Septic acute liver injury is one of the leading causes of fatalities in patients with sepsis. Toll-like receptor 4 (TLR4) plays a vital role in response to lipopolysaccharide (LPS) challenge, but the ...mechanisms underlying TLR4 function in septic injury remains unclear. In this study, we investigated the role of TLR4 in LPS-induced acute liver injury (ALI) in mice with a focus on inflammation and apoptosis. Wild-type (WT) and TLR4-knockout (TLR4
) mice were challenged with LPS (4 mg/kg) for 6 h. TLR4 signaling cascade markers (TLR4, MyD88, and NF-κB), inflammatory markers (TNFα, IL-1β, and IL-6), and apoptotic markers (Bax, Bcl-2, and caspase 3) were evaluated. We showed that LPS challenge markedly increased the levels of serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) and other liver pathological changes in WT mice. In addition, LPS challenge elevated the levels of liver carbonyl proteins and serum inflammatory cytokines, upregulated the expression of TLR4, MyD88, and phosphorylated NF-κB in liver tissues. Moreover, LPS challenge significantly increased hepatocyte apoptosis, caspase 3 activity, and Bax level while suppressing Bcl-2 expression in liver tissues. These pathological changes were greatly attenuated in TLR4
mice. Similar pathological responses were provoked in primary hepatic Kupffer cells isolated from WT and TLR4
mice following LPS (1 μg/mL, 6 h) challenge. In summary, these results demonstrate that silencing of TLR4 attenuates LPS-induced liver injury through inhibition of inflammation and apoptosis via TLR4/MyD88/NF-κB signaling pathway. TLR4 deletion confers hepatoprotection against ALI induced by LPS, possibly by repressing macrophage inflammation and apoptosis.
Despite optimization of renin-angiotensin-aldosterone system (RAAS) inhibition, patients with immunoglobulin A nephropathy (IgAN) and persistent proteinuria remain at risk for kidney failure. We ...evaluated the efficacy and safety of hydroxychloroquine (HCQ), an immunomodulator, when added to the treatment regimen of patients with IgAN.
Double-blind, randomized, placebo-controlled, phase 2 clinical trial.
Participants had IgAN (proteinuria with protein excretion of 0.75-3.5g/d and estimated glomerular filtration rate>30mL/min/1.73m2) and were receiving optimized RAAS inhibitor therapy.
Patients were randomly assigned 1:1 to receive daily oral HCQ or a placebo for 6 months.
The primary outcome was percentage change in proteinuria between baseline and 6 months.
60 participants (mean estimated glomerular filtration rate, 53.8mL/min/1.73m2; median urine protein excretion, 1.7g/d) were recruited and randomly assigned to receive HCQ (n=30) or placebo (n=30). Percentage change in proteinuria at 6 months was significantly different between the HCQ group and the placebo group (−48.4% IQR, −64.2%, −30.5% vs 10.0% IQR, −38.7%, 30.6%; P<0.001, respectively). At 6 months, median proteinuria level was significantly lower in the HCQ group than in the placebo group (0.9 IQR, 0.6, 1.0 g/d vs 1.9 IQR, 0.9, 2.6 g/d; P=0.002, respectively). No serious adverse events were recorded during the study in either study group.
The short treatment period and lack of postwithdrawal observations limit conclusions about long-term renoprotective efficacy and safety.
HCQ in addition to optimized RAAS inhibition significantly reduced proteinuria in patients with IgAN over 6 months without evidence of adverse events. These findings require confirmation in larger treatment trials.
This study was supported by grants from a government entity, the Capital of Clinical Characteristics, and the Applied Research Fund.
Registered at ClinicalTrials.gov with study number NCT02942381.
Tuning Ag surface states by metal oxides is a feasible method to enhance the oxygen reduction reaction (ORR) performance of Ag-based catalysts. Herein, we develop a heterostructural electrocatalyst ...of flowerlike Ag-supported nanosheets of metal oxides (Mn3O4 and Ce-doped Mn3O4) by a facile two-step solution method for a highly efficient alkaline ORR. Not only does Mn3O4/Ag exhibit activity comparable to that of commercial Pt/C but also small amounts of Ce3+ (2–5 mol %) doped into Mn3O4 make the ORR activity and stability outperform those of Pt/C. The roles of the adjustment of Ag surface states induced by the supported Mn3O4 and Ce doping in the enhanced ORR performance were studied. The strong electron transfer from Ag substrates to Mn3O4 makes the d center of Ag shift up, accelerating the kinetics of O–O bond splitting on Ag surfaces (increasing the activity of active sites for O–O bond dissociation). Additionally, 5% Ce3+ doping further tunes Ag surface electronic structures to improve the ORR performance of Mn3O4/Ag. Meanwhile, supported Mn3O4 can reduce the adsorption of oxygen-containing species on Ag surfaces by a spillover effect, and the moderately increased oxygen vacancies of Mn3O4 due to 5% Ce doping further increase the active sites on oxide/Ag surfaces and electrochemically active surface areas for the ORR.
Analytic aspects of Delannoy numbers Wang, Yi; Zheng, Sai-Nan; Chen, Xi
Discrete mathematics,
August 2019, 2019-08-00, Letnik:
342, Številka:
8
Journal Article
Recenzirano
Odprti dostop
The Delannoy numbers d(n,k) count the number of lattice paths from (0,0) to (n−k,k) using steps (1,0),(0,1) and (1,1). We show that the zeros of all Delannoy polynomials dn(x)=∑k=0nd(n,k)xk are in ...the open interval (−3−22,−3+22) and are dense in the corresponding closed interval. We also show that the Delannoy numbers d(n,k) are asymptotically normal (by central and local limit theorems).
Postpartum depression is a common psychiatric disorder in parturients after delivery. The etiology remains unclear, and multiple factors may be involved. In this study, we investigated whether ...epidural labor analgesia was associated with a decreased risk of postpartum depression development.
Two hundred fourteen parturients who were preparing for a vaginal delivery were enrolled in this prospective cohort study. Epidural labor analgesia was performed in 107 of 214 patients on their request. Parturients' mental status was assessed with the Edinburgh Postnatal Depression Scale at 3 days and 6 weeks after delivery. A score of 10 or higher on the scale at 6 weeks was used as an indication of postpartum depression. Parturients' characteristics together with perinatal variables were collected. Multivariate logistic regression analysis was performed to assess an association between the use of epidural analgesia and the occurrence of postpartum depression.
Postpartum depression occurred in 14.0% (15 of 107) of parturients who received epidural labor analgesia and in 34.6% (37 of 107) of those who did not (P < 0.001). Use of epidural labor analgesia was associated with a decreased risk of postpartum depression (odds ratio OR 0.31, 95% confidence interval CI, 0.12-0.82, P = 0.018). Attendance at childbirth classes during pregnancy (OR 0.30, 95% CI, 0.12-0.79, P = 0.015) and continued breast-feeding after delivery (OR 0.02, 95% CI, 0.00-0.07, P < 0.001) were also associated with decreased risks of postpartum depression. A high Edinburgh Postnatal Depression Scale score at 3 days postpartum was associated with an increased risk of postpartum depression (OR 1.20, 95% CI, 1.05-1.37, P = 0.009).
Epidural labor analgesia was associated with a decreased risk of postpartum depression. Further study with a large sample size is needed to evaluate the impact of epidural analgesia on the occurrence of postpartum depression.
This study was conducted to evaluate the effects of dietary host-associated Lactococcus lactis 3-c-18 supplementation on the growth, serum biochemical indices, liver and intestine health, intestinal ...microbiota, and Aeromonas hydrophila resistance in mandarin fish (Siniperca chuatsi). Mandarin fish were fed with four experimental diets containing 0 CFU/kg−1 (CR), 0.95 × 108 CFU/kg−1 (R1), 0.86 × 109 CFU/kg−1 (R2), and 0.91 × 1010 CFU/kg−1 (R3) L. lactis 3-c-18 for ten weeks. The results showed that fish fed the R1 and R2 diets exhibited a higher percentage weight gain and lower feed conversion ratio than fish fed the CR and R3 diets. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activity were significantly decreased by dietary L. lactis 3-c-18 supplementation. Glucose (GLU), total cholesterol (TCHO) and malondialdehyde (MDA) levels were significantly depressed by the inclusion of L. lactis 3-c-18 in the diet, however, serum CAT levels were enhanced by L. lactis 3-c-18. The hepatic and intestinal morphology of mandarin fish fed L. lactis 3-c-18 was better than the control group and the relative abundances of Spirochaetes and Proteobacteria in the mid-gut were significantly increased by dietary L. lactis 3-c-18 supplementation. Meanwhile, Linear discriminant analysis Effect Size (LEfSe) analysis showed that L. lactis 3-c-18 increased the abundance of Lactococcus in the intestines of mandarin fish. The challenge test demonstrated that fish in groups fed with L. lactis 3-c-18 diets had a lower mortality rate compared to the control group. In conclusion, L. lactis 3-c-18 can have beneficial effects on growth performance, liver and gut health, A. hydrophila resistance, and intestinal microbial diversity of mandarin fish. However, high levels of L. lactis 3-c-18 in the diet may reduce these beneficial effects. Based on the results of the current study, the recommended dose of L. lactis 3-c-18 in mandarin fish feed is approximately 1 × 108 CFU/kg.
•Dietary host-associated Lactococcus lactis 3-C-18 have beneficial effects on growth performance, liver and gut health, disease resistance to Aeromonas hydrophila, intestinal microbial diversity of mandarin fish.•Overdose Lactococcus lactis 3-C-18 in diet may have negative effects on this fish.•The detailed process of feeding the mandarin fish from eating live bait to artificial feed were firstly introduced.
Abstract
Background
After spinal cord injury (SCI), destructive immune cell subsets are dominant in the local microenvironment, which are the important mechanism of injury. Studies have shown that ...inflammasomes play an important role in the inflammation following SCI, and apoptosis-associated speck-like protein containing a card (ASC) is the adaptor protein shared by inflammasomes. Therefore, we speculated that inhibiting ASC may improve the local microenvironment of injured spinal cord. Here, CRID3, a blocker of ASC oligomerization, was used to study its effect on the local microenvironment and the possible role in neuroprotection following SCI.
Methods
Murine SCI model was created using an Infinite Horizon impactor at T9 vertebral level with a force of 50 kdynes and CRID3 (50 mg/kg) was intraperitoneally injected following injury. ASC and its downstream molecules in inflammasome signaling pathway were measured by western blot. The immune cell subsets were detected by immunohistofluorescence (IHF) and flow cytometry (FCM). The spinal cord fibrosis area, neuron survival, myelin preservation, and functional recovery were assessed.
Results
Following SCI, CRID3 administration inhibited inflammasome-related ASC and caspase-1, IL-1β, and IL-18 activation, which consequently suppressed M1 microglia, Th1 and Th1Th17 differentiation, and increased M2 microglia and Th2 differentiation. Accordingly, the improved histology and behavior have also been found.
Conclusions
CRID3 may ameliorate murine SCI by inhibiting inflammasome activation, reducing proinflammatory factor production, restoring immune cell subset balance, and improving local immune microenvironment, and early administration may be a promising therapeutic strategy for SCI.
Cancer Dependency Map (CDM) genes comprise an extensive series of genome-scale RNAi-based loss-of-function tests; hence, it served as a method based on the CRISPR-Cas9 technique that could assist ...scientists in investigating potential gene functions. These CDM genes have a role in tumor cell survival and proliferation, suggesting that they may be used as new therapeutic targets for some malignant tumors. So far, there have been less research on the involvement of CDM genes in breast cancer, and only a tiny percentage of CDM genes have been studied. In this study, information of patients with breast cancer was extracted from The Cancer Genome Atlas (TCGA), from which differentially expressed CDM genes in breast cancer were determined. A variety of bioinformatics techniques were used to assess the functions and prognostic relevance of these confirmed CDM genes. In all, 290 CDM genes were found differentially expressed. Six CDM genes (SRF, RAD51, PMF1, EXOSC3, EXOC1, and TSEN54) were found to be associated with the prognosis of breast cancer samples. Based on the expression of the identified CDM genes and their coefficients, a prognosis model was constructed for prediction, according to which patients with breast cancer were separated into two risk groups. Those with high risk had substantially poorer overall survival (OS) than patients in the other risk group in the TCGA training set, TCGA testing set, and an external cohort from Gene Expression Omnibus (GEO) database. The area under the receiver operating characteristic (ROC) curve for this prognostic signature was, respectively, 0.717 and 0.635 for TCGA training and testing sets, demonstrating its reliability in predicting the prognosis of patients with breast cancer. We next created a nomogram using the six CDM genes discovered to create a therapeutically useful model. The Human Protein Atlas database was used to acquire all immunohistochemistry staining images of the discovered CDM genes. The proportions of tumor-infiltrating immune cells, as well as the expression levels of checkpoint genes, varied substantially between the two risk groups, according to the analyses of immune response. In conclusion, the findings of this research may aid in the understanding of the prognostic value and biological roles of CDM genes in breast cancer.
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