A Novel Serum Exosomal miRNA Signature in the Early Prediction of Persistent Organ Failure in Patients with Acute Pancreatitis.

OBJECTIVE: Current study aims to investigate whether serum exosomal microRNAs (miRNAs) could be potential biomarkers in predicting APs with POF at early phase. BACKGROUND: Novel biomarkers are sorely needed for early prediction of persistent organ failure (POF) in acute pancreatitis (AP) patients. METHODS: In the discovery stage, exosomal miRNAs were profiled in sera from APs with or without POF (5 vs. 5) using microarrays. POF-associated miRNA signatures then were assessed in training cohort (n=227) and further validated in three independent cohorts (n=516), including one nested case-control cohort. RESULTS: A total of 743 APs were recruited in this large-scale biomarker identification study with a nested case-control study. Data from the discovery cohort demonstrated that 90 exosomal miRNAs were significantly dysregulated in APs with POF compared with controls. One miRNA classifier (Cmi) comprising 3 miRNAs (miR-4265, 1208, 3127-5p) was identified in the training cohort, and was further evaluated in two validation cohorts for their predictive value for POF. AUCs for Cmi ranged from 0.88 to 0.90, which was statistically superior to AUCs of APACHE-II and BISAP, and outperformed BUN and creatinine in POF prediction across all cohorts (P<.05). Higher levels of Cmi indicated increased need for ICU admission, prolonged hospitalization, and elevated mortality rate, thus poor prognosis. In the nested case-control study, Cmi could help identify prediagnostic POF in post-ERCP pancreatitis cases within "golden hours" after ERCP with high efficacy. CONCLUSIONS: Serum exosomal Cmi may be an early predictor for POF in AP, even within "golden hours" after AP onset. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02602808).

A diagnostic model for differentiating tuberculous spondylodiscitis from pyogenic spondylodiscitis based on pathogen-confirmed patients.

OBJECTIVE: This study aimed to distinguish tuberculous spondylodiscitis (TS) from pyogenic spondylodiscitis (PS) based on laboratory, magnetic resonance imaging (MRI) and computed tomography (CT) findings. Further, a novel diagnostic model for differential diagnosis was developed. METHODS: We obtained MRI, CT and laboratory data from TS and PS patients. Predictive models were built using binary logistic regression analysis. The receiver operating characteristic curve was analyzed. Both internal and external validation was performed. RESULTS: A total of 81 patients with PS (n = 46) or TS (n = 35) were enrolled. All patients had etiological evidence from the focal lesion. Disc signal or height preservation, skip lesion or multi segment (involved segments ≥ 3) involvement, paravertebral calcification, massive sequestra formation, subligamentous bone destruction, bone erosion with osteosclerotic margin, higher White Blood Cell Count (WBC) and positive result of tuberculosis infection T cell spot test (T-SPOT.TB) were more prevalent in the TS group. A diagnostic model was developed and included four predictors: WBC<7.265 * (10^9/L), skip lesion or involved segments ≥ 3, massive sequestra formation and subligamentous bone destruction. The model showed good sensitivity, specificity, and total accuracy (91.4%, 95.7%, and 93.8%, respectively); the area under the receiver operating characteristic curve (AUC) was 0.981, similar to the results of internal validation using bootstrap resampling (1000 replicates) and external validation set, indicating good clinical predictive ability. CONCLUSIONS: This study develop a good diagnostic model based on both CT and MRI, as well as laboratory findings, which may help clinicians distinguish between TS and PS.

Comprehensive expression analysis reveals several miRNAs against acute pancreatitis via modulating autophagy.

Acute pancreatitis (AP) had been one of the main reasons for hospitalization worldwide. However, the mechanisms related to AP remained to be unclear. This study identified 37 miRNAs and 189 mRNAs were differentially expressed in pancreatitis and normal samples. Bioinformatics analysis showed DEGs were significantly related to PI3K-Akt signaling, FoxO signaling, Oocyte meiosis, Focal adhesion, and Protein digestion and absorption. By constructing a signaling-DEGs regulation network, we found COL12A1, DPP4, COL5A1, COL5A2, and SLC1A5 were related to regulating Protein digestion and absorption, THBS2, BCL2, NGPT1, EREG, COL1A1 were related to regulating PI3K signaling, CCNB1, CDKN2B, IRS2, PLK2 were related to modulating FOXO signaling. Next, we constructed 1 miRNA-mRNA regulation network in AP, consisting of 34 miRNAs and 96 mRNAs. The protein-protein interaction networks and the miRNA-targets networks analysis show that hsa-miR-199a-5p, hsa-miR-150, hsa-miR-194, COL6A3 and CNN1 acted as hub regulators in AOf note, through comprehensive expression analysis, we found several miRNAs and mRNAs were significantly related to modulating autophagy signaling in AP, including hsa-miR-181c, hsa-miR-181d, hsa-miR-181b, hsa-miR-379 and hsa-miR-199a-5Overall, this study screening differently expressed miRNAs in AP and revealed miRNA- autophagy regulation may serve as a potential prognosis and Therapeutic marker for AP.

Phase separation ability and phosphatase activity of the SHP1-R360E mutant.

SHP1 is a non-receptor protein tyrosine phosphatase that is widely expressed in hematopoietic cells such as white blood cells, neutrophils, and immune cells. SHP1 can regulate the occurrence and differentiation of immune cells and plays an important role as a tumor suppressor. Previous studies have suggested that SHP2, the homologous protein of phosphatase SHP1, can undergo liquid-liquid phase separation (LLPS). Therefore, in this study, we investigated if SHP1 is also capable of LLPS. To the best of our knowledge, our study is the first to reveal that SHP1 has the ability to undergo LLPS. In addition, we identified an important residue, SHP1-R360E, that can completely inhibit the LLPS ability of SHP1, but this mutation has no remarkable effect on SHP1's enzymatic activity. This allows us to explore the phosphatase activity and phase separation ability of SHP1 separately, providing a basis for future exploration of the phase separation mechanism of phosphatases.

Scutellarin-mediated autophagy activates exosome release of rat nucleus pulposus cells by positively regulating Rab8a via the PI3K/PTEN/Akt pathway.

To provide a basis for promising exosome-based therapies against intervertebral disc degeneration (IDD), our present research aimed to identify a mechanism underlying the vesicle release from nucleus pulposus cells (NPCs). Scutellarin (SC) is a natural chemotherapeutic agent isolated from Erigeron breviscapus with a variety of biological activities. Here, we observed the significantly elevated autophagy levels in rat NPCs under the stimulation of SC, leading to a concomitant enhancement of intracellular vesicle release, which could be attributed to the inactivation of the phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/protein kinase B (Akt) pathway. To ensure that exosome release was driven by SC via the autophagic pathway, we implemented gain-of-function and loss-of-function studies by additionally using insulin-like growth factor-1 (IGF-1) and small-interfering RNA of autophagy-related gene 5 (ATG5), and the exosome secretion decreased in the case of attenuated autophagy. Evidently, the treatment with SC exerted the remarkable upregulation of Rab8a through the overexpression of ATG5. After the respective knockdown of ATG5 and Rab8a, the increased release of exosomes induced by SC was reversed, whereas the number of intracellular vesicles was restored. Overall, it can be concluded that SC contributes to the autophagy activation in NPCs by acting on the PI3K/PTEN/Akt pathway, which upregulates the expression of Rab8a and promotes the release of exosomes, inspiring novel therapeutic strategies in preventing IDD that might be fruitfully investigated.

Autophagy regulates exosome secretion in rat nucleus pulposus cells via the RhoC/ROCK2 pathway.

Our present study investigated whether exosome secretion of nucleus pulposus cells (NPCs) is regulated by autophagy. Different autophagic states of NPCs were induced by rapamycin (Rap), bafilomycin A1 (Baf) and other agents, and it was found that exosomes were secreted in an autophagy-dependent manner. Activation or inhibition of autophagy increased or decreased, respectively, the amount of exosomes that were released into the extracellular space. In addition, in order to confirm that Rap-promoted release of exosomes was mediated by autophagy rather than other pathways, we used autophagy associated gene 5 (ATG5) small-interfering RNA (siRNA) to silence the expression of ATG5 gene, which is indispensable for autophagy. The results showed that siRNA against ATG5 (siATG5) induced an accumulation of intraluminal vesicles (ILVs) in NPCs and a concomitant decrease in the amount of exosomes isolated from supernatant. Ras homolog gene (Rho) and Rho-associated coiled-coil forming protein kinase (ROCK) family molecules are capable of cytoskeletal remodeling and affecting vesicle transport. Therefore, we carried out targeted interventions and evaluated the effects of the RhoC/ROCK2 pathway on the secretion of exosomes within autophagic environment. Knockdown of RhoC and ROCK2 with corresponding siRNA significantly inhibited the secretion of exosomes originating from ILVs in NPCs, even when NPCs were subsequently treated with Rap. Taken together, our findings suggest that autophagy positively regulates expression levels of RhoC and ROCK2, and that the RhoC/ROCK2 pathway exerts a key function on NPCs-derived exosome secretion.

Learning Reward Function with Matching Network for Mapless Navigation.

Deep reinforcement learning (DRL) has been successfully applied in mapless navigation. An important issue in DRL is to design a reward function for evaluating actions of agents. However, designing a robust and suitable reward function greatly depends on the designer's experience and intuition. To address this concern, we consider employing reward shaping from trajectories on similar navigation tasks without human supervision, and propose a general reward function based on matching network (MN). The MN-based reward function is able to gain the experience by pre-training through trajectories on different navigation tasks and accelerate the training speed of DRL in new tasks. The proposed reward function keeps the optimal strategy of DRL unchanged. The simulation results on two static maps show that the DRL converge with less iterations via the learned reward function than the state-of-the-art mapless navigation methods. The proposed method performs well in dynamic maps with partially moving obstacles. Even when test maps are different from training maps, the proposed strategy is able to complete the navigation tasks without additional training.

Impact of a low-carbohydrate and high-fiber diet on nonalcoholic fatty liver disease.

BACKGROUND AND OBJECTIVES: To study the effects of a low-carbohydrate and high-fiber diet and education on patients with nonalcoholic fatty liver disease. METHODS AND STUDY DESIGN: We randomly divided 44 patients with nonalcoholic fatty liver disease into two groups: low-carbohydrate and high-fiber diet and education (intervention group), and education alone (control group). Liver and kidney function, fasting plasma glucose, insulin resistance index, body composition, and controlled attenuation parameter were detected before and after the intervention. RESULTS: After 2 months, the body fat, body weight, abdominal circumference, and visceral fat area, fasting plasma glucose, insulin resistance index, and levels of serum alanine aminotransferase, aspartate transaminase, uric acid, and insulin of the intervention group were significantly lower than before (p<0.05). In the female intervention group, the insulin resistance index and levels of serum alanine aminotransferase, uric acid, triglyceride, fasting plasma glucose, and C-peptide were lower and the level of serum high-density lipoprotein cholesterol was higher than in the female control group (p<0.05). In the male intervention group, the levels of serum alanine aminotransferase, triglyceride, and fasting plasma glucose were lower and the level of serum high-density lipoprotein cholesterol was higher compared with the male control group (p<0.05). CONCLUSIONS: A low-carbohydrate and high-fiber diet and education can effectively reduce the body weight and body fat of patients with nonalcoholic fatty liver disease and improve metabolic indicators such as liver enzymes, blood glucose, blood lipid, and uric acid. Our female patients showed significantly better improvement in the indicators than our male patients.

OGR1 mediates the inhibitory effects of acidic environment on proliferation and angiogenesis of endothelial progenitor cells.

Ovarian cancer G-protein-coupled receptor 1 (OGR1), an acid-sensitive receptor, plays a key proton-sensing role through stimulation of inositol phosphate formation. Avascular necrosis of the femoral head is characterized by apoptosis of bone cells mainly resulting from deficient local blood perfusion, eventually leading to acidification with disruption of endothelial progenitor cells' (EPCs) function. However, whether EPCs express OGR1 has not been demonstrated. This study attempted to whether OGR1 mediates the effects of acid on proliferation, migration, and angiogenesis in EPCs. FITC-UEA-I and Dil-Ac-LDL double-staining methods were used to identify EPCs. Expression of OGR1 was analyzed by RT-PCR (reverse transcription PCR) and western blot after incubation in media ranging in pH, cell counting kit-8 and cell cycle analysis were used to analyze proliferation and cell cycle distribution. Scratch test, transwell migration assay, and tube formation experiments were performed to analyze migration and vascularization of EPCs after silencing OGR1 with small interfering RNA (siRNA). The result show EPCs were positive for FITC-UEA-I and Dil-Ac-LDL double-staining and expressed OGR1. The expression of OGR1 increased gradually with decreased pH and was highest in pH 6.4 medium. Incubation in pH 6.4 medium inhibited proliferation of EPCs and caused cell cycle arrest. Silencing of OGR1 using siRNA partially reversed the effect of acidic environment on EPCs. Migration and angiogenesis of EPCs were inhibited in pH 6.4 medium, and silencing of OGR1 partially reversed this effect. The results demonstrated expression of OGR1 in EPCs, and the OGR1 mediated the effects of acidic environment on proliferation, migration, and angiogenesis of EPCs.

A Systems Vaccinology Approach Reveals Temporal Transcriptomic Changes of Immune Responses to the Yellow Fever 17D Vaccine.

In this study, we used a systems vaccinology approach to identify temporal changes in immune response signatures to the yellow fever (YF)-17D vaccine, with the aim of comprehensively characterizing immune responses associated with protective immunity. We conducted a cohort study in which 21 healthy subjects in China were administered one dose of the YF-17D vaccine; PBMCs were collected at 0 h and then at 4 h and days 1, 2, 3, 5, 7, 14, 28, 84, and 168 postvaccination, and analyzed by transcriptional profiling and immunological assays. At 4 h postvaccination, genes associated with innate cell differentiation and cytokine pathways were dramatically downregulated, whereas receptor genes were upregulated, compared with their baseline levels at 0 h. Immune response pathways were primarily upregulated on days 5 and 7, accompanied by the upregulation of the transcriptional factors JUP, STAT1, and EIF2AK2. We also observed robust activation of innate immunity within 2 d postvaccination and a durable adaptive response, as assessed by transcriptional profiling. Coexpression network analysis indicated that lysosome activity and lymphocyte proliferation were associated with dendritic cell (DC) and CD4+ T cell responses; FGL2, NFAM1, CCR1, and TNFSF13B were involved in these associations. Moreover, individuals who were baseline-seropositive for Abs against another flavivirus exhibited significantly impaired DC, NK cell, and T cell function in response to YF-17D vaccination. Overall, our findings indicate that YF-17D vaccination induces a prompt innate immune response and DC activation, a robust Ag-specific T cell response, and a persistent B cell/memory B cell response.

Augmentation strategies for clozapine refractory schizophrenia: A systematic review and meta-analysis.

BACKGROUND: Although clozapine is the most effective medication for treatment refractory schizophrenia, only 40% of people will meet response criteria. We therefore undertook a systematic review and meta-analysis of global literature on clozapine augmentation strategies. METHODS: We systematically reviewed PubMed, PsycInfo, Embase, Cochrane Database, Chinese Biomedical Literature Service System and China Knowledge Resource Integrated Database for randomised control trials of augmentation strategies for clozapine resistant schizophrenia. We undertook pairwise meta-analyses of within-class interventions and, where possible, frequentist mixed treatment comparisons to differentiate treatment effectiveness Results: We identified 46 studies of 25 interventions. On pairwise meta-analyses, the most effective augmentation agents for total psychosis symptoms were aripiprazole (standardised mean difference: 0.48; 95% confidence interval: -0.89 to -0.07) fluoxetine (standardised mean difference: 0.73; 95% confidence interval: -0.97 to -0.50) and, sodium valproate (standardised mean difference: 2.36 95% confidence interval: -3.96 to -0.75). Memantine was effective for negative symptoms (standardised mean difference: -0.56 95% confidence interval: -0.93 to -0.20). However, many of these results included poor-quality studies. Single studies of certain antipsychotics (penfluridol), antidepressants (paroxetine, duloxetine), lithium and Ginkgo biloba showed potential, while electroconvulsive therapy was highly promising. Mixed treatment comparisons were only possible for antipsychotics, and these gave similar results to the pairwise meta-analyses. CONCLUSIONS: On the basis of the limited data available, the best evidence is for the use of aripiprazole, fluoxetine and sodium valproate as augmentation agents for total psychosis symptoms and memantine for negative symptoms. However, these conclusions are tempered by generally short follow-up periods and poor study quality.

Dry eye disease in systemic lupus erythematosus: a cross sectional study.

AIM: To explore ocular surface manifestations of dry eye disease (DED) and its influencing factors in systemic lupus erythematosus (SLE) patients. METHODS: Ophthalmological examinations were conducted in SLE patients (n=43) and controls (n=41), including Ocular Surface Disease Index (OSDI), objective scatter index (OSI), tear meniscus height (TMH), lipid layer thickness (LLT), non-invasive Keratograph tear breakup time (NIKBUT), corneal fluorescein score (CFS), Schirmer I test. DED was diagnosed according to the Tear Film and Ocular Surface Society Dry Eye Workshop II Criteria. SLE patients were further divided into DED group and non-DED group, the disease activity, clinical manifestations and laboratory investigations were compared between the two groups. The disease activity was evaluated by Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K). Receiver operative characteristic (ROC) curve and multiple-factor binary logistic regression were performed. RESULTS: SLE patients showed higher OSDI [9.1 (2.8-15.9) vs 6.3 (2.2-7.5), P=0.035], higher OSI [1.67 (1.09-2.60) vs 0.96 (0.87-1.60), P=0.001], higher CFS [1 (0-2) vs 0 (0-1), P=0.001], lower LLT [65 (42-100) vs 100 (79.5-100), P=0.010], and lower NIKBUT [8.03 (4.02-9.73) vs 9.67 (5.26-12.71), P=0.030] than controls. The 32.6% of SLE patients had DED, which was higher than 12.2% of healthy controls. DED group showed higher SLEDAI-2K score [9.7±6.1 vs 5.4±3.4, P=0.025], higher anti-cardiolipin antibody (ACL) [8.7 (3.5-13.2) vs 3.6 (2.0-6.9), P=0.035], and higher proportion of patients with cutaneous eruption [42.9% vs 6.9%, P=0.015] than non-DED group. According to multiple-factor binary logistic regression analysis, the SLEDAI-2K score (OR=1.194, P=0.041) and cutaneous eruption (OR=7.094, P=0.045) could be consider as risk factors for DED in SLE patients. The ROC curve of the combined factors including age, disease duration, SLEDAI-2K score, ACL, and cutaneous eruption was analyzed, with a sensitivity of 0.786, a specificity of 0.793, and an area under curve of 0.820. CONCLUSION: Ocular surface affection is frequent in SLE patients, and patients with high disease activity and cutaneous eruption show increased risk of DED.

Organoid as a promising tool for primary liver cancer research: a comprehensive review.

Primary liver cancer (PLC) is one of the most common malignant gastrointestinal tumors worldwide. Limited by the shortage of liver transplantation donors and the heterogeneity of tumors, patients with liver cancer lack effective treatment options, which leads to rapid progression and metastasis. Currently, preclinical models of PLC fall short of clinical reality and are limited in their response to disease progression and the effectiveness of drug therapy. Organoids are in vitro three-dimensional cultured preclinical models with a high degree of heterogeneity that preserve the histomorphological and genomic features of primary tumors. Liver cancer organoids have been widely used for drug screening, new target discovery, and precision medicine; thus representing a promising tool to study PLC. Here, we summarize the progress of research on liver cancer organoids and their potential application as disease models. This review provides a comprehensive introduction to this emerging technology and offers new ideas for researchers to explore in the field of precision medicine.

Decoding the genomic landscape of chromatin-associated biomolecular condensates.

Biomolecular condensates play a significant role in chromatin activities, primarily by concentrating and compartmentalizing proteins and/or nucleic acids. However, their genomic landscapes and compositions remain largely unexplored due to a lack of dedicated computational tools for systematic identification in vivo. To address this, we develop CondSigDetector, a computational framework designed to detect condensate-like chromatin-associated protein co-occupancy signatures (CondSigs), to predict genomic loci and component proteins of distinct chromatin-associated biomolecular condensates. Applying this framework to mouse embryonic stem cells (mESC) and human K562 cells enable us to depict the high-resolution genomic landscape of chromatin-associated biomolecular condensates, and uncover both known and potentially unknown biomolecular condensates. Multi-omics analysis and experimental validation further verify the condensation properties of CondSigs. Additionally, our investigation sheds light on the impact of chromatin-associated biomolecular condensates on chromatin activities. Collectively, CondSigDetector provides an approach to decode the genomic landscape of chromatin-associated condensates, facilitating a deeper understanding of their biological functions and underlying mechanisms in cells.

Influence factors of metagenomic next-generation sequencing negative results in diagnosed patients with spinal infection.

The aim of this study was to evaluate the influence factors of metagenomic next-generation sequencing (mNGS) negative results in the diagnosed patients with spinal infection. mNGS test was applied in a cohort of 114 patients with suspected spinal infection, among which 56 patients had a final diagnosis of spinal infection. mNGS achieved a sensitivity of 75.0% (95% CI, 61.6% to 85.6%) and a specificity of 84.5% (95% CI, 72.6% to 92.7%), using histopathology and culture results as reference. Diagnosed patients with a negative culture result had lower white blood cell account, percentage of neutrophilic granulocyte, C-reactive protein (all P<0.05) and relatively higher rate of prior antimicrobial treatment history (P=0.059). However, diagnosed patients with a negative mNGS result did not have such difference with mNGS-positive patients, suggesting that mNGS was not strictly limited by the above indicators, which presented the advantages of this technique from another point of view.

Anat-SFSeg: Anatomically-guided superficial fiber segmentation with point-cloud deep learning.

Diffusion magnetic resonance imaging (dMRI) tractography is a critical technique to map the brain's structural connectivity. Accurate segmentation of white matter, particularly the superficial white matter (SWM), is essential for neuroscience and clinical research. However, it is challenging to segment SWM due to the short adjacent gyri connection in a U-shaped pattern. In this work, we propose an Anatomically-guided Superficial Fiber Segmentation (Anat-SFSeg) framework to improve the performance on SWM segmentation. The framework consists of a unique fiber anatomical descriptor (named FiberAnatMap) and a deep learning network based on point-cloud data. The spatial coordinates of fibers represented as point clouds, as well as the anatomical features at both the individual and group levels, are fed into a neural network. The network is trained on Human Connectome Project (HCP) datasets and tested on the subjects with a range of cognitive impairment levels. One new metric named fiber anatomical region proportion (FARP), quantifies the ratio of fibers in the defined brain regions and enables the comparison with other methods. Another metric named anatomical region fiber count (ARFC), represents the average fiber number in each cluster for the assessment of inter-subject differences. The experimental results demonstrate that Anat-SFSeg achieves the highest accuracy on HCP datasets and exhibits great generalization on clinical datasets. Diffusion tensor metrics and ARFC show disorder severity associated alterations in patients with Alzheimer's disease (AD) and mild cognitive impairments (MCI). Correlations with cognitive grades show that these metrics are potential neuroimaging biomarkers for AD. Furthermore, Anat-SFSeg could be utilized to explore other neurodegenerative, neurodevelopmental or psychiatric disorders.

Inflammatory regulation of squid cartilage gelatin with different molecular weights for treatment of chronic wounds in diabetes.

Squid, as a very important economic marine species, accounts for 5 % of the total catch of fish and cephalopods. The waste from the processing process of squid can be used for collagen extraction, which has great application value in the field of biomedical materials. Here, we obtained squid cartilage gelatin (SCG) with different molecular weights by adjusti.ng the reaction conditions and used for the treatment of chronic wounds in diabetes. SCG extracted at low temperatures and short heating times demonstrated a more intact structure, higher molecular weight, and superior gel stability. Based on cell study and transcriptome analysis, SCG with high molecular weight significantly promoted cell adhesion, because it provided more contact sites for cells, whereas small molecules of SCG could directly reduce inflammation. Animal studies have demonstrated that SCG significantly promotes diabetic wound healing as evidenced by reducing inflammation, inducing vascular regeneration, promoting tissue growth, re-epithelialization, collagen deposition and remodeling. This study elucidated the immunoregulatory mechanisms of SCG with different molecular weights, and validated its potential application in chronic wound healing in diabetes.

Overload of dissolved organic matter (DOM) in riparian infiltration zone increasing the pollution risk of naphthalene, insight from the competitive inhibition of naphthalene biodegradation by DOM.

Riparian infiltration zones are crucial for maintaining water quality by reducing the aqueous concentrations of polycyclic aromatic hydrocarbons (PAHs) through adsorption and biodegradation within the aquatic ecosystem. Dissolved organic matter (DOM) are ubiquitous in riparian infiltration zones where they extensively engage in the adsorption and biodegradation of PAHs, thereby influencing PAHs natural attenuation potential within riparian infiltration zones. Few studies have explored the natural attenuation mechanisms of PAHs influenced by DOM in riparian infiltration zones. In this study, the natural attenuation mechanisms of naphthalene (a typical PAHs component), under the influence of DOM, were explored, based on a case riverside source area. Analysis of microbial community structures, and the electron acceptor (e.g., Fe(III), DO/NO3-, SO42-)/electron donor (naphthalene and DOM) concentration changes within the riparian infiltration zone revealed a competitive inhibition relationship between DOM and naphthalene during microbial metabolism. Biodegradation experiments showed that when the concentration of DOM is higher than 4.0 mg·L-1, it inhibits the biodegradation of naphthalene. DOM competitively inhibits the biodegradation of naphthalene through the following mechanisms: (i) triggering microbial antioxidative defense mechanisms, diminishing the available resources for microbial participation in naphthalene degradation; (ii) altering microbial community structure; (iii) modulating microbial EPS composition, reducing the efficiency of microorganisms in utilizing carbon sources; and (iv) inhibiting the expression levels of downstream genes involved in naphthalene degradation. The competitive inhibition constants of DOM with concentrations of 1.0, 2.0, 4.0, 8.0, and 16.0 mg·L-1 on naphthalene biodegradation are -2.0 × 10-3, -5.0 × 10-3,1.0 × 10-3, 4.0 × 10-4, and 1.0 × 10-4, respectively. These findings enhance understanding of PAHs attenuation in riparian infiltration zone, providing a basis for assessing and managing PAHs pollution risks during riparian extraction.

Exosomes Derived From Cerulein-Stimulated Pancreatic Acinar Cells Mediate Peritoneal Macrophage M1 Polarization and Pyroptosis via an miR-24-3p/MARCH3/NLRP3 Axis in Acute Pancreatitis.

OBJECTIVES: Acute pancreatitis (AP) has a high incidence of hospitalizations, morbidity, and mortality worldwide. A growing number of studies on AP pathogenesis are based on cerulein-induced experimental model, which simulates human AP in vivo. It has been demonstrated that both pancreatic acinar cells and peritoneal macrophages are involved in pancreatic inflammation and damage. However, their connection has not been well understood. METHODS: A cerulein-induced AP model was established on the pancreatic acinar cell line AR42J. Rat macrophages were isolated from the peritoneal cavity. The effects of cerulein-induced pancreatic exosomes on the peritoneal macrophage and pancreas in vivo and in vitro were examined. The underlying molecular mechanism was investigated by exploring the regulatory role of downstream molecules. RESULTS: We found that exosomes derived from cerulein-treated AR42J cells induced rat peritoneal macrophage M1 polarization and pyroptosis. miR-24-3p was upregulated in cerulein-stimulated exosomes, whereas the miR-24-3p inhibitor counteracted the effect of pancreatic exosomes on peritoneal macrophage M1 polarization and pyroptosis. Furthermore, miR-24-3p inhibited March3 expression, whereas MARCH3 mediated NLRP3 ubiquitination in rat peritoneal macrophages, which, in turn, contributed to the apoptosis, reactive oxygen species production, and inflammation in AR42J cells. CONCLUSIONS: Exosomes derived from cerulein-stimulated pancreatic acinar cells mediate peritoneal macrophage M1 polarization and pyroptosis via an miR-24-3p/MARCH3/NLRP3 axis in AP.