The long non-coding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1) has been recently shown to be dysregulated, which plays an important role in the progression of several cancers. However, the ...biological role and clinical significance of UCA1 in the carcinogenesis of hepatocellular carcinoma (HCC) remain unclear. Herein, we found that UCA1 was aberrantly upregulated in HCC tissues and associated with TNM stage, metastasis and postoperative survival. UCA1 depletion inhibited the growth and metastasis of HCC cell lines in vitro and in vivo. Furthermore, UCA1 could act as an endogenous sponge by directly binding to miR-216b and downregulation miR-216b expression. In addition, UCA1 could reverse the inhibitory effect of miR-216b on the growth and metastasis of HCC cells, which might be involved in the derepression of fibroblast growth factor receptor 1 (FGFR1) expression, a target gene of miR-216b, and the activation of ERK signaling pathway. Taken together, our data highlights the pivotal role of UCA1 in the tumorigenesis of HCC. Moreover, the present study elucidates a novel lncRNA-miRNA-mRNA regulatory network that is UCA1-miR-216b-FGFR1-ERK signaling pathway in HCC, which may help to lead a better understanding the pathogenesis of HCC and probe the feasibility of lncRNA-directed diagnosis and therapy for this deadly disease.
By employing CuOAc as the catalyst, we realize a four-component reaction of 1,3-enynes, diselenides, DABCO·(SO2)2, and cycloketone oxime esters, providing facile access to diverse ...cyanoalkylsulfonylated allenyl selenides in moderate to good yields. This reaction features high functional group tolerance and a broad substrate scope, enabling the regioselective, sequential formation of C–SO2 and C–Se bonds under mild reaction conditions. Moreover, the utility of this methodology is further illustrated through the late-stage functionalization of drug-based molecules.
Streptococcus pneumoniae (S. pneumoniae) is a major cause of bacterial meningitis, septicemia and pneumonia in children. Inappropriate choice of antibiotic can have important adverse consequences for ...both the individual and the community. Here, we focused on penicillin/cefotaxime non-susceptibility of S. pneumoniae and evaluated appropriateness of targeted antibiotic therapy for children with IPD (invasive pneumococcal diseases) in China. A multicenter retrospective study was conducted in 14 hospitals from 13 provinces in China. Antibiotics prescription, clinical features and resistance patterns of IPD cases from January 2012 to December 2017 were collected. Appropriateness of targeted antibiotics therapy was assessed. 806 IPD cases were collected. The non-susceptibility rates of S. pneumoniae to penicillin and cefotaxime were 40.9% and 20.7% respectively in 492 non-meningitis cases, whereas those were 73.2% and 43.0% respectively in 314 meningitis cases. Carbapenems were used in 21.3% of non-meningitis cases and 42.0% of meningitis cases for targeted therapy. For 390 non-meningitis cases with isolates susceptible to cefotaxime, vancomycin and linezolid were used in 17.9% and 8.7% of cases respectively for targeted therapy. For 179 meningitis cases with isolates susceptible to cefotaxime, vancomycin and linezolid were prescribed in 55.3% and 15.6% of cases respectively. Overall, inappropriate targeted therapies were identified in 361 (44.8%) of 806 IPD cases, including 232 (28.8%) cases with inappropriate use of carbapenems, 169 (21.0%) cases with inappropriate use of vancomycin and 62 (7.7%) cases with inappropriate use of linezolid. Antibiotic regimens for IPD definite therapy were often excessive with extensive prescription of carbapenems, vancomycin or linezolid in China. Antimicrobial stewardship programs should be implemented to improve antimicrobial use.
Abstract
Background
Owing to the heterogeneity of microbiota among individuals and populations, only
Fusobacterium nucleatum
and
Bacteroides fragilis
have been reported to be enriched in colorectal ...cancer (CRC) in multiple studies. Thus, the discovery of additional bacteria contributing to CRC development in various populations can be expected. We aimed to identify bacteria associated with the progression of colorectal adenoma to carcinoma and determine the contribution of these bacteria to malignant transformation in patients of Han Chinese origin.
Methods
Microbiota composition was determined through 16S rRNA V3–V4 amplicon sequencing of autologous adenocarcinomas, adenomatous polyps, and non-neoplastic colon tissue samples (referred to as “tri-part samples”) in patients with CRC. Enriched taxa in adenocarcinoma tissues were identified through pairwise comparison. The abundance of candidate bacteria was quantified through genomic quantitative polymerase chain reaction (qPCR) in tissue samples from 116 patients. Associations of candidate bacteria with clinicopathological features and genomic and genetic alterations were evaluated through odds ratio tests. Additionally, the effects of candidate bacteria on CRC cell proliferation, migration, and invasion were evaluated through the co-culture of CRC cells with bacterial cells or with conditioned media from bacteria.
Results
Prevotella intermedia
was overrepresented in adenocarcinomas compared with paired adenomatous polyps. Furthermore, co-abundance of
P. intermedia
and
F. nucleatum
was observed in tumor tissues. More notably, the coexistence of these two bacteria in adenocarcinomas was associated with lymph node involvement and distant metastasis. These two bacteria also exerted additive effects on the enhancement of the migration and invasion abilities of CRC cells. Finally, conditioned media from
P. intermedia
promoted the migration and invasion of CRC cells.
Conclusion
This report is the first to demonstrate that
P. intermedia
is enriched in colorectal adenocarcinoma tissues and enhances the migration and invasion abilities of CRC cells. Moreover,
P. intermedia
and
F. nucleatum
exert additive effects on the malignant transformation of colorectal adenomas into carcinomas. These findings can be used to identify patients at a high risk of malignant transformation of colorectal adenomas or metastasis of CRC, and they can accordingly be provided optimal clinical management.
The chiral tridentate spiro P‐N‐S ligands (SpiroSAP) were developed, and their iridium complexes were prepared. Introduction of a 1,3‐dithiane moiety into the ligand resulted in a highly efficient ...chiral iridium catalyst for asymmetric hydrogenation of β‐alkyl‐β‐ketoesters, producing chiral β‐alkyl‐β‐hydroxyesters with excellent enantioselectivities (95–99.9 % ee) and turnover numbers of up to 355 000.
Bulkyness is the key: New chiral tridentate spiro P‐N‐S ligands (SpiroSAP) bearing a conformationally constrained 1,3‐dithiane moiety were developed. Their iridium catalysts showed excellent enantioselectivities and activity (TON up to 355 000) for asymmetric hydrogenation of β‐alkyl‐β‐ketoesters.
Abstract
β-Catenin has been implicated in major depressive disorder (MDD), which is associated with synaptic plasticity and dendritic arborization. MicroRNAs (miRNA) are small noncoding RNAs ...containing about 22 nucleotides and involved in a variety of physiological and pathophysiological process, but their roles in MDD remain largely unknown. Here, we investigated the expression and function of miRNAs in the mouse model of chronic social defeat stress (CSDS). The regulation of β-catenin by selected miRNA was validated by silico prediction, target gene luciferase reporter assay, and transfection experiment in neurons. We demonstrated that the levels of miR-214-3p, which targets β-catenin transcripts were significantly increased in the medial prefrontal cortex (mPFC) of CSDS mice. Antagomir-214-3p, a neutralizing inhibitor of miR-214-3p, increased the levels of β-catenin and reversed the depressive-like behavior in CSDS mice. Meanwhile, antagomir-214-3p increased the amplitude of miniature excitatory postsynaptic current (mEPSC) and the number of dendritic spines in mPFC of CSDS mice, which may be related to the elevated expression of cldn1. Furthermore, intranasal administered antagomir-214-3p also significantly increased the level of β-catenin and reversed the depressive-like behaviors in CSDS mice. These results may represent a new therapeutic target for MDD.
This work is geared toward a real-world manufacturing planning (MP) task, whose two objectives are to maximize the order fulfillment rate and minimize the total cost. More important, the requirements ...and constraints in real manufacturing make the MP task very challenging in several aspects. For example, the MP needs to cover many production components of multiple plants over a 30-day horizon, which means that it involves a large number of decision variables. Furthermore, the MP task's two objectives have extremely different magnitudes, and some constraints are difficult to handle. Facing these uncompromising practical requirements, we introduce an interactive multiobjective optimization-based MP system in this article. It can help the decision maker reach a satisfactory tradeoff between the two objectives without consuming massive calculations. In the MP system, the submitted MP task is modeled as a multiobjective integer programming (MOIP) problem. Then, the MOIP problem is addressed via a two-stage multiobjective optimization algorithm (TSMOA). To alleviate the heavy calculation burden, TSMOA transforms the optimization of the MOIP problem into the optimization of a series of single-objective problems (SOPs). Meanwhile, a new SOP solving strategy is used in the MP system to further reduce the computational cost. It utilizes two sequential easier SOPs as the approximator of the original complex SOP for optimization. As part of the MP system, TSMOA and the SOP solving strategy are demonstrated to be efficient in real-world MP applications. In addition, the effectiveness of TSMOA is also validated on benchmark problems. The results indicate that TSMOA as well as the MP system are promising.
Kawasaki disease (KD) is a vasculitic illness of childhood associated with coronary artery dilatation, coronary artery aneurysm, arrhythmia, sudden death, and other serious cardiovascular diseases. ...Up to date, the etiology of KD remains unclear; however, epidemiological characteristics indicate that it may be related to as-yet-undefined pathogen infection.
A 19-month-old boy had a fever of unknown origin at 38°C for 9 days without rash, runny nose and cough.
The boy was diagnosed with incomplete KD (IKD) coincident with influenza A (H1N1) pdm09 virus.
He was received treatments including human immunoglobulin (2 g/kg), aspirin (30∼50 mg/kg.d), and dipyridamole (3∼5 mg/kg.d).
After 24 hours of human immunoglobulin infusion, his body temperature returned normal. After hospitalization for 6 days, his symptoms disappeared and discharged from the hospital.
More attention should be paid to the correlation between KD and pathogen infection, especially the new influenza virus H1N1. The potential mechanism underlying viral infection-mediated KD is worthy of further investigation, which may provide scientific evidence for the pathogenesis of KD.
This research aimed to explore the association between the RIG-I-like receptor (RIG-I and MDA5 encoded by DDX58 and IFIH1, respectively) pathways and the risk or severity of hand, foot, and mouth ...disease caused by enterovirus 71 (EV71-HFMD). In this context, we explored the influence of gene methylation and polymorphism on EV71-HFMD.
60 healthy controls and 120 EV71-HFMD patients, including 60 mild EV71-HFMD and 60 severe EV71-HFMD patients, were enrolled. First, MiSeq was performed to explore the methylation of CpG islands in the DDX58 and IFIH1 promoter regions. Then, DDX58 and IFIH1 expression were detected in PBMCs using RT-qPCR. Finally, imLDR was used to detect DDX58 and IFIH1 single-nucleotide polymorphism (SNP) genotypes. Severe EV71-HFMD patients exhibited higher DDX58 promoter methylation levels than healthy controls and mild EV71-HFMD patients. DDX58 promoter methylation was significantly associated with severe HFMD, sex, vomiting, high fever, neutrophil abundance, and lymphocyte abundance. DDX58 expression levels were significantly lower in mild patients than in healthy controls and lower in severe patients than in mild patients. Binary logistic regression analysis revealed statistically significant differences in the genotype frequencies of DDX58 rs3739674 between the mild and severe groups. GeneMANIA revealed that 19 proteins displayed correlations with DDX58, including DHX58, HERC5, MAVS, RAI14, WRNIP1 and ISG15, and 19 proteins displayed correlations with IFIH1, including TKFC, IDE, MAVS, DHX58, NLRC5, TSPAN6, USP3 and DDX58.
DDX58 expression and promoter methylation were associated with EV71 infection progression, especially in severe EV71-HFMD patients. The effect of DDX58 in EV71-HFMD is worth further attention.
Stomata in leaves regulate gas exchange between the plant and its atmosphere. Various environmental stimuli elicit abscisic acid (ABA); ABA leads to phosphoactivation of slow anion channel 1 (SLAC1); ...SLAC1 activity reduces turgor pressure in aperture-defining guard cells; and stomatal closure ensues. We used electrophysiology for functional characterizations of
SLAC1 (
SLAC1) and cryoelectron microscopy (cryo-EM) for structural analysis of
SLAC1 (
SLAC1), at 2.97-Å resolution. We identified 14 phosphorylation sites in
SLAC1 and showed nearly 330-fold channel-activity enhancement with 4 to 6 of these phosphorylated. Seven SLAC1-conserved arginines are poised in
SLAC1 for regulatory interaction with the N-terminal extension. This
SLAC1 structure has its pores closed, in a basal state, spring loaded by phenylalanyl residues in high-energy conformations. SLAC1 phosphorylation fine-tunes an equilibrium between basal and activated SLAC1 trimers, thereby controlling the degree of stomatal opening.
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