Rspo2-LGR4 exacerbates hepatocellular carcinoma progression via activation of Wnt/b-catenin signaling pathway / Rspo2-LGR4 agrava la progresión del carcinoma hepatocelular al activar la vía de señalización Wnt/beta-catenina

Background: The leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4) plays an important role in stem cell differentiation, organ development and cancer. Whether LGR4 affects the progression of hepatocellular carcinoma (HCC) remains unknown. This study aimed to reveal the role of LGR4 in HCC. Methods: Clinical samples of HCC were collected to assess the expression of LGR4 and its correlation with patients’ clinical characteristics. The expression level of LGR4 in HCC cells was altered by pharmacological and genetic methods, and the role of LGR4 in HCC progression was analyzed by in vivo and in vitro assays. HCC was induced by diethylnitrosamine (DEN) and carbon tetrachloride (CCl4) in wild-type and LGR4 deficient mice, the effect of LGR4 on HCC was examined by histopathological evaluation and biochemical assays. Results: LGR4 expression was up-regulated in HCC samples, and its expression level was positively correlated with tumor size, microvascular invasion (MVI), TNM stage and pathological differentiation grade of HCC patients. In the mouse HCC model induced by DEN+CCl4, knockdown of LGR4 effectively inhibited the progression of HCC. Silencing of LGR4 inhibited the proliferation, migration, invasion, stem cell-like properties and Warburg effect of HCC cells. These phenotypes were promoted by R-spondin2 (Rspo2), an endogenous ligand for LGR4. Rspo2 markedly increased the nuclear translocation of β-catenin, whereas IWR-1, an inhibitor of Wnt/β-catenin signaling, reversed its effect. Deficiency of LGR4 significantly reduced the nuclear translocation of β-catenin and the expression of its downstream target genes cyclinD1 and c-Myc. Conclusions: LGR4 promotes HCC progression via Wnt/β-catenin signaling pathway. (AU)

Antecedentes: El receptor de acoplamiento de proteínas G de secuencia repetida 4 (LGR4), rico en leucina, juega un papel importante en la diferenciación de células madre, el desarrollo de órganos y el cáncer. Se desconoce si LGR4 afecta la progresión del carcinoma hepatocelular (HCC). El objetivo de este estudio es revelar el papel de LGR4 en el HCC. Métodos: Se recolectaron muestras clínicas de HCC para evaluar la expresión de LGR4 y su correlación con los resultados clínicos de HCC. Alterar los niveles de expresión de LGR4 en las células de HCC mediante métodos farmacológicos y genéticos y analizar el papel de LGR4 en la progresión del cáncer de hígado mediante mediciones in vivo e in vitro. El HCC fue inducido en ratones de tipo salvaje y con defectos de LGR4 con Nitrosamina de dietilo (DEN) y cloruro de carbono (CCl4), y los efectos de LGR4 sobre el HCC fueron detectados por evaluación histopatológica y determinación bioquímica. Resultados: La expresión de LGR4 está regulada en HCC, y su nivel de expresión está positivamente relacionado con el tamaño tumoral, la infiltración microvascular (MVI), la etapa de TNM y el grado de diferenciación patológica en pacientes con HCC. En el modelo de HCC de ratón inducido por DEN+CCl4, golpear bajo LGR4 inhibió efectivamente la progresión del HCC. El silencio de LGR4 inhibe la proliferación, migración, invasión, propiedades similares a las células madre y el efecto Warburg de las células HCC. Estos fenotipos son promovidos por el ligando endógeno roof slab-specific sponge 2 (Rspo2)de LGR4. El Rspo2 aumentó significativamente la translocación nuclear de la proteína beta-catenina, mientras que el inhibidor de la señalización Wnt/beta-cateninaIWR-1 revirtió su acción... (AU)

Fault-tolerant Hamiltonian cycle strategy for fast node fault diagnosis based on PMC in data center networks.

System-level fault diagnosis model, namely, the PMC model, detects fault nodes only through the mutual testing of nodes in the system without physical equipment. In order to achieve server nodes fault diagnosis in large-scale data center networks (DCNs), the traditional algorithm based on the PMC model cannot meet the characteristics of high diagnosability, high accuracy and high efficiency due to its inability to ensure that the test nodes are fault-free. This paper first proposed a fault-tolerant Hamiltonian cycle fault diagnosis (FHFD) algorithm, which tests nodes in the order of the Hamiltonian cycle to ensure that the test nodes are faultless. In order to improve testing efficiency, a hierarchical diagnosis mechanism was further proposed, which recursively divides high scale structures into a large number of low scale structures based on the recursive structure characteristics of DCNs. Additionally, we proved that $ 2(n-2){n^{k-1}} $ and $ (n-2){t_{n, k}}/{t_{n, 1}} $ faulty nodes could be detected for $ BCub{e_{n, k}} $ and $ DCel{l_{n, k}} $ within a limited time for the proposed diagnosis strategy. Simulation experiments have also shown that our proposed strategy has improved the diagnosability and test efficiency dramatically.

Lanthanum hydroxide protects kidney through gut microbiota in a rat model of chronic kidney disease.

The progression of chronic kidney diseases (CKD) is complex, influenced by a myriad of factors including gut microbiota. While emerging evidence suggests that gut microbiota can have beneficial effects in managing CKD, it is also recognized that dysbiosis may contribute to the progression of CKD and associated uremic complications. Our previous research has demonstrated the efficacy of lanthanum hydroxide in delaying kidney failure and preserving renal function. However, the role of lanthanum hydroxide in modulating gut microbiota in this context remains unclear. In our study, we induced CKD in rats using adenine, leading to gut microbial dysbiosis, kidney pathology, and disturbances in amino acid metabolism. In this adenine-induced CKD model with hyperphosphatemia, treatment with lanthanum hydroxide improved renal function. This improvement was associated with the restoration of gut microbial balance and an increase in urine ammonium metabolism. These results suggest that the therapeutic potential of lanthanum hydroxide in CKD may be partly due to its ability to reshape gut microbiota composition. This study underscores the significance of lanthanum hydroxide in kidney protection, attributing its benefits to the modulation of gut microbiota in a rat model of CKD.

JUNO high purity nitrogen plant.

The Jiangmen Underground Neutrino Observatory (JUNO) is a 20 kt low level radioactivity liquid scintillator detector in a laboratory 650 m underground. An excellent energy resolution and a large volume offer exciting opportunities for addressing many important topics in neutrino physics. High purity nitrogen is an important factor to ensure the low background of the JUNO detector. High Purity Nitrogen (HPN) is used for detector purging, pipe cleaning, and scintillator purification, among other things in JUNO. According to JUNO's requirements, the radon concentration in HPN should be less than 10 µBq/m3. To meet this requirement, A high-purity nitrogen plant with 100 Nm3/h maximum rate was designed and constructed. Low-temperature adsorption technology is used to remove radioactive impurities in nitrogen. High purification efficiency was ensured by using an activated carbon column with high column height-to-diameter ratio. Electrostatic collection and low-temperature enrichment methods are combined to measure radon in nitrogen. After ten days of continuous operation at 50 Nm3/h flux rate, the plant can to reduce the radon concentration in nitrogen from 37.4±1.8µBq/m3 to less than 1.33 µBq/m3. After HPN with flow rate of 50 Nm3/h passing through low-background pipeline (About 1.3 km), the radon concentration of HPN is 5.6±0.6µBq/m3.

Intermittent fasting promotes type 3 innate lymphoid cells secreting IL-22 contributing to the beigeing of white adipose tissue.

Mechanism underlying the metabolic benefit of intermittent fasting remains largely unknown. Here, we reported that intermittent fasting promoted interleukin-22 (IL-22) production by type 3 innate lymphoid cells (ILC3s) and subsequent beigeing of subcutaneous white adipose tissue. Adoptive transfer of intestinal ILC3s increased beigeing of white adipose tissue in diet-induced-obese mice. Exogenous IL-22 significantly increased the beigeing of subcutaneous white adipose tissue. Deficiency of IL-22 receptor (IL-22R) attenuated the beigeing induced by intermittent fasting. Single-cell sequencing of sorted intestinal immune cells revealed that intermittent fasting increased aryl hydrocarbon receptor signaling in ILC3s. Analysis of cell-cell ligand receptor interactions indicated that intermittent fasting may stimulate the interaction of ILC3s with dendritic cells and macrophages. These results establish the role of intestinal ILC3s in beigeing of white adipose tissue, suggesting that ILC3/IL-22/IL-22R axis contributes to the metabolic benefit of intermittent fasting.

Obesity refers to a condition where a person has excessive fat accumulation, which can have negative impacts on their health. Managing obesity has typically relied on reducing energy intake and increasing energy use through diets and exercise. For example, intermittent fasting is a diet strategy involving periods of time in a day or week where a person does not eat any food. Research has shown that intermittent fasting may improve the metabolism and increase energy use by enhancing a process known as "beigeing" of white fat tissue. In this process, white fat cells or their precursor cells differentiate into beige fat cells, which can consume excess energy by burning fat. Consequently, understanding how beigeing of white fat cells is activated in intermittent fasting may reveal a promising strategy for tackling obesity and metabolic diseases. Immune cells found in the gut known as innate lymphoid cells (ILCs) may play a role in the metabolic benefits from intermittent fasting. However, the roles of ILCs are complex: some types of ILCs can promote obesity, while others show metabolic benefits through their release of proteins like IL-17 and IL-22, which can help the body to metabolise glucose. To find out if these immune cells play a role in intermittent fasting, Chen, Sun et al. used diet-induced obese mice that had to fast every other day. Intermittent fasting was found to cause a form of ILCs (ILC3s) to release IL-22, which resulted in beigeing of white fat cells in obese mice. Single-cell sequencing techniques of gut immune cells further revealed that intermittent fasting increased forms of signalling in ILC3s and caused ILC3s to interact with other immune cells, such as dendritic cells and macrophages. The findings demonstrate how intermittent fasting causes beigeing of white adipose tissue through ILC3s, revealing mechanisms underpinning the metabolic benefits found from intermittent fasting. More research into this process may help identify new targets for treating obesity.

Hepatic LGR4 aggravates cholestasis-induced liver injury in mice.

Current therapy for hepatic injury induced by the accumulation of bile acids is limited. Leucine-rich repeat G protein-coupled receptor 4 (LGR4), also known as GPR48, is critical for cytoprotection and cell proliferation. Here, we reported a novel function for the LGR4 in cholestatic liver injury. In the bile duct ligation (BDL)-induced liver injury model, hepatic LGR4 expression was significantly downregulated. Deficiency of LGR4 in hepatocytes (Lgr4LKO) notably decreased BDL-induced liver injury measured by hepatic necrosis, fibrosis, and circulating liver enzymes and total bilirubin. Levels of total bile acids in plasma and liver were markedly reduced in these mice. However, deficiency of LGR4 in macrophages (Lyz2-Lgr4MKO) demonstrated no significant effect on liver injury induced by BDL. Deficiency of LGR4 in hepatocytes significantly attenuated S1PR2 and the phosphorylation of protein kinase B (AKT) induced by BDL. Recombinant Rspo1 and Rspo3 potentiated the taurocholic acid (TCA)-induced upregulation in S1PR2 and phosphorylation of AKT in hepatocytes. Inhibition of S1PR2-AKT signaling by specific AKT or S1PR2 inhibitors blocked the increase of bile acid secretion induced by Rspo1/3 in hepatocytes. Our studies indicate that the R-spondins (Rspos)-LGR4 signaling in hepatocytes aggravates the cholestatic liver injury by potentiating the production of bile acids in a S1PR2-AKT-dependent manner.NEW & NOTEWORTHY Deficiency of LGR4 in hepatocytes alleviates BDL-induced liver injury. LGR4 in macrophages demonstrates no effect on BDL-induced liver injury. Rspos-LGR4 increases bile acid synthesis and transport via potentiating S1PR2-AKT signaling in hepatocytes.

Indole-3-acetic acid alleviates DSS-induced colitis by promoting the production of R-equol from Bifidobacterium pseudolongum.

BACKGROUND: Inflammatory bowel disease (IBD) is characterized by immune-mediated, chronic inflammation of the intestinal tract. The occurrence of IBD is driven by the complex interactions of multiple factors. The objective of this study was to evaluate the therapeutic effects of IAA in colitis. METHOD: C57/BL6 mice were administered 2.5% DSS in drinking water to induce colitis. IAA, Bifidobacterium pseudolongum, and R-equol were administered by oral gavage and fed a regular diet. The Disease Activity Index was used to evaluate disease activity. The degree of colitis was evaluated using histological morphology, RNA, and inflammation marker proteins. CD45+ CD4+ FOXP3+ Treg and CD45+ CD4+ IL17A+ Th17 cells were detected by flow cytometry. Analysis of the gut microbiome in fecal content was performed using 16S rRNA gene sequencing. Gut microbiome metabolites were analyzed using Untargeted Metabolomics. RESULT: In our study, we found IAA alleviates DSS-induced colitis in mice by altering the gut microbiome. The abundance of Bifidobacterium pseudolongum significantly increased in the IAA treatment group. Bifidobacterium pseudolongum ATCC25526 alleviates DSS-induced colitis by increasing the ratio of Foxp3+T cells in colon tissue. R-equol alleviates DSS-induced colitis by increasing Foxp3+T cells, which may be the mechanism by which ATCC25526 alleviates DSS-induced colitis in mice. CONCLUSION: Our study demonstrates that IAA, an indole derivative, alleviates DSS-induced colitis by promoting the production of Equol from Bifidobacterium pseudolongum, which provides new insights into gut homeostasis regulated by indole metabolites other than the classic AHR pathway.

An "off-on" fluorescent nanosensor for the detection of cadmium ions based on APDC-etched CdTe/CdS/SiO2 quantum dots.

In this study, we have developed a novel fluorescent "OFF-ON" quantum dots (QDs) sensor based on CdTe/CdS/SiO2 cores. Ammonium pyrrolidine dithiocarbamate (APDC), ethylenediamine tetraacetic acid (EDTA), and 1,10-phenanthroline (Phen) served as potential chemical etchants. Among these three etchants, APDC exhibited the most pronounced quenching effect (94.06%). The APDC-etched CdTe/CdS/SiO2 QDs demonstrated excellent optical properties: the fluorescence of the APDC-etched CdTe/CdS/SiO2 QDs system (excitation wavelength: 365 nm and emission wavelength: 622 nm) was significantly and selectively restored upon the addition of cadmium ions (Cd2+) (89.22%), compared to 15 other metal ions. The linear response of the APDC-etched CdTe/CdS/SiO2 QDs was observed within the cadmium ion (Cd2+) concentration ranges of 0-20 µmol L-1 and 20-160 µmol L-1 under optimized conditions (APDC: 300 µmol L-1, pH: 7.0, reaction time: 10 min). The detection limit (LOD) of the APDC-etched CdTe/CdS/SiO2 QDs for Cd2+ was 0.3451 µmol L-1 in the range of 0-20 µmol L-1. The LOD achieved by the QDs in this study surpasses that of the majority of previously reported nanomaterials. The feasibility of using APDC-etched CdTe/CdS/SiO2 QDs for Cd2+ detection in seawater, freshwater, and milk samples was verified, with average recoveries of 95.27%-110.68%, 92%-106.47%, and 90.73%-111.60%, respectively, demonstrating satisfactory analytical precision (RSD ≤ 8.26).

Retrospective study of the impact of diabetes on the severity and prognosis of COVID­19.

Patients with diabetes coexisting with viral infection tend to have poor outcomes, but the association between diabetes and coronavirus disease 2019 (COVID-19) prognosis is controversial at present. The present study reviewed and analyzed the data of 1,892 patients with COVID-19 admitted to Shaanxi Provincial People's Hospital (Xi'an, China). Demographic, clinical, laboratory and treatment data as well as clinical outcomes were extracted from the electronic medical records and compared between patients with and without diabetes. Multivariate logistic regression analysis was used to determine the risk factors affecting the prognosis of COVID-19. Compared with patients without diabetes, the levels of glucose, C-reactive protein, procalcitonin, creatinine, total bilirubin and plasma D-dimer were significantly increased in patients with diabetes, while the levels of lymphocytes and albumin were significantly decreased (P<0.05). Multivariate logistic regression analysis revealed that platelet count, albumin, total bilirubin and lymphocytes were significantly correlated with the severity of COVID-19. Diabetes mellitus was an independent prognostic factor that affected the mortality outcome of patients with COVID-19. Additionally, an age of ≥80 years, male sex, cerebral infarction complications and a critical diagnosis of COVID-19 at admission were risk factors for critical illness during hospitalization. The results of the present study suggest that diabetes may be a risk factor for the rapid progression and poor prognosis of COVID-19. Therefore, further attention should be paid to individuals with diabetes in order to prevent rapid deterioration.

Dip effect on the orientation of rock failure plane under combined compression-shear loading.

Shear failure often occurs in engineering rock mass (such as inclined pillar) in gently inclined strata. Prediction and characterization the orientation of shear failure plane is the foundation of rock mass engineering reinforcement. In this paper, sandstone samples are used to perform uniaxial and shear tests to obtain the basic mechanical parameters. Then, by employing the numerical method, the combined compression-shear loading tests were carried out for inclined specimens varied from 0° to 25° at an interval of 5°, to obtain the dip effect on the orientation of rock failure plane. The results show that the failure plane of rock changes with the change of dip angle of rock sample. Based on the Mohr-Coulomb criterion, the ultimate stress state of rock was characterized under combined compression-shear loading. The ultimate strength of rock is equal to the ratio of the stress circle radius of rock under combined compression-shear condition to the stress circle radius of rock under uniaxial compression condition, multiplied by the uniaxial compressive strength. The fracture angle of rock was defined under combined compression-shear loading. A theoretical model was developed for predicting the fracture angle. The developed model could be characterized by internal friction angle, dip angle of rock sample and Poisson's ratio. Finally, the numerical results of the fracture angle were analyzed, which are consistent with the predicted results of the model. The investigation shows that the rock fracture angle has a dip effect, which decreases with the increase of the inclination angle of the sample. The research results provide a new means to identify the potential failure plane of engineering rock mass, and lay a theoretical foundation for calculating the orientation of rock fracture plane.

Interpregnancy interval and early infant neurodevelopment: the role of maternal-fetal glucose metabolism.

BACKGROUND: Interpregnancy interval (IPI) is associated with a variety of adverse maternal and infant outcomes. However, reports of its associations with early infant neurodevelopment are limited and the mechanisms of this association have not been elucidated. Maternal-fetal glucose metabolism has been shown to be associated with infant neurodevelopmental. The objective of this study was to determine whether this metabolism plays a role in the relationship between IPI and neurodevelopment. METHODS: This prospective birth cohort study included 2599 mother-infant pairs. The IPI was calculated by subtracting the gestational age of the current pregnancy from the interval at the end of the previous pregnancy. Neurodevelopmental outcomes at 12 months in infants were assessed by the Ages and Stages Questionnaire Edition 3 (ASQ-3). Maternal fasting venous blood was collected at 24-28 weeks and cord blood was collected at delivery. The association between IPI and neurodevelopment was determined by logistic regression. Mediation and sensitivity analyses were also conducted. RESULTS: In our cohort, 14.0% had an IPI < 12 months. IPI < 12 months increased the failure of the communication domain, fine motor domain, and personal social domain of the ASQ (relative risks (RRs) with 95% confidence interval (CI): 1.73 [1.11,2.70]; 1.73 [1.10,2.72]; 1.51 [1.00,2.29]). Maternal homeostasis model assessment of insulin resistance (HOMA-IR) and cord blood C-peptide was significantly associated with failure in the communication domain [RRs with 95% CI: 1.15 (1.02, 1.31); 2.15 (1.26, 3.67)]. The proportion of the association between IPI and failure of the communication domain risk mediated by maternal HOMA-IR and cord blood C-peptide was 14.4%. CONCLUSIONS: IPI < 12 months was associated with failing the communication domain in infants. Maternal-fetal glucose metabolism abnormality may partially explain the risk of neurodevelopmental delay caused by short IPI.

Elephantopus scaber L. Polysaccharides Alleviate Heat Stress-Induced Systemic Inflammation in Mice via Modulation of Characteristic Gut Microbiota and Metabolites.

Elephantopus scaber L. (ESL) is a Chinese herb that is used both as a food and medicine, often being added to soups in summer in south China to relieve heat stress (HS), but its exact mechanism of action is unknown. In this study, heat-stressed mice were gavaged with ESL polysaccharides (ESLP) at 0, 150, 300, and 450 mg/kg/d-1 (n = 5) for seven days. The gut microbiota composition, short-chain fatty acids (SCFAs), seven neurotransmitters in faeces, expression of intestinal epithelial tight junction (TJ) proteins (Claudin-1, Occludin), and serum inflammatory cytokines were measured. The low dose of ESLP (ESLL) improved the adverse physiological conditions; significantly reduced the cytokines (TNF-α, IL-1ß, IL-6) and lipopolysaccharide (LPS) levels (p < 0.05); upregulated the expression of Claudin-1; restored the gut microbiota composition including Achromobacter and Oscillospira, which were at similar levels to those in the normal control group; significantly increased beneficial SCFAs like butyric acid and 5-HT levels in the faeces of heat-stressed mice; and significantly decreased the valeric acid and glutamic acid level. The level of inflammatory markers significantly correlated with the above-mentioned indicators (p < 0.05). Thus, ESLL reduced the HS-induced systemic inflammation by optimizing gut microbiota (Achromobacter, Oscillospira) abundance, increasing gut beneficial SCFAs like butyric acid and 5-HT levels, and reducing gut valeric and glutamic acid levels.

Study on Synergistic Effects of Nanohydroxyapatite/High-Viscosity Carboxymethyl Cellulose Scaffolds Stimulated by LIPUS for Bone Defect Repair of Rats.

Despite the self-healing capacity of bone, the regeneration of critical-size bone defects remains a major clinical challenge. In this study, nanohydroxyapatite (nHAP)/high-viscosity carboxymethyl cellulose (hvCMC, 6500 mPa·s) scaffolds and low-intensity pulsed ultrasound (HA-LIPUS) were employed to repair bone defects. First, hvCMC was prepared from ramie fiber, and the degree of substitution (DS), purity, and content of NaCl of hvCMC samples were 0.91, 99.93, and 0.017%, respectively. Besides, toxic metal contents were below the permissible limits for pharmaceutically used materials. Our results demonstrated that the hvCMC is suitable for pharmaceutical use. Second, nHAP and hvCMC were employed to prepare scaffolds by freeze-drying. The results indicated that the scaffolds were porous, and the porosity was 35.63 ± 3.52%. Subsequently, the rats were divided into four groups (n = 8) randomly: normal control (NC), bone defect (BD), bone defect treated with nHAP/hvCMC scaffolds (HA), and bone defect treated with nHAP/hvCMC scaffolds and stimulated by LIPUS (HA-LIPUS). After drilling surgery, nHAP/hvCMC scaffolds were implanted in the defect region of HA and HA-LIPUS rats. Meanwhile, HA-LIPUS rats were treated by LIPUS (1.5 MHz, 80 mW cm-2) irradiation for 2 weeks. Compared with BD rats, the maximum load and bone mineral density of HA-LIPUS rats were increased by 20.85 and 51.97%, respectively. The gene and protein results indicated that nHAP/hvCMC scaffolds and LIPUS promoted the bone defect repair and regeneration of rats significantly by activating Wnt/ß-catenin and inhibiting OPG/RANKL signaling pathways. Overall, compared with BD rats, nHAP/hvCMC scaffolds and LIPUS promoted bone defect repair significantly. Furthermore, the research results also indicated that there are synergistic effects for bone defect repair between the nHAP/hvCMC scaffolds and LIPUS.

Nur77 mitigates endothelial dysfunction through activation of both nitric oxide production and anti-oxidant pathways.

BACKGROUND: Nur77 belongs to the member of orphan nuclear receptor 4A family that plays critical roles in maintaining vascular homeostasis. This study aims to determine whether Nur77 plays a role in attenuating vascular dysfunction, and if so, to determine the molecular mechanisms involved. METHODS: Both Nur77 knockout (Nur77 KO) and Nur77 endothelial specific transgenic mice (Nur77-Tg) were employed to examine the functional significance of Nur77 in vascular endothelium in vivo. Endothelium-dependent vasodilatation to acetylcholine (Ach) and reactive oxygen species (ROS) production was determined under inflammatory and high glucose conditions. Expression of genes was determined by real-time PCR and western blot analysis. RESULTS: In response to tumor necrosis factor alpha (TNF-α) treatment and diabetes, the endothelium-dependent vasodilatation to Ach was significantly impaired in aorta from Nur77 KO as compared with those from the wild-type (WT) mice. Endothelial specific overexpression of Nur77 markedly prevented both TNF-α- and high glucose-induced endothelial dysfunction. Compared with WT mice, after TNF-α and high glucose treatment, ROS production in aorta was significantly increased in Nur77 KO mice, but it was inhibited in Nur77-Tg mice, as determined by dihydroethidium (DHE) staining. Furthermore, we demonstrated that Nur77 overexpression substantially increased the expression of several key enzymes involved in nitric oxide (NO) production and ROS scavenging, including endothelial nitric oxide synthase (eNOS), guanosine triphosphate cyclohydrolase 1 (GCH-1), glutathione peroxidase-1 (GPx-1), and superoxide dismutases (SODs). Mechanistically, we found that Nur77 increased GCH1 mRNA stability by inhibiting the expression of microRNA-133a, while Nur77 upregulated SOD1 expression through directly binding to the human SOD1 promoter in vascular endothelial cells. CONCLUSION: Our results suggest that Nur77 plays an essential role in attenuating endothelial dysfunction through activating NO production and anti-oxidant pathways in vascular endothelium. Targeted activation of Nur77 may provide a novel therapeutic approach for the treatment of cardiovascular diseases associated with endothelial dysfunction.

Rapid Initiation of Antiretroviral Therapy with Coformulated Bictegravir, Emtricitabine, Tenofovir Alafenamide Versus Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate in HIV-positive Men Who Have Sex with Men in China: Week 48 Results of the Multicenter, Randomized Clinical Trial.

BACKGROUND: Most international treatment guidelines recommend rapid initiation of antiretroviral therapy (ART) for people newly diagnosed with HIV-1 infection, but experiences with rapid ART initiation remain limited in China. We aimed to evaluate the efficacy and safety of efavirenz (400-mg) plus lamivudine and tenofovir disoproxil fumarate (EFV + 3TC + TDF) versus coformulated bictegravir, emtricitabine, tenofovir alafenamide (BIC/FTC/TAF) in rapid ART initiation among HIV-positive men who have sex with men (MSM). METHODS: This multicenter, open-label, randomized clinical trial enrolled MSM aged ≥18 years to start ART within 14 days of confirmed HIV diagnosis. The participants were randomly assigned in a 1:1 ratio to receive EFV(400-mg) + 3TC + TDF or BIC/FTC/TAF. The primary end point was viral suppression (<50 copies/ml) at 48 weeks per FDA Snapshot analysis. RESULTS: Between March 2021 and July 2022, 300 participants were enrolled; 154 were assigned to receive EFV + 3TC + TDF (EFV group) and 146 BIC/FTC/TAF (BIC group). At week 48, 118 (79.2%) and 140 (95.9%) participants in the EFV and BIC group, respectively, were retained in care with viral suppression; and 24 (16.1%) and 1 (0.7%) participant in the EFV and BIC group (p < 0.001), respectively, discontinued treatment due to adverse effects, death, or loss to follow-up. The median increase of CD4 count was 181 and 223 cells/µL (p = 0.020), respectively, for the EFV and BIC group, at week 48. The overall incidence of adverse effects was significantly higher for the EFV group (65.8% vs 37.7%, P < 0.001). CONCLUSION: BIC/FTC/TAF was more efficacious and safer than EFV(400-mg) + 3TC + TDF for rapid ART initiation among HIV-positive MSM in China.

Adrenomedullin, transcriptionally regulated by vitamin D receptors, alleviates atherosclerosis in mice through suppressing AMPK-mediated endothelial ferroptosis.

PURPOSE: Vitamin D receptors (VDR) play important roles in cardiovascular, immune, metabolic and other functions. Activation of VDR may help improve endothelial dysfunction, atherosclerosis, vascular calcification, and cardiac hypertrophy. However, the specific target genes and mechanisms of VDR in improving Human Umbilical Vein Endothelial Cell (HUVEC) functions remain unclear. This study aims to investigate the function and mechanism of VDR in HUVECs. METHODS: Endothelial dysfunction cell model was constructed by oxidized low-density lipoprotein (ox-LDL). An animal model of atherosclerosis was established in male homozygous Apoe-/- mice (6 weeks) on a high fat diet for 6 weeks. The relationship between VDR and adrenomedullin (ADM) was studied by bioinformatics analysis, ChIP, and luciferase reporter gene analysis. Endothelial cell function was evaluated by Transwell migration and Tube Formation tests. Ferroptosis was detected by measuring intracellular iron content, levels of oxidative stress markers, and ferroptosis related proteins. RESULTS: Overexpression of VDR in HUVECs inhibits ox-LDL-induced endothelial dysfunction and ferroptosis. VDR binds to the ADM promoter sequence and regulates the transcription of ADM. Inhibition of ADM promotes ox-LDL-induced endothelial dysfunction and ferroptosis. ADM regulates ox-LDL-induced endothelial dysfunction and ferroptosis through the AMPK signaling pathway. Overexpression of VDR in Apoe-/- mice inhibited lipid deposition and plaque area in atherosclerotic mice. CONCLUSION: VDR inhibits ox-LDL-induced endothelial dysfunction and ferroptosis by regulating ADM transcription and acting on AMPK signaling pathway. Overexpression of VDR in Apoe-/- mice reduced lipid deposition and plaque area in the thoracic aorta of atherosclerotic mice.

Intermittent fasting promotes ILC3s secreting IL-22 contributing to the beigeing of white adipose tissue.

Mechanism underlying the metabolic benefit of intermittent fasting remains largely unknown. Here, we reported that intermittent fasting promoted IL-22 production by ILC3s and subsequent beigeing of subcutaneous white adipose tissue. Adoptive transfer of intestinal ILC3s increased beigeing of white adipose tissue in diet-induced-obese mice. Exogenous IL-22 significantly increased the beigeing of subcutaneous white adipose tissue. Deficiency of IL-22 receptor attenuated the beigeing induced by intermittent fasting. Single-cell sequencing of sorted intestinal immune cells revealed that intermittent fasting increased aryl hydrocarbon receptor signaling in ILC3s. Analysis of cell‒cell ligand receptor interactions indicated that intermittent fasting may stimulate the interaction of ILC3s with dendritic cells (DCs) and macrophages. These results establish the role of intestinal ILC3s in beigeing of white adipose tissue, suggesting that ILC3/IL-22/IL-22R axis contributes to the metabolic benefit of intermittent fasting.

Development of a multiple convolutional neural network-facilitated diagnostic screening program for immunofluorescence images of IgA nephropathy and idiopathic membranous nephropathy.

Background: Immunoglobulin A nephropathy (IgAN) and idiopathic membranous nephropathy (IMN) are the most common glomerular diseases. Immunofluorescence (IF) tests of renal tissues are crucial for the diagnosis. We developed a multiple convolutional neural network (CNN)-facilitated diagnostic program to assist the IF diagnosis of IgAN and IMN. Methods: The diagnostic program consisted of four parts: a CNN trained as a glomeruli detection module, an IF intensity comparator, dual-CNN (D-CNN) trained as a deposition appearance and location classifier and a post-processing module. A total of 1573 glomerular IF images from 1009 patients with glomerular diseases were used for the training and validation of the diagnostic program. A total of 1610 images of 426 patients from different hospitals were used as test datasets. The performance of the diagnostic program was compared with nephropathologists. Results: In >90% of the tested images, the glomerulus location module achieved an intersection over union >0.8. The accuracy of the D-CNN in recognizing irregular granular mesangial deposition and fine granular deposition along the glomerular basement membrane was 96.1% and 93.3%, respectively. As for the diagnostic program, the accuracy, sensitivity and specificity of diagnosing suspected IgAN were 97.6%, 94.4% and 96.0%, respectively. The accuracy, sensitivity and specificity of diagnosing suspected IMN were 91.7%, 88.9% and 95.8%, respectively. The corresponding areas under the curve (AUCs) were 0.983 and 0.935. When tested with images from the outside hospital, the diagnostic program showed stable performance. The AUCs for diagnosing suspected IgAN and IMN were 0.972 and 0.948, respectively. Compared with inexperienced nephropathologists, the program showed better performance. Conclusion: The proposed diagnostic program could assist the IF diagnosis of IgAN and IMN.

Field Measurement and Analysis on the Mechanical Response of Asphalt Pavement Using Large-Particle-Size Crushed Stone Base Treated with Fly Ash and Slag Powder.

The mechanical response of asphalt pavement under vehicular loading is an essential reference for crack-resistant pavement design. However, limited research focuses on the mechanical response measurement of asphalt pavement using a large-particle-size crushed stone base treated with fly ash and slag powder. Therefore, two types of asphalt pavements were constructed. The first type of asphalt pavement uses a large-particle-size crushed stone base treated with fly ash and slag powder, where the slag powder uses granulated blast furnace slag powder. The second type uses a conventional cement-stabilized crushed stone base and serves as a reference structure. Firstly, the strain gauges and temperature sensors were installed during the construction of asphalt pavements. Secondly, the mechanical response of the pavement was tested at different speeds and service time conditions. Then, sensitivity analysis and three-factor analysis of variance (ANOVA) were carried out. Finally, the prediction equations were developed. The results show that the longitudinal strain pulse of the asphalt layer exhibited a "compression-tension-compression" characteristic. For the transverse strain pulse of the asphalt layer, the base layer's transverse and longitudinal strain pulses were only shown as "tensile" characteristics. The vehicular speed significantly affected the strain values for the base and asphalt layers, showing a decreasing trend with increasing speed. For the asphalt layer, the strain values showed an increasing trend with increasing temperature; for the base layer, the strain values showed a decreasing trend with increasing service time. The type of base layer had a significant effect on the strain value. Compared with the conventional base layer, the large-particle-size crushed stone base treated with fly ash and slag powder had lower strain at the base layer and a lower position of the asphalt layer, which could better prevent bottom-up fatigue cracking. Finally, the strain prediction model of the pavement under the speed and temperature (service time) was fitted to obtain a model that can predict the mechanical response of the pavement under different operating conditions. The findings of this research can provide a reference for the design of asphalt pavement using a large-particle-size crushed stone base treated with fly ash and slag powder.