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Ultra-high-performance liquid chromatography-Q exactive orbitrap tandem mass spectrometry(UHPLC-QEOrbitrap-MS/MS) was used to explore the inhibitory effect and mechanism of ginkgo flavone aglycone(GA) combined with doxorubicin(DOX) on H22 cells. The effects of different concentrations of GA and DOX on the viability of H22 cells were investigated, and combination index(CI) was used to evaluate the effects. In the experiments, control(CON) group, DOX group, GA group, and combined GA and DOX(GDOX) group were constructed. Then the metabolomics strategy was employed to explore the metabolic markers that were significantly changed after combination therapy on the basis of single medication treatment, and by analyzing their biological significance, the effect and mechanism of the anti-tumor effect of GA combined with DOX were explained. The results revealed that when 30 μg·mL~(-1) GA and 0.5 μmol·L~(-1) DOX was determined as the co-administration concentration, the CI value was 0.808, indicating that the combination of GA and DOX had a synergistic anti-tumor effect. Metabolomics analysis identified 23 metabolic markers, including L-arginine, L-tyrosine and L-valine, mostly amino acids. Compared with the CON group, 22 and 17 metabolic markers were significantly down-regulated after DOX treatment and GA treatment, respectively. Compared with the DOX and GA groups, the treatment of GA combined with DOX further down-regulated the levels of these metabolic markers in liver cancer, which might contribute to the synergistic effect of the two. Five key metabolic pathways were found in pathway enrichment analysis, including glutathione metabolism, phenylalanine metabolism, arginine and proline metabolism, β-alanine metabolism, and valine, leucine and isoleucine degradation. These findings demonstrated that the combination of GA and DOX remarkably inhibited the viability of H22 cells and exerted a synergistic anti-tumor effect. The mechanism might be related to the influence of the energy supply of tumor cells by interfering with the metabolism of various amino acids.

Atherosclerosis-associated cardiovascular disease is one of the main causes of death and disability among patients with diabetes mellitus. However, little is known about the impact of S-nitrosylation in diabetes-accelerated atherosclerosis. Here, we show increased levels of S-nitrosylation of guanine nucleotide-binding protein G(i) subunit alpha-2 (SNO-GNAI2) at Cysteine 66 in coronary artery samples from diabetic patients with atherosclerosis, consistently with results from mice. Mechanistically, SNO-GNAI2 acted by coupling with CXCR5 to dephosphorylate the Hippo pathway kinase LATS1, thereby leading to nuclear translocation of YAP and promoting an inflammatory response in endothelial cells. Furthermore, Cys-mutant GNAI2 refractory to S-nitrosylation abrogated GNAI2-CXCR5 coupling, alleviated atherosclerosis in diabetic mice, restored Hippo activity, and reduced endothelial inflammation. In addition, we showed that melatonin treatment restored endothelial function and protected against diabetes-accelerated atherosclerosis by preventing GNAI2 S-nitrosylation. In conclusion, SNO-GNAI2 drives diabetes-accelerated atherosclerosis by coupling with CXCR5 and activating YAP-dependent endothelial inflammation, and reducing SNO-GNAI2 is an efficient strategy for alleviating diabetes-accelerated atherosclerosis., S-nitrosylation can influence many pathophysiological processes. Here the authors show that the coupling efficiency of GNAI2 with CXCR5 is enhanced by S-nitrosylation of GNAI2, leading to Hippo-YAP dysfunction in endothelium, and plays a role in diabetes-accelerated atherosclerosis.

Cardiac fibrosis (CF) is an irreversible pathological process that occurs in almost all kinds of cardiovascular diseases. Phosphorylation-dependent activation of c-Jun N-terminal kinase (JNK) induces cardiac fibrosis. However, whether S-nitrosylation of JNK mediates cardiac fibrosis remains an open question. A biotin-switch assay confirmed that S-nitrosylation of JNK (SNO-JNK) increased significantly in the heart tissues of hypertrophic patients, transverse aortic constriction (TAC) mice, spontaneously hypertensive rats (SHRs), and neonatal rat cardiac fibroblasts (NRCFs) stimulated with angiotensin II (Ang II). Site to site substitution of alanine for cysteine in JNK was applied to determine the S-nitrosylated site. S-Nitrosylation occurred at both Cys116 and Cys163 and substitution of alanine for cysteine 116 and cysteine 163 (C116/163A) inhibited Ang II-induced myofibroblast transformation. We further confirmed that the source of S-nitrosylation was inducible nitric oxide synthase (iNOS). 1400 W, an inhibitor of iNOS, abrogated the profibrotic effects of Ang II in NRCFs. Mechanistically, SNO-JNK facilitated the nuclear translocation of JNK, increased the phosphorylation of c-Jun, and induced the transcriptional activity of AP-1 as determined by chromatin immunoprecipitation and EMSA. Finally, WT and iNOS(−/−) mice were subjected to TAC and iNOS knockout reduced SNO-JNK and alleviated cardiac fibrosis. Our findings demonstrate an alternative mechanism by which iNOS-induced SNO-JNK increases JNK pathway activity and accelerates cardiac fibrosis. Targeting SNO-JNK might be a novel therapeutic strategy against cardiac fibrosis.

In recent years, intensifying waterlogging, salt water intrusion, wetland loss, and ecosystem degradation in Chinese delta cities and adjacent regions have generated the pressing need to create an urban form that is suited to both current and future climates incorporating sea level rise. However, adaptation planning uptake is slow. This is particularly unfortunate because patterns of urban form interact with mean sea level rise (MSLR) in ways that reduce or intensify its impact. There are currently two main barriers that are significant in arresting the implementation of adaptation planning with reference to the MSLR projections composed of geomorphologic MSLR projections and eustatic MSLR projections from global climate warming, and making a comprehensive risk assessment of MSLR projections. The present review shows recent progresses in mapping MSLR projections and their risk assessment approaches on Chinese delta cities, and then a perspective of adapting these cities to MSLR projections as following six aspects. 1) The geomorphologic MSLR projections are contributed by the natural tectonic subsidence projections and the MSLR projections by anthropogenic geomorphologic change. The former needs to be updated in a global framework. The latter is accumulated by land subsidence from underground water depletion, water level fall caused by the erosion of riverbeds from a sediment supply decline attributed to the construction of watershed dams, artificial sand excavation, water level raise by engineering projects including land reclamation, deep waterway regulation, and fresh water reservoirs. 2) Controlling MSLR projections by anthropogenic geomorphologic changes. 3) The IPCC AR5 RCPs MSLRs scenarios are expected to be projected to the local eustatic MSLR projections on the Chinese deltas. 4) The MSLR projections need to be matched to a local elevation datum. 5) Modeling approaches of regional river-sea numerical with semi-analytical hydrodynamics, estuarine channel network, system dynamics and adaptation points are perspective. 6) Adaptation planning to MSLR projections requires a comprehensive risk assessment of the risk of flood, fresh water supply shortage, coastal erosion, wetland loss, siltation of ports and waterway in Chinese delta cities and adjacent regions.

Water is an indirect construction disturbance factor, which has important influence on the stability evaluation and analysis of foundation pit slope engineering. The study is mainly aimed at the deep backfill, the mechanical parameters are not uniform, and the effect of water on its mechanical parameters is great. The mechanical parameters of the backfill under different moisture content were measured by static triaxial shear test. The results show that the cohesion, internal friction angle and shear strength of the backfill are attenuated with the raise of the water content, the cohesion and internal friction angle of the attenuation law showed a linear re-gentle trend, and the shear strength of the decay trend gradually slowed down. The simulation results show that the mechanical parameters of backfill are reduced with the increasing number of saturation-dehydration cycles. The first degree of decay is the most significant, and finally tends to a certain value. The connection between the deterioration coefficient and the cycles follows the negative exponential function, and the mathematical expression of water deterioration was obtained finally. The study analyzes the damage mechanism of water in the construction disturbance, which has some theoretical support for the stability evaluation and disaster mitigation of the foundation pit.

Rationale Steroid-resistant nephrotic syndrome (SRNS) is a special kidney disease. SRNS is characterized by steroid-resistant, clinical variability, and genetic heterogeneity. Patients with SRNS often may eventually need renal transplantation. Patient concerns A 10-month-old Chinese male infant presented with oliguria, renal dysfunction, hypertension, and anemia. Diagnoses Combined with clinical manifestations, laboratory testing and sequencing results, the patient was diagnosed as SRNS. Interventions Combined intravenous methylprednisolone and cefoperazone sulbactam did not improve the patient's condition. Thus, SRNS associated with hereditary nephrotic syndrome was strongly suspected. Genetic testing for hereditary renal disease of the patient revealed 2 novel heterozygous mutations in the Nucleoporin 93 (NUP93) gene, which were predicted pathogenic and harmful by bioinformatic softwares of SIFT, PolyPhen_2 and REVEL. Outcomes As general physical health deterioration and renal dysfunction, the patient died of a severe infection. Lessons The novel NUP93 heterozygous mutations identified in the current study broadened the genetic spectrum of SRNS and further deepened our insight into pathogenic mutations of NUP93 to improve disease diagnosis.

Slope height gradually increased with the increase of mining depth. While the probability of slope instability and the difficulty of preventing a growing stope from destruction give mine a huge security risk and economic losses. By means of the slope simulation experiments we can directly observe and record the deformation, damage evolution of the object and each stage of the deformation of the stress can be obtained in stress analysis. Analyzing the stability of slope in 2-2 profile of Luming molybdenum West-I district by a similar simulation has these advantages: intuitive, clear, short test cycle and low-cost. And some important factors hard to be considered in calculating mathematical analysis can be considered. First, get the ratio number of each simulation stratified by similar material ratio test. Followed by the establishment of a similar model and simulating the excavation process, directly observing and recording the displacement of test model with every step of the slope excavation as well as the stress changes of strain gauges. Through the analysis of experimental data, a conclusion is drawn: stress concentration is most likely to occur in 180-meter platform and 240-meter platform located in F3 and F4 fault. And they should be a priority in slope monitoring and reinforcement of governance. The study plays a role to protect the safety of Luming molybdenum production.

With the development of computing technology, numerical exact diagonalization method plays a vital role in modern computational condensed matter physics, especially in the research area of strongly correlated electron systems: it becomes a benchmark for other numerical computational techniques, such as quantum Monte Carlo, numerical renormalization group, density matrix renormalization group, and dynamic mean field theory. In this paper, we first numerically exactly diagonalize the three-dimensional hydrogen atom with the combination of finite-difference method, and find that the numerical wave function of ground state is in good agreement with the analytical calculations. We then turn to discuss the space dimension confinement hydrogen system, two-dimensional hydrogen atom, and notice that the numerical wave function is no longer in agreement with the analytical calculation, where the ground state wave function has a numerical singularity as radius approaches to zero. Compared with the case of the three-dimensional hydrogen atom, this issue mainly comes from the nature of space dimension confinement. To resolve such an issue of numerical singularity in two-dimensional hydrogen atom, we need to construct a new discrete and normalized Bessel function as a basis to study the ground state behavior of dimension confinement system based on the framework of Lanczos-type numerical exact diagonalization. The constructed normalized Bessel basis is orthogonal and discrete, and thus becomes suitable for practical calculation. Besides, these prominent properties of such a Bessel basis greatly reduce the complexity and difficulty in practical calculation, and thus makes computing work efficient. In addition, Lanczos-type numerical exact diagonalization method can extremely speed up the process of solving the eigenvalue equation. As a result, such a high efficient calculation of our method demonstrates the consistence between numerical and analytical ground state energy value, and the corresponding wave function with enough truncated basis number. Since this kind of numerical singularity occurs in many space dimension confinement systems, our finding for constructing a new discrete Bessel basis function may be helpful in studying the quantum systems with numerical singularity behaviors in wavefunctions in future. On the other hand, it should be pointed out that the Bessel basis is incorporated into the linear augment plane wave method in the density functional theory to study the electronic band structure of the condensed material and obtain high accurate results, especially in the theoretical prediction of topological insulators and in experimental realization as well.