Repurposing Loperamide as an Anti-Infection Drug for the Treatment of Intracellular Bacterial Pathogens

Infections caused by intracellular bacterial pathogens are difficult to treat since most antibiotics have low cell permeability and undergo rapid degradation within cells.The rapid development and dissemination of antimicrobial–resistant strains have exacerbated this dilemma.With the increasing knowledge of host–pathogen interactions,especially bacterial strategies for survival and proliferation within host cells,host-directed therapy(HDT)has attracted increased interest and has emerged as a promising antiinfection method for treating intracellular infection.Herein,we applied a cell-based screening approach to a US Food and Drug Administration(FDA)-approved drug library to identify compounds that can inhibit the intracellular replication of Salmonella Typhimurium(S.Typhimurium).This screening allowed us to identify the antidiarrheal agent loperamide(LPD)as a potent inhibitor of S.Typhimurium intracellular proliferation.LPD treatment of infected cells markedly promoted the host autophagic response and lysosomal activity.A mechanistic study revealed that the increase in host autophagy and elimination of intracellular bacteria were dependent on the high expression of glycoprotein nonmetastatic melanoma protein B(GPNMB)induced by LPD.In addition,LPD treatment effectively protected against S.Typhimurium infection in Galleria mellonella and mouse models.Thus,our study suggested that LPD may be useful for the treatment of diseases caused by intracellular bacterial pathogens.Moreover,LPD may serve as a promising lead compound for the development of anti-infection drugs based on the HDT strategy.

应对可转移多黏菌素耐药性--饲料添加剂来源的白屈菜红碱具有双重效应

The emergence and spread of the mobile colistin-resistance gene,mcr-1,and its variants pose achallenge to the use of colistin,a last-resort antibiotic used to treat severe infections caused by extensively drug-resistant(XDR)Gram-negative pathogens.Antibiotic adjuvants are a promising strategy to enhance the efficacy of colistin against colistin-resistant pathogens;however,few studies have considered the effects of adjuvants on limiting resistance-gene transmission.We found that chelerythrine(4 mg·L^(-1))derived from Macleaya cordata extract,which is used as an animal feed additive,reduced the minimal inhibitory concentration(MIC)of colistin against an mcr-1 positive Escherichia coli(E.coli)strain by 16-fold(from 2.000 to 0.125 mg·L^(-1)).eliminated approximately 10^(4) colony-forming units(CFUs)of an mcr-1-carrying strain in a murine intestinal infection model,and inhibited the conjugation of an mcr-1-bearing plasmid in vitro(by>100-fold)and in a mouse model(by up to 5-fold).A detailed analysis revealed that chelery-thrine binds to phospholipids on bacterial membranes and increases cytoplasmic membrane fluidity,thereby impairing respiration,disrupting proton motive force(PMF),generating reactive oxygen species(ROS),and decreasing intracellular adenosine triphosphate(ATP)levels,which subsequently downregu-lates mcr-1 and conjugation-associated genes.These dual effects of chelerythrine can expand the use of antibiotic adjuvants and may provide a new strategy for circumventing mobile colistin resistance.

Genetic modification of miR-34a enhances efficacy of transplanted human dental pulp stem cells after ischemic stroke

Human dental pulp stem cells(hDPSCs) promote recovery after ischemic stro ke;however,the therapeutic efficacy is limited by the poor survival of transplanted cells.For in vitro expe riments in the present study,we used oxygen-glucose deprivation/reoxygenation in hDPSCs to mimic cell damage induced by ischemia/reperfusion.We found that miRNA-34a-5p(miR-34a) was elevated under oxygen-glucose deprivation/reoxygenation conditions in hDPSCs.Inhibition of miR-34a facilitated the prolife ration and antioxidant capacity and reduced the apoptosis of hDPSCs.Moreove r,dual-luciferase reporter gene assay showed WNT1and SIRT1 as the targets of miR-34a.In miR-34a knockdown cell lines,WNT1 suppression reduced cell prolife ration,and SIRT1 suppression decreased the antioxidant capacity.Togethe r,these results indicated that miR-34a regulates cell prolife ration and antioxidant stress via targeting WNT1 and SIRT1,respectively.For in vivo expe riments,we injected genetically modified hDPSCs(anti34a-hDPSCs) into the brains of mice.We found that anti34a-hDPSCs significantly inhibited apoptosis,reduced cerebral edema and cerebral infarct volume,and improved motor function in mice.This study provides new insights into the molecular mechanism of the cell prolife ration and antioxidant capacity of hDPSCs,and suggests a potential gene that can be targeted to improve the survival rate and efficacy of transplanted hDPSCs in brain after ischemic stroke.

Constitutive modelling of idealised granular materials using machine learning method

Predicting the constitutive response of granular soils is a fundamental goal in geomechanics.This paper presents a machine learning(ML)framework for the prediction of the stress-strain behaviour and shearinduced contact fabric evolution of an idealised granular material subject to triaxial shearing.The MLbased framework is comprised of a set of mini-triaxial tests which provide a benchmark for the setup and validation of the discrete element method(DEM)model of the granular materials,a parametric DEM simulation programme of virtual triaxial tests which provides datasets of micro-and macro-mechanical information,as well as a multi-layer perceptron(MLP)neural network which is trained and tested using the DEM-based datasets.The ML model only requires the initial void ratio of the granular sample as the input for predicting its constitutive response.The excellent agreement between the ML model prediction and experimental test and DEM simulation results indicates that the MLebased modelling approach is capable of capturing accurately the effects of initial void ratio on the constitutive behaviour of idealised granular materials,bypassing the need to incorporate the complex micromechanics underlying the macroscopic mechanical behaviour of granular materials.Lastly,a detailed comparison between the used MLP model and long short-term memory(LSTM)model was made from the perspective of technical algorithm,prediction accuracy,and computational efficiency.

Discovery of Kaempferol,a Novel ADAM10 Inhibitor,as a Potential Treatment for Staphylococcus aureus Infection

Host-directed therapy(HDT)is an emerging novel approach for treating multidrug-resistant Staphylococcus aureus(S.aureus)infection.Functioning as the indispensable specific cellular receptor for a-toxin(Hla),a-disintegrin and metalloproteinase 10(ADAM10)is exploited to accelerate S.aureus infection through diverse mechanisms.The extraordinary contribution of ADAM10 to S.aureus pathogenesis renders it an attractive HDT target for combating S.aureus infection.Our study is the first to demonstrate the indispensable role of ADAM10 in S.aureus-induced necroptosis,and it enhances our knowledge of the role of ADAM10 in S.aureus infection.Using a fluorogenic substrate assay,we further identified kaempferol as a potent ADAM10 inhibitor that effectively protected mice from S.aureus infection by suppressing Hla-mediated barrier disruption and necroptosis.Collectively,our work presents a novel hostdirected therapeutic strategy for using the promising candidate kaempferol to treat S.aureus infection and other diseases relevant to the disordered upregulation of ADAM10.

Mg alloy cardio-/cerebrovascular scaffolds: Developments and prospects

Vascular scaffolds are one of the important application fields of biodegradable Mg alloys, and related research has been carried out for more than 20 years. In recent years, the application expansion of Mg alloy vascular scaffolds has brought new challenges to the research of related fields. This review focuses on the relevant advances in the field of Mg alloys for both cardio-/cerebrovascular scaffolds. The frequently investigated alloy series for vascular scaffolds were reviewed. The bottleneck of processing of Mg alloy minitubes was elucidated.The idea of functionalized surface modification was also pointed out in this review, and the authors put forward guidelines based on research experience in terms of scaffold structural design and degradation behavior evaluation. Finally, suggestions for further research directions of Mg alloy vascular scaffolds were provided.

Initial micro-galvanic corrosion behavior between Mg_(2)Ca and α-Mg via quasi-in situ SEM approach and first-principles calculation

The initial micro-galvanic corrosion behavior of Mg-30wt%Ca alloy only containing Mg_(2)Ca andα-Mg was studied by immersion testing in a 0.9%Na Cl solution at 37°C.The quasi-in situ SEM and TEM results show that Mg_(2)Ca corroded easier thanα-Mg,indicating that Mg_(2)Ca acted as an anode.The work function(Φ)for Mg_(2)Ca calculated by first-principles is significantly lower compared to that forα-Mg.The Volta potential measured by a scanning Kelvin probe force microscope reveals that the Mg_(2)Ca had a relatively low Volta potential(ψ)value.The lowerΦandψvalues for Mg_(2)Ca indicate a lower electrochemical nobility,which is consistent with the experimental phenomenon.

Capability of discrete element method to investigate the macro-micro mechanical behaviours of granular soils considering different stress conditions and morphological gene mutation

Discrete element method(DEM)has been widely utilised to model the mechanical behaviours of granular materials.However,with simplified particle morphology or rheology-based rolling resistance models,DEM failed to describe some responses,such as the particle kinematics at the grain-scale and the principal stress ratio against axial strain at the macro-scale.This paper adopts a computed tomography(CT)-based DEM technique,including particle morphology data acquisition from micro-CT(mCT),spherical harmonic-based principal component analysis(SH-PCA)-based particle morphology reconstruction and DEM simulations,to investigate the capability of DEM with realistic particle morphology for modelling granular soils’micro-macro mechanical responses with a consideration of the initial packing state,the morphological gene mutation degree,and the confining stress condition.It is found that DEM with realistic particle morphology can reasonably reproduce granular materials’micro-macro mechanical behaviours,including the deviatoric stressevolumetric straineaxial strain response,critical state behaviour,particle kinematics,and shear band evolution.Meanwhile,the role of multiscale particle morphology in granular soils depends on the initial packing state and the confining stress condition.For the same granular soils,rougher particle surfaces with a denser initial packing state and a higher confining stress condition result in a higher degree of shear strain localisation.

聚对苯二甲酸乙二醇酯/石墨烯的氧气阻隔性能

通过熔融共混和微型注塑成型的方法制备了不同石墨烯(RGO)含量的聚对苯二甲酸乙二醇酯(PET)纳米复合材料。研究了不同注塑压力条件下,PET/RGO纳米复合材料的气体阻隔性能。结果表明,与纯PET相比,添加质量分数0. 5%的RGO,复合材料的氧气渗透率降低了85%。在微型注塑加工过程中,随着注塑压力增加,RGO在基体中取向,能够延长氧气的渗透路径,进而在较低RGO添加量的情况下能有效提高PET/RGO氧气阻隔性能。

炭黑对苯乙烯-丙烯腈共聚物/聚己内酯复合材料流变、力学及电学性能的影响

以苯乙烯-丙烯腈共聚物/聚己内酯(SAN/PCL)复合材料为基体,导电炭黑(CB)为填料,采用熔融共混的方法制备了SAN/PCL/CB纳米复合材料。考察了CB含量对SAN/PCL/CB纳米复合材料流变特性、力学性能、电学性能和微观形貌的影响。结果表明,CB的加入能够诱导体系发生相分离,随着CB含量的增加,SAN/PCL/CB纳米复合材料的储能模量曲线在低频区呈现明显的“第二平台”,表现出明显的凝胶化现象,凝胶点为6.5%。在凝胶点前后,SAN/PCL/CB纳米复合材料的力学和电学性能发生明显变化,表明力学和电学性能均与流变特性具有一定相关性。形态分析表明,CB的加入可有效降低分散相的尺寸,CB的团聚是产生流变逾渗的根本原因。

Shanghai expert consensus on totally implantable access ports 2019

Totally implantable access ports(TIAPs)are used for patients with poor peripheral vascular support requiring central venous access.In recent years,TIAPs have been gradually accepted and promoted by patients,doctors,and nurses owing to their advantages of convenient carrying,a long maintenance period,low complications,and a high quality of life for patients.Currently,medical personnel that handle TIAP implantation and management in China are from different areas of healthcare,including surgery,internal medicine,radiology,nurse anesthesia,vascular access,etc.,and many only handle TIAP as a part of their duties.Therefore,the operating procedures and steps for the diagnosis and treatment of complications of TIAP vary from person to person,resulting in different incidence and treatment methods for complications in the implantation and use of TIAP in different medical units.Based on this,we have updated the Shanghai expert consensus on TIAPs from 2015 and explored the diagnosis and treatment procedures of related complications while continuing to emphasize standardized implantation and maintenance.

Microstructure and texture evolution of fine-grained Mg-Zn-Y-Nd alloy micro-tubes for biodegradable vascular stents processed by hot extrusion and rapid cooling

Magnesium alloys have narrow available slip result from close-packed hexagonal structure that limit their processing properties.In the recent work,the Mg-2Zn-0.46Y-0.5Nd,as materials for degradable stents,was applied to produce as-extruded micro-tube with an outer diameter of 3.0mm and a wall thickness of 0.35mm by hot extrusion with an extrusion ratio of 105:1 at 653K and rapid cooling.The fine microstructure of the dynamic recrystallization of as-extruded micro-tube could be preserved by rapid cooling such as water-cooled,resulting in more excellent mechanical properties relative to air-cooled micro-tube.The addition of rare earth elements Y and Nd results in continuous dynamic recrystallization dominated the dynamic recrystallization mechanism.During the hot extrusion process,the activation of the non-basal slip system,especially the pyramidal(c+a)slip,could significantly weaken the texture strength,and the as-extruded micro-tube exhibits weak"RE"texture components(011^(-)1)||ED and(1^(-)21^(-)1)||ED.Hence,the magnesium alloy micro-tube prepared by the rapid cooling has fine microstructure and weak texture,which is favorable for further process and governance.

Self-Exfoliation of Flake Graphite for Bioinspired Compositing with Aramid Nanofiber toward Integration of Mechanical and Thermoconductive Properties

Flexible yet highly thermoconductive materials are essential for the development of next-generation flexible electronic devices.Herein,we report a bioinspired nanostructured film with the integration of large ductility and high thermal conductivity based on self-exfoliated pristine graphene and three-dimensional aramid nanofiber network.A self-grinding strategy to directly exfoliate flake graphite into few-layer and few-defect pristine graphene is successfully developed through mutual shear friction between graphite particles,generating largely enhanced yield and productivity in comparison to normal liquid-based exfoliation strategies,such as ultrasonication,high-shear mixing and ball milling.Inspired by nacre,a new bioinspired layered structural design model containing three-dimensional nanofiber network is proposed and implemented with an interconnected aramid nanofiber network and high-loading graphene nanosheets by a developed continuous assembly strategy of sol-gel-film transformation.It is revealed that the bioinspired film not only exhibits nacre-like ductile deformation behavior by releasing the hidden length of curved aramid nanofibers,but also possesses good thermal transport ability by directionally conducting heat along pristine graphene nanosheets.

Corrosion fatigue of the extruded Mg-Zn-Y-Nd alloy in simulated body fluid

Magnesium alloys were considered to be used as biodegradable implants due to their biocompatibility,biodegradability and nontoxicity.However,under the simultaneous action of corrosive environment and mechanical loading in human body,magnesium alloys are easy to be affected by corrosion fatigue and stress corrosion cracking.In this work,the fatigue behavior of the extruded Mg-Zn-Y-Nd alloy used for vascular stents was studied both in air and in simulated body fluid(SBF).It was revealed that the fatigue limit of as-extruded Mg-Zn-Y-Nd alloy in air is about 65 MPa at 10^7 cycles,while there is no limit in SBF and shows a linear relationship between the fatigue life and stress amplitudes.The fatigue crack source in air was formed by the inclusions and defects.However,the stress corrosion and hydrogen embrittlement are the main reasons for the formation of the fatigue initial crack source in SBF.

Effects of Different Dietary Energy and Protein Levels on Meat Performance and Meat Quality of Jinghai Yellow Chickens

To investigate the effect of different dietary energy and protein levels on meat performance and meat quality of Jinghai yellow chickens, 480 43-day old Jinghai yellow chickens with similar weight were randomly divided into four experimental groups： experimental group 1 （protein 15%, metabolic energy 9.95 MJ/kg）, experimental group 2 （protein 16%, metabolic energy 10.95 MJ/kg）, experimental group 3 （protein 17%, metabolic energy 12.65 MJ/kg） and experimental group 4 （ protein 18%, metabolic energy 13.95 MJ/kg）, respectively. All chickens were slaughtered at 112-day old. The breast and leg muscles of Jinghai yellow chickens were collected, to determine the slaughter performance, conventional meat quality and muscle chemical indicators. The results indicated that dressing-out percentage and eviscerated yield percentage in four experimental groups were above 87.27% and 67.00%, respectively; other slaughter performance indicators exhibited no significant differences among various groups （P 〉 0.05 ） ; breast muscle color of hens in experimental group 4 varied significantly from that in other three groups （ P 〈 0.05 ） ; leg muscle color of hens in experimental group 2 varied extremely significantly from that in other three groups （ P 〈 0.01 ） ; water-holding capacity of breast muscles of hens in experimental group 3 was significantly higher than that in experimental group 4 （P 〈 0.05 ） ; thiamine content of breast muscles of cocks in experimental group 3 was significandy higher than that in experimental group 2 （ P 〈 0.05 ） ; however, other properties exhibited no significant differenees among various groups （P 〉 0.05 ）.

低压等离子喷涂耐高温涂层残余应力检测及分析

采用低压等离子工艺制备耐高温可磨耗涂层,通过光学显微镜观察了耐高温涂层的显微结构,采用逐层法与曲率法相结合的检测技术,对不同厚度涂层残余应力进行检测,形成了涂层厚度与残余应力分布及趋势图,运用热处理技术控制和消除涂层内部残余的涂层应力。结果表明,低压等离子喷涂的耐高温涂层表面残余应力随着涂层厚度的增加而增大,当涂层厚度达到0.6mm左右极限时,涂层会发生自然开裂,采用热处理的工艺方法可以减少涂层内的热应力导致的涂层残余应力。

Characteristics and influencing factors of frontal upwelling in the Yellow Sea in summer

Frontal upwelling is an important phenomenon in summer in the Yellow Sea(YS)and plays an essential role in the distribution of nutrients and biological species.In this paper,a three-dimensional hydrodynamic model is applied to investigate the characteristics and influencing factors of frontal upwelling in the YS.The results show that the strength and distribution of frontal upwelling are largely dependent on the topography and bottom temperature fronts.The frontal upwelling in the YS is stronger and narrower near the eastern coast than near the western coast due to the steeper shelf slope.Moreover,external forcings,such as the meridional wind speed and air temperature in summer and the air temperature in the preceding winter and spring,have certain influences on the strength of frontal upwelling.An increase in air temperature in the previous winter and spring weakens the frontal upwelling in summer;in contrast,an increase in air temperature in summer strengthens the frontal upwelling.When the southerly wind in summer increases,the upwelling intensifies in the western YS and weakens in the eastern YS.The air temperature influences the strength of upwelling by changing the baroclinicity in the frontal region.Furthermore,the meridional wind speed in summer affects frontal upwelling via Ekman pumping.

Zn content mediated fibrinogen adsorption on biodegradable Mg-Zn alloys surfaces

The protein adsorption has an immense influence on the biocompatibility of biodegradable Mg alloy.In this work,the effect of Zn content on the fibrinogen(Fg)adsorption behavior in Mg-Zn binary alloy was systematically investigated.Experimental results showed that the Fg adsorption amount increased at first and then decreased with the increase of Zn content.The adsorption mechanism was investigated by molecular dynamic and density functional theory simulations.The simulations results showed that Zn with low content existed in the inner layer of Mg alloys due to the lower system energy,which promoted Fg adsorption and the promotion effect was more obvious with the increase of Zn content.When Zn content increased to a higher concentration,parts of Zn atoms started to precipitate in the surface,and the Fg-surface interaction energy started to increase.Moreover,the Zn sites favored the formation of ordered water molecules layers,which inhibit the stable adsorptions of Fg.The inhibition effects of Fg adsorption was enhanced with the Zn content increase.In short,the simulation results explain the experimental phenomena and reveal the microscopic mechanism.This study would provide a significant guidance on the design of biodegradable Mg-Zn alloys.

A Hybrid Statistical-Dynamical Downscaling of Air Temperature over Scandinavia Using the WRF Model

An accurate simulation of air temperature at local scales is crucial for the vast majority of weather and climate applications.In this work,a hybrid statistical–dynamical downscaling method and a high-resolution dynamical-only downscaling method are applied to daily mean,minimum and maximum air temperatures to investigate the quality of localscale estimates produced by downscaling.These two downscaling approaches are evaluated using station observation data obtained from the Finnish Meteorological Institute over a near-coastal region of western Finland.The dynamical downscaling is performed with the Weather Research and Forecasting(WRF)model,and the statistical downscaling method implemented is the Cumulative Distribution Function-transform(CDF-t).The CDF-t is trained using 20 years of WRF-downscaled Climate Forecast System Reanalysis data over the region at a 3-km spatial resolution for the central month of each season.The performance of the two methods is assessed qualitatively,by inspection of quantile-quantile plots,and quantitatively,through the Cramer-von Mises,mean absolute error,and root-mean-square error diagnostics.The hybrid approach is found to provide significantly more skillful forecasts of the observed daily mean and maximum air temperatures than those of the dynamical-only downscaling(for all seasons).The hybrid method proves to be less computationally expensive,and also to give more skillful temperature forecasts(at least for the Finnish near-coastal region).

Epitaxy of Ⅲ-nitrides on two-dimensional materials and its applications

Ⅲ-nitride semiconductor materials have excellent optoelectronic properties,mechanical properties,and chemical stability,which have important applications in the field of optoelectronics and microelectronics.Two-dimensional(2D)materials have been widely focused in recent years due to their peculiar properties.With the property of weak bonding between layers of 2D materials,the growth ofⅢ-nitrides on 2D materials has been proposed to solve the mismatch problem caused by heterogeneous epitaxy and to develop substrate stripping techniques to obtain high-quality,low-cost nitride materials for high-quality nitride devices and their extension in the field of flexible devices.In this progress report,the main methods for the preparation of 2D materials,and the recent progress and applications of different techniques for the growth ofⅢ-nitrides based on 2D materials are reviewed.