Naringin Alleviates Intestinal Fibrosis by Inhibiting ER Stress-Induced PAR2 Activation.

Fibrosis characterized by intestinal strictures is a common complication of Crohn's disease (CD), without specific antifibrotic drugs, which usually relies on surgical intervention. The transcription factor XBP1, a key component of endoplasmic reticulum (ER) stress, is required for degranulation of mast cells and linked to PAR2 activation and fibrosis. Many studies have confirmed that naringin (NAR) can inhibit ER stress and reduce organ fibrosis. We hypothesized that ER stress activated the PAR2-induced epithelial-mesenchymal transition process by stimulating mast cell degranulation to release tryptase and led to intestinal fibrosis in CD patients; NAR might play an antifibrotic role by inhibiting ER stress-induced PAR2 activation. We report that the expression levels of XBP1, mast cell tryptase, and PAR2 are upregulated in fibrotic strictures of CD patients. Molecular docking simulates the interaction of NAR and spliced XBP1. ER stress stimulates degranulation of mast cells to secrete tryptase, activates PAR2-induced epithelial-mesenchymal transition process, and promotes intestinal fibrosis in vitro and vivo experiments, which is inhibited by NAR. Moreover, F2rl1 (the coding gene of PAR2) deletion in intestinal epithelial cells decreases the antifibrotic effect of NAR. Hence, the ER stress-mast cell tryptase-PAR2 axis can promote intestinal fibrosis, and NAR administration can alleviate intestinal fibrosis by inhibiting ER stress-induced PAR2 activation.

Fibrosis characterized by intestinal strictures is a common complication of Crohn's disease. The endoplasmic reticulum stress­mast cell tryptase­PAR2 axis promotes intestinal fibrosis, and naringin administration alleviates intestinal fibrosis by inhibiting endoplasmic reticulum stress­induced PAR2 activation.

The Molecular Profile of Soil Microbial Communities Inhabiting a Cambrian Host Rock.

The process of soil genesis unfolds as pioneering microbial communities colonize mineral substrates, enriching them with biomolecules released from bedrock. The resultant intricate surface units emerge from a complex interplay among microbiota and plant communities. Under these conditions, host rocks undergo initial weathering through microbial activity, rendering them far from pristine and challenging the quest for biomarkers in ancient sedimentary rocks. In addressing this challenge, a comprehensive analysis utilizing Gas Chromatography Mass Spectrometry (GC-MS) and Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS) was conducted on a 520-Ma-old Cambrian rock. This investigation revealed a diverse molecular assemblage with comprising alkanols, sterols, fatty acids, glycerolipids, wax esters, and nitrogen-bearing compounds. Notably, elevated levels of bacterial C16, C18 and C14 fatty acids, iso and anteiso methyl-branched fatty acids, as well as fungal sterols, long-chained fatty acids, and alcohols, consistently align with a consortium of bacteria and fungi accessing complex organic matter within a soil-type ecosystem. The prominence of bacterial and fungal lipids alongside maturity indicators denotes derivation from heterotrophic activity rather than ancient preservation or marine sources. Moreover, the identification of long-chain (>C22) n-alkanols, even-carbon-numbered long chain (>C20) fatty acids, and campesterol, as well as stigmastanol, provides confirmation of plant residue inputs. Furthermore, findings highlight the ability of contemporary soil microbiota to inhabit rocky substrates actively, requiring strict contamination controls when evaluating ancient molecular biosignatures or extraterrestrial materials collected.

Self-supervised representation learning using feature pyramid siamese networks for colorectal polyp detection.

Colorectal cancer is a leading cause of cancer-related deaths globally. In recent years, the use of convolutional neural networks in computer-aided diagnosis (CAD) has facilitated simpler detection of early lesions like polyps during real-time colonoscopy. However, the majority of existing techniques require a large training dataset annotated by experienced experts. To alleviate the laborious task of image annotation and utilize the vast amounts of readily available unlabeled colonoscopy data to further improve the polyp detection ability, this study proposed a novel self-supervised representation learning method called feature pyramid siamese networks (FPSiam). First, a feature pyramid encoder module was proposed to effectively extract and fuse both local and global feature representations among colonoscopic images, which is important for dense prediction tasks like polyp detection. Next, a self-supervised visual feature representation containing the general feature of colonoscopic images is learned by the siamese networks. Finally, the feature representation will be transferred to the downstream colorectal polyp detection task. A total of 103 videos (861,400 frames), 100 videos (24,789 frames), and 60 videos (15,397 frames) in the LDPolypVideo dataset are used to pre-train, train, and test the performance of the proposed FPSiam and its counterparts, respectively. The experimental results have illustrated that our FPSiam approach obtains the optimal capability, which is better than that of other state-of-the-art self-supervised learning methods and is also higher than the method based on transfer learning by 2.3 mAP and 3.6 mAP for two typical detectors. In conclusion, FPSiam provides a cost-efficient solution for developing colorectal polyp detection systems, especially in conditions where only a small fraction of the dataset is labeled while the majority remains unlabeled. Besides, it also brings fresh perspectives into other endoscopic image analysis tasks.

Clinical outcomes and risk factors of non-curative endoscopic submucosal dissection for early gastric cancer: a retrospective multicenter study in Zhejiang, China.

Background: Endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) does not always lead to curative resection. Risk factors of lymph node metastasis (LNM)/local cancer residue after non-curative ESD for EGC have not been fully elucidated. We therefore aimed to clarify them and evaluate whether the "eCura system" is reliable for the risk stratification of LNM after non-curative ESD. Methods: We conducted a multicenter retrospective study at seven institutions in Zhejiang, China, on 128 patients who underwent non-curative ESD for EGC. We divided the patients into two groups according to their therapeutic regimen after non-curative ESD. We analyzed the risk factors for LNM, local cancer residue, cancer recurrence, and cancer-specific mortality. Furthermore, we compared the outcomes in each risk category after applying the "eCura system". Results: Among 68 patients undergoing additional surgery, LNM was found in three (4.41%) patients, while local cancer residue was found in eight (11.76%) patients. Multivariate analysis showed that upper third location and deep submucosal invasion were independent risk factors of LNM and local cancer residue. Among 60 patients who underwent simple follow-up, local cancer recurrence was found in four (6.67%) patients and cancer-specific mortality was found in one (1.67%) patient. There were no independent risk factors of cancer recurrence and cancer-specific mortality in our study. During the follow-up period, 5-year overall survival (OS) and disease-free survival (DFS) were 93.8% and 88.9%, respectively. Additionally, LNM and cancer recurrence were significantly associated with the eCura scoring system (p = 0.044 and p = 0.017, respectively), while local cancer residue and cancer-specific mortality were not (p = 0.478 and p = 0.131, respectively). Conclusion: Clinicians should be aware of the risk factors for the prognosis of patients with non-curative ESD to determine subsequent treatment. Through the application of the "eCura system", additional surgery should be performed in patients with intermediate/high risk of LNM.

Halogen Doping Mechanism and Interface Strengthening in the Na3SbS4 Electrolyte via Solid-State Synthesis.

Good-performing sodium solid electrolytes (SSEs) are essential for constructing all-solid-state sodium-ion batteries operating at ambient temperature. Sulfide solid electrolyte, Na3SbS4 (NBS), an excellent SSE with good chemical stability in humid air, can be synthesized with low-cost processing. However, Na3SbS4-based electrolytes with liquid-phase synthesis exhibit conductivities below milli-Siemens per centimeter. Thus, a series of halogen-doped samples formulated as Na3-xSbS4-xMx (0 ≤ x ≤ 0.3, M = Cl, Br, and I) were experimentally prepared in this study using the solid-state method to improve the battery performance. X-ray diffraction with refinement analysis and Raman spectroscopy were employed to understand deeply the connection between the crystal structure and conductivity of Na+ ions. In addition, symmetric sodium batteries with Na2.85SbS3.85Br0.15 were tested at room temperature, and pristine Na3SbS4 was used as the control group. The result showed that the symmetric sodium battery assembled with the Na2.85SbS3.85Br0.15 electrolyte can stably cycle for longer than 100 h at a current density of 0.1 mA/cm2. This research provides a method to manufacture novel SSEs by elaborating the effect of halogen doping in NBS.

Single-cell RNA sequencing reveals the mediatory role of cancer-associated fibroblast PTN in hepatitis B virus cirrhosis-HCC progression.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are essential stromal components in the tumor microenvironment of hepatocellular carcinoma (HCC). Hepatitis B virus (HBV) infection induces pathological changes such as liver fibrosis/cirrhosis and HCC. The aim of this research was to explore the novel mediators of CAFs to modulate HBV cirrhosis-HCC progression. METHODS: The single-cell transcriptome data of HCC were divided into subsets, and the significant subset related to fibrotic cells, along with biological function, and clinical information of HCC was revealed by integrated data analyses. The cell communication, cells communicated weight analysis of signaling pathways, and key genes in signaling pathways analysis of significant CAFs subclasses were conducted to discover the novel gene of CAFs. Bioinformatics, vitro and HBV transfection assays were used to verify the novel gene is an important target for promoting the progression HBV cirrhosis-HCC progression. RESULTS: Fibroblasts derived from HCC single-cell data could be separated into three cell subclasses (CAF0-2), of which CAF2 was associated with the HCC clinical information. Fibroblasts have opposite developmental trajectories to immune B cells and CD8 + T cells. CAF0-2 had strong interaction with B cells and CD8 + T cells, especially CAF2 had the highest interaction frequency and weight with B cells and CD8 + T cells. Moreover, PTN participated in CAF2-related pathways involved in the regulation of cell communication, and the interactions among CAF2 and PTN contributed the most to B cells and CD8 + T cells. Furthermore, the genes of PTN, SDC1, and NCL from PTN signaling were highest expression in CAF2, B cells, and CD8 + T cells, respectively, and the interaction of PTN- SDC1 and PTN- NCL contributed most to the interaction of CAF2- B cells and CAF2-CD8 + T cells. Bioinformatics and vitro experiments confirm PTN was upregulated in HCC and promoted the proliferation of tumor cells, and HBV infection could initiate PTN to perform cirrhosis-HCC progression. CONCLUSION: Our findings revealed CAF was associated with hepatocarcinogenesis, and the functional importance of B cells and CD8 + T cells in modulating CAF in HCC. Importantly, PTN maybe a novel mediator of CAF to mediate HBV cirrhosis-HCC progression.

Phytosulfokine peptides, their receptors, and functions.

Phytosulfokines (PSKs) are a class of disulfated pentapeptides and are regarded as plant peptide hormones. PSK-α, -γ, -δ, and -ϵ are four bioactive PSKs that are reported to have roles in plant growth, development, and immunity. In this review, we summarize recent advances in PSK biosynthesis, signaling, and function. PSKs are encoded by precursor genes that are widespread in higher plants. PSKs maturation from these precursors requires a sulfation step, which is catalyzed by a tyrosylprotein sulfotransferase, as well as proteolytic cleavage by subtilisin serine proteases. PSK signaling is mediated by plasma membrane-localized receptors PSKRs that belong to the leucine-rich repeat receptor-like kinase family. Moreover, multiple biological functions can be attributed to PSKs, including promoting cell division and cell growth, regulating plant reproduction, inducing somatic embryogenesis, enhancing legume nodulation, and regulating plant resistance to biotic and abiotic stress. Finally, we propose several research directions in this field. This review provides important insights into PSKs that will facilitate biotechnological development and PSK application in agriculture.

A novel type of phytosulfokine, PSK-ε, positively regulates root elongation and formation of lateral roots and root nodules in Medicago truncatula.

Phytosulfokines (PSKs) are a class of tyrosine-sulfated pentapeptides. PSK-α, PSK-γ, and PSK-δ are three reported PSK members involved in regulating plant growth, development, and resistance to biotic and abiotic stresses. Here, we reported a novel type of PSK, PSK-ε with the sequence YSO3VYSO3TN, and its precursor proteins (MtPSKε, LjPSKε, and GmPSKε), specifically from legume species. PSK-ε peptide differs from PSK-δ by one amino acid and is close to PSK-δ in the phylogenetic relationship. Expression profile analysis showed that MtPSKε was highly expressed in Medicago truncatula roots, especially in root tips and emerged lateral roots. Application of the synthetic sulfated PSK-ε peptide and overexpression of MtPSKε significantly promoted M. truncatula root elongation and increased lateral root number, probably by inducing cell division and expansion in roots. Furthermore, MtPSKε expression was induced by rhizobia infection and was detected in root nodules including nodule primordia. Both PSK-ε peptide treatment and MtPSKε overexpression significantly increased nodule number in M. truncatula. Taken together, these results demonstrate that PSK-ε, a novel type of phytosulfokine, positively regulates root elongation and formation of lateral root and root nodule in M. truncatula.

Transcription Regulation of Cell Cycle Regulatory Genes Mediated by NtrX to Affect Sinorhizobium meliloti Cell Division

The cell division of the alfalfa symbiont, Sinorhizobium meliloti, is dictated by a cell cycle regulatory pathway containing the key transcription factors CtrA, GcrA, and DnaA. In this study, we found that NtrX, one of the regulators of nitrogen metabolism, can directly regulate the expression of ctrA, gcrA, and dnaA from the cell cycle pathway. Three sets of S. meliloti ntrX mutants showed similar cell division defects, such as slow growth, abnormal morphology of some cells, and delayed DNA synthesis. Transcription of ctrA and gcrA was upregulated, whereas the transcription of dnaA and ftsZ1 was downregulated in the insertion mutant and the strain of Sm1021 expressing ntrXD53E. Correspondingly, the inducible transcription of ntrX activates the expression of dnaA and ftsZ1, but represses ctrA and gcrA in the depletion strain. The expression levels of CtrA and GcrA were confirmed by Western blotting. The transcription regulation of these genes requires phosphorylation of the conserved 53rd aspartate in the NtrX protein that binds directly to the promoter regions of ctrA, gcrA, dnaA, and ftsZ1 by recognizing the characteristic sequence CAAN2-5TTG. Our findings suggest that NtrX affects S. meliloti cell division by regulating the transcription of the key cell cycle regulatory genes.

Sinorhizobium meliloti ohrR genes affect symbiotic performance with alfalfa (Medicago sativa).

Sinorhizobium meliloti infects the host plant alfalfa to induce formation of nitrogen-fixation root nodules, which inevitably elicit reactive oxygen species (ROS) bursts and organic peroxide generation. The MarR family regulator OhrR regulates the expression of chloroperoxidase and organic hydrogen resistance protein, which scavenge organic peroxides in free-living S. meliloti cells. The single mutant of ohrR genes SMc01945 (ohrR1) and SMc00098 (ohrR2) lacked symbiotic phenotypes. In this work, we identified the novel ohrR gene SMa2020 (ohrR3) and determined that ohrR genes are important for rhizobial infection, nodulation and nitrogen fixation with alfalfa. By analysing the phenotypes of the single, double and triple deletion mutants of ohrR genes, we demonstrate that ohrR1 and ohrR3 slightly affect rhizobial growth, but ohrR2 and ohrR3 influence cellular resistance to the organic peroxide, tert-butyl hydroperoxide. Deletion of ohrR1 and ohrR3 negatively affected infection thread formation and nodulation, and consequently, plant growth. Correspondingly, the expression of the ROS detoxification genes katA and sodB as well as that of the nitrogenase gene nifH was downregulated in bacteroids of the double and triple deletion mutants, which may underlie the symbiotic defects of these mutants. These findings demonstrate that OhrR proteins play a role in the S. meliloti-alfalfa symbiosis.

Molecular oxygen levels regulate Sinorhizobium meliloti cell division through a FixJ-dependent transcription control mechanism.

Rhizobia infect the roots of host legumes and induce formation of nitrogen-fixing nodules, where nitrogenase genes are inducibly expressed by micro-aerobic signals. FixL/FixJ is an oxygen signal sensing system that is unique to rhizobia. FixL monitors molecular oxygen levels and phosphorylates the response regulator FixJ, thereby regulating downstream gene expression. The cell division of rhizobia is regulated by a phosphorylation relaying cascade that includes the transcription factors CtrA, GcrA, and DnaA. In Sinorhizobium meliloti the expression of these proteins is regulated by NtrX, which affects cell division. In the present work, by analyzing the cell division phenotypes and gene expression patterns of S. meliloti fixJ and ntrX mutants, we found that S. meliloti cell division is regulated by oxygen gas levels. Under normal conditions, FixJ induced NtrX and DnaA expression, but repressed CtrA and GcrA expression. In contrast, under hypoxic conditions, phosphorylated FixJ specifically bound to gene promoter regions to directly induce CtrA and GcrA expression, but to repress DnaA expression. Our findings reveal that molecular oxygen levels regulate S. meliloti cell division by a FixJ-dependent transcription control mechanism.

Genome-Wide Association Study Reveals the Genetic Basis of Five Quality Traits in Chinese Wheat.

Bread wheat is a highly adaptable food crop grown extensively around the world and its quality genetic improvement has received wide attention. In this study, the genetic loci associated with five quality traits including protein content (PC), gluten content (GC), baking value (BV), grain hardness (HA), and sedimentation value (SV) in a population of 253 Chinese wheat grown in Inner Mongolia were investigated through genome wide association mapping. A total of 103 QTL containing 556 SNPs were significantly related to the five quality traits based on the phenotypic data collected from three environments and BLUP data. Of these QTL, 32 QTL were continuously detected under at least two experiments. Some QTL such as qBV3D.2/qHA3D.2 on 3D, qPC5A.3/qGC5A on 5A, qBV5D/qHA5D on 5D, qBV6B.2/qHA6B.3 on 6B, and qBV6D/qHA6D.1 on 6D were associated with multiple traits. In addition, distribution of favorable alleles of the stable QTL in the association panel and their effects on five quality traits were validated. Analysis of existing transcriptome data revealed that 34 genes were specifically highly expressed in grains during reproductive growth stages. The functions of these genes will be characterized in future experiments. This study provides novel insights into the genetic basis of quality traits in wheat.

A legume-specific novel type of phytosulfokine, PSK-δ, promotes nodulation by enhancing nodule organogenesis.

Phytosulfokine-α (PSK-α), a tyrosine-sulfated pentapeptide with the sequence YSO3IYSO3TQ, is widely distributed across the plant kingdom and plays multiple roles in plant growth, development, and immune response. Here, we report a novel type of phytosulfokine, PSK-δ, and its precursor proteins (MtPSKδ, LjPSKδ, and GmPSKδ1), specifically from legume species. The sequence YSO3IYSO3TN of sulfated PSK-δ peptide is different from PSK-α at the last amino acid. Expression pattern analysis revealed PSK-δ-encoding precursor genes to be expressed primarily in legume root nodules. Specifically, in Medicago truncatula, MtPSKδ expression was detected in root cortical cells undergoing nodule organogenesis, in nodule primordia and young nodules, and in the apical region of mature nodules. Accumulation of sulfated PSK-δ peptide in M. truncatula nodules was detected by LC/MS. Application of synthetic PSK-δ peptide significantly increased nodule number in legumes. Similarly, overexpression of MtPSKδ in transgenic M. truncatula markedly promoted symbiotic nodulation. This increase in nodule number was attributed to enhanced nodule organogenesis induced by PSK-δ. Additional genetic evidence from the MtPSKδ mutant and RNA interference assays suggested that the PSK-δ and PSK-α peptides function redundantly in regulating nodule organogenesis. These results suggest that PSK-δ, a legume-specific novel type of phytosulfokine, promotes symbiotic nodulation by enhancing nodule organogenesis.

Long non-coding RNA muscleblind like splicing regulator 1 antisense RNA 1 (LncRNA MBNL1-AS1) promotes the progression of acute myocardial infarction by regulating the microRNA-132-3p/SRY-related high-mobility-group box 4 (SOX4) axis.

Long non-coding RNA muscleblind like splicing regulator 1 antisense RNA 1 (LncRNA MBNL1-AS1) exerts vital role in various physiological processes. However, its functions in acute myocardial infarction (AMI) are not elucidated. AMI model was constructed using Wistar rats and it was found that LncRNA MBNL1-AS1 was upregulated in AMI model according to the quantitative real-time polymerase chain reaction (qRT-PCR) results. The left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP) and maximum rate of rise/fall of left ventricle pressure (±dp/dt max) were detected through hemodynamics test, which showed that knockdown of MBNL1-AS1 improved cardiac function in AMI model. Next, the myocardial infarction area was estimated by triphenyltetrazole chloride (TTC) staining, and the levels of cardiac troponin I (cTn-I) and creatine kinase-MB (CK-MB) were detected by enzyme-linked immunosorbent assay (ELISA) kit. The results revealed that silencing MBLN1-AS1 alleviated myocardial injury in AMI model. Additionally, MBNL1-AS1 knockdown inhibited apoptosis of myocardial cells and reduced the expression of apoptotic proteins. According to DIANA database and luciferase reporter assay, miR-132-3p was the direct target of MBNL1-AS1 and was negatively regulated by MBNL1-AS1. Furthermore, Targetscan database predicted that SRY-related high-mobility-group box 4 (SOX4) was the direct target of miR-132-3p and was regulated by MBNL1-AS1 through miR-132-3p. Moreover, overexpression of SOX4 partially eliminated effects of MBNL1-AS1 on myocardial cells. In conclusion, this investigation for the first time revealed that LncRNA MBNL1-AS1 was the potential target for treating AMI and expounded the underlying mechanisms of it.

Effect of ISM1 on the Immune Microenvironment and Epithelial-Mesenchymal Transition in Colorectal Cancer.

Background: An increasing number of studies have shown that Isthmin 1 (ISM1), a secreted protein, is important in tumorigenesis and invasion, including in colorectal cancer (CRC). However, the mechanisms are still unclear. This study aims to explore the function and prognosis capacity of ISM1 in CRC. Methods: We investigated the expression of ISM1 in 18 CRC tissues vs. adjacent normal tissues from GSE50760, 473 CRC tissues vs. 41 normal tissues from The Cancer Genome Atlas (TCGA), and across gastrointestinal cancer types. Differences were further confirmed in CRC tissues via quantitative real-time polymerase chain reaction (qRT-PCR). Then, we analyzed correlations between clinicopathologic features and ISM1 expression, including prognostic prediction value, using the Kaplan-Meier method and multivariate Cox regression. Gene set enrichment analysis (GSEA) was performed to identify ISM1-related pathways. In vitro experiments were performed to verify the role of ISM1 in epithelial-mesenchymal transition (EMT) and CRC progression. Results: Multiple datasets showed that ISM1 is upregulated in CRC tissues, which was validated. Patients with higher ISM1 expression had shorter overall survival (OS), and ISM1 expression served as an independent prognostic factor. Enrichment analysis showed that ISM1 upregulation was positively correlated with cancer-related pathways, such as EMT, hypoxia, and the Notch and KRAS signaling pathways. We were exclusively interested in the connection between ISM1 and EMT because 71% of genes in this pathway were significantly positively co-expressed with ISM1, which may account for why patients with higher ISM1 expression are prone to regional lymph node involvement and progression to advanced stages. In addition, we found that ISM1 was positively correlated with multiple immunosuppressive pathways such as IL2/STAT5, TNF-α/NF-κB, and TGF-ß, and immune checkpoints, including PD-L1, PD-1, CTLA-4, and LAG3, which may account for upregulation of ISM1 in immunotherapy-resistant patients. Notably, through in vitro experiments, we found that ISM1 promoted EMT and colon cancer cell migration and proliferation. Conclusion: ISM1 is critical for CRC development and progression, which enhances our understanding of the low response rate of CRC to immunotherapy via immunosuppressive signaling pathways.

Role of HOXC10 in Cancer.

The HOXC10 gene, a member of the HOX genes family, plays crucial roles in mammalian physiological processes, such as limb morphological development, limb regeneration, and lumbar motor neuron differentiation. HOXC10 is also associated with angiogenesis, fat metabolism, and sex regulation. Additional evidence suggests that HOXC10 dysregulation is closely associated with various tumors. HOXC10 is an important transcription factor that can activate several oncogenic pathways by regulating various target molecules such as ERK, AKT, p65, and epithelial mesenchymal transition-related genes. HOXC10 also induces drug resistance in cancers by promoting the DNA repair pathway. In this review, we summarize HOXC10 gene structure and expression as well as the role of HOXC10 in different human cancer processes. This review will provide insight into the status of HOXC10 research and help identify novel targets for cancer therapy.