Abstract
TcpC is a multifunctional virulence factor of uropathogenic
E. coli
(UPEC). Neutrophil extracellular trap formation (NETosis) is a crucial anti-infection mechanism of neutrophils. Here we ...show the influence of TcpC on NETosis and related mechanisms. We show NETosis in the context of a pyelonephritis mouse model induced by TcpC-secreting wild-type
E. coli
CFT073 (CFT073
wt
) and LPS-induced in vitro NETosis with CFT073
wt
or recombinant TcpC (rTcpC)-treated neutrophils are inhibited. rTcpC enters neutrophils through caveolin-mediated endocytosis and inhibits LPS-induced production of ROS, proinflammatory cytokines and protein but not mRNA levels of peptidylarginine deiminase 4 (PAD4). rTcpC treatment enhances PAD4 ubiquitination and accumulation in proteasomes. Moreover, in vitro ubiquitination kit analyses show that TcpC is a PAD4-targetd E3 ubiquitin-ligase. These data suggest that TcpC inhibits NETosis primarily by serving as an E3 ligase that promotes degradation of PAD4. Our findings provide a novel mechanism underlying TcpC-mediated innate immune evasion.
Glioblastoma (GBM) is the most malignant primary brain tumor in adults. Due to its invasive nature, it cannot be thoroughly eliminated. WD repeat domain 12 (WDR12) processes the 32S precursor rRNA ...but cannot affect the synthesis of the 45S/47S primary transcript. In this study, we found that WDR12 is highly expressed in GBM according to the analysis results of mRNA expression by The Cancer Genome Atlas database. The high expression level of WDR12 is dramatically related to shorter overall survival and reduced disease‐free survival. Next, we knocked down WDR12 and found that knockdown of WDR12 promoted the apoptosis and inhibited the proliferation by cell biology experiments. Differential expression genes in gene‐chip revealed that WDR12 knockdown mainly inhibited cell cycle. Finally, we also found that WDR12 is associated with PLK1 and EZH2 in cell proliferation of GBM. Resumptively, this report showed a possible evidence that WDR12 drove malignant behavior of GBM, whose expression may present a neoteric independent prognostic biomarker in GBM.
This report showed a possible evidence thatWD repeat domain 12 (WDR12) drove malignant behavior of GBM, whose expression may present a neoteric independent prognostic biomarker in GBM.
TcpC is a virulence factor of uropathogenic E. coli (UPEC). It was found that TIR domain of TcpC impedes TLR signaling by direct association with MyD88. It has been a long-standing question whether ...bacterial pathogens have evolved a mechanism to manipulate MyD88 degradation by ubiquitin-proteasome pathway. Here, we show that TcpC is a MyD88-targeted E3 ubiquitin ligase. Kidney macrophages from mice with pyelonephritis induced by TcpC-secreting UPEC showed significantly decreased MyD88 protein levels. Recombinant TcpC (rTcpC) dose-dependently inhibited protein but not mRNA levels of MyD88 in macrophages. Moreover, rTcpC significantly promoted MyD88 ubiquitination and accumulation in proteasomes in macrophages. Cys12 and Trp106 in TcpC are crucial amino acids in maintaining its E3 activity. Therefore, TcpC blocks TLR signaling pathway by degradation of MyD88 through ubiquitin-proteasome system. Our findings provide not only a novel biochemical mechanism underlying TcpC-medicated immune evasion, but also the first example that bacterial pathogens inhibit MyD88-mediated signaling pathway by virulence factors that function as E3 ubiquitin ligase.
Objective
This study aimed to assess systematically the overall diagnostic value of urinary monocyte chemoattractant protein-1 (uMCP-1) in systemic lupus erythematosus (SLE) patients with active ...lupus nephritis (LN).
Methods
Articles from PubMed, Web of Science, EMBASE and Cochrane Library were retrieved up to 5 November 2019. Study quality was evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2 tool, and statistical analyses were performed.
Results
A total of seven original studies with 521 participants were included in this meta-analysis. The summary estimates were: sensitivity 0.89 (95% confidence interval (CI) 0.86–0.93), specificity 0.63 (95% CI 0.55–0.69), positive likelihood ratio 2.16 (95% CI 1.66–2.80), negative likelihood ratio 0.15 (95% CI 0.08–0.30), diagnostic odds ratio 19.40 (95% CI 7.24–51.96) and area under the curve 0.9042.
Conclusion
As a non-invasive biomarker, uMCP-1 has high diagnostic accuracy for active LN.
Triple-negative breast cancer (TNBC) is characterized by the loss of expression of several biomarkers, which limits treatment strategies for the disease. In recent years, immunotherapy has shown ...promising results in the treatment of various tumors. Emerging evidence demonstrated that TNBC is an immune-activated cancer, suggesting that immunotherapy could be a feasible treatment option for TNBC. Cytokine-induced killer (CIK) cell therapy is considered as a potential treatment for cancer treatment. However, it is still not approved as a standard treatment in the clinical setting. Our previous study demonstrated that focal adhesion kinase (FAK) plays important role in regulating the sensitivity of TNBC cells to CIK cells. In this study, we further verify the role of FAK in regulating the immune response in vivo. Our in vitro study indicated that knockdown of FAK in TNBC cells or treat with the FAK inhibitor followed by co-culture with CIK cells induced more cell death than CIK cells treatment only. RNA-seq analysis indicated that suppression of FAK could affect several immune-related gene expressions in TNBC cells that affects the immune response in the tumor microenvironment of TNBC cells. The combination of FAK inhibitor and CIK cells significantly suppressed tumor growth than the treatment of FAK inhibitor or CIK cells alone in vivo. Our findings provide new insights into the cytotoxic effect of CIK cell therapy in TNBC treatment and indicate that the combination of CIK cell therapy with FAK inhibitors may be an alternative therapeutic strategy for patients with TNBC.
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Although lipopolysaccharides (LPS) have been used to establish animal models of memory loss akin to what is observed in Alzheimer's disease (AD), the exact mechanisms involved have not been ...substantiated. In this study, we established an animal model of learning and memory impairment induced by LPS and explored the biological processes and pathways involved. Mice were continuously intraperitoneally injected with LPS for 7 days. Learning- and memory-related behavioral performance and the pathological processes involved were assessed using the Morris water maze test and immunostaining, respectively. We detected comprehensive expression of C1q, C3, microglia, and their regulatory cytokines in the hippocampus. After 7 days of LPS administration, we were able to observe LPS-induced learning and memory impairment in the mice, which was attributed to neural impairment and synapse loss in the hippocampus. We elucidated that the immune system was activated, with the classical complement pathway and microglial phagocytosis being involved in the synapse loss. This study demonstrates that an LPS-injected mouse can serve as an early memory impairment model for studies on anti-AD drugs.
To explore the relationship between genetic polymorphisms of metabolic enzymes such as CYP1A1, CYP2D6, GSTM1, GSTT1, and GSTP1 and idiopathic male infertility. By observing the efficacy of ...antioxidants in the treatment of idiopathic male infertility, the effect of metabolic enzyme gene polymorphisms on antioxidant therapy in patients with idiopathic male infertility was prospectively studied. This case-control study included 310 men with idiopathic infertility and 170 healthy controls. The cytochrome P450 1A1 (CYP1A1), cytochrome P450 2D6 (CYP2D6), glutathione S-transferase M1 (GSTM1), glutathione S-transferase T1 (GSTT1), and glutathione S-transferase P1 (GSTP1) genotypes in peripheral blood samples were analyzed by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP). The idiopathic male infertility group was treated with vitamin C, vitamin E, and coenzyme Q10 for 3 months and followed up for 6 months. GSTM1(−), GSTT1(−), and GSTM1/T1(−/−) in the idiopathic male infertility groups were more common than those in the control group. The sperm concentration, motility, viability, mitochondrial membrane potential (MMP), and seminal plasma total antioxidant capacity (T-AOC) level in patients with GSTM1(−), GSTT1(−), and GSTM1/T1(−/−) were lower than those in wild-type carriers, and the sperm DNA fragmentation index (DFI), 8-hydroxy-2'-deoxyguanosine (8-OH-dG), and malondialdehyde (MDA) and nitric oxide (NO) levels were higher. Therefore, oxidative damage may play an important role in the occurrence and development of idiopathic male infertility, but antioxidant therapy is not effective in male infertility patients with GSTM1 and GSTT1 gene deletions.
Composite graphite felt (GF) electrodes modified by using a carbon network are fabricated for vanadium redox flow batteries (VRFBs). The electrodes are derived through the in situ polymerization of ...p‐phenylenediamine and phytic acid on GF fibers, followed by high‐temperature calcinations performed in an inert atmosphere. The composite electrodes exhibited higher electrocatalytic activities for the VO2+/VO2+ and V2+/V3+ redox species compared with the original GF electrode. The peak potential was reduced by 357 mV, which could be attributed to the increased number of active sites and diffusion pathways; the energy efficiency of the composite electrode increased by 6 % (current density: 200 mA cm−2). Based on the above‐mentioned structural design, a battery containing the composite electrodes exhibited excellent cycling stability without any obvious efficiency decay after 1000 cycles, indicating its applicability for large‐scale VRFBs.
A carbon network structure: A carbon network (CN)‐modified graphite felt (GF) material is fabricated to enhance the catalytic kinetics of electrodes. The composite electrodes exhibit excellent cycling stability (1000 cycles) compared with the original unmodified GF electrode (100 cycles).
Abstract
Widespread soil acidification due to atmospheric acid deposition and agricultural fertilization may greatly accelerate soil carbonate dissolution and CO2 release. However, to date, few ...studies have addressed these processes. Here, we use meta-analysis and nationwide-survey datasets to investigate changes in soil inorganic carbon (SIC) stocks in China. We observe an overall decrease in SIC stocks in topsoil (0–30 cm) (11.33 g C m–2 yr–1) from the 1980s to the 2010s. Total SIC stocks have decreased by ∼8.99 ± 2.24% (1.37 ± 0.37 Pg C). The average SIC losses across China (0.046 Pg C yr–1) and in cropland (0.016 Pg C yr–1) account for ∼17.6%–24.0% of the terrestrial C sink and 57.1% of the soil organic carbon sink in cropland, respectively. Nitrogen deposition and climate change have profound influences on SIC cycling. We estimate that ∼19.12%–19.47% of SIC stocks will be further lost by 2100. The consumption of SIC may offset a large portion of global efforts aimed at ecosystem carbon sequestration, which emphasizes the importance of achieving a better understanding of the indirect coupling mechanisms of nitrogen and carbon cycling and of effective countermeasures to minimize SIC loss.
Significant loss of soil inorganic carbon forced by the input and transformation of anthropogenic reactive nitrogen at the continental scale offsets much of carbon sequestration in the terrestrial ecosystems.
Genetic studies have elucidated mechanisms that regulate aging; however, there has been little progress in identifying drugs that retard ageing.
is among the classical model organisms in ageing ...research. Methyl 3,4-dihydroxybenzoate (MDHB) can prolong the life-span of
, but the underlying molecular mechanisms are not yet fully understood. Here, we report that MDHB prolongs the life-span of
and delays age-associated declines of physiological processes. Besides, MDHB can lengthen the life-span of
(ad1113) mutations, revealing that MDHB does not work via caloric restriction (CR). Surprisingly, the life-span⁻extending activity of MDHB is completely abolished in
(e1370) mutations, which suggests that
is crucial for a MDHB-induced pro-longevity effect in
. Moreover, MDHB enhances the nuclear localization of
/
, and then modulates the expressions of genes that positively correlate with defenses against stress and longevity in
. Therefore, our results indicate that MDHB at least partially acts as a modulator of the
pathway to extend the lifespan of
, and MDHB might be a promising therapeutic agent for age-related diseases.
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