Tumor necrosis factor-alpha (TNF-α) enhances functional thermal and chemical responses of TRP cation channels in human synoviocytes

<p>Abstract</p> <p>Background</p> <p>We have shown functional expression of several TRP channels on human synovial cells, proposing significance in known calcium dependent proliferative and secretory responses in joint inflammation. The present study further characterizes synoviocyte TRP expression and activation responses to thermal and osmotic stimuli after pre-treatment with proinflammatory mediator tumor necrosis factor alpha (TNF-α, EC50 1.3221 × 10^-10g/L).</p> <p>Results</p> <p>Fluorescent imaging of Fura-2 loaded human SW982 synoviocytes reveals immediate and delayed cytosolic calcium oscillations elicited by (1) TRPV1 agonists capsaicin and resiniferatoxin (20 – 40% of cells), (2) moderate and noxious temperature change, and (3) osmotic stress TRPV4 activation (11.5% of cells). TNF-alpha pre-treatment (1 ng/ml, 8 – 16 hr) significantly increases (doubles) capsaicin responsive cell numbers and [Ca2+]i spike frequency, as well as enhances average amplitude of temperature induced [Ca²⁺]_iresponses. With TNF-alpha pre-treatment for 8, 12, and 16 hr, activation with 36 or 45 degree bath solution induces bimodal [Ca²⁺]_iincrease (temperature controlled chamber). Initial temperature induced rapid transient spikes and subsequent slower rise reflect TRPV1 and TRPV4 channel activation, respectively. Only after prolonged TNF-alpha exposure (12 and 16 hr) is recruitment of synoviocytes observed with sensitized TRPV4 responses to hypoosmolarity (3–4 fold increase). TNF-alpha increases TRPV1 (8 hr peak) and TRPV4 (12 hr peak) immunostaining, mRNA and protein expression, with a TRPV1 shift to membrane fractions.</p> <p>Conclusion</p> <p>TNF-α provides differentially enhanced synoviocyte TRPV1 and TRPV4 expression and [Ca²⁺]_iresponse dependent on the TRP stimulus and time after exposure. Augmented relevance of TRPV1 and TRPV4 as inflammatory conditions persist would provide calcium mediated cell signaling required for pathophysiological responses of synoviocytes in inflammatory pain states.</p

Doublecortin-Like Kinase 1 (DCLK1) Regulates B Cell-Specific Moloney Murine Leukemia Virus Insertion Site 1 (Bmi-1) and is Associated with Metastasis and Prognosis in Pancreatic Cancer

Background/Aims: Cancer stem cells (CSCs) are largely responsible for tumor relapse and metastatic behavior. Doublecortin-like kinase 1 (DCLK1) was recently reported to be a biomarker for gastrointestinal CSCs and involved in the epithelial-mesenchymal transition (EMT) and tumor progression. B cell-specific Moloney murine leukemia virus insertion site 1 (Bmi-1) is a crucial regulator of CSC self-renewal, malignant transformation and EMT, and a previous study from our group showed that Bmi-1 is upregulated in pancreatic cancer progression and participates in EMT. However, it remains unclear whether DCLK1 is involved in pancreatic cancer or whether DCLK1 is associated with the altered level of Bmi-1 expression. Methods: The correlation of DCLK1 expression and clinical features of pancreatic cancer was analyzed in 210 paraffin-embedded archived pancreatic cancer specimens by immunohistochemical analysis. The biological effects of DCLK1 siRNA on cells were investigated by examining cell proliferation using a cell counting kit and cell colony assays, cell migration by wound healing assay and cell invasion by Transwell invasion assay. We further investigated the effect of therapeutic siRNA targeting DCLK1 on pancreatic cancer cell growth in vivo. Moreover, the molecular mechanism by which DCLK1 upregulates Bmi-1 expression was explored using real-time PCR, western blotting and Co-immunoprecipitation assay. Results: DCLK1 is overexpressed in pancreatic cancer and is related to metastasis and prognosis. Knockdown of DCLK1 markedly suppressed cell growth in vitro and in vivo and also inhibited the migration and invasion of pancreatic cancer cells. Furthermore, we found that DCLK1 silencing could inhibit EMT in cancer cells via downregulation of Bmi-1 and the mesenchymal markers Snail and Vimentin and upregulation of the epithelial marker E-cadherin. Moreover, high DCLK1 expression in human pancreatic cancer samples was associated with a mesenchymal phenotype and increased cell proliferation. Further co-immunoprecipitation indicated that DCLK1 did not interact with Bmi-1 directly. Conclusion: Our data suggest that upregulation of DCLK1 may contribute to pancreatic cancer metastasis and poor prognosis by increasing Bmi-1 expression indirectly. The findings indicate that inhibiting DCLK1 expression might be a novel strategy for pancreatic cancer therapy

Localization of Mobile Robots Based on Depth Camera

In scenarios of indoor localization of mobile robots, Global Positioning System (GPS) signals are prone to loss due to interference from urban building environments and cannot meet the needs of robot localization. On the other hand, traditional indoor localization methods based on wireless signals such as Bluetooth and WiFi often require the deployment of multiple devices in advance, and these methods can only obtain distance information and are unable to obtain the attitude of the positioning target in space. This paper proposes a method for the indoor localization of mobile robots based on a depth camera. Firstly, we extracted ORB feature points from images captured by a depth camera and performed homogenization processing. Then, we performed feature matching between adjacent two frames of images, and the mismatched points are eliminated to improve the accuracy of feature matching. Finally, we used the Iterative Closest Point (ICP) algorithm to estimate the camera’s pose, thus achieving the localization of mobile robots in indoor environments. In addition, an experimental evaluation was conducted on the TUM dataset of the Technical University of Munich to validate the feasibility of the proposed depth-camera-based indoor localization system for mobile robots. The experimental results show that the average localization accuracy of our algorithm on three datasets is 0.027 m, which can meet the needs of indoor localization for mobile robots

Molecular subtypes based on cuproptosis-related genes and tumor microenvironment infiltration characteristics in pancreatic adenocarcinoma

Abstract Background Multiple molecular subtypes with distinct clinical outcomes in pancreatic adenocarcinoma (PAAD) have been identified in recent years. Cuproptosis is a new form of cell death that likely involved in tumor progression. However, the cuproptosis-related molecular subtypes as well as its mediated tumor microenvironment (TME) cell infiltration characteristics largely remain unclear. Methods Expression profiles of 10 cuproptosis-related genes (CRGs) and their association with patient survival, TME, cancer stemness and drug resistance were studied in 33 cancer types using the TCGA pan-cancer data. Using 437 PAAD samples from five cohorts (TCGA-PAAD cohort and four GEO cohorts), we explored the molecular subtypes mediated by CRGs, along with the associated TME cell infiltration. Unsupervised methods were utilized to perform cuproptosis subtype clustering. The cuproptosis score was constructed using the COX regression model with least absolute shrinkage and selection operator regression (LASSO) algorithm to quantify the cuproptosis characteristics of a single tumor. Results The expression of 10 CRGs varies in different cancer types with striking inter- and intra- cancer heterogeneity. We integrated the genomic profiling of the CRGs and identified three distinct cuproptosis subtypes, and found that multi-layer CRG alterations were correlated with patient prognosis and TME cell infiltration characteristics. In addition, a cuproptosis score signature was constructed to predict prognosis, and its clinical impacts were characterized in the TCGA-PAAD cohort. The cuproptosis signature was significantly associated with prognosis, tumor subtypes, CD8 T-cell infiltration, response to immune checkpoint inhibitors (ICIs) and chemotherapeutic drug sensitivity. Furthermore, the expression patterns of CRGs in pancreatic cancer cells and normal controls were validated, which was almost consistent with the results from the public database. The expression level and prognostic predictive capability of DLAT were verified in 97 PAAD patients from our patient cohort. Conclusions These findings may help understand the roles of CRGs in PAAD and the molecular characterization of cuproptosis subtypes. In addition, the cuproptosis score could serve as a promising biomarker for predicting prognosis and response to immunotherapy in PAAD patients

Effects of Nonlinearity in Input Filter on the Dynamic Behavior of an Interleaved Boost PFC Converter

A power factor correction (PFC) converter with interleaved multi-channel topology is gaining increasing attention due to its ability in reducing input and output current ripples, but an Electromagnetic Interference (EMI) noise filter is still required for suppressing the large high-frequency switching noise that could potentially degrade the input power quality of the supplying grid and cause malfunctions to other grid-connected systems. In this paper, a magnetic modeling of an interleaved PFC converter with an input differential mode (DM) EMI filter has been successfully implemented, which considers the nonlinear behavior of the inductive component in the EMI filter. The Jiles-Atherton (J-A) model is applied to describe the filtering inductor whose core displays saturation and hysteresis. The simulation results are verified with the experimental test

Parameter Optimization of Ultrafine Comminution Based on Analytic Hierarchy Process: Fuzzy Comprehensive Evaluation

This paper proposes a fuzzy comprehensive evaluation of ultrafine powders, namely, yield and quality value-based feature selection. Three indicators reflecting product yield and quality were selected to construct a simple and practical fuzzy comprehensive evaluation protocol. The weight set of the indices and the fuzzy evaluation set were calculated based on the analytic hierarchy process (AHP) method. The fuzzy comprehensive evaluation value was worked out as the only comprehensive index for the evaluation of product. The best ultrafine comminution condition will be established through the comparison of the fuzzy comprehensive evaluation values. Single-factor experiments and orthogonal experiments of the main influencing factors of ultrafine comminution were conducted. It was concluded that the importance of each factor is sequentially the concentration, specific surface area (SSA) of the media, and percentage of critical speed (PCS). Moreover, the concentration and SSA of the media were equally important. Ultrafine comminution by ball mill had the best overall performance under the PCS of 85%, the SSA of the media of 0.24 m2/kg, and the concentration of 75%

External control of qubit-photon interaction and multi-qubit reset in a dissipative quantum network

arXiv:1604.08393v4A quantum network is a promising quantum many-body system because of its tailored geometry and controllable interaction. Here, we propose an external control scheme for the qubit-photon interaction and multiqubit reset in a dissipative quantum network, which comprises superconducting circuit chains with microwave drives and filter-filter couplings. The traditional multiqubit reset of the quantum network requires physically disconnected qubits to prevent their entanglement. However, we use an original effect of dissipation, i.e., consuming the entanglement generated by qubits’ interaction, to achieve an external control of the multiqubit reset in an always-connected superconducting circuit. The reset time is independent of the number of qubits in the quantum network. Our proposal can tolerate considerable fluctuations in the system parameters and can be applicable to higher-dimensional quantum networks.This work was supported by the National Natural Science Foundation of China (Grant Nos. 11875108, 11774058, 11405031, and 11347114), and the Natural Science Foundation of Fujian Province (Grant Nos. 2018J01412, and 2014J05005). Zhang-Qi Yin was supported by the National Natural Science Foundation of China (Grant No. 61771278), and the Beijing Institute of Technology Research Fund Program for Young Scholars. Luyan Sun was supported by the National Key Research and Development Program of China (Grant No. 2017YFA0304303), and the National Natural Science Foundation of China (Grant No. 11925404).Peer reviewe