Objective
This study was undertaken to uncover the pathophysiologic role of discoidin domain receptor 2 (DDR‐2), a putative fibrillar collagen receptor, in inflammation promotion and joint ...destruction in rheumatoid arthritis (RA).
Methods
In synovial tissue from patients with RA and from mice with collagen antibody–induced arthritis (CAIA) (using Ddr2−/− and DBA/1 mice), gene and protein expression levels of DDR‐2, interleukin‐15 (IL‐15), and Dkk‐1 were measured by quantitative reverse transcription–polymerase chain reaction, Western blotting, and immunohistochemistry. Gene knockdown of DDR2 in human RA fibroblast‐like synoviocytes (FLS) was conducted via small interfering RNA. Interaction between the long noncoding RNA H19 and microRNA 103a (miR‐103a) was assessed in RA FLS using RNA pulldown assays. Cellular localization of H19 was examined using fluorescence in situ hybridization assays. Chromatin immunoprecipitation and dual luciferase reporter assays were applied to verify H19 transcriptional and posttranscriptional regulation by miR‐103a.
Results
DDR2 messenger RNA (mRNA) expression was significantly associated with the levels of IL‐15 and Dkk‐1 mRNA in the synovial tissue of RA patients (r2 = 0.2022–0.3293, all P < 0.05; n = 33) and with the serum levels of IL‐15 and Dkk‐1 in mice with CAIA (P < 0.05). In human RA FLS, activated DDR‐2 induced the expression of H19 through c‐Myc. Moreover, H19 directly interacted with and promoted the degradation of miR‐103a.
Conclusion
These results indicate a novel role for activated DDR‐2 in RA FLS, showing that DDR‐2 is responsible for regulating the expression of IL‐15 and Dkk‐1 in RA FLS and is involved in the promotion of inflammation and joint destruction during pathophysiologic development of RA. Moreover, DDR‐2 inhibition, acting through the H19–miR‐103a axis, leads to reductions in the inflammatory reaction and severity of joint destruction in mice with CAIA, suggesting that inhibition of DDR‐2 may be a potential therapeutic strategy for RA.
Stroke is the leading cause of death and long-term disability worldwide, and cognitive impairment and dementia are major complications of ischemic stroke. Cystatin C (CysC) has been found to be a ...neuroprotective factor in animal studies. However, the relationship between CysC levels and cognitive dysfunction in previous studies has revealed different results. This prospective observational study investigated the correlation between serum CysC levels and post-stroke cognitive dysfunction at 3 months. Data from 638 patients were obtained from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). Cognitive dysfunction was assessed using the Mini-Mental State Examination (MMSE) at 3 months after stroke. According to the MMSE score, 308 patients (52.9%) had post-stroke cognitive dysfunction. After adjusting for potential confounding factors, the odds ratio (95% CI) of post-stroke cognitive dysfunction for the highest quartile of serum CysC levels was 0.54 (0.30-0.98), compared with the lowest quartile. The correlation between serum CysC and cognitive dysfunction was modified by renal function status. We observed a negative linear dose-response correlation between CysC and cognitive dysfunction in patients with normal renal function (Plinearity = 0.044), but not in those with abnormal renal function. Elevated serum CysC levels were correlated with a low risk of 3-month cognitive dysfunction in patients with acute ischemic stroke, especially in those with normal renal function. The current results suggest that CysC is a protective factor for post-stroke cognitive dysfunction, and could be used to treat post-stroke cognitive dysfunction. The CATIS study was approved by the Institutional Review Boards at Soochow University from China (approval No. 2012-02) on December 30, 2012, and was registered at ClinicalTrials.gov (identifier No. NCT01840072) on April 25, 2013.
Abstract Quantum heat engines and refrigerators are open quantum systems, whose dynamics can be well understood using a non-Hermitian formalism. A prominent feature of non-Hermiticity is the ...existence of exceptional points (EPs), which has no counterpart in closed quantum systems. It has been shown in classical systems that dynamical encirclement in the vicinity of an EP, whether the loop includes the EP or not, could lead to chiral mode conversion. Here, we show that this is valid also for quantum systems when dynamical encircling is performed in the vicinity of their Liouvillian EPs (LEPs), which include the effects of quantum jumps and associated noise—an important quantum feature not present in previous works. We demonstrate, using a Paul-trapped ultracold ion, the first chiral quantum heating and refrigeration by dynamically encircling a closed loop in the vicinity of an LEP. We witness the cycling direction to be associated with the chirality and heat release (absorption) of the quantum heat engine (quantum refrigerator). Our experiments have revealed that not only the adiabaticity breakdown but also the Landau–Zener–Stückelberg process play an essential role during dynamic encircling, resulting in chiral thermodynamic cycles. Our observations contribute to further understanding of chiral and topological features in non-Hermitian systems and pave a way to exploring the relation between chirality and quantum thermodynamics.
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► We designed and synthesized a highly luminescent Eu-containing polymer precursor. ► The precursor shows a remarkable quantum yield (40.1%) and a long lifetime (590
μs). ► The ...excellent luminescence of the precursor made it an excellent luminescent monomer.
A polymerizable ligand, 5-acrylamido-1,10-phenanthroline (
L), was synthesized. Its Eu(III) complex with 2-thenoyltrifluoroacetone (HTTA) was prepared and characterized by elemental analysis, IR, MS, and
1H NMR spectra. The photophysical properties of the complex were studied in detail by using UV, luminescence spectra, luminescence lifetime and quantum yield. The complex shows a remarkable luminescence quantum yield at room temperature (40.1%) upon ligand excitation and a long
5D
0 lifetime (590
μs), which makes it not only a promising light-conversion molecular device but also an excellent luminescent polymer precursor.
The prevalence of multiple sclerosis (MS) in China is low, although it has been increasing recently. Owing to the paucity of data on immunotherapy acceptance in the Chinese population, we conducted ...this study to analyze factors affecting the acceptance of immunotherapy and selection of disease-modifying therapies (DMTs) based on personal and clinical data of patients with MS.
In this study, data were obtained from the
, which was the first national survey of patients with MS in China. There were 1,212 patients with MS from 31 provinces who were treated at 49 Chinese hospitals over a 4-month period from May 2018 to August 2018, and the patients were asked to complete online questionnaires to assess their understanding of the disease.
In general, highly educated patients with frequent relapses were more willing to receive treatment regardless of DMTs or other immunotherapy, and patients with more understanding of the disease opted to be treated. Younger patient population, patients with severe disease course, and those with more symptoms were likely to choose the treatment. Moreover, a higher proportion of women chose to be treated with DMTs than with other immunotherapies.
Education status and patient awareness of the disease impact the treatment acceptance in Chinese patients with MS. Therefore, we call for improving the awareness of MS disease and social security to help patients to improve their quality of life.
Chronic renal allograft dysfunction (CRAD) is the most common cause of graft failure following renal transplantation. However, the underlying mechanisms remain to be fully elucidated. ...Immunosuppressants and hyperlipidemia are associated with renal fibrosis following long-term use. The present study aimed to determine the effects of tacrolimus (FK506) and lipid metabolism disorder on CRAD. In vitro and in vivo models were used for this investigation. Cells of the mouse proximal renal tubular epithelial cell strain, NRK-52E, were cultured either with oxidized low-density lipoprotein (ox-LDL), FK506, ox-LDL combined with FK506, or vehicle, respectively. Changes in cell morphology and changes in the levels of lectin-like ox-LDL receptor-1 (LOX-1), reactive oxygen species (ROS), hydrogen peroxide and fibrosis-associated genes were evaluated at 24, 48 and 72 h. In separate experiment, total of 60 Sprague-Dawley rats were divided randomly into four groups, which included a high-fat group, FK506 group, high-fat combined with FK506 group, and control group. After 2, 4 and 8 weeks, the serum lipid levels, the levels of ox-LDL, ROS, and the expression levels of transforming growth factor (TGF)-β1 and connective tissue growth factor were determined. The in vitro and in vivo models revealed that lipid metabolism disorder and FK506 caused oxidative stress and a fibrogenic response. In addition, decreased levels of LOX-1 markedly reduced the levels of TGF-β1 in the in vitro model. Taken together, FK506 and dyslipidemia were found to be associated with CRAD following transplantation.
Background: Disease-modifying therapy is the standard treatment for patients with multiple sclerosis (MS) in remission. The primary objective of the current analysis was to assess the efficacy and ...safety of two teriflunomide doses (7 mg and 14 mg) in the subgroup of Chinese patients with relapsing MS included in the TOWER study.
Methods: TOWER was a multicenter, multinational, randomized, double-blind, parallel-group (three groups), placebo-controlled study. This subgroup analysis includes 148 Chinese patients randomized to receive either teriflunomide 7 mg (n = 51), teriflunomide 14 mg (n = 43), or placebo (n = 54).
Results: Of the 148 patients in the intent-to-treat population, adjusted annualized relapse rates were 0.63 (95% confidence interval CI: 0.44, 0.92) in the placebo group, 0.48 (95% CI: 0.33, 0.70) in the teriflunomide 7 mg group, and 0.18 (95% CI: 0.09, 0.36) in the teriflunomide 14 mg group; this corresponded to a significant relative risk reduction in the teriflunomide 14 mg group versus placebo (−71.2%, P = 0.0012). Teriflunomide 14 mg also tended to reduce 12-week confirmed disability worsening by 68.1% compared with placebo (hazard ratio: 0.319, P = 0.1194). There were no differences across all treatment groups in the proportion of patients with treatment-emergent adverse events (TEAEs; 72.2% in the placebo group, 74.5% in the teriflunomide 7 mg group, and 69.8% in the teriflunomide 14 mg group); corresponding proportions for serious adverse events were 11.1%, 3.9%, and 11.6%, respectively. The most frequently reported TEAEs with teriflunomide versus placebo were neutropenia, increased alanine aminotransferase, and hair thinning.
Conclusions: Teriflunomide was as effective and safe in the Chinese subpopulation as it was in the overall population of patients in the TOWER trial. Teriflunomide has the potential to meet unmet medical needs for MS patients in China.
Trial Registration: ClinicalTrials.gov, NCT00751881; https://clinicaltrials.gov/ct2/show/NCT00751881?term=NCT00751881&rank=1
A multi-functional ligand, 5-acryloxyethoxymethyl-8-hydroxyquinoline (Hamq), was synthesized, which contained a polymerizable C=C double bond for the copolymerization with other vinyl monomers and ...acted as photon antenna able to transfer energy to Eu
3+ ions effectively. The triplet state energy of Hamq was determined to be 22,370
cm
−1 via the phosphorescence spectra of Hamq and its gadolinium complex. The title complex monomer Eu(tta)
2(amq) was prepared by coordination reaction of Hamq with europium isopropoxide and 2-thenoyltrifluoroacetone (Htta) in dry organic solvents under argon atmosphere and characterized by elemental analysis and IR spectrum. The photophysical properties of the complex were studied in detail with UV–vis, luminescence spectra, luminescence lifetime and quantum yield. The complex exhibited nearly monochromatic red emission at 612
nm, a remarkable luminescence quantum yield at room temperature (30.6%) upon ligand excitation and a long
5D
0 lifetime (389
μs), which indicated that the ligand Hamq could sensitize the luminescence of Eu(III) ion efficiently in Eu(tta)
2(amq), resulting in a strong luminescence of its copolymer polyMMA-
co-Eu(TTA)
2(amq) under UV excitation. The excellent luminescence properties of the complex made it not only a promising light-conversion molecular device but also an excellent luminescent monomer.
►iWe designed and synthesized a highly luminescent Eu-complex monomer. ► Quantum yield and lifetime of the complex are 30.6% and 389
μs, respectively. ► Excellent luminescence of the complex made it an excellent luminescent monomer.
NF-κB transcription factors regulate the expression of tissue factor (TF), a principal initiator of the coagulation cascade. Dominant among them is the p50/p65 heterodimer. Here we report that ...Andrographolide (Andro; a p50 inhibitor) and genetic deletion of p50 attenuated TF activity in stimulated endothelial cells and monocytes/macrophages. Results of the electrophoretic mobility “supershift” assay and chromatin immunoprecipitation demonstrated the direct interaction of the p50/p65 heterodimer with the NF-κB site of the human TF promoter. Andro-treated and p50 null mice both exhibited blunted TF expression and reduced venous thrombosis, which were recapitulated by an anti-murine TF antibody in vivo. Our findings thus indicate that regulation of TF by NF-κB transcription factor p50 is essential for the pathogenesis of deep vein thrombosis and suggest that specific inhibitors of p50, such as Andro, may be therapeutically valuable for preventing and perhaps treating venous thrombosis.
Aegilops tauschii Coss. is a malignant weed in wheat fields in China, its herbicide resistance has been threatening crop production. This study identified one mesosulfuron-methyl-resistant(R) ...population, JJMHN2018-05 (R), without target resistance mutations. To fully understand the resistance mechanism, non-target site resistance was investigated by using transcriptome sequencing combined with a reference genome. Results showed that the cytochrome P450 monooxygenase (P450) inhibitor malathion significantly increased the mesosulfuron-methyl sensitivity in R plants, and greater herbicide-induced glutathione S-transferase (GST) activity was also confirmed. Liquid chromatography with tandem mass spectrometry analysis further supported the enhanced mesosulfuron-methyl metabolism in R plants. Gene expression data analysis and qRT-PCR validation indicated that eight P450s, six GSTs, two glycosyltransferases (GTs), four peroxidases, and one aldo-keto reductase (AKRs) stably upregulated in R plants. This research demonstrates that the P450s and GSTs involved in enhanced mesosulfuron-methyl metabolism contribute to mesosulfuron-methyl resistance in A. tauschii and identifies potential contributors from metabolic enzyme families.
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