Oxidative stress in retinal pigment epithelium degeneration:from pathogenesis to therapeutic targets in dry age-related macular degeneration

Age-related macular degeneration is a primary cause of blindness in the older adult population. Past decades of research in the pathophysiology of the disease have resulted in breakthroughs in the form of anti-vascular endothelial growth factor therapies against neovascular age-related macular degeneration;however, effective treatment is not yet available for geographical atrophy in dry agerelated macular degeneration or for preventing the progression from early or mid to the late stage of age-related macular degeneration. Both clinical and experimental investigations involving human agerelated macular degeneration retinas and animal models point towards the atrophic alterations in retinal pigment epithelium as a key feature in age-related macular degeneration progression. Retinal pigment epithelium cells are primarily responsible for cellular-structural maintenance and nutrition supply to keep photoreceptors healthy and functional. The retinal pigment epithelium constantly endures a highly oxidative environment that is balanced with a cascade of antioxidant enzyme systems regulated by nuclear factor erythroid-2-related factor 2 as a main redox sensing transcription factor. Aging and accumulated oxidative stress triggers retinal pigment epithelium dysfunction and eventually death. Exposure to both environmental and genetic factors aggravates oxidative stress damage in aging retinal pigment epithelium and accelerates retinal pigment epithelium degeneration in age-related macular degeneration pathophysiology. The present review summarizes the role of oxidative stress in retinal pigment epithelium degeneration, with potential impacts from both genetic and environmental factors in age-related macular degeneration development and progression. Potential strategies to counter retinal pigment epithelium damage and protect the retinal pigment epithelium through enhancing its antioxidant capacity are also discussed, focusing on existing antioxidant nutritional supplementation, and exploring nuclear factor erythroid-2-related factor 2 and its regulators including REV-ERBα as therapeutic targets to protect against age-related macular degeneration development and progression.

Network-pharmacology-based research on protective effects and underlying mechanism of Shuxin decoction against myocardial ischemia/reperfusion injury with diabetes

BACKGROUND Patients with diabetes mellitus are at higher risk of myocardial ischemia/reperfusion injury(MI/RI).Shuxin decoction(SXT)is a proven recipe modification from the classic herbal formula"Wu-tou-chi-shi-zhi-wan"according to the traditional Chinese medicine theory.It has been successfully used to alleviate secondary MI/RI in patients with diabetes mellitus in the clinical setting.However,the underlying mechanism is still unclear.AIM To further determine the mechanism of SXT in attenuating MI/RI associated with diabetes.METHODS This paper presents an ensemble model combining network pharmacology and biology.The Traditional Chinese Medicine System Pharmacology Database was accessed to select key components and potential targets of the SXT.In parallel,therapeutic targets associated with MI/RI in patients with diabetes were screened from various databases including Gene Expression Omnibus,DisGeNet,Genecards,Drugbank,OMIM,and PharmGKB.The potential targets of SXT and the therapeutic targets related to MI/RI in patients with diabetes were intersected and subjected to bioinformatics analysis using the Database for Annotation,Visualization and Integrated Discovery.The major results of bioinformatics analysis were subsequently validated by animal experiments.RESULTS According to the hypothesis derived from bioinformatics analysis,SXT could possibly ameliorate lipid metabolism disorders and exert anti-apoptotic effects in MI/RI associated with diabetes by reducing oxidized low density lipoprotein(LDL)and inhibiting the advanced glycation end products(AGE)-receptor for AGE(RAGE)signaling pathway.Subsequent animal experiments confirmed the hypothesis.The treatment with a dose of SXT(2.8 g/kg/d)resulted in a reduction in oxidized LDL,AGEs,and RAGE,and regulated the level of blood lipids.Besides,the expression of apoptosis-related proteins such as Bax and cleaved caspase 3 was down-regulated,whereas Bcl-2 expression was up-regulated.The findings indicated that SXT could inhibit myocardial apoptosis and improve cardiac function in MI/RI in diabetic rats.CONCLUSION This study indicated the active components and underlying molecular therapeutic mechanisms of SXT in MI/RI with diabetes.Moreover,animal experiments verified that SXT could regulate the level of blood lipids,alleviate cardiomyocyte apoptosis,and improve cardiac function through the AGE-RAGE signaling pathway.

Structural insights into a novel histone demethylase PHF8

Dynamic regulation of histone methylation/demethylation plays an important role during development. Mutations and truncations in human plant homeodomain （PHD） finger protein 8 （PHF8） are associated with X-linked mental retardation and facial anomalies, such as a long face, broad nasal tip, cleft lip/cleft palate and large hands, yet its molecular function and structural basis remain unclear. Here, we report the crystal structures of the catalytic core of PHF8 with or without α-ketoglutarate （α-KG） at high resolution. Biochemical and structural studies reveal that PHF8 is a novel histone demethylase specific for di- and mono-methylated histone H3 lysine 9 （H3K9me2/1）, but not for H3K9me3. Our analyses also reveal how human PHF8 discriminates between methylation states and achieves sequence specificity for methylated H3K9. The in vitro demethylation assay also showed that the F279S mutant observed in clinical patients possesses no demethylation activity, suggesting that loss of enzymatic activity is crucial for pathogenesis of PHF8 patients. Taken together, these results will shed light on the molecular mechanism underlying PHF8-associated developmental and neurological diseases.

Spatially defined single-cell transcriptional profiling characterizes diverse chondrocyte subtypes and nucleus pulposus progenitors in human intervertebral discs

A comprehensive understanding of the cellular heterogeneity and molecular mechanisms underlying the development,homeostasis,and disease of human intervertebral disks(IVDs)remains challenging.Here,the transcriptomic landscape of 108108 IVD cells was mapped using single-cell RNA sequencing of three main compartments from young and adult healthy IVDs,including the nucleus pulposus(NP),annulus fibrosus,and cartilage endplate(CEP).The chondrocyte subclusters were classified based on their potential regulatory,homeostatic,and effector functions in extracellular matrix(ECM)homeostasis.Notably,in the NP,a PROCR+resident progenitor population showed enriched colony-forming unit-fibroblast(CFU-F)activity and trilineage differentiation capacity.Finally,intercellular crosstalk based on signaling network analysis uncovered that the PDGF and TGF-βcascades are important cues in the NP microenvironment.In conclusion,a single-cell transcriptomic atlas that resolves spatially regulated cellular heterogeneity together with the critical signaling that underlies homeostasis will help to establish new therapeutic strategies for IVD degeneration in the clinic.

SNP-based linkage mapping for validation of adult plant stripe rust resistance QTL in common wheat cultivar Chakwal 86

Wheat crops in China are constantly challenged by stripe rust. Deployment of cultivars with diverse resistances is the best strategy to control the disease. A recombinant inbred line(RIL) population derived from a cross between the resistant cultivar Chakwal 86 and susceptible landrace Mingxian 169 was studied in multiple environments to examine the underlying genetics and to identify quantitative trait loci(QTL) for stripe rust resistance.One hundred and twenty-eight RILs were genotyped with wheat 35 K SNP array and a genome-wide linkage map with 1480 polymorphic SNP markers, or bins, was constructed.Two major QTL on chromosomes 1BL and 3BS, and one minor QTL on 6BS had significant effects in reducing stripe rust severity. The QTL were validated using composite interval mapping(CIM) and inclusive composite interval mapping(ICIM). These methods explained59.0%–74.1% of the phenotype variation in disease response. The QTL on chromosome 1 BL was confirmed to be Yr29/Lr46 and the one on 3BS was the resistance allele identified in CIMMYT germplasm but was not Yr30/Sr2. The QTL on 6BS probably corresponded to previously known QTL. RILs with combined QTL were more resistant than those with single or no QTL. Kompetitive allele-specific PCR(KASP) assays for the QTL with largest effect QTL on chromosome 3BS were performed on a subset of RILs and 150 unrelated wheat lines. The QTL on 3BS with its linked KASP markers can be used in marker-assisted selection to improve stripe rust resistance in breeding programs.

Hot deformation map and its application of GH4706 alloy

The hot deformation behaviors of GH4706 alloy were investigated using compression tests in a deformation temperature range from 900℃ to 1200℃ with a strain rate range of 0.001-1 s-1. Hot processing maps were developed on the basis of the dynamic material model and compression data. A three-dimensional distribution of power dissipation parameter （η） with strain rate and temperature reveals that η decreases in sensitivity with an increase in strain rate and a decrease in temperature. Microstructure studies show that the grain size of GH4706 alloy increases when η is larger than 0.32, and the microstructure exhibits local deformation when r/is smaller than 0.23. The hot processing map at the strain of 0.7 exposes a domain peak at 7=0.32 for the temperature between 940℃ and 970℃ with the strain rate from 0.015 s-1 to 0.003 s-1, and these are the optimum parameters for hot working.

A Coupled Analysis of Nonlinear Sloshing and Ship Motion

Nonlinear interactions among incident wave, tank-sloshing and floating body coupling motion are investigated. The fully nonlinear sloshing and body-surface nonlinear free surface hydrodynamics is simulated using a Non-Uniform Rational B-Spline （NURBS） higher-order panel method in time domain based on the potential theory. A robust and stable improved iterative procedure （Yan and Ma, 2007） for floating bodies is used for calculating the time derivative of velocity potential and floating body motion. An energy dissipation condition based on linear theory adopted by Huang （2011） is developed to consider flow viscosity effects of sloshing flow in nonlinear model. A two-dimensional tank model test was performed to identify its validity. The present nonlinear coupling sway motion results are subsequently compared with the corresponding Rognebakke and Faltinsen （2003）＇s experimental results, showing fair agreement. Thus, the numerical approach presented in this paper is expected to be very efficient and realistic in evaluating the coupling effects of nonlinear sloshing and body motion.

An Active Flexure Compensation Method for LAMOST spectrograph based on BP-Neural Network

The Large sky Area Multi-Object fiber Spectroscopic Telescope(LAMOST)is a Chinese national scientific research facility operated by National Astronomical Observatories,Chinese Academy of Sciences(NAOC).The LAMOST survey for the Milky Way Galaxy and extra-galactic objects has been carried out for several years.The accuracies in measuring radial velocity are expected to be 5 km s-1 for the low resolution spectroscopic survey(R=1800),and 1 km s-1 for the medium resolution mode.The stability of spectrograph is the main factor affecting the accuracies in measuring radial velocity,so an Active Flexure Compensation Method(AFCM)based on Back Propagation Neural Network(BPNN)is proposed in this paper.It utilizes a deep BP(4-layer,5-layer etc.)model of thermal-induced flexure to periodically predict and apply flexure corrections by commanding the corresponding tilt and tip motions to the camera.The spectrograph camera system is adjusted so that the positions of these spots match those in a reference image.The simulated calibration of this compensation method analytically illustrates its performance on LAMOST spectrograph.

Evolution behavior of γ″ phase of IN718 superalloy in temperature/stress coupled field

The evolution behavior of theγ″phase of IN718 superalloy in a temperature/stress coupled field was investigated.Results showed that the coarsening rate of theγ″phase was significantly accelerated in the temperature/stress coupled field.Based on the detail microstructural and crystal defect analysis,it was found that the coarsening rate of theγ″phase with applied stress was significantly higher than that without stress.The main reasons for the increase in the coarsening rate of theγ″phase are as follows:the vacancy formation energy is decreased by the applied stress,which leads to an increase in the vacancy concentration;in the temperature/stress coupled field,the Nb atoms easily combine with vacancies to form complexes and diffuse with the complexes,resulting in a significant increase in the Nb atom diffusion coefficient;Nb atom diffusion is the key control factor for the coarsening of theγ″phase.

Comparison of Clinical Efficacy of Ticagrelor and Clopidogrel for Treatment of Coronary Heart Disease with Myocardial Ischemia

Objective.To compare clinical efficacy of ticagrelor and clopidogrel for treatment of coronary heart disease with myocardial ischemia to provide references for later phase of clinical treatment.Methods.Ninety-six coronary heart disease patients with myocardial ischemia admitted to our hospital from July 20 to July 2019 were recruited as subjects.They were randomly divided into study group and control group according to parity of case number,with 48 patients in each group.Control group was given treatment with clopidogrel,while patients in study group were given treatment with ticagrelor.Clinical efficacy was compared between the both groups.Results.Comparison showed that total effective rate of clinical treatment was higher in study group when compared to control group(P<0.05).Frequency of ST segment depression,duration of ST segment depression,systolic blood pressure,diastolic blood pressure,heart rate and other clinical indicators in study group were superior to control group(P<0.05).Whole blood viscosity at low shear rate,whole blood viscosity at high shear rate,plasma viscosity shear rate,total cholesterol,triglyceride and other haemorheological parameters in study group were superior to control group(P<0.05).Conclusion.Application of ticagrelor has higher clinical efficacy than clopidogreal for coronary heart disease patients with myocardial ischemia.Clinical indicators and haemorheological parameters of myocardial ischemia patients were significantly improved.It should be promoted for application.

Clinical Efficacy of Metoprolol Succinic Acid Sustained Release Tablets Combined with Trimetazidine in the Treatment of Gastrointestinal Tumors with Angina Pectoris

Objective:To investigate the clinical efficacy of metoprolol succinate sustained-release tablets combined with trimetazidine in the treatment of gastrointestinal tumors with angina pectoris.Methods:We enrolled the 58 patients with digestive tract tumor merger angina in November 2017-October 2019 and analysis the hospital clinical data by retrospective method.We included patients with routine treatment in control group(n=31 cases)and the subjects treated with increased dose of succinic acid metoprololzyban joint with trimetazidineinobservation group(n=27 cases)according to the different treatment group.Results:The effective rate of angina pectoris treatment in the observation group was higher than that in the control group.Furthermore,the incidence of adverse reactions was lower than that in the control group and the difference was statistically significant(P<0.05).Conclusion:Metoprolol succinic acid sustained release tablets combined with trimetazidine in the treatment of gastrointestinal tumors with angina pectoris can improve the efficacy of angina pectoris.The drug use is safe and worthy of clinical use.

Ⅴ元素对铁镍基变形高温合金GH4061组织和性能的影响

采用金相显微镜(OM)、扫描电镜(SEM)、透射电镜(TEM)和电化学萃取相分析等手段,研究了Ⅴ元素对GH4061合金晶粒度、碳化物和γ’/γ"强化相等影响,测试了不同Ⅴ含量试样的室温和750℃拉伸性能以及750℃/460 MPa持久性能,分析了Ⅴ元素对合金显微组织和力学性能的影响。结果表明:GH4061合金中添加Ⅴ元素促进了MC型碳化物和γ’/γ"相析出,使晶粒尺寸小幅减小;Ⅴ元素通过增大γ基体的晶格常数,降低γ基体与γ’相的错配度,抑制了γ’/γ"相在750℃的快速粗化;Ⅴ元素添加对室温拉伸性能影响不大,但可显著提升750℃拉伸强度和持久寿命;当Ⅴ含量为0.4%(质量分数)时,GH4061合金具有最佳的750℃持久性能。

响应面法优化鹿茸胶原蛋白制备抗氧化肽的水解条件

以鹿茸中下段胶原蛋白为酶解底物,用木瓜蛋白酶酶解制备小分子抗氧化肽,以清除1,1-二苯基-2-苦基肼基(DPPH·)自由基的能力为指标,采用响应面法优化酶水解条件。结果表明,最优实验条件为时间56 min,酶添加量1.40wt%,pH=5.60,温度60℃。该条件下所得抗氧化肽对DPPH·自由基的清除率为83.09%。用超滤膜、半制备色谱柱和超高效液相色谱-质谱联用仪分级分离获得分子量0.2~0.6 kDa的具有最高抗氧化活性的多肽,其具有与头段类似的保健功效,更易被人体吸收,且易进一步加工和储存。

响应曲面法优化植物甾醇固体自微乳的工艺条件

为了提高植物甾醇在体内的生物利用度,促进其在医药中的广泛应用,在制备的植物甾醇液体自微乳基础上,进一步利用喷雾干燥制备固体自微乳,以提高其长期储存稳定性。首先筛选了载体材料的种类和用量,然后以集粉率为考察指标,在单因素实验的基础上进行响应面优化,确定喷雾干燥的最优工艺参数。结果表明,最优载体为胶体二氧化硅,在载体与自微乳的质量比为1:1、喷雾干燥的进风温度为120℃、进料速度10 mL/min、进风流量540 L/h,此时得到的集粉率为49.36%,与理论预测值基本一致。制得的S-SMEDDS为白色粉末,平均载药量为1.00%,重新分散在水中能形成淡蓝色澄清透明的乳液,再分散粒径为27.20±1.15 nm,多分散系数为0.137±0.010。药物以无定形的状态被吸附在胶体二氧化硅的孔径中,在不同的pH条件下,释放度有所不同,但与原料药相比,释放效果有了很大改善。

FGF/FGFR signaling in health and disease

Growing evidences suggest that the fibroblast growth factor/FGF receptor(FGF/FGFR)signaling has crucial roles in a multitude of processes during embryonic development and adult homeostasis by regulating cellular lineage commitment,differentiation,proliferation,and apoptosis of various types of cells.In this review,we provide a comprehensive overview of the current understanding of FGF signaling and its roles in organ development,injury repair,and the pathophysiology of spectrum of diseases,which is a consequence of FGF signaling dysregulation,including cancers and chronic kidney disease(CKD).In this context,the agonists and antagonists for FGF-FGFRs might have therapeutic benefits in multiple systems.

用于非线性非平稳船舶运动极短期预报的一种复合自回归经验模态分解支持向量机回归模型（英文）

目的:基于支持向量机回归(SVR)模型在非线时间序列的预测能力及经验模态分解(EMD)方法在处理非线性非平稳性的优势,提出一种复合自回归经验模态分解支持向量机回归(AR-EMDSVR)模型,提高非线性非平稳船舶运动极短期预报精度。创新点:1.研究非线性非平稳船舶运动的极短期预报问题,提出一种复合的预报方法;2.基于不同层次的预报模型和模型试验数据,分析非线性非平稳性对极短期预报精度的影响。方法:1.在SVR模型中引入基于自回归(AR)预报端点延拓的EMD方法,形成复合的AR-EMDSVR预报模型;2.基于集装箱船模水池试验运动数据将AR-EMD-SVR模型与AR、SVR和EMD-AR三种模型进行比较,分析非线性非平稳性对极短期预报的影响以及不同模型的预报性能。结论:1.AR-EMD方法能够有效的克服非平稳对极短期预报模型(AR和SVR)在精度上所带来的不良影响;2.基于船模试验数据的预报结果表明:相较于AR、SVR和EMD-AR三种预报模型,基于AR-EMD-SVR模型的非线性非平稳船舶运动极短期预报结果具有更高的精度。

An anti-freezing and anti-drying multifunctional gel electrolyte for flexible aqueous zinc-ion batteries

Aqueous zinc-ion batteries(ZIBs)have attracted immense attention for flexible energy storage devices due to their high safety and low cost.However,conventional flexible aqueous ZIBs will undergo severe capacity loss at subzero temperature due to the inevitably freeze of electrolytes.In addition,under large bending or stretching strains,the encapsulation of devices would be damaged,which causes the evaporation of water in electrolytes and results in device failure.Herein,an anti-freezing and anti-drying gel electrolyte based on polyacrylamide(PAM)and glycerol(Gly)is developed.The strong hydrogen-bonding interactions between PAM or Gly and water molecules not only avoid the crystallization of the gel electrolyte at low temperatures,but also constrain the free water and restrict its evaporation.Therefore,such gel electrolyte displays a high ionic conductivity of 9.65×10^(−5)S cm^(−1)at−40℃.Furthermore,it can restrict the dehydration process when the electrolyte is exposed to ambient environment.The flexible ZIBs based on such gel electrolyte exhibit excellent electrochemical performance at−40℃and the devices without encapsulation retain 98%of their initial capacity in ambient condition after 30 days.This work provides a route to design anti-freezing and anti-drying gel electrolytes for aqueous energy storage devices.

Data-driven Optimal Control Strategy for Virtual Synchronous Generator via Deep Reinforcement Learning Approach

This paper aims at developing a data-driven optimal control strategy for virtual synchronous generator (VSG) in the scenario where no expert knowledge or requirement for system model is available. Firstly, the optimal and adaptive control problem for VSG is transformed into a reinforcement learning task. Specifically, the control variables, i.e., virtual inertia and damping factor, are defined as the actions. Meanwhile, the active power output, angular frequency and its derivative are considered as the observations. Moreover, the reward mechanism is designed based on three preset characteristic functions to quantify the control targets: ① maintaining the deviation of angular frequency within special limits;② preserving well-damped oscillations for both the angular frequency and active power output;③ obtaining slow frequency drop in the transient process. Next, to maximize the cumulative rewards, a decentralized deep policy gradient algorithm, which features model-free and faster convergence, is developed and employed to find the optimal control policy. With this effort, a data-driven adaptive VSG controller can be obtained. By using the proposed controller, the inverter-based distributed generator can adaptively adjust its control variables based on current observations to fulfill the expected targets in model-free fashion. Finally, simulation results validate the feasibility and effectiveness of the proposed approach.

Temporal regulation of prenatal embryonic development by paternal imprinted loci

Paternal imprinted genes(H19 and Gtl2)are pivotal for prenatal embryonic development in mice.Nongrowing oocytes and sperm-or oocyte-originated haploid embryonic stem cells(ha ESCs)carrying both H19-DMR(differentially DNA-methylated region)and IG(intergenic)-DMR deletions that partially mimic paternal imprinting of H19-Igf2 and Dlk1-Dio3 can be employed as sperm replacement to efficiently support full-term embryonic development.However,how H19-DMR and IG-DMR act together to regulate embryonic development is still largely unknown.Here,using androgenetic ha ESC(AG-ha ESC)-mediated semi-cloned(SC)technology,we showed that paternal H19-DMR and IG-DMR are not essential for pre-implantation development of SC embryos generated through injection of AG-ha ESCs into oocytes.H19-DMR plays critical roles before 12.5 days of gestation while IG-DMR is essential for late-gestation of SC embryos.Interestingly,we found that combined deletions of H19 and H19-DMR can further improve the efficiency of normal development of SC embryos at mid-gestation compared to DKO SC embryos.Transcriptome and histology analyses revealed that H19 and H19-DMR combined deletions rescue the placental defects.Furthermore,we showed that H19,H19-DMR and IG-DMR deletions(TKO)give rise to better prenatal and postnatal embryonic development of SC embryos compared to DKO.Together,our results indicate the temporal regulation of paternal imprinted loci during embryonic development.

Bimetal-organic frameworks derived Co/N-doped carbons for lithium-sulfur batteries

Lithium-sulfur(Li-S) batteries have received extensive attention due to their high theoretical specific energy density.However,the utilization of sulfur is seriously reduced by the shuttle effect of lithium polysulfides and the low conductivity of sulfur and lithium sulfide(Li2S).Herein,we introduced bimetalorganic frameworks(Co/Zn-ZIF) derived cobalt and nitrogen-doped carbons(Co/N-C) into Li-S batteries through host design and sepa rator modification.The Co/N-C in Li-S batteries effectively limits the shuttle effect through simultaneously serving as polysulfide traps and chemical catalyst.As a result,the Li-S batteries deliver a high reversible capacity of 1614.5 mAh/g and superior long-term cycling stability with a negligible capacity decay of only 0.04% per cycle after 1000 cycles.Furthermore,they have a high area capacity of 5.5 mAh/cm2.