The Fish-Specific Protein Kinase (PKZ) Initiates Innate Immune Responses via IRF3- and ISGF3-Like Mediated Pathways

PKZ is a fish-specific protein kinase containing Zα domains. PKZ is known to induce apoptosis through phosphorylating eukaryotic initiation factor 2α kinase (eIF2α) in the same way as double-stranded RNA-dependent protein kinase (PKR), but its exact role in detecting pathogens remains to be fully elucidated. Herein, we have found that PKZ acts as a fish-specific DNA sensor by initiating IFN expression through IRF3- or ISGF3-like mediated pathways. The expression pattern of PKZ is similar to those of innate immunity mediators stimulated by poly (dA:dT) and poly (dG:dC). DNA-PKZ interaction can enhance PKZ phosphorylation and dimerization in vitro. These findings indicate that PKZ participates in cytoplasmic DNA-mediated signaling. Subcellular localization assays have also shown that PKZ is located in the cytoplasm, which suggests that PKZ acts as a cytoplasmic PRR. Meanwhile, co-IP assays have shown that PKZ can separately interact with IRF3, STING, ZDHHC1, eIF2α, IRF9, and STAT2. Further investigations have revealed that PKZ can activate IRF3 and STAT2; and that IRF3-dependent and ISGF3-like dependent mediators are critical for PKZ-induced IFN expression. These results demonstrate that PKZ acts as a special DNA pattern-recognition receptor, and that PKZ can trigger immune responses through IRF3-mediated or ISGF3-like mediated pathways in fish

Establishment and Verification of a Bagged-Trees-Based Model for Prediction of Sentinel Lymph Node Metastasis for Early Breast Cancer Patients

Purpose: Lymph node metastasis is a multifactorial event. Several scholars have developed nomograph models to predict the sentinel lymph nodes (SLN) metastasis before operation. According to the clinical and pathological characteristics of breast cancer patients, we use the new method to establish a more comprehensive model and add some new factors which have never been analyzed in the world and explored the prospect of its clinical application.Materials and methods: The clinicopathological data of 633 patients with breast cancer who underwent SLN examination from January 2011 to December 2014 were retrospectively analyzed. Because of the imbalance in data, we used smote algorithm to oversample the data to increase the balanced amount of data. Our study for the first time included the shape of the tumor and breast gland content. The location of the tumor was analyzed by the vector combining quadrant method, at the same time we use the method of simply using quadrant or vector for comparing. We also compared the predictive ability of building models through logistic regression and Bagged-Tree algorithm. The Bagged-Tree algorithm was used to categorize samples. The SMOTE-Bagged Tree algorithm and 5-fold cross-validation was used to established the prediction model. The clinical application value of the model in early breast cancer patients was evaluated by confusion matrix and the area under receiver operating characteristic (ROC) curve (AUC).Results: Our predictive model included 12 variables as follows: age, body mass index (BMI), quadrant, clock direction, the distance of tumor from the nipple, morphology of tumor molybdenum target, glandular content, tumor size, ER, PR, HER2, and Ki-67.Finally, our model obtained the AUC value of 0.801 and the accuracy of 70.3%.We used logistic regression to established the model, in the modeling and validation groups, the area under the curve (AUC) were 0.660 and 0.580.We used the vector combining quadrant method to analyze the original location of the tumor, which is more precise than simply using vector or quadrant (AUC 0.801 vs. 0.791 vs. 0.701, Accuracy 70.3 vs. 70.3 vs. 63.6%).Conclusions: Our model is more reliable and stable to assist doctors predict the SLN metastasis in breast cancer patients before operation

Investigating the Distribution of Potassium Perfluoro (2-Ethoxyethane) Sulfonic Acid in Water/Gas Systems using Molecular Dynamics Method

Molecular dynamics method (MD) was used to study the distribution of potassium perfluoro (2-ethoxyethane) sulfonic acid (PESK) in water/gas systems. During the MD process, PES− spontaneously moves to the water surface, which is also the principle by which surfactants act. At equilibrium, most of the fluorocarbon chain faces the gas phase while the sulfonic acid radical faces the water, with a very small quantity of PES− and K+ is still in the bulk solution. The distribution of quantity density and charge density both confirm that PES− is mainly distributed at the water/gas interface. Weak intermolecular interactions were analyzed using the IGMH method, with the main interaction energy between PES− and water coming from h-bonds formed by the oxygen atom in the sulfonic acid group and hydrogen atom in water molecules. There is only van der Waals interaction between K+ and H2O molecules. The strength of the interaction between surfactants and water molecules was studied through energy decomposition

Vibration Response Analysis of Simply Supported Box Girder Bridge-Maglev Train in Accelerated Test of Changsha Maglev Express

In order to study and analyze the vibration response of simply supported box girder bridge-maglev vehicle, a 25 m span simply supported box girder bridge of Changsha Maglev Express was selected as the research object. Field tests were carried out to explore the dynamic response of maglev vehicle running on the bridge. Firstly, the dynamic characteristics of the bridge under the action of medium-low speed maglev train at different speeds were analyzed, and the vibration response of vehicle and bridge was studied at the design speed of 60∼130 km/h. Among them, the longitudinal acceleration of simply supported box girder ranged from 60 km/h to 130 km/h, which increased linearly with the speed of the train and reached the maximum 0.59 m/s2. Its longitudinal deflection also increased with the increase in train speed, which reached the maximum 1.605 mm at 130 km/h. When the speed is 130 km/h, the suspension gap of the maglev vehicle was concentrated in the range of 7.24∼11.50 mm. Through the test analysis, this study provides a basis for the vibration response analysis of simply supported box girder bridge-maglev train. It also provides a reference for the modification and formulation of relevant specifications and experimental verification for the acceleration work of medium-low speed maglev train in the future

Mechanical Regulation of Redox Balance via the Induction of the PIN1/NRF2/ARE Axis in Pancreatic Cancer

Pancreatic cancer is one of the most lethal malignancies. Desmoplastic stroma and metabolic reprogramming are two hallmarks of pancreatic cancer that support its malignant biological behaviors. However, the underlying mechanism by which the stroma maintain the redox balance remains unclear in pancreatic ductal adenocarcinoma (PDAC). Here, we demonstrated that the physical properties of the stroma could regulate the expression of PIN1 in pancreatic cancer cells. Moreover, we found that hard matrix-cultured pancreatic cancer cells induced the upregulation of PIN1 expression. Since PIN1 maintained redox balance via synergistic activation of NRF2 transcription, PIN1 promoted the expression of NRF2 to induce the expression of intracellular antioxidant response element (ARE)-driven genes. Consequently, the antioxidant stress ability of PDAC was increased, and the intracellular level of reactive oxygen species (ROS) was decreased. Thus, PIN1 is expected to be an important target for the treatment of PDAC, especially PDAC with an exuberant desmoplastic stroma

Mechanical Regulation of Redox Balance via the Induction of the PIN1/NRF2/ARE Axis in Pancreatic Cancer

Pancreatic cancer is one of the most lethal malignancies. Desmoplastic stroma and metabolic reprogramming are two hallmarks of pancreatic cancer that support its malignant biological behaviors. However, the underlying mechanism by which the stroma maintain the redox balance remains unclear in pancreatic ductal adenocarcinoma (PDAC). Here, we demonstrated that the physical properties of the stroma could regulate the expression of PIN1 in pancreatic cancer cells. Moreover, we found that hard matrix-cultured pancreatic cancer cells induced the upregulation of PIN1 expression. Since PIN1 maintained redox balance via synergistic activation of NRF2 transcription, PIN1 promoted the expression of NRF2 to induce the expression of intracellular antioxidant response element (ARE)-driven genes. Consequently, the antioxidant stress ability of PDAC was increased, and the intracellular level of reactive oxygen species (ROS) was decreased. Thus, PIN1 is expected to be an important target for the treatment of PDAC, especially PDAC with an exuberant desmoplastic stroma