32,715 research outputs found

    Table4_TNIK regulation of interferon signaling and endothelial cell response to virus infection.docx

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    BackgroundTraf2 and Nck-interacting kinase (TNIK) is known for its regulatory role in various processes within cancer cells. However, its role within endothelial cells (ECs) has remained relatively unexplored.MethodsLeveraging RNA-seq data and Ingenuity Pathway Analysis (IPA), we probed the potential impact of TNIK depletion on ECs.ResultsExamination of RNA-seq data uncovered more than 450 Differentially Expressed Genes (DEGs) in TNIK-depleted ECs, displaying a fold change exceeding 2 with a false discovery rate (FDR) below 0.05. IPA analysis unveiled that TNIK depletion leads to the inhibition of the interferon (IFN) pathway [-log (p-value) >11], downregulation of IFN-related genes, and inhibition of Hypercytokinemia/Hyperchemokinemia [-log (p-value) >8]. The validation process encompassed qRT-PCR to evaluate mRNA expression of crucial IFN-related genes, immunoblotting to gauge STAT1 and STAT2 protein levels, and ELISA for the quantification of IFN and cytokine secretion in siTNIK-depleted ECs. These assessments consistently revealed substantial reductions upon TNIK depletion. When transducing HUVECs with replication incompetent E1-E4 deleted adenovirus expressing green fluorescent protein (Ad-GFP), it was demonstrated that TNIK depletion did not affect the uptake of Ad-GFP. Nonetheless, TNIK depletion induced cytopathic effects (CPE) in ECs transduced with wild-type human adenovirus serotype 5 (Ad-WT).SummaryOur findings suggest that TNIK plays a crucial role in regulating the EC response to virus infections through modulation of the IFN pathway.</p

    Oral anti-coagulants use in Chinese hospitalized patients with atrial fibrillation.

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    BackgroundOral anti-coagulants (OAC) are the intervention for the prevention of stroke, which consistently improve clinical outcomes and survival among patients with atrial fibrillation (AF). The main purpose of this study is to identify problems in OAC utilization among hospitalized patients with AF in China.MethodsUsing data from the Improving Care for Cardiovascular Disease in China-Atrial Fibrillation (CCC-AF) registry, guideline-recommended OAC use in eligible patients was assessed.ResultsA total of 52,530 patients with non-valvular AF were enrolled from February 2015 to December 2019, of whom 38,203 were at a high risk of stroke, 9717 were at a moderate risk, and 4610 were at a low risk. On admission, only 20.0% (6075/30,420) of patients with a diagnosed AF and a high risk of stroke were taking OAC. The use of pre-hospital OAC on admission was associated with a lower risk of new-onset ischemic stroke/transient ischemic attack among the diagnosed AF population (adjusted odds ratio: 0.54, 95% confidence interval: 0.43-0.68; P  ConclusionsIn hospitals participated in the CCC-AF project, >70% of AF patients were at a high risk of stroke. Although poor performance on guideline-recommended OAC use was found in this study, over time the CCC-AF project has made progress in stroke prevention in the Chinese AF population.Registration:ClinicalTrials.gov, NCT02309398

    The IRF1/GBP5 axis promotes osteoarthritis progression by activating chondrocyte pyroptosis

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    Background: Osteoarthritis (OA) is a chronic degenerative joint disease that primarily affects middle-aged and elderly individuals. The decline in chondrocyte function plays a crucial role in the development of OA. Inflammasome-mediated chondrocyte pyroptosis is implicated in matrix degradation and cartilage degeneration in OA patients. Guanylate binding protein 5 (GBP5), a member of the GTPase family induced by Interferon-γ (IFN-γ), significantly influences cellular inflammatory responses, including intracellular inflammasome activation and cytokine release. However, the role of GBP5 in chondrocyte pyroptosis and OA progression remains unclear. Methods: In this study, we used tumor necrosis factor-α (TNF-α) to induce inflammation and created an OA mouse model with surgically-induced destabilization of the medial meniscus (DMM). We isolated and cultured primary chondrocytes from the knee joints of suckling C57 mice. TNF-α-stimulated primary chondrocytes served as an in vitro model for OA and underwent RNA sequencing. Chondrocytes were transfected with GBP5-overexpression plasmids and small interfering RNA and were subsequently treated with TNF-α. We assessed the expression of cartilage matrix components (COL2A1 and aggrecan), catabolic factors (MMP9 and MMP13), and NLRP3 inflammasome pathway genes (NLRP3, Caspase1, GSDMD, Pro-IL-1β, and Pro-Caspase1) using RT-qPCR and Western blotting. We analyzed the expression of GBP5, NLRP3, and Caspase1 in the cartilage of DMM-induced post-traumatic OA mice and human OA patients. Immunohistochemistry (IHC) was used to detect the expression of GBP5, NLRP3 and GSDMD in cartilage specimens from OA patients and mouse DMM models. Chondrocyte pyroptosis was assessed using flow cytometry, and the levels of interleukin-1β (IL-1β) and interleukin-18 (IL-18) were measured with ELISA. We conducted double luciferase reporter gene and chromatin immunoprecipitation (ChIP) assays to confirm the relationship between IRF1 and GBP5. Results: GBP5 expression increased in TNF-α-induced chondrocytes, as revealed by RNA sequencing. GBP5 inhibited COL2A1 and aggrecan expression while promoting the expression of MMP9, MMP13, NLRP3, Caspase1, GSDMD, Pro-IL-1β, and Pro-Caspase1. GBP5 expression also increased in the cartilage of DMM-induced post-traumatic OA mice and human OA patients. Knockout of GBP5 reduced chondrocyte injury in OA mice. GBP5 promoted chondrocyte pyroptosis and the production of IL-1β and IL-18. Additionally, we found that IRF1 bound to the promoter region of GBP5, enhancing its expression. After co-transfected with ad-IRF1 and siGBP5, the expression of pyroptosis-related genes was significantly decreased compared with ad-IRF1 group. Conclusions: The IRF1/GBP5 axis enhances extracellular matrix (ECM) degradation and promotes pyroptosis during OA development, through the NLRP3 inflammasome signaling pathway. The translational potential of this article: This study underscores the significance of the IRF1/GBP5 axis in NLRP3 inflammasome-mediated chondrocyte pyroptosis and osteoarthritic chondrocyte injury. Modulating IRF1 and GBP5 expression could serve as a novel therapeutic target for OA

    CEPC Technical Design Report -- Accelerator

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    International audienceThe Circular Electron Positron Collider (CEPC) is a large scientific project initiated and hosted by China, fostered through extensive collaboration with international partners. The complex comprises four accelerators: a 30 GeV Linac, a 1.1 GeV Damping Ring, a Booster capable of achieving energies up to 180 GeV, and a Collider operating at varying energy modes (Z, W, H, and ttbar). The Linac and Damping Ring are situated on the surface, while the Booster and Collider are housed in a 100 km circumference underground tunnel, strategically accommodating future expansion with provisions for a Super Proton Proton Collider (SPPC). The CEPC primarily serves as a Higgs factory. In its baseline design with synchrotron radiation (SR) power of 30 MW per beam, it can achieve a luminosity of 5e34 /cm^2/s^1, resulting in an integrated luminosity of 13 /ab for two interaction points over a decade, producing 2.6 million Higgs bosons. Increasing the SR power to 50 MW per beam expands the CEPC's capability to generate 4.3 million Higgs bosons, facilitating precise measurements of Higgs coupling at sub-percent levels, exceeding the precision expected from the HL-LHC by an order of magnitude. This Technical Design Report (TDR) follows the Preliminary Conceptual Design Report (Pre-CDR, 2015) and the Conceptual Design Report (CDR, 2018), comprehensively detailing the machine's layout and performance, physical design and analysis, technical systems design, R&D and prototyping efforts, and associated civil engineering aspects. Additionally, it includes a cost estimate and a preliminary construction timeline, establishing a framework for forthcoming engineering design phase and site selection procedures. Construction is anticipated to begin around 2027-2028, pending government approval, with an estimated duration of 8 years. The commencement of experiments could potentially initiate in the mid-2030s

    Investigating the nature of the K0∗(700)^*_0(700) state with π±\pi^\pmKS0^0_{\rm S} correlations at the LHC

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    International audienceThe first measurements of femtoscopic correlations with the particle pair combinations π±\pi^\pmKS0^0_{\rm S} in pp collisions at s=13\sqrt{s}=13 TeV at the Large Hadron Collider (LHC) are reported by the ALICE experiment. Using the femtoscopic approach, it is shown that it is possible to study the elusive K0∗(700)^*_0(700) particle that has been considered a tetraquark candidate for over forty years. Boson source parameters and final-state interaction parameters are extracted by fitting a model assuming a Gaussian source to the experimentally measured two-particle correlation functions. The final-state interaction is modeled through a resonant scattering amplitude, defined in terms of a mass and a coupling parameter, decaying into a π±\pi^\pmKS0^0_{\rm S} pair. The extracted mass and Breit-Wigner width, derived from the coupling parameter, of the final-state interaction are found to be consistent with previous measurements of the K0∗(700)^*_0(700). The small value and increasing behavior of the correlation strength with increasing source size support the hypothesis that the K0∗(700)^*_0(700) is a four-quark state, i.e. a tetraquark state. This latter trend is also confirmed via a simple geometric model that assumes a tetraquark structure of the K0∗(700)^*_0(700) resonance

    Droplet-Based Preparation of ZnO-nanostructure Array for Microfluidic Fluorescence Biodetection

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    Nanostructure-enhanced biodetection is widely used for early diagnosis and treatment, which plays an essential role in improving the cure rates of cancer patients. ZnO nanostructure-based fluorescence immunoassay has been demonstrated to enable effective and sensitive detection of cancer biomarkers for their excellent biocompatibility, high electrical point, and unique fluorescence enhancement properties. Further optimization of such fluorescence detection technology is still in demand to meet the requirements of highly sensitive, multiplex detection, and user-friendly devices. Droplet microfluidics is a promising platform for high-throughput analysis of biological assays, and they have been intensively used in analytical chemistry and synthesis of nanoparticles. Here, we propose a simple droplet chip, where a static droplet array was successfully obtained for in situ growth of ZnO nanostructures with varied diameters by changing the entire growth time and replenishment interval. This device provides a novel and alternative approach for patterned growth of ZnO nanostructures and understanding the growth condition of ZnO nanostructures in static droplet, which offers some guidance toward the design of multiple fluorescence amplification platforms potentially for biosensing. As a demonstration, we used the patterned grown ZnO nanostructures for multiple detection of cancer biomarkers, achieving a low limit of detection as low as 138 fg/mL in the human α-fetoprotein assay and 218 fg/mL in the carcinoembryonic antigen assay with a large dynamic range of 8 orders. These results suggest that such multifunctional microfluidic devices may be useful tools for efficient fluorescence diagnostic assays

    A portrait of the Higgs boson by the CMS experiment ten years after the discovery