T Cell Subsets and Immune Homeostasis.

T cells are a heterogeneous group of cells that can be classified into different subtypes according to different classification methods. The body's immune system has a highly complex and effective regulatory network that allows for the relative stability of immune system function. Maintaining proper T cell homeostasis is essential for promoting protective immunity and limiting autoimmunity and tumor formation. Among the T cell family members, more and more T cell subsets have gradually been characterized. In this chapter, we summarize the functions of some key T cell subsets and their impact on immune homeostasis.

Isolation and Culture of Mouse Primary Microglia and Oligodendrocyte Precursor Cells.

Microglia and oligodendrocyte precursor cells (OPCs) are critical glia subsets in the central nervous system (CNS) and are actively engaged in a body of diseases, such as stroke, Alzheimer's disease, multiple sclerosis, etc. Microglia and OPC serve as compelling tools for the study of CNS diseases as well as the repair and damage of myelin sheath in vitro. In this protocol, we summarized a method which is capable of using the same batch of new-born mice to isolate and culture microglia and OPCs. It integrates the characteristics of practicality, convenience, and efficiency, providing a convenient, easy, and reliable technique for research.

Exercise accelerates recruitment of CD8+ T cell to promotes anti-tumor immunity in lung cancer via epinephrine.

BACKGROUND AND PURPOSE: In recent years, there has been extensive research on the role of exercise as an adjunctive therapy for cancer. However, the potential mechanisms underlying the anti-tumor therapy of exercise in lung cancer remain to be fully elucidated. As such, our study aims to confirm whether exercise-induced elevation of epinephrine can accelerate CD8+ T cell recruitment through modulation of chemokines and thus ultimately inhibit tumor progression. METHOD: C57BL/6 mice were subcutaneously inoculated with Lewis lung cancer cells (LLCs) to establish a subcutaneous tumor model. The tumor mice were randomly divided into different groups to performed a moderate-intensity exercise program on a treadmill for 5 consecutive days a week, 45 min a day. The blood samples and tumor tissues were collected after exercise for IHC, RT-qPCR, ELISA and Western blot. In addition, another group of mice received daily epinephrine treatment for two weeks (0.05 mg/mL, 200 µL i.p.) (EPI, n = 8) to replicate the effects of exercise on tumors in vivo. Lewis lung cancer cells were treated with different concentrations of epinephrine (0, 5, 10, 20 µM) to detect the effect of epinephrine on chemokine levels via ELISA and RT-qPCR. RESULTS: This study reveals that both pre- and post-cancer exercise effectively impede the tumor progression. Exercise led to an increase in EPI levels and the infiltration of CD8+ T cell into the lung tumor. Exercise-induced elevation of EPI is involved in the regulation of Ccl5 and Cxcl10 levels further leading to enhanced CD8+ T cell infiltration and ultimately inhibiting tumor progression. CONCLUSION: Exercise training enhance the anti-tumor immunity of lung cancer individuals. These findings will provide valuable insights for the future application of exercise therapy in clinical practice.

Angiotensin II type-2 receptor signaling facilitates liver injury repair and regeneration via inactivation of Hippo pathway.

The angiotensin II type 2 receptor (AT2R) is a well-established component of the renin-angiotensin system and is known to counteract classical activation of this system and protect against organ damage. Pharmacological activation of the AT2R has significant therapeutic benefits, including vasodilation, natriuresis, anti-inflammatory activity, and improved insulin sensitivity. However, the precise biological functions of the AT2R in maintaining homeostasis in liver tissue remain largely unexplored. In this study, we found that the AT2R facilitates liver repair and regeneration following acute injury by deactivating Hippo signaling and that interleukin-6 transcriptionally upregulates expression of the AT2R in hepatocytes through STAT3 acting as a transcription activator binding to promoter regions of the AT2R. Subsequently, elevated AT2R levels activate downstream signaling via heterotrimeric G protein Gα12/13-coupled signals to induce Yap activity, thereby contributing to repair and regeneration processes in the liver. Conversely, a deficiency in the AT2R attenuates regeneration of the liver while increasing susceptibility to acetaminophen-induced liver injury. Administration of an AT2R agonist significantly enhances the repair and regeneration capacity of injured liver tissue. Our findings suggest that the AT2R acts as an upstream regulator in the Hippo pathway and is a potential target in the treatment of liver damage.

Effects of Aripiprazole on Olanzapine Population Pharmacokinetics and Initial Dosage Optimization in Schizophrenia Patients.

Objective: Olanzapine has already been used to treat schizophrenia patients; however, the initial dosage recommendation when multiple drugs are used in combination, remains unclear. The purpose of this study was to explore the drug-drug interaction (DDI) of multiple drugs combined with olanzapine and to recommend the optimal administration of olanzapine in schizophrenia patients. Methods: In this study, we obtained olanzapine concentrations from therapeutic drug monitoring (TDM) database. In addition, related medical information, such as physiological, biochemical indexes, and concomitant drugs was acquired using medical log. Sixty-five schizophrenia patients were enrollmented for analysis using population pharmacokinetic model by means of nonlinear mixed effect (NONMEM). Results: Weight and combined use of aripiprazole significantly affected olanzapine clearance. Without aripiprazole, for once-daily olanzapine administration dosages, 0.6, 0.5 mg/kg/day were recommended for 40-70, and 70-100 kg schizophrenia patients, respectively; for twice-daily olanzapine administration dosages, 0.6, 0.5 mg/kg/day were recommended for 40-60, and 60-100 kg schizophrenia patients, respectively. With aripiprazole, for once-daily olanzapine administration dosages, 0.4, 0.3 mg/kg/day were recommended for 40-53, and 53-100 kg schizophrenia patients, respectively; for twice-daily olanzapine administration dosages, 0.4 mg/kg/day was recommended for 40-100 kg schizophrenia patients, respectively. Conclusion: Aripiprazole significantly affected olanzapine clearance, and when schizophrenia patients use aripiprazole, the olanzapine dosages need adjust. Meanwhile, we firstly recommended the optimal initial dosages of olanzapine in schizophrenia patients.

CD63+ cancer-associated fibroblasts confer CDK4/6 inhibitor resistance to breast cancer cells by exosomal miR-20.

Cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (CDK4/6i) have rapidly received Food and Drug Administration (FDA) approval as a new type of therapy for patients with advanced hormone receptor-positive breast cancer. However, with the widespread application of CDK4/6i, drug resistance has become a new challenge for clinical practice and has greatly limited the treatment effect. Here, the whole microenvironment landscape of ER+ breast cancer tumors was revealed through single-cell RNA sequencing, and a specific subset of cancer-associated fibroblasts (CD63+ CAFs) was identified as highly enriched in CDK4/6i resistant tumor tissues. Then, we found that CD63+ CAFs can distinctly promote resistance to CDK4/6i in breast cancer cells and tumor xenografts. In addition, it was discovered that miR-20 is markedly enriched in the CD63+ CAFs-derived exosomes, which are used to communicate with ER+ breast cancer cells, leading to CDK4/6i resistance. Furthermore, exosomal miR-20 could directly target the RB1 mRNA 3'UTR and negatively regulate RB1 expression to decrease CDK4/6i sensitivity in breast cancer cells. Most importantly, we designed and synthesized cRGD-miR-20 sponge nanoparticles and found that they can enhance the therapeutic effect of CDK4/6i in breast cancer. In summary, our findings reveal that CD63+ CAFs can promote CDK4/6i resistance via exosomal miR-20, which induces the downregulation of RB1 in breast cancer cells, and suggest that CD63+ CAFs may be a novel therapeutic target to enhance CDK4/6i sensitivity.

Experimental study on mine water purification mechanism for broken coal and rock masses in the underground reservoir of ecologically vulnerable mining area.

Water-rock interaction mechanism and water purification capacity of broken coal and rock masses are very important for the efficient operation of the underground reservoir. In this paper, a water purification simulation device for an underground mine reservoir was designed. The experimental study on the dynamic interaction between broken coal and rock masses and mine water was carried out. The water purification mechanism is analyzed from the changes in rock mineral composition and mine water quality before and after the test. The results show that after the broken coal and rock mass purification, the water turbidity and the concentration of chlorides and suspended solids decreased obviously. The water purification capacities of mudstone and sandstone are stronger than that of coal samples. After 60 days of reaction between the working face sewage and the broken samples (mudstone, sandstone, and coal), the turbidity, chromaticity, and residual chlorine decreased by > 90%, 90%, and 60%, respectively; and COD decreased by 35.29%, 30.59%, and 28.99%, respectively. While the TDS and the total hardness increased by about 40%, 30%, and 10% for the mudstone, sandstone, and coal, respectively. It shows that coal also has the worst degradation performance. The water purification effect of broken coal and rock masses has a significant time effect. The early stage of water-rock interaction is dominated by mineral dissolution, and the middle stage is dominated by precipitation and adsorption. The pH value of the solution has a certain influence on the ion change. In the later stage, the water-rock interaction is weak in a dynamic equilibrium state, and the change in the mine water quality index is not obvious. Considering the influence of rock lithology on water quality and the law of water-rock interaction time, the construction site selection and water storage time optimization of underground reservoirs in Jinjie Coal Mine were carried out, respectively.

The association of prealbumin, transferrin, and albumin with immunosenescence among elderly males.

OBJECTIVE: As people get older, the innate and acquired immunity of the elderly are affected, resulting in immunosenescence. Prealbumin (PAB), transferrin (TRF), and albumin (ALB) are commonly used markers to monitor protein energy malnutrition (PEM). However, their relationship with the immune system has not been fully explored. METHODS: In our study, a total of 93 subjects (≥65 years) were recruited from Tongji Hospital between January 2015 and February 2017. According to the serum levels of these proteins (PAB, TRF, and ALB), we divided the patients into the high serum protein group and the low serum protein group. Then, we compared the percent expression of lymphocyte subsets between two groups. RESULTS: All the low serum protein groups (PAB, TRF, and ALB) had significant decreases in the percentage of CD4+ cells, CD3+CD28+ cells, CD4+CD28+ cells and significant increases in the percentage of CD8+ cells, CD8+CD28- cells. PAB, TRF, and ALB levels revealed positive correlations with CD4/CD8 ratio, proportions of CD4+ cells, CD3+CD28+ cells, CD4+CD28+ cells, and negative correlation with proportions of CD8+ cells, CD8+CD28- cells. CONCLUSIONS: This study suggested PAB, TRF, and ALB could be used as immunosenescence indicators. PEM might accelerate the process of immunosenescence in elderly males.

Cohort profile for the Tongji Cardiovascular Health Study: a prospective multiomics cohort study.

PURPOSE: The Tongji Cardiovascular Health Study aimed to further explore the onset and progression mechanisms of cardiovascular disease (CVD) through a combination of traditional cohort studies and multiomics analysis, including genomics, metabolomics and metagenomics. STUDY DESIGN AND PARTICIPANTS: This study included participants aged 20-70 years old from the Geriatric Health Management Centre of Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology. After enrollment, each participant underwent a comprehensive series of traditional and novel cardiovascular risk factor assessments at baseline, including questionnaires, physical examinations, laboratory tests, cardiovascular health assessments and biological sample collection for subsequent multiomics analysis (whole genome sequencing, metabolomics study from blood samples and metagenomics study from stool samples). A biennial follow-up will be performed for 10 years to collect the information above and the outcome data. FINDINGS TO DATE: A total of 2601 participants were recruited in this study (73.4% men), with a mean age of 51.5±11.5 years. The most common risk factor is overweight or obesity (54.8%), followed by hypertension (39.7%), hyperlipidaemia (32.4%), current smoking (23.9%) and diabetes (12.3%). Overall, 13.1% and 48.7% of men and women, respectively, did not have any of the CVD risk factors (hypertension, hyperlipidaemia, diabetes, cigarette smoking and overweight or obesity). Additionally, multiomics analyses of a subsample of the participants (n=938) are currently ongoing. FUTURE PLANS: With the progress of the cohort follow-up work, it is expected to provide unique multidimensional and longitudinal data on cardiovascular health in China.

Optimizing the initial tacrolimus dosage in Chinese children with lung transplantation within normal hematocrit levels.

Background: The appropriate initial dosage of tacrolimus is undefined in Chinese pediatric lung transplant patients with normal hematocrit values. The purpose of this study is to optimize the initial dose of tacrolimus in Chinese children who are undergoing lung transplantation and have normal hematocrit levels. Methods: The present study is based on a published population pharmacokinetic model of tacrolimus in lung transplant patients and uses the Monte Carlo simulation to optimize the initial tacrolimus dosage in Chinese children with lung transplantation within normal hematocrit levels. Results: Within normal hematocrit levels, for children with lung transplantation who do not carry the CYP3A5*1 gene and have no coadministration with voriconazole, it is recommended to administer tacrolimus at a dosage of 0.02 mg/kg/day, divided into two doses, for children weighing 10-32 kg, and a dosage of 0.03 mg/kg/day, also divided into two doses, for children weighing 32-40 kg. For children with lung transplantation who carry the CYP3A5*1 gene and have no coadministration with voriconazole, tacrolimus dosages of 0.02, 0.03, and 0.04 mg/kg/day split into two doses are recommended for children weighing 10-15, 15-32, and 32-40 kg, respectively. For children with lung transplantation who do not carry the CYP3A5*1 gene and have coadministration with voriconazole, tacrolimus dosages of 0.01 and 0.02 mg/kg/day split into two doses are recommended for children weighing 10-17 and 17-40 kg, respectively. For children with lung transplantation who carry the CYP3A5*1 gene and have coadministration with voriconazole, a tacrolimus dosage of 0.02 mg/kg/day split into two doses is recommended for children weighing 10-40 kg. Conclusions: It is the first time to optimize the initial dosage of tacrolimus in Chinese children undergoing lung transplantation within normal hematocrit.

[Remote Sensing Model for Estimating Atmospheric PM2.5 Concentration in the Guangdong-Hong Kong-Macao Greater Bay Area].

PM2.5 is extremely harmful to the atmospheric environment and human health, and a timely and accurate understanding of PM2.5 with high spatial and temporal resolution plays an important role in the prevention and control of air pollution. Based on multi-angle implementation of atmospheric correction algorithm (MAIAC), 1 km AOD products, ERA5 meteorological data, and pollutant concentrations (CO, O3, NO2, SO2, PM10, and PM2.5) in the Guangdong-Hong Kong-Macao Greater Bay Area during 2015-2020, a geographically and temporally weighted regression model (GTWR), BP neural network model (BPNN), support vector machine regression model (SVR), and random forest model (RF) were established, respectively, to estimate PM2.5 concentration. The results showed that the estimation ability of the RF model was better than that of the BPNN, SVR, and GTWR models. The correlation coefficients of the BPNN, SVR, GTWR, and RF models were 0.922, 0.920, 0.934, and 0.981, respectively. The RMSE values were 7.192, 7.101, 6.385, and 3.670 µg·m-3. The MAE values were 5.482, 5.450, 4.849, and 2.323 µg·m-3, respectively. The RF model had the best effect during winter, followed by that during summer, and again during spring and autumn, with correlation coefficients above 0.976 in the prediction of different seasons. The RF model could be used to predict the PM2.5 concentration in the Greater Bay Area. In terms of time, the daily ρ(PM2.5) of cities in the Greater Bay Area showed a trend of "decreasing first and then increasing" in 2021, with the highest values ranging from 65.550 µg·m-3 to 112.780 µg·m-3 and the lowest values ranging from 5.000 µg·m-3 to 7.899 µg·m-3. The monthly average concentration showed a U-shaped distribution, and the concentration began to decrease in January and gradually increased after reaching a trough in June. Seasonally, it was characterized by the highest concentration during winter, the lowest during summer, and the transition during spring and autumn. The annual average ρ(PM2.5) of the Greater Bay Area was 28.868 µg·m-3, which was lower than the secondary concentration limit. Spatially, there was a "northwest to southeast" decreasing distribution of PM2.5 in 2021, and the high-pollution areas clustered in the central part of the Greater Bay Area, represented by Foshan. Low concentration areas were mainly distributed in the eastern part of Huizhou, Hong Kong, Macao, Zhuhai, and other coastal areas. The spatial distribution of PM2.5 in different seasons also showed heterogeneity and regionality. The RF model estimated the PM2.5 concentration with high accuracy, which provides a scientific basis for the health risk assessment associated with PM2.5 pollution in the Greater Bay Area.

Combining Non-Contrast CT Signs With Onset-to-Imaging Time to Predict the Evolution of Intracerebral Hemorrhage.

OBJECTIVE: This study aimed to determine the predictive performance of non-contrast CT (NCCT) signs for hemorrhagic growth after intracerebral hemorrhage (ICH) when stratified by onset-to-imaging time (OIT). MATERIALS AND METHODS: 1488 supratentorial ICH within 6 h of onset were consecutively recruited from six centers between January 2018 and August 2022. NCCT signs were classified according to density (hypodensities, swirl sign, black hole sign, blend sign, fluid level, and heterogeneous density) and shape (island sign, satellite sign, and irregular shape) features. Multivariable logistic regression was used to evaluate the association between NCCT signs and three types of hemorrhagic growth: hematoma expansion (HE), intraventricular hemorrhage growth (IVHG), and revised HE (RHE). The performance of the NCCT signs was evaluated using the positive predictive value (PPV) stratified by OIT. RESULTS: Multivariable analysis showed that hypodensities were an independent predictor of HE (adjusted odds ratio [95% confidence interval] of 7.99 [4.87-13.40]), IVHG (3.64 [2.15-6.24]), and RHE (7.90 [4.93-12.90]). Similarly, OIT (for a 1-h increase) was an independent inverse predictor of HE (0.59 [0.52-0.66]), IVHG (0.72 [0.64-0.81]), and RHE (0.61 [0.54-0.67]). Blend and island signs were independently associated with HE and RHE (10.60 [7.36-15.30] and 10.10 [7.10-14.60], respectively, for the blend sign and 2.75 [1.64-4.67] and 2.62 [1.60-4.30], respectively, for the island sign). Hypodensities demonstrated low PPVs of 0.41 (110/269) or lower for IVHG when stratified by OIT. When OIT was ≤ 2 h, the PPVs of hypodensities, blend sign, and island sign for RHE were 0.80 (215/269), 0.90 (142/157), and 0.83 (103/124), respectively. CONCLUSION: Hypodensities, blend sign, and island sign were the best NCCT predictors of RHE when OIT was ≤ 2 h. NCCT signs may assist in earlier recognition of the risk of hemorrhagic growth and guide early intervention to prevent neurological deterioration resulting from hemorrhagic growth.

The frequency of imaging markers adjusted for time since symptom onset in intracerebral hemorrhage: A novel predictor for hematoma expansion.

BACKGROUND: Hematoma expansion (HE) is common in patients with intracerebral hemorrhage (ICH) and associated with a worse outcome. Imaging makers and shorter time from symptom onset are both associated with HE, but prognostic scores based on these parameters individually have not been satisfactory. We hypothesized that a score including both imaging markers of expansion, and time of onset, would improve prediction. METHODS: Patients with supratentorial ICH within 6 h after onset were consecutively recruited from six centers between January 2018 and August 2022. Three markers were used: hypodensities, the blend sign, and the island sign. We first defined frequency of imaging markers (FIM) as the relationship between the number of imaging markers and onset-to-CT time (OCT). The time-adjusted FIM was defined as the ratio of the number of imaging markers to the onset-to-initial imaging time. Multivariate analysis was performed to determine the relationship between FIM and HE. Receiver operating curve analysis was used to identify potential threshold values of FIM that optimally predict HE. In addition, the sensitivity, specificity, positive and negative predictive values (PPVs and NPVs), and the area under the curve (AUC) of the optimal cut-off in predicting HE were calculated. RESULTS: In total, 1488 patients were eligible for inclusion, of whom 418 had incident HE. Multivariate analysis showed that age, male sex, baseline Glasgow Coma Scale score, presence of intraventricular hemorrhage, and FIM were independent predictors of HE (odds ratio (OR) = 0.98, 95% confidence interval (CI) = 0.97-0.99; OR = 1.73, 95% CI = 1.28-2.35; OR = 0.87, 95% CI = 0.83-0.92; OR = 0.42, 95% CI = 0.28-0.62; OR = 7.82, 95% CI = 5.86-10.42, respectively). The optimal cut-off point for FIM in predicting HE was 0.63, with sensitivity, specificity, PPV, NPV, and AUC values of 0.69, 0.89, 0.71, 0.88, and 0.83, respectively. CONCLUSION: The FIM adjusted for time since symptom onset is a significant predictor of HE. Its use may allow improved prediction of those patients with ICH who develop HE, and the score may be clinically applicable in the management of patients with ICH.

Comparison of ethanol-soaked gelatin sponge and microspheres for hepatic arterioportal fistulas embolization in hepatic cellular carcinoma.

BACKGROUND: Hepatic arterioportal fistulas (APFs) are common in hepatocellular carcinoma (HCC). Moreover, correlated with poor prognosis, APFs often complicate anti-tumor treatments, including transarterial chemoembolization (TACE). AIM: To compare the efficacy of ethanol-soaked gelatin sponges (ESG) and microspheres in the management of APFs and their impact on the prognosis of HCC. METHODS: Data from patients diagnosed with HCC or hepatic APFs between June 2016 and December 2019 were retrospectively analyzed. Furthermore, APFs were embolized with ESG (group E) or microspheres (group M) during TACE. The primary outcomes were disease control rate (DCR) and objective response rate (ORR). The secondary outcomes included immediate and first follow-up APF improvement, overall survival (OS), and progression-free survival (PFS). RESULTS: Altogether, 91 participants were enrolled in the study, comprising 46 in group E and 45 in group M. The DCR was 93.5% and 91.1% in groups E and M, respectively (P = 0.714). The ORRs were 91.3% and 66.7% in groups E and M, respectively (P = 0.004). The APFs improved immediately after the procedure in 43 (93.5%) patients in group E and 40 (88.9%) patients in group M (P = 0.485). After 2 mo, APF improvement was achieved in 37 (80.4%) and 33 (73.3%) participants in groups E and M, respectively (P = 0.421). The OS was 26.2 ± 1.4 and 20.6 ± 1.1 mo in groups E and M, respectively (P = 0.004), whereas the PFS was 16.6 ± 1.0 and 13.8 ± 0.7 mo in groups E and M, respectively (P = 0.012). CONCLUSION: Compared with microspheres, ESG embolization demonstrated a higher ORR and longer OS and PFS in patients of HCC with hepatic APFs.

Effects of different strains fermentation on nutritional functional components and flavor compounds of sweet potato slurry.

In this paper, we study the effect of microbial fermentation on the nutrient composition and flavor of sweet potato slurry, different strains of Aspergillus niger, Saccharomyces cerevisiae, Lactobacillus plantarum, Bacillus coagulans, Bacillus subtilis, Lactobacillus acidophilus, and Bifidobacterium brevis were employed to ferment sweet potato slurry. After 48 h of fermentation with different strains (10% inoculation amount), we compared the effects of several strains on the nutritional and functional constituents (protein, soluble dietary fiber, organic acid, soluble sugar, total polyphenol, free amino acid, and sensory characteristics). The results demonstrated that the total sugar level of sweet potato slurry fell significantly after fermentation by various strains, indicating that these strains can utilize the nutritious components of sweet potato slurry for fermentation. The slurry's total protein and phenol concentrations increased significantly, and many strains demonstrated excellent fermentation performance. The pH of the slurry dropped from 6.78 to 3.28 to 5.95 after fermentation. The fermentation broth contained 17 free amino acids, and the change in free amino acid content is closely correlated with the flavor of the sweet potato fermentation slurry. The gas chromatography-mass spectrometry results reveal that microbial fermentation can effectively increase the kinds and concentration of flavor components in sweet potato slurry, enhancing its flavor and flavor profile. The results demonstrated that Aspergillus niger fermentation of sweet potato slurry might greatly enhance protein and total phenolic content, which is crucial in enhancing nutrition. However, Bacillus coagulans fermentation can enhance the concentration of free amino acids in sweet potato slurry by 64.83%, with a significant rise in fresh and sweet amino acids. After fermentation by Bacillus coagulans, the concentration of lactic acid and volatile flavor substances also achieved its highest level, which can considerably enhance its flavor. The above results showed that Aspergillus niger and Bacillus coagulans could be the ideal strains for sweet potato slurry fermentation.

Quantitative effects of sodium-glucose cotransporter-2 inhibitors on liver functions in patients with nonalcoholic fatty liver disease.

BACKGROUND: The present study aimed to explore the quantitative effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on liver functions in patients with nonalcoholic fatty liver disease (NAFLD). RESEARCH DESIGN AND METHODS: A total of 4771 patients with NAFLD were included for analysis by means of nonlinear mixed effect modeling, where the change rates of liver functions were taken as the evaluation indexes so as to eliminate the potential baseline effects. RESULTS: For ALT and AST, the Emax of SGLT-2 inhibitors was -17.8% and -13.9%, respectively, and the ET50 was 6.86 weeks and 10 weeks, respectively. Furthermore, the duration time to achieve 25%, 50%, 75%, and 80% Emax were 2.3 weeks, 6.86 weeks, 20.6 weeks, 27.5 weeks in ALT, 3.4 weeks, 10 weeks, 30 weeks, 40 weeks in AST, respectively. Thus, to realize the plateau period (80% of Emax) of SGLT-2 inhibitors on ALT and AST in patients with NAFLD, 100 mg/day canagliflozin (or 10 mg/day dapagliflozin or 10 mg/day empagliflozin) needs to be taken for 20.6 weeks and 30 weeks, respectively. CONCLUSIONS: The present study explored the quantitative effects of SGLT-2 inhibitors on liver functions and recommends a therapeutic regimen in patients with NAFLD.

N-acetyltransferase 10 promotes the progression of oral squamous cell carcinoma through N4-acetylcytidine RNA acetylation of MMP1 mRNA.

The pathogenesis of oral squamous cell carcinoma (OSCC) remains unclear. Therefore, clarifying its pathogenesis and molecular-level development mechanism has become the focus of OSCC research. N-acetyltransferase 10 (NAT10) is a crucial enzyme involved in mRNA acetylation, regulating target gene expression and biological functions of various diseases through mediating N4-acetylcytidine (ac4C) acetylation. However, its role in OSCC progression is not well understood. In this study, we showed that NAT10 was significantly upregulated in OSCC tissues compared to normal oral tissues. Moreover, lentivirus-mediated NAT10 knockdown markedly suppressed cell proliferation, migration, and invasion in two OSCC cell lines (SCC-9 and SCC-15). Interestingly, MMP1 was found to be significantly upregulated in OSCC tissues and was a potential target of NAT10. N-acetyltransferase 10 knockdown significantly reduced both the total and ac4C acetylated levels of MMP1 mRNA and decreased its mRNA stability. Xenograft experiments further confirmed the inhibitory effect of NAT10 knockdown on the tumorigenesis and metastasis ability of OSCC cells and decreased MMP1 expression in vivo. Additionally, NAT10 knockdown impaired the proliferation, migration, and invasion abilities in OSCC cell lines in an MMP1-dependent manner. Our results suggest that NAT10 acts as an oncogene in OSCC, and targeting ac4C acetylation could be a promising therapeutic strategy for OSCC treatment.

Study on the Protective Immunity Induced by Pseudotyped Baculovirus Expressing the E Protein of Tembusu Virus in Ducklings.

The Duck Tembusu virus (DTMUV), a pathogenic flavivirus, has been causing significant economic losses in the Chinese poultry industry since 2010. This virus can severely decrease egg production and inhibit the growth of laying ducks and ducklings. While many vaccines have been developed to prevent DTMUV infection, fresh outbreaks continue to occur, as few effective vaccines are available. The E glycoprotein of DTMUV is the primary target for inducing protective immunity in the natural host. Therefore, we conducted an investigation and successfully developed a recombinant baculovirus containing the DTMUV E gene. Ducklings were then vaccinated with the purified protein derived from this virus as a potential vaccine candidate. Our findings demonstrated that the E glycoprotein of DTMUV was highly expressed in Sf9 cells. The vaccination of ducklings with the recombinant baculovirus Bac-E resulted in the induction of strong humoral and cellular immune responses. Most significantly, we observed that the vaccine provided 100% protective immunity against lethal challenges with the DTMUV YY5 strain.

Noncanonical contribution of microglial transcription factor NR4A1 to post-stroke recovery through TNF mRNA destabilization.

Microglia-mediated neuroinflammation is involved in various neurological diseases, including ischemic stroke, but the endogenous mechanisms preventing unstrained inflammation is still unclear. The anti-inflammatory role of transcription factor nuclear receptor subfamily 4 group A member 1 (NR4A1) in macrophages and microglia has previously been identified. However, the endogenous mechanisms that how NR4A1 restricts unstrained inflammation remain elusive. Here, we observed that NR4A1 is up-regulated in the cytoplasm of activated microglia and localizes to processing bodies (P-bodies). In addition, we found that cytoplasmic NR4A1 functions as an RNA-binding protein (RBP) that directly binds and destabilizes Tnf mRNA in an N6-methyladenosine (m6A)-dependent manner. Remarkably, conditional microglial deletion of Nr4a1 elevates Tnf expression and worsens outcomes in a mouse model of ischemic stroke, in which case NR4A1 expression is significantly induced in the cytoplasm of microglia. Thus, our study illustrates a novel mechanism that NR4A1 posttranscriptionally regulates Tnf expression in microglia and determines stroke outcomes.