Small RNA GadY in Escherichia coli enhances conjugation system of IncP-1 by targeting SdiA.

Plasmid-mediated conjugation is a common mechanism for most bacteria to transfer antibiotic resistance genes (ARGs). The conjugative transfer of ARGs is emerging as a major threat to human beings. Although several transfer-related factors are known to regulate this process, small RNAs (sRNAs)-based regulatory roles remain to be clarified. Here, the Hfq-binding sRNA GadY in donor strain Escherichia coli (E. coli) SM10λπ was identified as a new regulator for bacterial conjugation. Two conjugation models established in our previous studies were used, which SM10λπ carrying a chromosomally integrated IncP-1α plasmid RP4 and a mobilizable plasmid pUCP24T served as donor cells, and P. aeruginosa PAO1 or E. coli EC600 as the recipients. GadY was found to promote SM10λπ-PAO1 conjugation by base-pairing with its target mRNA SdiA, an orphan LuxR-type receptor that responds to exogenous N-acylated homoserine lactones (AHLs). However, SM10λπ-EC600 conjugation was not affected due to EC600 lacking AHLs synthase. It indicates that the effects of GadY on conjugation depended on AHLs-SdiA signalling. Further study found GadY bound SdiA to negatively regulate the global RP4 repressors KorA and KorB. When under ciprofloxacin or levofloxacin treatment, GadY expression in donor strain was enhanced, and it positively regulated quinolone-induced SM10λπ-PAO1 conjugation. Thus, our study provides a novel role for sRNA GadY in regulating plasmid-mediated conjugation, which helps us better understand bacterial conjugation to counter antibiotic resistance.

Ferroptosis-related LINC02535/has-miR-30c-5p/EIF2S1 axis as a novel prognostic biomarker involved in immune infiltration and progression of PDAC.

BACKGROUND: PDAC, also known as pancreatic ductal adenocarcinoma, is often diagnosed at a late stage due to nonspecific symptoms and a distinct lack of reliable biomarkers for timely diagnosis. Ferroptosis, a novel non-apoptotic cell death mode discovered in recent years, is strongly linked to the progression of PDAC and the evasion of the immune system. The objective of this study is to discover a novel ceRNA biomarker associated with ferroptosis and investigate its possible molecular mechanisms and therapeutic potential in PDAC. METHODS: Based on the FerrDb and TCGA databases, the R survival package was used to screen for ferroptosis-related mRNAs associated with PDAC prognosis. The ferroptosis-related ceRNA network was identified by miRTarBase, miRNet, and starBase and visualized using Cytoscape. The LASSO regression analysis was used to build a risk model associated with ceRNA. Additionally, we investigated the correlation between the ceRNA axis and the infiltration of immune cells in PDAC by employing the ssGSEA algorithm. Spearman correlation analysis was used to investigate the association between the ceRNA network and the expression levels of immune checkpoint genes in PDAC. The prediction of potential medications for PAAD patients with high risk scores was conducted using the R package oncoPredict and the Genomics of Drug Sensitivity in Cancer (GDSC) repository. Expression levels of LINC02535 in clinical specimens and PDAC cell lines were determined using qRT-PCR. CCK-8, colony formation, EdU, wound healing, and transwell assays were performed to assess the impact of reducing LINC02535 on the growth, migration, and invasion of PDAC cell lines BxPC3 and PANC1. RESULTS: We first discovered a new LINC02535/miR-30c-5p/EIF2S1 axis associated with ferroptosis and created a prognostic nomogram for predicting overall survival. Meanwhile, the risk scores of the LINC02535/miR-30c-5p/EIF2S1 axis associated with ferroptosis were linked to immune subtypes in PDAC. The high immune infiltration subtype exhibited elevated ceRNA risk scores and EIF2S1 expression. The correlation analysis revealed a positive correlation between ceRNA risk scores and four immune cells, namely Activated CD4 T cell, Memory B cell, Neutrophil, and Type 2 T helper cell, as well as four immune checkpoint genes, namely CD274, HAVCR2, PDCD1LG2, and TIGIT. The analysis of drug sensitivity indicated that individuals with a high-risk score may exhibit greater sensitivity to inhibitors targeting MEK1/2 compared to those with a low-risk score. In our validation experiments, it was observed that the expression of LINC02535 was increased in both PDAC tissues and cell lines. Additionally, the inhibition of LINC02535 resulted in decreased proliferation, migration, and invasion of PDAC cells. Rescue experiments demonstrated that LINC02535 promoted PDAC cell growth and metastasis by upregulating EIF2S1 expression. CONCLUSION: To summarize, a novel ferroptosis-associated LINC02535/miR-30c-5p/EIF2S1 ceRNA network for PDAC patients was established. The analysis of this network's functionality offers potential insights for clinical decision-making and the advancement of precision medicine.

Origin of Manipulating Selectivity in Prins Cyclization by [Ga4L6]12- Supramolecular Catalysis through Host-Guest Interactions.

The host effect of the supramolecular [Ga4L6]12- tetrahedral metallocage on Prins cyclization reaction of the substrate by encapsulated citronellal has been investigated by means of molecular dynamics and quantum mechanics. The encapsulation process of the substrate into the [Ga4L6]12- cavity was simulated via attach-pull-release (APR) methods. Thermodynamic calculations and classical molecular dynamics simulations assessed the substrate's microenvironment inside the cavity, guiding DFT-level modeling of the reaction. DFT calculations show diol product predominance in acidic solution but high enol selectivity inside [Ga4L6]12-, consistent with experimental findings. [Ga4L6]12- alters the selectivity of the Prins cyclization reaction by inhibiting diol formation. The activation strain model-based decomposition analysis (ASM-DA) of the barrier difference among distortion and interaction terms indicates that the more positive interaction between a host and guest in the diol transition state than enol determines the product selectivity, particularly the fewer C-H···O and O-H···O hydrogen-bonding interactions. These theoretical insights could contribute to a deeper understanding of the nature of supramolecular catalysis and to further develop new supramolecular catalysts.

Short-term associations between precipitation and gastrointestinal illness-related hospital admissions: A multi-city study in Texas.

The ongoing climate change crisis presents challenges to the global public health system. The risk of gastrointestinal illness (GI) related hospitalization increases following extreme weather events but is largely under-reported and under-investigated. This study assessed the association between precipitation and GI-related hospital admissions in four major cities in Texas. Daily data on GI-related hospital admissions and precipitation from 2004 to 2014 were captured from the Texas Department of State Health Services and the National Climate Data Center. Distributed lagged nonlinear modeling approaches were employed to examine the association between precipitation and GI-related hospital admissions. Results showed that the cumulative risk ratios (RRs) of GI-related hospital admissions were elevated in the 2 weeks following precipitation events; however, there were differences observed across study locations. The cumulative RR of GI-related hospitalizations was significantly higher when the amount of daily precipitation ranged from 3.3 mm to 13.5 mm in Dallas and from 6.0 mm to 24.5 mm in Houston. Yet, substantial increases in the cumulative RRs of GI-related hospitalizations were not observed in Austin or San Antonio. Age-specific and cause-specific GI-related hospitalizations were also found to be associated with precipitation events following the same pattern. Among them, Houston depicted the largest RR for overall GI and subgroup GI by age and cause, particularly for the overall GI among children aged 6 and under (RR = 1.35; 95 % CI = 1.11, 1.63), diarrhea-caused GI among children aged 6 and under (RR = 1.38, 95 % CI = 1.13, 1.69), and other-caused GI among children age 6 and under (RR = 1.46; 95 % CI = 1.12, 1.80). The findings underscore the need for public health interventions and adaptation strategies to address climate change-related health outcomes such as GI illness associated with extreme precipitation events.

Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Alleviate Nuclear Pulposus Cells Degeneration Through the miR-145a-5p/USP31/HIF-1α Signaling Pathway.

Bone marrow mesenchymal stem cell (BMSC)-derived exosomes possess therapeutic potential against degenerative diseases. This study aimed to investigate the effects of BMSC-derived exosomes on intervertebral disc degeneration (IVDD) and explore the underlying molecular mechanisms. Through transcriptome sequencing and histological analysis, we observed a significant increase in HIF-1α expression in degenerative nucleus pulposus (NP) tissues. The addition of HIF-1α resulted in elevated expression of inflammatory factors IL-1ß and IL-6, higher levels of matrix-degrading enzyme MMP13, and lower expression of aggrecan in NP cells. Co-culturing with BMSCs diminished the expression of HIF-1α, MMP13, IL-1ß, and IL-6 in degenerative NP cells induced by overload pressure. miRNA chip analysis and PCR validation revealed that miR-145a-5p was the primary miRNA carried by BMSC-derived exosomes. Overexpression of miR-145a-5p was effective in minimizing the expression of HIF-1α, MMP13, IL-1ß, and IL-6 in degenerative NP cells. Luciferase reporter assays confirmed USP31 as the target gene of miR-145a-5p, and the regulation of NP cells by BMSC-derived exosomes via miR-145a-5p was dependent on USP31. In conclusion, BMSC-derived exosomes alleviated IVDD through the miR-145a-5p/USP31/HIF-1α signaling pathway, providing valuable insights into the treatment of IVDD.

A multi-bin rarefying method for evaluating alpha diversities in TCR sequencing data.

MOTIVATION: T cell receptors (TCRs) constitute a major component of our adaptive immune system, governing the recognition and response to internal and external antigens. Studying the TCR diversity via sequencing technology is critical for a deeper understanding of immune dynamics. However, library sizes differ substantially across samples, hindering the accurate estimation/comparisons of alpha diversities. To address this, researchers frequently use an overall rarefying approach in which all samples are sub-sampled to an even depth. Despite its pervasive application, its efficacy has never been rigorously assessed. RESULTS: In this paper, we develop an innovative "multi-bin" rarefying approach that partitions samples into multiple bins according to their library sizes, conducts rarefying within each bin for alpha diversity calculations, and performs meta-analysis across bins. Extensive simulations using real-world data highlight the inadequacy of the overall rarefying approach in controlling the confounding effect of library size. Our method proves robust in addressing library size confounding, outperforming competing normalization strategies by achieving better-controlled type-I error rates and enhanced statistical power in association tests. AVAILABILITY AND IMPLEMENTATION: The code is available at https://github.com/mli171/MultibinAlpha. The datasets are freely available at https://doi.org/10.21417/B7001Z and https://doi.org/10.21417/AR2019NC.

Novel Intraoperative and Pathological Findings Related to Computed Tomography Angiography Spot Signs in Intracerebral Hemorrhage Patients: A Case Report.

Introduction: A spot sign on computed tomography angiography (CTA) scan is a widely recognized radiographic indicator of primary intracerebral hemorrhage (ICH) used to predict early hematoma expansion. Nonetheless, recent multicenter studies have indicated that its predictive value for hematoma expansion is not as significant as previously stated. Therefore, identifying the reasons for the poor performance of these studies is imperative. Case presentation: A 48-year-old man presented with a 9-hour history of alalia and right limb hemiplegia. Noncontrast computed tomography (CT) revealed a hematoma in the left frontal lobe, while CTA showed a spot sign within the hematoma, leading to a diagnosis of frontal lobe hemorrhage. During the surgical procedure, a blood clot was removed, revealing the presence of 3 mm of saccular tissue resembling an aneurysm. The process of exposing its complete form resulted in its rupture and bleeding. The location of this tissue at the top of the hematoma cavity corresponded to the CTA spot sign. Pathological examination confirmed that the characteristics of the tissue wall were consistent with those of a pseudoaneurysm. Conclusion: This case suggests that more stringent identification criteria should be established in studies predicting ICH expansion using the spot sign on CTA to differentiate and exclude pseudoaneurysms, thereby improving the accuracy of predicting early hematoma expansion using the CTA spot sign.

NanoRanger enables rapid single-base-pair resolution of genomic disorders.

BACKGROUND: Delineating base-resolution breakpoints of complex rearrangements is crucial for an accurate clinical understanding of pathogenic variants and for carrier screening within family networks or the broader population. However, despite advances in genetic testing using short-read sequencing (SRS), this task remains costly and challenging. METHODS: This study addresses the challenges of resolving missing disease-causing breakpoints in complex genomic disorders with suspected homozygous rearrangements by employing multiple long-read sequencing (LRS) strategies, including a novel and efficient strategy named nanopore-based rapid acquisition of neighboring genomic regions (NanoRanger). NanoRanger does not require large amounts of ultrahigh-molecular-weight DNA and stands out for its ease of use and rapid acquisition of large genomic regions of interest with deep coverage. FINDINGS: We describe a cohort of 16 familial cases, each harboring homozygous rearrangements that defied breakpoint determination by SRS and optical genome mapping (OGM). NanoRanger identified the breakpoints with single-base-pair resolution, enabling accurate determination of the carrier status of unaffected family members as well as the founder nature of these genomic lesions and their frequency in the local population. The resolved breakpoints revealed that repetitive DNA, gene regulatory elements, and transcription activity contribute to genome instability in these novel recessive rearrangements. CONCLUSIONS: Our data suggest that NanoRanger greatly improves the success rate of resolving base-resolution breakpoints of complex genomic disorders and expands access to LRS for the benefit of patients with Mendelian disorders. FUNDING: M.L. is supported by KAUST Baseline Award no. BAS/1/1080-01-01 and KAUST Research Translation Fund Award no. REI/1/4742-01.

Artificial mucus layer formed in response to ROS for the oral treatment of inflammatory bowel disease.

The artificial mucus layer, such as hydrogels, used to repair the damaged intestinal barrier, is a promising treatment for inflammatory bowel disease (IBD). However, the currently reported hydrogel-based artificial barriers are administered via rectal injection, causing unnecessary discomfort to patients. Herein, we report an oral hydrogel precursor solution based on thiol-modified hyaluronic acid (HASH). Owing to the reactive oxygen species (ROS)-responsive gelling behavior, our precursor solution formed an artificial mucus coating over the inflamed regions of the intestines, blocking microbial invasion and reducing abnormally activated immune responses. Notably, HASH also modulated the gut microbiota, including increasing the diversity and enhancing the abundance of short-chain fatty acid-associated bacteria, which play a key role in gut homeostasis. We believe that the ROS-responsive artificial mucus layer is a promising strategy for the oral treatment of IBD.

Association of chrononutrition patterns with biological aging: evidence from a nationally representative cross-sectional study.

Previous studies mostly focused on the benefits of caloric restriction and fasting on longevity. However, whether the timing and frequency of eating affect aging remains unclear. Here, we investigated the associations between chrononutrition patterns and biological aging, and explored whether and to what extent dietary inflammation mediated this association. 16 531 adults aged 20 to 84 years from the National Health and Nutrition Examination Survey were collected. Chrononutrition patterns were determined with two 24-hour dietary recalls. Phenotypic age was calculated to reflect the biological aging status. The dietary inflammatory index (DII) was used to assess the dietary inflammation. After adjustment of the survey weight and multiple covariates including total energy intake, participants in the third tertile of the time of the first meal (mean 10 : 26) exhibited more advanced biological age (ß 0.64; 95% CI, 0.26-1.00) and a higher incidence of accelerated aging (odds ratio (OR) 1.25; 95% CI, 1.06-1.47) compared to those of the first tertile (mean 6 : 14). Higher eating frequency was associated with delayed biological aging in both multivariable linear (ß -0.31; 95% CI, -0.44 to -0.19) and logistic regression model (OR 0.90; 95% CI, 0.85-0.95). Furthermore, we found that DII rather than metabolic factors mediated the inverse association between eating frequency and biological aging (mediation proportion 24.67%; 95% CI, 19.83%-32.00%). Our findings demonstrated the association between chrononutrition patterns and biological aging among the US general population and the potential role of dietary inflammation in this association, suggesting that modifying chrononutrition patterns may be a practical and cost-effective strategy for combating aging.

Response of soil microbial ecological functions and biological characteristics to organic fertilizer combined with biochar in dry direct-seeded paddy fields.

Biochar and organic fertilizer are commonly used to maintain soil health and sustainable agroecosystems, and the alternate wet-dry management of soil moisture in dry direct-seeded paddy fields can complicate the effects of biochar and organic fertilizer on soil microhabitats. Therefore, this study used chicken manure organic fertilizer to replace some of the inorganic fertilizer and applied biochar to explore the ability of biochar and organic fertilizer to regulate the functions of the soil microhabitat in dry direct-seeded paddy fields. The coupling effect of organic fertilizer and biochar increased the diversity and richness of soil bacteria but had no significant effect on soil fungi. Biochar and organic fertilizer affected the distribution and composition of soil bacteria and fungi, and the total number of soil bacteria and fungi increased by 1365 and -71 (5 t/hm2 biochar and no organic fertilizer), 660 and 79 (10 t/hm2 biochar and no organic fertilizer), 3121 and 7 (no biochar and 20 % organic fertilizer substitution), 1873 and -72 (5 t/hm2 biochar and 20 % organic fertilizer substitution), and -544 and -65 (10 t/hm2 biochar and 20 % organic fertilizer substitution), respectively, compared with that of the control treatment. Compared with the application of biochar alone, the coupling effect of biochar and organic fertilizer increased the average degree (0.95 and 0.16), links (190 and 32), and ratio of fungal positive links (1.651 %), and decreased the modularity (0.034 and 0.052) and ratio of bacterial positive links (6.482 %) of bacterial and fungal networks. In addition, the coupling effect resulted in a more complex association between soil microbial diversity and richness and microbial ecological functions. Random forest predictions indicated that, organic fertilizer as a random factor, changes in the abundance of bacterial Bacteroidetes and Nitrospirae and fungal Monoblepharomycota were the main factors driving the differences in soil microbial ecological functions.

Human induced pluripotent stem cell/embryonic stem cell-derived pyramidal neuronal precursors show safety and efficacy in a rat spinal cord injury model.

Nerve regeneration and circuit reconstruction remain a challenge following spinal cord injury (SCI). Corticospinal pyramidal neurons possess strong axon projection ability. In this study, human induced pluripotent stem cells (iPSCs) were differentiated into pyramidal neuronal precursors (PNPs) by addition of small molecule dorsomorphin into the culture. iPSC-derived PNPs were transplanted acutely into a rat contusion SCI model on the same day of injury. Following engraftment, the SCI rats showed significantly improved motor functions compared with vehicle control group as revealed by behavioral tests. Eight weeks following engraftment, the PNPs matured into corticospinal pyramidal neurons and extended axons into distant host spinal cord tissues, mostly in a caudal direction. Host neurons rostral to the lesion site also grew axons into the graft. Possible synaptic connections as a bridging relay may have been formed between host and graft-derived neurons, as indicated by pre- and post-synaptic marker staining and the regulation of chemogenetic regulatory systems. PNP graft showed an anti-inflammatory effect at the injury site and could bias microglia/macrophages towards a M2 phenotype. In addition, PNP graft was safe and no tumor formation was detected after transplantation into immunodeficient mice and SCI rats. The potential to reconstruct a neuronal relay circuitry across the lesion site and to modulate the microenvironment in SCI makes PNPs a promising cellular candidate for treatment of SCI.

Effect of ozone treatment on phenylpropanoid metabolism in harvested cantaloupes.

Phenylpropanoid metabolism plays an important role in cantaloupe ripening and senescence, but the mechanism of ozone regulation on phenylpropanoid metabolism remains unclear. This study investigated how ozone treatment modulates the levels of secondary metabolites associated with phenylpropanoid metabolism, the related enzyme activities, and gene expression in cantaloupe. Treating cantaloupes with 15 mg/m3 of ozone after precooling can help maintain postharvest hardness. This treatment also enhances the production and accumulation of secondary metabolites, such as total phenols, flavonoids, and lignin. These metabolites are essential components of the phenylpropanoid metabolic pathway, activating enzymes like phenylalanine ammonia-lyase, cinnamate 4-hydroxylase, 4CL, chalcone synthase, and chalcone isomerase. The results of the transcriptional expression patterns showed that differential gene expression related to phenylpropanoid metabolism in the peel of ozone-treated cantaloupes was primarily observed during the middle and late storage stages. In contrast, the pulp exhibited significant differential gene expression mainly during the early storage stage. Furthermore, it was observed that the level of gene expression in the peel was generally higher than that in the pulp. The correlation between the relative amount of gene changes in cantaloupe, activity of selected enzymes, and concentration of secondary metabolites could be accompanied by positive regulation of the phenylpropanoid metabolic pathway. Therefore, ozone stress induction positively enhances the biosynthesis of flavonoids in cantaloupes, leading to an increased accumulation of secondary metabolites. Additionally, it also improves the postharvest storage quality of cantaloupes.

Intraoperative hypotension is associated with decreased long-term survival in older patients after major noncardiac surgery: Secondary analysis of three randomized trials.

STUDY OBJECTIVE: To assess the association of intraoperative hypotension with long-term survivals in older patients after major noncardiac surgery mainly for cancer. DESIGN: A secondary analysis of databases from three randomized trials with long-term follow-up. SETTING: The underlying trials were conducted in 17 tertiary hospitals in China. PATIENTS: Patients aged 60 to 90 years who underwent major noncardiac thoracic or abdominal surgeries (≥ 2 h) in a single center were included in this analysis. EXPOSURES: Restricted cubic spline models were employed to determine the lowest mean arterial pressure (MAP) threshold that was potentially harmful for long-term survivals. Patients were arbitrarily divided into three groups according to the cumulative duration or area under the MAP threshold. The association between intraoperative hypotension exposure and long-term survivals were analyzed with the Cox proportional hazard regression models. MEASUREMENTS: Our primary endpoint was overall survival. Secondary endpoints included recurrence-free and event-free survivals. MAIN RESULTS: A total of 2664 patients (mean age 69.0 years, 34.9% female sex, 92.5% cancer surgery) were included in the final analysis. MAP < 60 mmHg was adopted as the threshold of intraoperative hypotension. Patients were divided into three groups according to duration under MAP < 60 mmHg (<1 min, 1-10 min, and > 10 min) or area under MAP <60 mmHg (< 1 mmHg⋅min, 1-30 mmHg⋅min, and > 30 mmHg⋅min). After adjusting confounders, duration under MAP < 60 mmHg for > 10 min was associated with a shortened overall survival when compared with the < 1 min patients (adjusted hazard ratio [HR] 1.31, 95% confidence interval [CI] 1.09 to 1.57, P = 0.004); area under MAP < 60 mmHg for > 30 mmHg⋅min was associated with a shortened overall survival when compared with the < 1 mmHg⋅min patients (adjusted HR 1.40, 95% CI 1.16 to 1.68, P < 0.001). Similar associations exist between duration under MAP < 60 mmHg for > 10 min or area under MAP < 60 mmHg for > 30 mmHg⋅min and recurrence-free or event-free survivals. CONCLUSIONS: In older patients who underwent major noncardiac surgery mainly for cancer, intraoperative hypotension was associated with worse overall, recurrence-free, and event-free survivals.

GaN Nano Air Channel Diodes: Enabling High Rectification Ratio and Neutron Robust Radiation Operation.

Nano air channel transistors (NACTs) provide numerous advantages over traditional silicon devices, including faster switching speeds, higher operating frequencies, and enhanced radiation hardness attributable to the ballistic transport of electrons. In the development of field-emission-based integrated circuits, low-power consumption rectifying nano air channel diodes (NACDs) play a crucial role. However, achieving rectification characteristics in NACDs is challenging due to their structural and material symmetry. This paper proposes a vertical GaN NACD with a consistent nano air channel fabricated using IC-compatible processes. The GaN NACD exhibits an exceptionally low turn-on voltage of 0.3 V while delivering a high output current of 5.02 mA at 3 V. Notably, it demonstrates a high rectification ratio of up to 2.2 × 105, attributing to significant work function disparities within the GaN-Au structure, coupled with the reduction of Au surface roughness to minimize reverse current. Furthermore, the junction-free structure and superior material properties of GaN enable the NACD to be suitable for use in radiation-rich environments. With its potential as a fundamental component of ultrafast and ultrahigh-frequency integrated circuits, this intriguing and cost-effective rectifying diode is anticipated to garner widespread interest within the electronics community.

Teleost-specific TLR23 in Takifugu rubripes recruits MyD88 to trigger ERK pathway and promotes antibacterial defense.

Takifugu rubripes is a highly valued cultured fish in Asia, while pathogen infections can result in severe diseases and lead to substantial economic losses. Toll-like receptors (TLRs), as pattern recognition receptors, play a crucial role on recognition pathogens and initiation innate immune response. However, the immunological properties of teleost-specific TLR23 remain largely unknown. In this study, we investigated the biological functions of TLR23 (TrTLR23) from T. rubripes, found that TrTLR23 existed in various organs. Following bacterial pathogen challenge, the expression levels of TrTLR23 were significantly increased in immune related organs. TrTLR23 located on the cellular membrane and specifically recognized pathogenic microorganism. Co-immunoprecipitation and antibody blocking analysis revealed that TrTLR23 recruited myeloid differentiation primary response protein (MyD88), thereby mediating the activation of the ERK signaling pathway. Furthermore, in vivo showed that, when TrTLR23 is overexpressed in T. rubripes, bacterial replication in fish tissues is significantly inhibited. Consistently, when TrTLR23 expression in T. rubripes is knocked down, bacterial replication is significantly enhanced. In conclusion, these findings suggested that TrTLR23 played a critical role on mediation TLR23-MyD88-ERK axis against bacterial infection. This study revealed that TLR23 involved in the innate immune mechanism, and provided the foundation for development disease control strategies in teleost.

Postbiotics Prepared Using Lactobacillus reuteri Ameliorates Ethanol-Induced Liver Injury by Regulating the FXR/SHP/SREBP-1c Axis.

SCOPE: While probiotics-based therapies have exhibited potential in alleviating alcohol-associated liver disease (ALD), the specific role of postbiotics derived from Lactobacillus reuteri (L. reuteri) in ALD remains elusive. This study aims to investigate the impact of postbiotics on ameliorating alcohol-induced hepatic steatosis and the underlying mechanisms. METHODS AND RESULTS: Using network pharmacology, the study elucidates the targets and pathways impacted by postbiotics from L. reuteri, identifying the farnesoid X receptor (FXR) as a promising target for postbiotics against ALD, and lipid metabolism and alcoholism act as crucial pathways associated with postbiotics-targeting ALD. Furthermore, the study conducts histological and biochemical analyses coupled with LC/MS to evaluate the protective effects and mechanisms of postbiotics against ALD. Postbiotics may modulate bile acid metabolism in vivo by regulating FXR signaling, activating the FXR/FGF15 pathway, and influencing the enterohepatic circulation of bile acids (BAs). Subsequently, postbiotics regulate hepatic FXR activated by BAs and modulate the expression of FXR-mediated protein, including short regulatory partner (SHP) and sterol regulatory element binding protein-1c (SREBP-1c), thereby ameliorating hepatic steatosis in mice with ALD. CONCLUSION: Postbiotics effectively alleviate ethanol-induced hepatic steatosis by regulating the FXR/SHP/SREBP-1c axis, as rigorously validated in both in vivo and in vitro.

Self-crosslinking hyaluronic acid hydrogel as an enteroprotective agent for the treatment of inflammatory bowel disease.

The pathological changes in inflammatory bowel disease (IBD) include the disruption of intestinal barrier function and the infiltration of pathogenic microbes. The application of an artificial protective barrier at the site of inflammation can prevent bacterial infiltration, promote epithelial cell migration, and accelerate wound healing. In this study, dopamine-modified hyaluronic acid (HA-DA) was developed as a bioadhesive self-cross-linkable hydrogel, which acted as an enteroprotective agent to promote the healing of inflamed intestinal tissue. The adhesion strength HA-DA to mouse colon was 3.81-fold higher than HA. Moreover, HA-DA promoted Caco-2 cell proliferation and migration as well as had a strong physical barrier effect after gelation. After oral administration, the HA-DA reduced weight loss and attenuated impaired goblet cell function in mice with dextran sodium sulfate-induced IBD. In addition, HA-DA promoted restoration of the epithelial barrier by the upregulation of tight junction proteins. The results reported herein substantiated that self-cross-linkable hydrogel-based enteroprotective agents are a promising approach for the treatment of IBD.

circZNF532 promotes endothelial-to-mesenchymal transition in diabetic retinopathy by recruiting TAF15 to stabilize PIK3CD.

Endothelial-to-mesenchymal transition (EndMT) is a pivotal event in diabetic retinopathy (DR). This study explored the role of circRNA zinc finger protein 532 (circZNF532) in regulating EndMT in DR progression. Human retinal microvascular endothelial cells (HRMECs) were exposed to high glucose (HG) to induce the DR cell model. Actinomycin D-treated HRMECs were used to confirm the mRNA stability of phosphoinositide-3 kinase catalytic subunit δ (PIK3CD). The interaction between TATA-box-binding protein-associated factor 15 (TAF15) and circZNF532/PIK3CD was subsequently analyzed using RNA immunoprecipitation (RIP), RNA pull-down. It was found that HG treatment accelerated EndMT process, facilitated cell migration and angiogenesis, and enhanced PIK3CD and p-AKT levels in HRMECs, whereas si-circZNF532 transfection neutralized these effects. Further data showed that circZNF532 recruited TAF15 to stabilize PIK3CD, thus elevating PIK3CD expression. Following rescue experiments suggested that PIK3CD overexpression partially negated the inhibitory effect of circZNF532 silencing on EndMT, migration, and angiogenesis of HG-treated HRMECs. In conclusion, our results suggest that circZNF532 recruits TAF15 to stabilize PIK3CD, thereby facilitating EndMT in DR.