Genetically predicted gut microbiota mediate the association between plasma lipidomics and primary sclerosing cholangitis.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a complex disease with pathogenic mechanisms that remain to be elucidated. Previous observational studies with small sample sizes have reported associations between PSC, dyslipidemia, and gut microbiota dysbiosis. However, the causality of these associations is uncertain, and there has been no systematic analysis to date. METHODS: The datasets comprise data on PSC, 179 lipid species, and 412 gut microbiota species. PSC data (n = 14,890) were sourced from the International PSC Study Group, while the dataset pertaining to plasma lipidomics originated from a study involving 7174 Finnish individuals. Data on gut microbiota species were derived from the Dutch Microbiome Project study, which conducted a genome-wide association study involving 7738 participants. Furthermore, we employed a two-step Mendelian randomization (MR) analysis to quantify the proportion of the effect of gut microbiota-mediated lipidomics on PSC. RESULTS: Following a rigorous screening process, our MR analysis revealed a causal relationship between higher levels of gene-predicted Phosphatidylcholine (O-16:1_18:1) (PC O-16:1_18:1) and an increased risk of developing PSC (inverse variance-weighted method, odds ratio (OR) 1.30, 95% confidence interval (CI) 1.03-1.63). There is insufficient evidence to suggest that gene-predicted PSC impacts the levels of PC O-16:1_18:1 (OR 1.01, 95% CI 0.98-1.05). When incorporating gut microbiota data into the analysis, we found that Eubacterium rectale-mediated genetic prediction explains 17.59% of the variance in PC O-16:1_18:1 levels. CONCLUSION: Our study revealed a causal association between PC O-16:1_18:1 levels and PSC, with a minor portion of the effect mediated by Eubacterium rectale. This study aims to further explore the pathogenesis of PSC and identify promising therapeutic targets. For patients with PSC who lack effective treatment options, the results are encouraging.

Matrine induces cardiotoxicity by promoting ferroptosis through the Nrf2 antioxidant system in H9c2 cells.

Matrine (MT) has shown promising efficacy in various cancers and chronic hepatitis; however, its clinical application is limited because of its side effects. Our previous studies have indicated that MT can induce severe hepatotoxicity and nephrotoxicity. The current study aimed to investigate its cardiotoxicity and potential underlying mechanisms in H9c2 cells. Our results showed that MT induced H9c2 cell death and disrupted the cellular membrane integrity. Moreover, MT decreased glutathione (GSH) and cysteine (Cys) levels, and increased Fe2+, lipid peroxidation, reactive oxygen species (ROS), and MDA levels, ultimately leading to ferroptosis. Interestingly, these phenomena were alleviated by the ferroptosis inhibitor Fer-1, whereas MT-induced ferroptosis was exacerbated by the ferroptosis agonist RSL3. In addition, MT significantly reduced FTH, Nrf2, xCT, GPX4, and FSP1 protein levels and inhibited the transcriptional activity of Nrf2 while increasing TFR1 protein levels. Supplementation with Nrf2 agonist (Dimethyl fumarate, DMF) or selenium (Sodium selenite, SS) and CoQ10 alleviated MT-induced cytotoxic effects in H9c2 cells. These results suggest that ferroptosis, which is mediated by an imbalance in the Nrf2 antioxidant system, is involved in MT-induced cardiac toxicity.

MAPK20-mediated ATG6 phosphorylation is critical for pollen development in Solanum lycopersicum L.

In flowering plants, male gametogenesis is tightly regulated by numerous genes. Mitogen-activated protein kinase (MAPK) plays a critical role in plant development and stress response, while its role in plant reproductive development is largely unclear. The present study demonstrated MAPK20 phosphorylation of ATG6 to mediate pollen development and germination in tomato (Solanum lycopersicum L.). MAPK20 was preferentially expressed in the stamen of tomato, and mutation of MAPK20 resulted in abnormal pollen grains and inhibited pollen viability and germination. MAPK20 interaction with ATG6 mediated the formation of autophagosomes. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis showed that ATG6 was phosphorylated by MAPK20 at Ser-265. Mutation of ATG6 in wild-type (WT) or in MAPK20 overexpression plants resulted in malformed and inviable pollens. Meanwhile, the number of autophagosomes in mapk20 and atg6 mutants was significantly lower than that of WT plants. Our results suggest that MAPK20-mediated ATG6 phosphorylation and autophagosome formation are critical for pollen development and germination.

Novel strategy to raise the content of aglycone isoflavones in soymilk and gel: Effect of germination on the physicochemical properties.

Germination holds the key to nutritional equilibrium in plant grains. In this study, the effect of soybean germination on the processing of soymilk (SM) and glucono-δ-lactone (GDL) induced soymilk gel (SG) was investigated. Germination promoted soybean sprout (SS) growth by activating the energy metabolism system. The energy metabolism was high during the three-day germination and was the most vigorous on the second day of germination. After germination, protein dissolution was improved in SM, and endogenous enzymes produced small molecule proteins. Small molecule proteins were more likely to aggregate to produce SM protein particles. Germination increased the water-holding capacity of SG induced by GDL but weakened the strength. Furthermore, the dynamic fluctuations in isoflavone content were closely monitored throughout the processing of soybean products, including SS, SM, and SG. Although the total amount of isoflavones in SM and SG processed from germinated soybeans decreased, a significant enrichment in the content of aglycone isoflavones was observed. The content of aglycone isoflavones in SG processed from germinated soybeans on the second day of germination was 736.17 ± 28.49 µg/g DW, which was 83.19 % higher than that of the control group. This study demonstrates that germination can enhance the nutritional value of soybean products, providing innovative opportunities for the development of health-promoting soybean-based products.

SARS-CoV-2 strains bearing Omicron BA.1 spike replicate in C57BL/6 mice.

Introduction: SARS-CoV-2, the cause of the COVID pandemic, is an RNA virus with a high propensity to mutate. Successive virus variants, including variants of concern (VOC), have emerged with increased transmission or immune escape. The original pandemic virus and early variants replicated poorly, if at all, in mice at least partly due to a mismatch between the receptor binding domain on the viral spike protein and the murine angiotensin converting enzyme 2 (ACE2). Omicron VOC emerged in late 2021 harboring > 50 new mutations, 35 of them in the spike protein. This variant resulted in a very large wave of infections, even in the face of prior immunity, albeit being inherently less severe than earlier variants. Reflecting the lower severity reported in humans, Omicron displayed attenuated infection in hamsters and also in the K18-hACE2 mouse model. K18-hACE2 mice express both the human ACE2 as well as the endogenous mouse ACE2. Methods: Here we infected hACE2 knock-in mice that express only human ACE2 and no murine ACE2, or C57BL/6 wildtype mice with SARS-CoV-2 D614G (first-wave isolate), Delta or Omicron BA.1 variants and assessed infectivity and downstream innate immune responses. Results: While replication of SARS-CoV-2 Omicron was lower in the lungs of hACE2 knock-in mice compared with SARS-CoV-2 D614G and VOC Delta, it replicated more efficiently than the earlier variants in C57BL/6 wildtype mice. This opens the opportunity to test the effect of host genetics on SARS-CoV-2 infections in wildtype mice. As a proof of principle, we tested Omicron infection in mice lacking expression of the interferon-alpha receptor-1 (IFNAR1). In these mice we found that loss of type I IFN receptor signaling resulted in higher viral loads in the lungs were detected. Finally, using a chimeric virus of first wave SARS-CoV-2 harboring the Omicron spike protein, we show that Omicron spike increase infection of C57BL/6 wildtype mice, but non-spike genes of Omicron confer attenuation of viral replication. Discussion: Since this chimeric virus efficiently infected C57BL/6 wildtype mice, and replicated in their lungs, our findings illustrate a pathway for genetic mapping of virushost interactions during SARS-CoV-2 infection.

Responses of soil and rhizosphere microbial communities to Cd-hyperaccumulating willows and Cd contamination.

BACKGROUND: The pollution of soil by heavy metals, particularly Cd, is constitutes a critical international environmental concern. Willow species are renowned for their efficacy in the phytoremediation of heavy metals owing to their high Cd absorption rate and rapid growth. However, the mechanisms underlying microbial regulation for high- and low-accumulating willow species remain poorly understood. Therefore, we investigated the responses of soil and rhizosphere microbial communities to high- and low-Cd-accumulating willows and Cd contamination. We analyzed soil properties were analyzed in bulk soil (SM) and rhizosphere soil (RM) planted with high-accumulating (H) and low-accumulating (L) willow species. RESULTS: Rhizosphere soil for different willow species had more NH4+ than that of bulk soil, and RM-H soil had more than RM-L had. The available phosphorus content was greater in hyper-accumulated species than it was in lower-accumulated species, especially in RM-H. Genome sequencing of bacterial and fungal communities showed that RM-L exhibited the highest bacterial diversity, whereas RM-H displayed the greatest richness than the other groups. SM-L exhibited the highest diversity and richness of fungal communities. Ralstonia emerged as the predominant bacterium in RM-H, whereas Basidiomycota and Cercozoa were the most enriched fungi in SM-H. Annotation of the N and C metabolism pathways revealed differential patterns: expression levels of NRT2, NarB, nirA, nirD, nrfA, and nosZ were highest in RM-H, demonstrating the effects of NO3-and N on the high accumulation of Cd in RM-H. The annotated genes associated with C metabolism indicated a preference for the tricarboxylic pathway in RM-H, whereas the hydroxypropionate-hydroxybutyrate cycle was implicated in C sequestration in SM-L. CONCLUSIONS: These contribute to elucidation of the mechanism underlying high Cd accumulation in willows, particularly in respect of the roles of microbes and N and C utilization. This will provide valuable insights for repairing polluted soil using N and employing organic acids to improve heavy metal remediation efficiency.

Cross-modality cerebrovascular segmentation based on pseudo-label generation via paired data.

Accurate segmentation of cerebrovascular structures from Computed Tomography Angiography (CTA), Magnetic Resonance Angiography (MRA), and Digital Subtraction Angiography (DSA) is crucial for clinical diagnosis of cranial vascular diseases. Recent advancements in deep Convolution Neural Network (CNN) have significantly improved the segmentation process. However, training segmentation networks for all modalities requires extensive data labeling for each modality, which is often expensive and time-consuming. To circumvent this limitation, we introduce an approach to train cross-modality cerebrovascular segmentation network based on paired data from source and target domains. Our approach involves training a universal vessel segmentation network with manually labeled source domain data, which automatically produces initial labels for target domain training images. We improve the initial labels of target domain training images by fusing paired images, which are then used to refine the target domain segmentation network. A series of experimental arrangements is presented to assess the efficacy of our method in various practical application scenarios. The experiments conducted on an MRA-CTA dataset and a DSA-CTA dataset demonstrate that the proposed method is effective for cross-modality cerebrovascular segmentation and achieves state-of-the-art performance.

Multifunctional Antimonene-Silver Nanocomposites for Ultra-Multi-Mode and Multi-Analyte Sensing, Parallel and Batch Logic Computing, Long-Text Information Protection.

To simulate life's emergent functions, mining the multiple sensing capabilities of nanosystems, and digitizing networks of transduction signals and molecular interactions, is an ongoing endeavor. Here, multifunctional antimonene-silver nanocomposites (AM-Ag NCs) are synthesized facilely and fused for molecular sensing and digitization applications (including ultra-multi-mode and multi-analyte sensing, parallel and batch logic computing, long-text information protection). By mixing surfactant, AM, Ag+ and Sodium borohydride (NaBH4) at room temperature for 5 min, the resulting NCs are comprised of Ag nanoparticles scattered within AM nanosheets and protected by the surfactant. Interestingly, AM-Ag NCs exhibit ultra-multi-mode sensing ability for multiplex metal ions (Hg2+, Fe3+, or Al3+), which significantly improved selectivity (≈2 times) and sensitivity (≈400 times) when analyzing the combined channels. Moreover, multiple sensing capabilities of AM-Ag NCs enable diverse batch and parallel molecular logic computations (including advanced cascaded logic circuits). Ultra-multi-mode selective patterns of AM-Ag NCs to 18 kinds of metal ions can be converted into a series of binary strings by setting the thresholds, and realized high-density, long-text information protection for the first time. This study provides new ideas and paradigms for the preparation and multi-purpose application of 2D nanocomposites, but also offers new directions for the fusion of molecular sensing and informatization.

Electro-dewatering performance of sewage sludge under interrupted pulsating voltage: A comparison between square shape and half-sine shape waveform.

Electro-dewatering of sewage sludge with pulsating voltage was conducted under the two different wave shapes (square wave (SQW) and half-sine wave (HSW)) to investigate the influence of wave shape and duty cycle on sludge dewatering performance. The results indicated that, under the same average voltage, the moisture content of dewatered sludge with HSW was 10.3%∼35.4% lower than that with SQW, suggesting the better dewatering performance of HSW. The optimal dewatering performance was achieved at duty cycle of 80% for SQW and 60% for SHW. The chemical oxygen demand of filtrate from HSW could be 13% higher than that from SQW, indicating the higher capacity of HSW in breaking sludge cells/floc structure. The applied voltage during electrochemical treatment promoted the hydrolysis of protein in filtrate, and the main components in the electro-dewatered filtrate were fulvic acid- and humic acid-like substances. The specific energy consumption for sludge electro-dewatering were 0.015-0.269 kWh/(kg removed water), and it was almost in linear relationship with duty cycle. By overall considering the energy consumption and electro-dewatering performance, the condition of 60% duty cycle with HSW was obviously better than other conditions, which provides a meaningful guidance for future application of sludge electro-dewatering technology with pulsating voltage.

Pancreatic mucinous adenocarcinoma has different clinical characteristics and better prognosis compared to non-specific PDAC: A retrospective observational study.

Background: Pancreatic mucinous adenocarcinoma (PMAC) is a rare malignant tumour, and there is limited understanding of its epidemiology and prognosis. Initially, PMAC was considered a metastatic manifestation of other cancers; however, instances of non-metastatic PMAC have been documented through monitoring, epidemiological studies, and data from the Surveillance, Epidemiology, and End Results (SEER) database. Therefore, it is crucial to investigate the epidemiological characteristics of PMAC and discern the prognostic differences between PMAC and the more prevalent pancreatic ductal adenocarcinoma (PDAC). Methods: The study used data from the SEER database from 2000 to 2018 to identify patients diagnosed with PMAC or PDAC. To ensure comparable demographic characteristics between PDAC and PMAC, propensity score matching was employed. Kaplan-Meier analysis was used to analyse overall survival (OS) and cancer-specific survival (CSS). Univariate and multivariate Cox regression analyses were used to determine independent risk factors influencing OS and CSS. Additionally, the construction and validation of risk-scoring models for OS and CSS were achieved through the least absolute shrinkage and selection operator-Cox regression technique. Results: The SEER database included 84,857 patients with PDAC and 3345 patients with PMAC. Notably, significant distinctions were observed in the distribution of tumour sites, diagnosis time, use of radiotherapy and chemotherapy, tumour size, grading, and staging between the two groups. The prognosis exhibited notable improvement among married individuals, those receiving acceptable chemotherapy, and those with focal PMAC (p < 0.05). Conversely, patients with elevated log odds of positive lymph node scores or higher pathological grades in the pancreatic tail exhibited a more unfavourable prognosis (p < 0.05). The risk-scoring models for OS or CSS based on prognostic factors indicated a significantly lower prognosis for high-risk patients compared to their low-risk counterparts (area under the curve OS: 0.81-0.82, CSS: 0.80-0.82). Conclusion: PMAC exhibits distinct clinical characteristics compared to non-specific PDAC. Leveraging these features and pathological classifications allows for accurate prognostication of PMAC or PDAC.

Research on the impact of climate change on the income gap between urban and rural areas-empirical analysis based on provincial panel data in China.

Narrowing the income gap between urban and rural areas is the key to achieving common prosperity in China. On the basis of analyzing the mechanism of climate change's impact on urban-rural income gap, this article empirically analyzes the impact of climate change on urban-rural income gap using provincial-level panel data of 30 provinces in China from 2011 to 2020. Research indicates that climate change significantly impacts the urban-rural income gap at the 1% significance level, implying that climate change exacerbates the urban-rural income gap. This widening effect varies significantly across different regions, particularly in the western regions and areas with lower fiscal support for agriculture. Further analysis reveals that there is a mediating role between the total agricultural output value and resource mismatch in the impact of climate change on urban-rural income inequality; the digital rural construction plays a regulatory role in the impact of climate change on the urban-rural income gap. On this basis, policy recommendations are proposed to promote the development of climate-resilient agriculture, improve the meteorological forecast and early warning system, increase financial support, and optimize the allocation of agricultural resources.

Changes in amino acids, catechins and alkaloids during the storage of oolong tea and their relationship with antibacterial effect.

The storage process has a significant impact on tea quality. Few is known about effect of storage on quality of oolong tea. This study aimed to assess the effect of different storage times on the key chemical components of oolong tea by measuring changes in catechin, free amino acid, and alkaloid content. Variation in the main substances was determined by principal component analysis and heat map analysis. The results revealed notable effects of the storage process on the levels of theanine, epigallocatechin gallate (EGCG), and glutamine. These findings suggest that these compounds could serve as indicators for monitoring changes in oolong tea quality during storage. Additionally, the study observed an increase in the antibacterial ability of tea over time. Correlation analysis indicated that the antibacterial ability against Micrococcus tetragenus and Escherichia coli was influenced by metabolites such as aspartic acid, threonine, serine, gamma-aminobutyric acid, ornithine, alanine, arginine, and EGCG. Overall, this study presents an approach for identifying key metabolites to monitor tea quality effectively with relatively limited data.

Relationship between socioeconomic status and hypertension incidence among adults in southwest China: a population-based cohort study.

PURPOSE: To investigate the correlation between socioeconomic status (SES) and the incidence of hypertension among adults aged 18 or above in southwest China. METHODS: A multistage proportional stratified cluster sampling method was employed to recruited 9280 adult residents from 12 counties in southwest China, with all participants in the cohort tracked from 2016 to 2020. The questionnaire survey gathered information on demographics, lifestyle habits, and household income. The physical exam recorded height, weight, and blood pressure. Biochemical tests measured cholesterol levels. The chi-square test was employed to assess the statistical differences among categorical variables, while the Cox proportional hazards regression model was applied to evaluate the association between socioeconomic status (SES) and the incidence of hypertension. RESULTS: The finally effective sample size for the cohort study was 3546 participants, after excluding 5734 people who met the exclusion criteria. Adults in the highest household income group had a significantly lower risk of hypertension compared to those in the lowest income group (HR = 0.636, 95% CI: 0.478-0.845). Besides, when compared to individuals in the illiterate population, the risk of hypertension among adults with elementary school, junior high school, senior high school and associate degree educational level decreased respectively by 34.4% (HR = 0.656, 95%CI: 0.533-0.807), 44.9% (HR = 0.551, 95%CI: 0.436-0.697), 44.9% (HR = 0.551, 95%CI: 0.405-0.750), 46.1% (HR = 0.539, 95%CI: 0. 340-0.854). After conducting a thorough analysis of socioeconomic status, compared with individuals with a score of 6 or less, the risk of hypertension in participants with scores of 8, 10, 11, 12, and greater than 12 decreased respectively by 23.9% (HR = 0.761, 95%CI: 0.598-0.969), 29.7% (HR = 0.703, 95%CI: 0.538-0.919), 34.0% (HR = 0.660, 95%CI: 0.492-0.885), 34.3% (HR = 0.657, 95%CI: 0.447-0.967), 43.9% (HR = 0.561, 95%CI: 0.409-0.769). CONCLUSION: The findings indicate a negative correlation between socioeconomic status and hypertension incidence among adults in southwest China, suggesting that individuals with higher socioeconomic status are less likely to develop hypertension.

Novel polyurethane-degrading cutinase BaCut1 from Blastobotrys sp. G-9 with potential role in plastic bio-recycling.

Environmental pollution caused by plastic waste has become global problem that needs to be considered urgently. In the pursuit of a circular plastic economy, biodegradation provides an attractive strategy for managing plastic wastes, whereas effective plastic-degrading microbes and enzymes are required. In this study, we report that Blastobotrys sp. G-9 isolated from discarded plastic in landfills is capable of depolymerizing polyurethanes (PU) and poly (butylene adipate-co-terephthalate) (PBAT). Strain G-9 degrades up to 60% of PU foam after 21 days of incubation at 28 â„ƒ by breaking down carbonyl groups via secretory hydrolase as confirmed by structural characterization of plastics and degradation products identification. Within the supernatant of strain G-9, we identify a novel cutinase BaCut1, belonging to the esterase family, that can reproduce the same effect. BaCut1 demonstrates efficient degradation toward commercial polyester plastics PU foam (0.5 mg enzyme/25 mg plastic) and agricultural film PBAT (0.5 mg enzyme/10 mg plastic) with 50% and 18% weight loss at 37 â„ƒ for 48 h, respectively. BaCut1 hydrolyzes PU into adipic acid as a major end-product with 42.9% recovery via ester bond cleavage, and visible biodegradation is also identified from PBAT, which is a beneficial feature for future recycling economy. Molecular docking, along with products distribution, elucidates a special substrate-binding modes of BaCut1 with plastic substrate analogue. BaCut1-mediated polyester plastic degradation offers an alternative approach for managing PU plastic wastes through possible bio-recycling.

Deep Learning-Based Detect-Then-Track Pipeline for Treatment Outcome Assessments in Immunotherapy-Treated Liver Cancer.

Accurate treatment outcome assessment is crucial in clinical trials. However, due to the image-reading subjectivity, there exist discrepancies among different radiologists. The situation is common in liver cancer due to the complexity of abdominal scans and the heterogeneity of radiological imaging manifestations in liver subtypes. Therefore, we developed a deep learning-based detect-then-track pipeline that can automatically identify liver lesions from 3D CT scans then longitudinally track target lesions, thereby providing the evaluation of RECIST treatment outcomes in liver cancer. We constructed and validated the pipeline on 173 multi-national patients (344 venous-phase CT scans) consisting of a public dataset and two in-house cohorts of 28 centers. The proposed pipeline achieved a mean average precision of 0.806 and 0.726 of lesion detection on the validation and test sets. The model's diameter measurement reliability and consistency are significantly higher than that of clinicians (p = 1.6 × 10-4). The pipeline can make precise lesion tracking with accuracies of 85.7% and 90.8% then finally yield the RECIST accuracies of 82.1% and 81.4% on the validation and test sets. Our proposed pipeline can provide precise and convenient RECIST outcome assessments and has the potential to aid clinicians with more efficient therapeutic decisions.

Age-specific nasal epithelial responses to SARS-CoV-2 infection.

Children infected with SARS-CoV-2 rarely progress to respiratory failure. However, the risk of mortality in infected people over 85 years of age remains high. Here we investigate differences in the cellular landscape and function of paediatric (<12 years), adult (30-50 years) and older adult (>70 years) ex vivo cultured nasal epithelial cells in response to infection with SARS-CoV-2. We show that cell tropism of SARS-CoV-2, and expression of ACE2 and TMPRSS2 in nasal epithelial cell subtypes, differ between age groups. While ciliated cells are viral replication centres across all age groups, a distinct goblet inflammatory subtype emerges in infected paediatric cultures and shows high expression of interferon-stimulated genes and incomplete viral replication. In contrast, older adult cultures infected with SARS-CoV-2 show a proportional increase in basaloid-like cells, which facilitate viral spread and are associated with altered epithelial repair pathways. We confirm age-specific induction of these cell types by integrating data from in vivo COVID-19 studies and validate that our in vitro model recapitulates early epithelial responses to SARS-CoV-2 infection.

A general approach for selection of epitope-directed binders to proteins.

Directing antibodies to a particular epitope among many possible on a target protein is a significant challenge. Here, we present a simple and general method for epitope-directed selection (EDS) using a differential phage selection strategy. This involves engineering the protein of interest (POI) with the epitope of interest (EOI) mutated using a systematic bioinformatics algorithm to guide the local design of an EOI decoy variant. Using several alternating rounds of negative selection with the EOI decoy variant followed by positive selection on the wild-type POI, we were able to identify highly specific and potent antibodies to five different EOI antigens that bind and functionally block known sites of proteolysis. Among these, we developed highly specific antibodies that target the proteolytic site on the CUB domain containing protein 1 (CDCP1) to prevent its proteolysis allowing us to study the cellular maturation of this event that triggers malignancy. We generated antibodies that recognize the junction between the pro- and catalytic domains for three different matrix metalloproteases (MMPs), MMP1, MMP3, and MMP9, that selectively block activation of each of these enzymes and impair cell migration. We targeted a proteolytic epitope on the cell surface receptor, EPH Receptor A2 (EphA2), that is known to transform it from a tumor suppressor to an oncoprotein. We believe that the EDS method greatly facilitates the generation of antibodies to specific EOIs on a wide range of proteins and enzymes for broad therapeutic and diagnostic applications.

Characterizing fitness and immune escape of SARS-CoV-2 EG.5 sublineage using elderly serum and nasal organoid.

SARS-CoV-2 Omicron variant has evolved into sublineages. Here, we compared the neutralization susceptibility and viral fitness of EG.5.1 and XBB.1.9.1. Serum neutralization antibody titer against EG.5.1 was 1.71-fold lower than that for XBB.1.9.1. However, there was no significant difference in virus replication between EG.5.1 and XBB.1.9.1 in human nasal organoids and TMPRSS2/ACE2 over-expressing A549 cells. No significant difference was observed in competitive fitness and cytokine/chemokine response between EG.5.1 and XBB.1.9.1. Both EG.5.1 and XBB.1.9.1 replicated more robustly in the nasal organoid from a younger adult than that from an older adult. Our findings suggest that enhanced immune escape contributes to the dominance of EG.5.1 over earlier sublineages. The combination of population serum susceptibility testing and viral fitness evaluation with nasal organoids may hold promise in risk assessment of upcoming variants. Utilization of serum specimens and nasal organoid derived from older adults provides a targeted risk assessment for this vulnerable population.

Asiaticoside alleviates lipopolysaccharide-induced acute lung injury by blocking Sema4D/CD72 and inhibiting mitochondrial dysfunction in RAW264.7 cell and mice.

Acute lung injury (ALI) is a common disease with complex pathogenesis. However, the treatment is mainly symptomatic with limited clinical options. Asiaticoside (AS), a Chinese herbal extract, has protective effects against LPS-induced ALI in mice and inhibits nitric oxide and prostaglandin E2 synthesis; however, the specific mechanism of AS in the prevention and treatment of LPS-induced ALI needs further study. Sema4D/CD72 pathway, mitochondrial dysfunction, and miRNA-21 are closely associated with inflammation. Therefore, the present study aimed to explore whether AS exerts its therapeutic effect on ALI by influencing Sema4D/CD72 pathway and mitochondrial dysfunction, restoring the balance of inflammatory factors, and influencing miRNA-21 expression. Cell and animal experiments were performed to investigate the effect of AS on ALI. Lipopolysaccharide (LPS) was used to establish the ALI model. CCK8 and flow cytometry were used to detect the cell viability and apoptosis rate. HE staining and wet-to-dry weight ratio (W/D) of lung tissue were determined. The expressions of Sema4D, CD72, NF-κB p65, Bax, Bcl2, and caspase 3 in RAW264.7 cells and lung tissues were detected by western blot, and the levels of IL-10 and IL-1ß induced by LPS in supernatant of RAW264.7 cells and BALF were measured by ELISA. And the expression of miRNA-21 in cells and lung tissues was detected by fluorescence quantitative PCR. The result shows that AS treatment suppressed LPS-induced cell damage and lung injury in mice. AS treatment could alleviate the pathological changes such as inflammatory infiltration and histopathological changes in the lungs caused by LPS, and reduce the ratio of W/D. AS significantly alleviated the decrease of mitochondrial membrane potential induced by LPS, inhibited the increase of ROS production, and reduced the expression of mitochondrial fission proteins Drp1 and Fis1. The high-dose AS group significantly downregulated the expression of Sema4D, CD72, phosphorylated NF-κB p65, and apoptosis-related proteins, decreased the pro-inflammatory factor IL-1ß, and enhanced the level of anti-inflammatory factor IL-10. In addition, AS promoted miRNA-21 expression. These effects inhibited apoptosis and restored the balance between anti- and pro-inflammatory factors. This represents the inaugural report elucidating the mechanism by which AS inhibits the Sema4D/CD72 signaling pathway. These findings offer novel insights into the potential application of AS in both preventing and treating ALI.