Activated Protein C Ameliorates Tubular Mitochondrial Reactive Oxygen Species and Inflammation in Diabetic Kidney Disease

Diabetic kidney disease (DKD) is an emerging pandemic, paralleling the worldwide increase in obesity and diabetes mellitus. DKD is now the most frequent cause of end-stage renal disease and is associated with an excessive risk of cardiovascular morbidity and mortality. DKD is a consequence of systemic endothelial dysfunction. The endothelial-dependent cytoprotective coagulation protease activated protein C (aPC) ameliorates glomerular damage in DKD, in part by reducing mitochondrial ROS generation in glomerular cells. Whether aPC reduces mitochondrial ROS generation in the tubular compartment remains unknown. Here, we conducted expression profiling of kidneys in diabetic mice (wild-type and mice with increased plasma levels of aPC, APChigh mice). The top induced pathways were related to metabolism and in particular to oxidoreductase activity. In tubular cells, aPC maintained the expression of genes related to the electron transport chain, PGC1-α expression, and mitochondrial mass. These effects were associated with reduced mitochondrial ROS generation. Likewise, NLRP3 inflammasome activation and sterile inflammation, which are known to be linked to excess ROS generation in DKD, were reduced in diabetic APChigh mice. Thus, aPC reduces mitochondrial ROS generation in tubular cells and dampens the associated renal sterile inflammation. These studies support approaches harnessing the cytoprotective effects of aPC in DKD

Irisin Is Controlled by Farnesoid X Receptor and Regulates Cholesterol Homeostasis

ObjectiveThe aim of this study was to investigate whether the nuclear receptor farnesoid X receptor (FXR) could regulate FNDC5/Irisin expression and the role of Irisin in hyperlipidemia and atherosclerosis in ApoE-/- mice.Methods and ResultsWe treated primary human hepatocytes, HepG2 cells, and Rhesus macaques with FXR agonist (CDCA, GW4064, and ivermectin). FNDC5 expression was highly induced by CDCA and GW4064 in hepatocytes, HepG2 cells, and the circulating level of Irisin increased in Rhesus macaques. Luciferase reporter and CHIP assays were used to determine whether FXR could regulate FNDC5 promoter activity. Irisin-ApoE-/- and ApoE-/- mice were used to study the metabolic function of Irisin in dyslipidemia and atherosclerosis. Irisin-ApoE-/- mice showed improved hyperlipidemia and alleviated atherosclerosis as compared with ApoE-/- mice. Irisin upregulated the expression of Abcg5/Abcg8 in liver and intestine, which increased the transport of biliary cholesterol and fecal cholesterol output.ConclusionActivation of FXR induces FNDC5 mRNA expression in human and increased the circulating level of Irisin in Rhesus macaques. FNDC5/Irisin is a direct transcriptional target of FXR. Irisin may be a novel therapeutic strategy for dyslipidemia and atherosclerosis

Insect-Specific microRNA Involved in the Development of the Silkworm Bombyx mori

MicroRNAs (miRNAs) are endogenous non-coding genes that participate in post-transcription regulation by either degrading mRNA or blocking its translation. It is considered to be very important in regulating insect development and metamorphosis. We conducted a large-scale screening for miRNA genes in the silkworm Bombyx mori using sequence-by-synthesis (SBS) deep sequencing of mixed RNAs from egg, larval, pupal, and adult stages. Of 2,227,930 SBS tags, 1,144,485 ranged from 17 to 25 nt, corresponding to 256,604 unique tags. Among these non-redundant tags, 95,184 were matched to the silkworm genome. We identified 3,750 miRNA candidate genes using a computational pipeline combining RNAfold and TripletSVM algorithms. We confirmed 354 miRNA genes using miRNA microarrays and then performed expression profile analysis on these miRNAs for all developmental stages. While 106 miRNAs were expressed in all stages, 248 miRNAs were egg- and pupa-specific, suggesting that insect miRNAs play a significant role in embryogenesis and metamorphosis. We selected eight miRNAs for quantitative RT-PCR analysis; six of these were consistent with our microarray results. In addition, we searched for orthologous miRNA genes in mammals, a nematode, and other insects and found that most silkworm miRNAs are conserved in insects, whereas only a small number of silkworm miRNAs has orthologs in mammals and the nematode. These results suggest that there are many miRNAs unique to insects

Methylprednisolone as Adjunct to Endovascular Thrombectomy for Large-Vessel Occlusion Stroke

Importance It is uncertain whether intravenous methylprednisolone improves outcomes for patients with acute ischemic stroke due to large-vessel occlusion (LVO) undergoing endovascular thrombectomy. Objective To assess the efficacy and adverse events of adjunctive intravenous low-dose methylprednisolone to endovascular thrombectomy for acute ischemic stroke secondary to LVO. Design, Setting, and Participants This investigator-initiated, randomized, double-blind, placebo-controlled trial was implemented at 82 hospitals in China, enrolling 1680 patients with stroke and proximal intracranial LVO presenting within 24 hours of time last known to be well. Recruitment took place between February 9, 2022, and June 30, 2023, with a final follow-up on September 30, 2023.InterventionsEligible patients were randomly assigned to intravenous methylprednisolone (n = 839) at 2 mg/kg/d or placebo (n = 841) for 3 days adjunctive to endovascular thrombectomy. Main Outcomes and Measures The primary efficacy outcome was disability level at 90 days as measured by the overall distribution of the modified Rankin Scale scores (range, 0 [no symptoms] to 6 [death]). The primary safety outcomes included mortality at 90 days and the incidence of symptomatic intracranial hemorrhage within 48 hours. Results Among 1680 patients randomized (median age, 69 years; 727 female [43.3%]), 1673 (99.6%) completed the trial. The median 90-day modified Rankin Scale score was 3 (IQR, 1-5) in the methylprednisolone group vs 3 (IQR, 1-6) in the placebo group (adjusted generalized odds ratio for a lower level of disability, 1.10 [95% CI, 0.96-1.25]; P = .17). In the methylprednisolone group, there was a lower mortality rate (23.2% vs 28.5%; adjusted risk ratio, 0.84 [95% CI, 0.71-0.98]; P = .03) and a lower rate of symptomatic intracranial hemorrhage (8.6% vs 11.7%; adjusted risk ratio, 0.74 [95% CI, 0.55-0.99]; P = .04) compared with placebo. Conclusions and Relevance Among patients with acute ischemic stroke due to LVO undergoing endovascular thrombectomy, adjunctive methylprednisolone added to endovascular thrombectomy did not significantly improve the degree of overall disability.Trial RegistrationChiCTR.org.cn Identifier: ChiCTR210005172

New Model-Based Analysis Method with Multiple Constraints for Integrated Modular Avionics Dynamic Reconfiguration Process

With the development of integrated modular avionics (IMA), the dynamic reconfiguration of IMA not only provides great advantages in resource utilization and aircraft configuration, but also acts as a valid means for resource failure management. It is vital to ensure the correction of the IMA dynamic reconfiguration process. The analysis of the dynamic reconfiguration process is a significant task. The Architecture Analysis & Design Language (AADL) is widely used in complicated real-time embedded systems. The language can describe the system configuration and the execution behaviors, such as configuration changes. Petri net is a widely used tool to conduct simulation analysis in many aspects. In this study, a model-based analyzing method with multiple constraints for the IMA dynamic reconfiguration process was proposed. First, several design constraints on the process were investigated. Second, the dynamic reconfiguration process was modeled based on the AADL. Then, a set of rules for the transition of the model from AADL to Petri net was generated, and the multi-constraints proposed were incorporated into Petri net for analysis. Finally, a simulation multi-constraint analysis with Petri net for the process of IMA dynamic reconfiguration was conducted. Finally, a case study was employed to demonstrate this method. This method is advantageous to the validity of IMA dynamic reconfiguration at the beginning of the system design

The time-dependent deformation and damage constitutive model of rock based on dynamic disturbance tests

In the deep rock excavation process, the rock will produce deformation and damage under multiple dynamic disturbances, while there is also unrecoverable time-dependent deformation. In order to research this deformation characteristic, a sine wave disturbance triaxial loading test was carried out on red sandstone to simulate the failure process of deep underground rock mass under dynamic disturbance loads with low confining pressure. Based on the results that the deformation of the rock increases suddenly during dynamic disturbances and varies with the number of disturbances, a novel disturbance damage model relating the number of disturbances to the deformation of the disturbances is created to describe the deformation and damage accumulation of the rock under multiple disturbances and an operator is developed to ensure that the model works. In order to describe the time-dependent deformation of rocks, the elasticity model in the traditional Bingham model was improved to a nonlinear elasticity model that varies with time, and its viscous and plasticity models were retained. The time-dependent deformation and damage constitutive model is obtained by combining the improved Bingham model with the disturbance damage model. The model parameters were identified according to the test data, and the finite-element calculation of the model was realized with the secondary development program. The results show the strain of rock increases suddenly under multiple disturbances, and the main reason for rock damage is the action of dynamic disturbances. The fitted curves and finite-element results are consistent with the experimental results. The time-dependent deformation and damage constitutive model of rock not only reflects the decaying rheological and steady-state rheological properties of rock under static loading but describes the characteristics of strain surge and disturbance damage accumulation caused by dynamic disturbances. This article contributes to the characteristics of the deformation of deep rock mass

E2 ubiquitin-conjugating enzyme UBE2L6 promotes Senecavirus A proliferation by stabilizing the viral RNA polymerase.

Senecavirus A (SVA), discovered in 2002, is an emerging pathogen of swine that has since been reported in numerous pork producing countries. To date, the mechanism of SVA replication remains poorly understood. In this study, utilizing iTRAQ analysis we found that UBE2L6, an E2 ubiquitin-conjugating enzyme, is up-regulated in SVA-infected BHK-21 cells, and that its overexpression promotes SVA replication. We determined that UBE2L6 interacts with, and ubiquitinates the RNA-dependent RNA polymerase of SVA, (the 3D protein) and this ubiquitination serves to inhibit the degradation of 3D. UBE2L6-mediated ubiquitination of 3D requires a cystine at residue 86 in UBE2L6, and lysines at residues 169 and 321 in 3D. Virus with mutations in 3D (rK169R and rK321R) exhibited significantly decreased replication compared to wild type SVA and the repaired viruses, rK169R(R) and rK321R(R). These data indicate that UBE2L6, the enzyme, targets the 3D polymerase, the substrate, during SVA infection to facilitate replication

Application of UAV Realistic 3D Modeling in Integral Relocation and Protection of “Yangtze River Estuary II” Ancient Ship

Realistic 3D modeling is the digital base for the construction of digital economy and digital engineering. This paper introduces the key technologies and control of the overall relocation and protection of “Yangtze River Estuary II” ancient ship during the process of image acquisition and realistic 3D modeling using the oblique photography technology of unmanned aerial vehicle (UAV), analyzes the accuracy of aerial triangulation in realistic 3D modeling, and finally discusses the visual display and application of the real-time 3D model through the Web 3D GIS platform

Docking Process of Special Ships in Complex Conditions

In order to protect the organic relics and fragile relics inside “Yangtze River Estuary II” ancient ship, the ancient ship will be salvaged and transferred to a dry dock. The condition of the salvaged ancient ships is poor, and the requirements for the protection of cultural relics inside the ship are high. The dry dock used is the former abandoned dock which is not in good condition. Based on the analysis of the current situation of the abandoned dock, hydrological data, the timing of docking and comprehensive analysis of ancient ship handling scheme, the process flow of docking under complex conditions is summarized, which also provides a new process idea for subsequent similar projects