhanced subsequent anti-PD-1 efficacy in advanced nasopharyngeal carcinoma.

Sequential immunotherapy has shown certain advantages in malignancy. Here, we aim to evaluate the efficacy of sequential anti-CTLA-4 and anti-PD-1 treatment for recurrent or metastatic nasopharyngeal carcinoma patients (R/M NPC). We retrospectively analysis 2 phase I trial of ipilimumab and camrelizumab in Chinese R/M NPC patients. These patients were initially treated with ipilimumab, a CTLA4 blockade, followed by anti-PD-1 treatment. We observed a durable tumor remission in these patients (mPFS: 12.3 months; mDoR: 20.9 months). Multimodal investigations of biopsy samples disclosed remodeling of tumor-immune microenvironment triggered by ipilimumab. In responders, we found increased tumoral PD-L1/PD-L2 expression and T-cell infiltration after ipilimumab treatment, accompanied by reduced stroma and malignant cell components. In contrast, non-responders exhibited increased B-cell infiltration and increased peripheral CD19 + B cells, suggesting a defective transition from memory B cells to plasma cells. This study proposes that sequential therapy can potentially enhance treatment efficacy in chemotherapy-resistant NPC patients and provides insights into how preexisting anti-CTLA4 blockade can influence subsequent anti-PD-1 efficacy by remodeling the TME. Additionally, our results highlight the need for therapeutic strategies targeting naïve/memory B cells.

Attenuation of intestinal ischemia-reperfusion-injury by anesthetics: a potentially protective effect of anesthetic management in experimental studies.

Intestinal ischemia-reperfusion injury (IRI) is a potentially severe clinical syndrome after major surgical procedures. In addition to causing intestinal mucosa injury, intestinal IRI further damages distant organs, causing the severity of the condition in patients. So far, effective therapy for intestinal IRI is still absent, and the survival rate of the patients is low. Previous experimental studies have shown that some anesthetics can alleviate intestinal IRI and protect organs while exerting their pharmacological effects, indicating that reasonable perioperative anesthesia management may provide potential benefits for patients to avoid intestinal IRI. These meaningful findings drive scholars to investigate the mechanism of anesthetics in treating intestinal IRI in-depth to discuss the possible new clinical uses. In the present mini-review, we will introduce the protective effects of different anesthetics in intestinal IRI to help us enrich our knowledge in this area.

Sex-specific regulation of miR-22 and ERα in white adipose tissue of obese dam's female offspring impairs the early postnatal development of functional beige adipocytes in mice.

During inguinal adipose tissue (iWAT) ontogenesis, beige adipocytes spontaneously appear between postnatal 10 (P10) and P20 and their ablation impairs iWAT browning capacity in adulthood. Since maternal obesity has deleterious effects on offspring iWAT function, we aimed to investigate its effect in spontaneous iWAT browning in offspring. Female C57BL/6 J mice were fed a control or obesogenic diet six weeks before mating. Male and female offspring were euthanized at P10 and P20 or weaned at P21 and fed chow diet until P60. At P50, mice were treated with saline or CL316,243, a ß3-adrenoceptor agonist, for ten days. Maternal obesity induced insulin resistance at P60, and CL316,243 treatment effectively restored insulin sensitivity in male but not female offspring. This discrepancy occurred due to female offspring severe browning impairment. During development, the spontaneous iWAT browning and sympathetic nerve branching at P20 were severely impaired in female obese dam's offspring but occurred normally in males. Additionally, maternal obesity increased miR-22 expression in the iWAT of male and female offspring during development. ERα, a target and regulator of miR-22, was concomitantly upregulated in the male's iWAT. Next, we evaluated miR-22 knockout (KO) offspring at P10 and P20. The miR-22 deficiency does not affect spontaneous iWAT browning in females and, surprisingly, anticipates iWAT browning in males. In conclusion, maternal obesity impairs functional iWAT development in the offspring in a sex-specific way that seems to be driven by miR-22 levels and ERα signaling. This impacts adult browning capacity and glucose homeostasis, especially in female offspring.

[Genetic analysis of a Chinese pedigree affected with Congenital dysfibrinogenemia due to variant of FGG gene].

OBJECTIVE: To explore the coagulation deficit and genetic basis for a Chinese pedigree affected with Congenital dysfibrinogenemia (CD). METHODS: Peripheral venous blood samples of the proband and her family members (including 4 individuals from three generations) were subjected to routine blood test and assays of liver and kidney functions and viral hepatitis to exclude related diseases. Clauss method and DFg-PT method were used to determine the fibrinogen activity (Fg:C), and an immunoturbidimetric assay was used to determine the level of fibrinogen antigen (Fg:Ag). All of the exons (22 in total) and their flanking sequences of the FGA, FGB and FGG genes were amplified by PCR and directly sequenced. Variants in the coding regions of the three genes and transcriptional splicing sites were screened by using Mutation SurveyorTM software. RESULTS: The Clauss method showed that Fg:C was significantly reduced in the proband and her father, whilst her mother and son were normal. With the DFg-PT method, the proband, her parents and son were all within the normal range. The Fg:C/Fg:Ag ratio of the proband and her father was lower than 0.7, whilst her mother and son were above 0.7. No significant change in the prothrombin time, activated partial thromboplastin clotting time and thrombin time was noted. Two genetic variants were detected, which included a homozygous missense variant in the FGA gene [c.991A>G (p.Thr331Ala)], which was predicted to be benign, and a heterozygous missense variant of the γ chain of the FGG gene [c.1211C>G (p.Ser404Phe)], which is located in a conserved region and unreported in the CLINVAR/HGMD/EXAC/1000G databases and literature. CONCLUSION: This pedigree has conformed to the autosomal dominant inheritance of CD. The c.1211C>T (p.Ser404Phe) missense variant of the γ chain of the FGG gene probably underlay the pathogenesis of CD in this pedigree. The variant was unreported previously and named as "Fibrinogen Harbin II Ser404Phe".

A DNAzyme dual-feedback autocatalytic exponential amplification biocircuit for microRNA imaging in living cells.

Autocatalytic biocircuit are powerful tools for analysing intracellular biomarkers, but these tools are constrained by limitations in amplification capacity and intracellular delivery efficiency. In this work, we developed a DNAzyme-based dual-feedback autocatalytic exponential amplification biocircuit sustained by a honeycomb MnO2 nanosponge (EDA2@hMNS) for live-cell imaging of intracellular low-abundance microRNAs (miRNA). The EDA2 biocircuit comprises a blocked DNAzyme (b-DNAzyme), a Fuel strand and a Substrate strand. In the EDA2 biocircuit, target miRNAs are recycled and feedback for rounds of DNAzymatic amplification, and the DNAzymatic reactions continuously generate target miRNA analogues for dual-feedback to achieve multiple parallel cascade DNAzymatic reactions that improve amplification capacity substantially. In addition, the hMNS ensures high loading and delivery efficiency of biocircuit probes into living cells and also provides sufficient Mn2+ DNAzyme cofactor from in situ decomposition by intracellular glutathione (GSH). The EDA2@hMNS realized a detection limit of 17 pM, which is 288-fold lower than the b-DNAzyme lacking the DNAzymatic amplification. These results demonstrate the great promise for this critical tool in analysing low-abundance biomarkers and cancer diagnostics.

On-Site-Activated Transmembrane Logic DNA Nanodevice Enables Highly Specific Imaging of Cancer Cells by Targeting Tumor-Related Nucleolin and Intracellular MicroRNA.

The ability to specifically image cancer cells is essential for cancer diagnosis; however, this ability is limited by the false positive associated with single-biomarker sensors and off-site activation of "always active" nucleic acid probes. Herein, we propose an on-site, activatable, transmembrane logic DNA (TLD) nanodevice that enables dual-biomarker sensing of tumor-related nucleolin and intracellular microRNA for highly specific cancer cell imaging. The TLD nanodevice is constructed by assembling a tetrahedral DNA nanostructure containing a linker (L)-blocker (B)-DNAzyme (D)-substrate (S) unit. AS-apt, a DNA strand containing an elongated segment and the AS1411 aptamer, is pre-anchored to nucleolin protein, which is specifically expressed on the membrane of cancer cells. Initially, the TLD nanodevice is firmly sealed by the blocker containing an AS-apt recognition zone, which prevents off-site activation. When the nanodevice encounters a target cancer cell, AS-apt (input 1) binds to the blocker and unlocks the sensing ability of the nanodevice for miR-21 (input 2). The TLD nanodevice achieves dual-biomarker sensing from the cell membrane to the cytoplasm, thereby ensuring cancer cell-specific imaging. This TLD nanodevice represents a promising strategy for the highly reliable analysis of intracellular biomarkers and a promising platform for cancer diagnosis and related biomedical applications.

High-density lipoprotein regulates angiogenesis by long non-coding RNA HDRACA.

Normal high-density lipoprotein (nHDL) can induce angiogenesis in healthy individuals. However, HDL from patients with coronary artery disease undergoes various modifications, becomes dysfunctional (dHDL), and loses its ability to promote angiogenesis. Here, we identified a long non-coding RNA, HDRACA, that is involved in the regulation of angiogenesis by HDL. In this study, we showed that nHDL downregulates the expression of HDRACA in endothelial cells by activating WW domain-containing E3 ubiquitin protein ligase 2, which catalyzes the ubiquitination and subsequent degradation of its transcription factor, Kruppel-like factor 5, via sphingosine 1-phosphate (S1P) receptor 1. In contrast, dHDL with lower levels of S1P than nHDL were much less effective in decreasing the expression of HDRACA. HDRACA was able to bind to Ras-interacting protein 1 (RAIN) to hinder the interaction between RAIN and vigilin, which led to an increase in the binding between the vigilin protein and proliferating cell nuclear antigen (PCNA) mRNA, resulting in a decrease in the expression of PCNA and inhibition of angiogenesis. The expression of human HDRACA in a hindlimb ischemia mouse model inhibited the recovery of angiogenesis. Taken together, these findings suggest that HDRACA is involved in the HDL regulation of angiogenesis, which nHDL inhibits the expression of HDRACA to induce angiogenesis, and that dHDL is much less effective in inhibiting HDRACA expression, which provides an explanation for the decreased ability of dHDL to stimulate angiogenesis.

Diversity-oriented synthesis of P-stereogenic and axially chiral monodentate biaryl phosphines enabled by C-P bond cleavage.

Chiral monodentate biaryl phosphines (MOPs) have attracted intense attention as chiral ligands over the past decades. However, the creation of structurally diverse chiral MOPs with both P- and axial chirality is still in high demand but challenging. Here, we show a distinct strategy for diversity-oriented synthesis of structurally diverse MOPs containing both P- and axial chirality enabled by enantioselective C-P bond cleavage. The key chiral PdII intermediates, generated through the stereoselective oxidative addition of C-P bond, could be trapped by alkynes, R3Si-Bpin, diboron esters or reduced by H2O/B2pin2, leading to enantioenriched structurally diverse MOPs in excellent diastereo- and enantioselectivities. Based on the outstanding properties of the parent scaffolds, the P- and axially chiral monodentate biaryl phosphines serve as excellent catalysts in asymmetric [3 + 2] annulation of MBH carbonate affording the chiral functionalized bicyclic imide.

Field evaluation of a six-rotor unmanned agricultural aerial sprayer: effects of application parameters on spray deposition and control efficacy against rice planthopper.

BACKGROUND: Unmanned Aerial Spraying System (UASS) has emerged as an advanced, precise, and efficient tool for pesticide application in numerous nations in recent years. Despite this, there is a noticeable gap in research advocating viable, quantifiable methodologies for application parameter optimization. This investigation was primarily oriented toward identifying optimal UASS application parameters. It did so by exploring the effects of varying spray volumes and flight parameters on spray performance in a comprehensive manner, and by assessing the biological potency of aerial insecticide application against Rice Planthopper (RPH) using the optimal parameters, aided by two types of nozzles in rice field settings. RESULTS: Increased spray volume increased the spray deposition. Working height impacted the distribution of spray deposition, with a higher working height leading to superior distribution uniformity. Both spray volume and working height were observed to influence spray deposition and its percentage in tandem. Upon factor analysis, the optimal parameters determined for rice at the heading stage were an application volume of 15.0 L·ha-1 , a working height of 2.0 m, and a driving speed of 5.0 m·s-1 . Under these parameters, the air-induction twin flat fan nozzle IDKT120-015 demonstrated approximately 5% higher spray deposition than the flat fan nozzle SX11001VS, albeit with inferior distribution uniformity. Both nozzle types achieved over 93.0% control efficacy against RPH using triflumezopyrim, persisting for up to 40 days post-treatment. CONCLUSION: This study furnishes invaluable insights and data for controlling rice planthopper via UASS pesticide application, contributing to the progress of modern intensive and sustainable agriculture. © 2023 Society of Chemical Industry.

DNAzyme-Amplified Cascade Catalytic Hairpin Assembly Nanosystem for Sensitive MicroRNA Imaging in Living Cells.

Sensitive imaging of microRNAs (miRNAs) in living cells is significant for accurate cancer clinical diagnosis and prognosis research studies, but it is challenged by inefficient intracellular delivery, instability of nucleic acid probes, and limited amplification efficiency. Herein, we engineered a DNAzyme-amplified cascade catalytic hairpin assembly (CHA)-based nanosystem (DCC) that overcomes these challenges and improves the imaging sensitivity. This enzyme-free amplification nanosystem is based on the sequential activation of DNAzyme amplification and CHA. MnO2 nanosheets were used as nanocarriers for the delivery of nucleic acid probes, which can resist the degradation by nucleases and supply Mn2+ for the DNAzyme reaction. After entering into living cells, the MnO2 nanosheets can be decomposed by intracellular glutathione (GSH) and release the loaded nucleic acid probes. In the presence of target miRNA, the locking strand (L) was hybridized with target miRNA, and the DNAzyme was released, which then cleaved the substrate hairpin (H1). This cleavage reaction resulted in the formation of a trigger sequence (TS) that can activate CHA and recover the fluorescence readout. Meanwhile, the DNAzyme was released from the cleaved H1 and bound to other H1 for new rounds of DNAzyme-based amplification. The TS was also released from CHA and involved in the new cycle of CHA. By this DCC nanosystem, low-abundance target miRNA can activate many DNAzyme and generate numerous TS for CHA, resulting in sensitive and selective analysis of miRNAs with a limit of detection of 5.4 pM, which is 18-fold lower than that of the traditional CHA system. This stable, sensitive, and selective nanosystem holds great potential for miRNA analysis, clinical diagnosis, and other related biomedical applications.

Impact of High-Fiber or High-Protein Diet on the Capacity of Human Gut Microbiota To Produce Tryptophan Catabolites.

This study investigated the effect of high-fiber-low-protein (HF) and high-protein-low-fiber (HP) diets on microbial catabolism of tryptophan in the proximal colon (PC) and distal colon(DC) compartments of the Simulator of the Human Intestinal Microbial Ecosystem. The microbiota in PC and DC was dominated by Bacteroidetes and Firmicutes, in which Bacteroidetes were more abundant in DC (∼60% versus 50%) and Firmicutes were more abundant in PC (∼40% versus 25%). Most of the tryptophan catabolites were determined at a higher concentration in PC samples than in DC samples, but the overall concentration of tryptophan catabolites was over 10-fold higher in DC samples than that in PC samples. Interestingly, indole-3-propionic acid and oxindole were only identified in DC samples. A two-week dietary intervention by the HF diet enriched the abundance of Firmicutes in PC, whereas the HP diet enriched the abundance of Proteobacteria. Compared to the HP diet, the HF diet favored the microbial production of indole-3-acetic acid, indole-3-lactic acid, indole-3-aldehyde, and indole-3-propionic acid in both PC and DC compartments. To conclude, these findings increase the understanding of the effect of diets on the microbial production of tryptophan catabolites in the colon.

COL19A1 is a predictive biomarker for the responsiveness of esophageal squamous cell carcinoma patients to immune checkpoint therapy.

BACKGROUND: The use of neoadjuvant immunotherapy plus chemotherapy has revolutionized the management of esophageal squamous cell carcinoma (ESCC) patients. Nevertheless, patients who would maximally benefit from these therapies have not been identified. METHODS: We collected postoperative specimens from 103 ESCC patients, of which 66 patients comprised a retrospective cohort and 37 comprised a prospective cohort. Patient specimens were subjected to applied multi-omics analysis to uncover the mechanistic basis for patient responsiveness to cancer immunotherapy. The tumor microenvironment characteristics of these patient specimens was explored and identified by multiplex immunofluorescence and immunohistochemistry. RESULTS: Results demonstrated high COL19A1 expression to be a novel biomarker for successful immunotherapy (COL19A1high , odds ratio [95% confidence interval]: 0.31 [0.10-0.97], p = 0.044). Compared with COL19A1low patients, COL19A1high patients benefited more from neoadjuvant immunotherapy (p < 0.01), obtained better major pathological remissions (63.3%, p < 0.01), with a trend toward better recurrence-free survival (p = 0.013), and overall survival (p = 0.056). Moreover, analysis of an immune-activation subtype of patients demonstrated increased B cell infiltration to be associated with favorable patient survival and a better response to neoadjuvant immunotherapy plus chemotherapy. CONCLUSIONS: The findings of this study provide insight into the optimal design of individual treatments for ESCC patients.

Neural Network With a Preference Sampling Paradigm for Imbalanced Data Classification.

Most data in real life are characterized by imbalance problems. One of the classic models for dealing with imbalanced data is neural networks. However, the data imbalance problem often causes the neural network to display negative class preference behavior. Using an undersampling strategy to reconstruct a balanced dataset is one of the methods to alleviate the data imbalance problem. However, most existing undersampling methods focus more on the data or aim to preserve the overall structural characteristics of the negative class through potential energy estimation, while the problems of gradient inundation and insufficient empirical representation of positive samples have not been well considered. Therefore, a new paradigm for solving the data imbalance problem is proposed. Specifically, to solve the problem of gradient inundation, an informative undersampling strategy is derived from the performance degradation and used to restore the ability of neural networks to work under imbalanced data. In addition, to alleviate the problem of insufficient empirical representation of positive samples, a boundary expansion strategy with linear interpolation and the prediction consistency constraint is considered. We tested the proposed paradigm on 34 imbalanced datasets with imbalance ratios ranging from 16.90 to 100.14. The test results show that our paradigm obtained the best area under the receiver operating characteristic curve (AUC) on 26 datasets.

The translational landscape of human vascular smooth muscle cells identifies novel short open reading frame-encoded peptide regulators for phenotype alteration.

AIMS: The plasticity of vascular smooth muscle cells (VSMCs) enables them to alter phenotypes under various physiological and pathological stimuli. The alteration of VSMC phenotype is a key step in vascular diseases, including atherosclerosis. Although the transcriptome shift during VSMC phenotype alteration has been intensively investigated, uncovering multiple key regulatory signalling pathways, the translatome dynamics in this cellular process, remain largely unknown. Here, we explored the genome-wide regulation at the translational level of human VSMCs during phenotype alteration. METHODS AND RESULTS: We generated nucleotide-resolution translatome and transcriptome data from human VSMCs undergoing phenotype alteration. Deep sequencing of ribosome-protected fragments (Ribo-seq) revealed alterations in protein synthesis independent of changes in messenger ribonucleicacid levels. Increased translational efficiency of many translational machinery components, including ribosomal proteins, eukaryotic translation elongation factors and initiation factors were observed during the phenotype alteration of VSMCs. In addition, hundreds of candidates for short open reading frame-encoded polypeptides (SEPs), a class of peptides containing 200 amino acids or less, were identified in a combined analysis of translatome and transcriptome data with a high positive rate in validating their coding capability. Three evolutionarily conserved SEPs were further detected endogenously by customized antibodies and suggested to participate in the pathogenesis of atherosclerosis by analysing the transcriptome and single cell RNA-seq data from patient atherosclerotic artery samples. Gain- and loss-of-function studies in human VSMCs and genetically engineered mice showed that these SEPs modulate the alteration of VSMC phenotype through different signalling pathways, including the mitogen-activated protein kinase pathway and p53 pathway. CONCLUSION: Our study indicates that an increase in the capacity of translation, which is attributable to an increased quantity of translational machinery components, mainly controls alterations of VSMC phenotype at the level of translational regulation. In addition, SEPs could function as important regulators in the phenotype alteration of human VSMCs.