Detailed Regulatory Mechanism of the Interaction between ZO-1 PDZ2 and Connexin43 Revealed by MD Simulations

The gap junction protein connexin43 (Cx43) binds to the second PDZ domain of Zonula occludens-1 (ZO-1) through its C-terminal tail, mediating the regulation of gap junction plaque size and dynamics. Biochemical study demonstrated that the very C-terminal 12 residues of Cx43 are necessary and sufficient for ZO-1 PDZ2 binding and phosphorylation at residues Ser (-9) and Ser (-10) of the peptide can disrupt the association. However, only a crystal structure of ZO-1 PDZ2 in complex with a shorter 9 aa peptide of connexin43 was solved experimentally. Here, the interactions between ZO-1 PDZ2 and the short, long and phosphorylated Cx43 peptides were studied using molecular dynamics (MD) simulations and free energy calculation. The short peptide bound to PDZ2 exhibits large structural variations, while the extension of three upstream residues stabilizes the peptide conformation and enhanced the interaction. Phosphorylation at Ser(-9) significantly weakens the binding and results in conformational flexibility of the peptide. Glu210 of ZO-1 PDZ2 was found to be a key regulatory point in Cx43 binding and phosphorylation induced dissociation

Pathogenic Connexin-31 Forms Constitutively Active Hemichannels to Promote Necrotic Cell Death

Mutations in Connexin-31 (Cx31) are associated with multiple human diseases including erythrokeratodermia variabilis (EKV). The molecular action of Cx31 pathogenic mutants remains largely elusive. We report here that expression of EKV pathogenic mutant Cx31R42P induces cell death with necrotic characteristics. Inhibition of hemichannel activity by a connexin hemichannel inhibitor or high extracellular calcium suppresses Cx31R42P-induced cell death. Expression of Cx31R42P induces ER stress resulting in reactive oxygen species (ROS) production, in turn, to regulate gating of Cx31R42P hemichannels and Cx31R42P induced cell death. Moreover, Cx31R42P hemichannels play an important role in mediating ATP release from the cell. In contrast, no hemichannel activity was detected with cells expressing wildtype Cx31. Together, the results suggest that Cx31R42P forms constitutively active hemichannels to promote necrotic cell death. The Cx31R42P active hemichannels are likely resulted by an ER stress mediated ROS overproduction. The study identifies a mechanism of EKV pathogenesis induced by a Cx31 mutant and provides a new avenue for potential treatment strategy of the disease

Transgenic Expression of Entire Hepatitis B Virus in Mice Induces Hepatocarcinogenesis Independent of Chronic Liver Injury

Hepatocellular carcinoma (HCC), the third leading cause of cancer deaths worldwide, is most commonly caused by chronic hepatitis B virus (HBV) infection. However, whether HBV plays any direct role in carcinogenesis, other than indirectly causing chronic liver injury by inciting the host immune response, remains unclear. We have established two independent transgenic mouse lines expressing the complete genome of a mutant HBV (“preS2 mutant”) that is found at much higher frequencies in people with HCC than those without. The transgenic mice show evidence of stress in the endoplasmic reticulum (ER) and overexpression of cyclin D1 in hepatocytes. These mice do not show any evidence of chronic liver injury, but by 2 years of age a majority of the male mice develop hepatocellular neoplasms, including HCC. Unexpectedly, we also found a significant increase in hepatocarcinogenesis independent of necroinflammation in a transgenic line expressing the entire wildtype HBV. As in the mutant HBV mice, HCC was found only in aged—2-year-old—mice of the wildtype HBV line. The karyotype in all the three transgenic lines appears normal and none of the integration sites of the HBV transgene in the mice is near an oncogene or tumor suppressor gene. The significant increase of HCC incidence in all the three transgenic lines—expressing either mutant or wildtype HBV—therefore argues strongly that in absence of chronic necroinflammation, HBV can contribute directly to the development of HCC

Ce-Doped LaMnO₃ Redox Catalysts for Chemical Looping Oxidative Dehydrogenation of Ethane

As a novel reaction mode of oxidative dehydrogenation of ethane to ethylene, the chemical looping oxidative dehydrogenation (CL-ODH) of ethane to ethylene has attracted much attention. Instead of using gaseous oxygen, CL-ODH uses lattice oxygen in an oxygen carrier or redox catalyst to facilitate the ODH reaction. In this paper, a perovskite type redox catalyst LaMnO3+δ was used as a substrate, Ce3+ with different proportions was introduced into its A site, and its CL-ODH reaction performance for ethane was studied. The results showed that the ratio of Mn4+/Mn3+ on the surface of Ce-modified samples decreased significantly, and the lattice oxygen species in the bulk phase increased; these were the main reasons for improving ethylene selectivity. La0.7Ce0.3MnO3 showed the best performance during the ODH reaction and showed good stability in twenty redox cycle tests

Influence of Installation Deviation of Thrust Bearing on Oil Film Flow of 1000 MW Hydraulic Turbine Unit

The thrust bearing, as the only part bearing the axial load, is extremely important in vertical hydroelectric generating units. Its working condition directly affects the safe and reliable operation of the hydroelectric generating unit. However, during operation, the oil film is easily damaged under the influence of complex factors. Installation deviation is a key point that can cause temperature and pressure changes in the oil film, affecting the force on the bearing. This article takes the thrust bearing model of the 1000 MW Francis turbine unit of the Baihetan Power Station as the research object. Based on the fluid–solid coupling theory and CFD technology, the oil film characteristics of thrust bearings are analyzed, and the influence of inclination angles and installation deviation on the oil film flow performance of thrust bearings is discussed. The results show that as the inclination angle changes from 0.0030° to 0.0048°, the axial force changes from 856 t to 368 t, and there is an approximate linear correlation between them. The radial installation deviation has an effect on the axial force. Under the optimal working condition of an inclination angle of 0.0039°, when the radial deviation of the pad changes from 0 mm to 1 mm, the axial force changes from 1573 t to 1275 t. In the process of unit installation, it is necessary to pay attention to the installation deviation of the pad. The results provide guidance for the installation of the bearing, which helps to ensure the safe and stable operation of the station

Robot-assisted percutaneous pars–pedicle screw fixation for treating Hangman’s fracture

Abstract Background This study aimed to evaluate the safety and efficacy of robot-assisted percutaneous pars–pedicle screw fixation surgery for treating Hangman’s fracture. Methods The study involved 33 patients with Hangman’s fracture who underwent robot-assisted fixation surgery using cannulated pars–pedicle screws through a percutaneous approach. The primary parameter evaluated was the accuracy of the screws according to the Gertzbein–Robbins scale, using postoperative CT images. Secondary parameters included the duration of surgery, intraoperative blood loss, postoperative hospital stay, and neurovascular injury. Results A total of 60 pars–pedicle screws were placed in 33 patients. Based on the Levine and Edwards classification, the patients included 12 cases of type I, 15 cases of type II, five cases of type IIa, and one atypical case. The average operative time was 92.4 ± 37.4 min, and the average blood loss was 22.4 ± 17.9 ml. Fifty-five of 60 screws were successfully placed within the bone. No screw-related neurovascular injury was observed, and satisfactory reduction was achieved in all cases. Conclusion Robot-assisted percutaneous pars–pedicle screw fixation is a safe and feasible method for treating Hangman’s fracture. Trial registration: The study was retrospectively registered and approved by our center’s institutional review board

Continuous Damping Control for Rollover Prevention with Optimal Distribution Strategy of Damping Force

Vehicle rollover has always been a highly dangerous condition that can cause severe traffic casualties. In this work, a 14-degree-of-freedom vehicle model in MATLAB/Simulink is constructed with the vehicle suspension system dynamics. The validity of the model is verified by comparing with the CarSim model. Then an optimal distribution of damping force strategy with continuous damping control is proposed by combining the traditional lateral load transfer ratio control with optimized equations of suspension damping force. The damping force compensation of the left and right sides is the core of the optimal distribution of damping force strategy. The effectiveness and optimization effect of the optimal distribution of damping force strategy is proved by the simulation results under the fishhook and crosswind tests. The result shows that continuous damping control has evident control effects on vehicle rollover compared with passive suspension. The optimal distribution of the damping force strategy with continuous damping control has a great better performance than traditional continuous damping control, and it provides a certain assistance to vehicle handling stability

Pt/WN based fuel cell type methanol sensor

Methanol detection is known to be a challenge using the normal Pt/C based gas sensor. This is primarily due to CO poisoning of the Pt active sites, resulting in an irreversible loss of sensor performance. In this paper, a novel fuel cell type gas sensor based on platinized mesoporous tungsten nitride (Pt/WN) is fabricated by employing a hot-press method. The device shows considerable performance for methanol detection at room temperature without external potential applied. The mesoporous WN is prepared through a simple solid-state method with subsequent ammonolysis. An ethylene glycol reduction method is applied to load Pt nanoparticles on WN or on carbon blacks. Results show that Pt/WN gas sensor has the sensitivity of 0.037 mu A/ppm, which is four times higher than that of the Pt/C counterpart. In addition, replacing carbon with WN will increase the response to to methanol with excellent selectivity and stability. The synergistic effect between WN and Pt may play an important role. This investigation shows the potential of tungsten metal nitride in the gas sensor device reported; this offers a new way to change the selectivity of gas sensors using suitably chosen support materials

Atorvastatin rescues vascular endothelial injury in hypertension by WWP2-mediated ubiquitination and degradation of ATP5A

As a widely used lipid-lowering drug in clinical practice, atorvastatin is widely recognized for its role in protecting vascular endothelium in the cardiovascular system. However, a clear mechanistic understanding of its action is lacking. Here, we found that atorvastatin counteracted angiotensin II-induced vascular endothelial injury in mice with hypertension. Mechanistically, atorvastatin up-regulated WWP2, a E6AP C-terminus (HECT)-type E3 ubiquitin ligase with an essential role in regulating protein ubiquitination and various biological processes, thereby rescuing vascular endothelial injury. By ubiquitinating ATP5A (ATP synthase mitochondrial F1 complex subunit alpha), WWP2 degraded ATP5A via the proteasome pathway, stabilizing Bcl-2/Bax in the mitochondrial pathway of apoptosis. Moreover, atorvastatin further ameliorated death of vascular endothelial cells and improved vascular endothelial functions under WWP2 overexpression, whereas WWP2 knockout abrogated these beneficial effects of atorvastatin. Furthermore, we generated endothelial cell-specific WWP2 knockout mice, and this WWP2-mediated mechanism was faithfully recapitulated in vivo. Thus, we propose that activation of a WWP2-dependent pathway that is pathologically repressed in damaged vascular endothelium under hypertension is a major mechanism of atorvastatin. Our findings are also pertinent to develop novel therapeutic strategies for vascular endothelial injury-related cardiovascular diseases