Microstructure evolution,mechanical properties and fracture behavior of Al-xSi/AZ91D bimetallic composites prepared by a compound casting

In this paper,the effect of the Si content on microstructure evolution,mechanical properties,and fracture behavior of the Al-xSi/AZ91D bimetallic composites prepared by compound casting was investigated systematically.The obtained results showed that all the Al-xSi/AZ91D bimetallic composites had a metallurgical reaction layer(MRL),whose thickness increased with increasing Si content for the hypoeutectic Al-Si/AZ91D composites,while the hypereutectic Al-Si/AZ91D composites were opposite.The MRL included eutectic layer(E layer),intermetallic compound layer(IMC layer)and transition region layer(T layer).In the IMC layer,the hypereutectic Al-Si/AZ91D composites contained some Si solid solution and flocculent Mg_(2)Si+Al-Mg IMCs phases not presented in the hypoeutectic Al-Si/AZ91D composites.Besides,increasing Si content,the thickness proportion of the T layer increased,forming an inconsistent preferred orientation of the MRL.The shear strengths of the Al-xSi/AZ91D bimetallic composites enhanced with increasing Si content,and the Al-15Si/AZ91D composite obtained a maximum shear strength of 58.6 MPa,which was 73.4% higher than the Al-6Si/AZ91D composite.The fractures of the Al-xSi/AZ91D bimetallic composites transformed from the T layer into the E layer with the increase of the Si content.The improvement of the shear strength of the Al-xSi/AZ91D bimetallic composites was attributed to the synergistic action of the Mg_(2)Si particle reinforcement,the reduction of oxidizing inclusions and the ratio of Al-Mg IMCs as well as the orientation change of the MRL.

The evolution of the cold chain logistics vehicle routing problem:a bibliometric and visualization revie

This paper uses the bibliometric analysis software CiteSpace to examine the current status and evolution of cold-chain logistics vehicle routing problems(CCVRP).7381 relevant articles published in the Web of Science core collection from 2008 to 2024 were analyzed,an in-depth understanding of the publication trends and category distribution were gained.Subsequently,CiteSpace was used to create a scientific knowledge graph and perform visualization analysis.The analysis includes collaboration among authors,countries,and institutions;co-citation analysis of authors,journals,and references;citation burst detection of keywords;and co-citation cluster analysis of references.Based on a deep understanding of current research hotspots,an in-depth discussion of existing research was conducted from three perspectives:optimization objectives,distribution scenarios,and solution algorithms.The results show that CCVRP involves complex factors such as temperature requirements,time window constraints,and multi-objective optimization.These intricate constraints are causing research to become increasingly interdisciplinary and comprehensive.The evolution of hot topics shows that the research directions span multiple fields,from algorithm design to logistics management.This review helps researchers better understand the history,current status,and future development directions of CCVRP research,and provides valuable references and inspiration for academia and practice.

Integration of Ideological and Political Education into the Probability Theory and Mathematical Statistics Course:A Teaching Design Based on Estimation and Hypothesis Testing

With the rapid development of higher education in China,colleges and universities are facing new challenges and impacts in talent training.Probability Theory and Mathematical Statistics is one of the important courses in higher education for science and engineering majors and economics and management majors.Its critical role in cultivating students’thinking skills and improving their problem-solving skills is self-evident.Course ideological and political education construction is an important link in college talent training work.Combining ideological and political education with course teaching can help students establish correct value concepts and play a certain role in improving their comprehensive ability and quality.At present,the construction of ideological and political education in the Probability Theory and Mathematical Statistics course still faces some problems,mainly manifested in the lack of attention paid by teachers to course ideological and political education,insufficient exploitation of ideological and political elements,and the simplification of ideological and political education implementation methods.In order to comprehensively deepen the construction of course ideological and political education in line with the actual needs of Probability Theory and Mathematical Statistics course teaching,we should strengthen the construction of teacher teams,improve teachers’ability to carry out course ideological and political education,integrate educational resources,develop educational resources for ideological and political education,and innovate teaching methods to improve the overall effect of ideological and political education integration.

The type, position and age effect on the cutting reproduction of Picea crassifolia and its rooting mechanism in the Qilian Mountains

Picea crassifolia Kom, a perennial arbor spe- cies is recognized as one of the most adaptable plants found to date in Qilian Mountains. To explore the cutting reproduction technology of P. crassifolia and reveal its rooting mechanism, cuttings of P. crassifolia with different cutting types （softwood, hardwood and root）, positions （top, upper, middle and bottom） and ages （7, 10, 15, 20, 25 year-old） were cultivated in a field experiment. One- year old softwood and hardwood cuttings were collected from 7-, 10-, 15-, 20-, and 25 year-old healthy ortets to analyze the changes from endogenous hormones and organic nutrients. Results indicate that the softwood cut- tings （0.5-1.0 cm in diameter） from upper branches of 15 year-old ortets shows better growth performance by improving rooting indexes, including a significant increasein rooting rate and a decrease in basal rot rate. Concomi- tantly, increasing rooting quantity and root length also increased. It is noteworthy that the high rooting rate of P. crassifolia cuttings due to its ability to accumulate high concentrations of indole-3-acetic acid （IAA） and total carbon （TC） rather than abscisic acid （ABA） and total nitrogen （TN）. The rooting rate was mainly regulated by the IAA/ABA and TC/TN ratio. In summary, our results suggest that the softwood cuttings （0.5-1.0 cm in diameter） from upper branches of 15 year-old P. crassifolia can be considered as an effective strategy to improve cutting rooting rate, and the IAA/ABA and TC/TN ratio was one of the main factors limiting the cutting rooting rate of P. crassifolia.

Effects of separate and mutual application of Na and Si on drought resistance of Haloxylon ammodendron

We studied pot cultivated Haloxylon ammodendron＇s growth, physiological changes and drought resistance under NaC1, H2SiO3, and NaCl＋H2SiO3 treatments. Results show that 0.3 g/kg NaC1, 0.2 g/kg HzSiO3 or 0.3 g/kg NaCI＋0.1 g/kg H2SiO3 treatments can effectively promote growth and improve the drought resistance of/-L, ammodendron. Compared with that without NaCI treatment, H. ammodendron＇s height, crown diameter and fresh weight increased by 42%, 91% and 62% respectively under 0.3 g/kg NaC1 treatment, and its main stem diameter, main root diameter and main root length increased by 40%, 39% and 23%, respectively. Compared with that without H2SiO3 treatments, H. ammodendron＇s height, crown diameter and flesh weight increased by 36%, 45% and 27% respectively under 0.2 g/kg HeSiO3 treatment, and its main stem diameter, main root diameter and main root length increased by 23%, 23% and 20%, respectively. Compared with that under 0.3 g/kg NaC1 treatment, H. ammodendron＇s height, crown diameter and fresh weight and main root length increased by 9%, 10%, 17% and 12% respectively under 0.3 g/kg NaCI＋0.1 g/kg H2SiO3 treatment. Compared with that under 0.1 g/kg H2SiO3 treatment, H. ammodendron＇s height, crown diame- ter and fresh weight increased by 28%, 76% and 68% respectively under 0.3 g/kg NaCI＋0.1 g/kg H2SiO3 treatment, and its main stem diameter, main root diameter and main root length increased by 30%, 32% and 27%, respectively. This suggests that moder- ate levels of NaCI＋H2SiO3 interaction can effectively promote growth and improve drought resistance of/-L, ammodendron than separate applications of NaC1 or H2SiO3.

Online plasma diagnostics of a laser-produced plasma

In this study,we report a laser interferometry experiment for the online-diagnosing of a laserproduced plasma.The laser pulses generating the plasma are ultra-fast（30 femtoseconds）,ultraintense（tens of Terawatt） and are focused on a helium gas jet to generate relativistic electron beams via the laser wakefield acceleration（LWFA） mechanism.A probe laser beam（λ=800 nm） which is split-off the main beam is used to cross the plasma at the time of arrival of the main pulse,allowing online plasma density diagnostics.The interferometer setup is based on the No Marski method in which we used a Fresnel bi-prism where the probe beam interferes with itself after crossing the plasma medium.A high-dynamic range CCD camera is used to record the interference patterns.Based upon the Abel inversion technique,we obtained a 3D density distribution of the plasma density.

Preparation, interfacial regulation and strengthening of Mg/Al bimetal fabricated by compound casting: A review

Mg/Al bimetal combines the advantages of both aluminum and magnesium and has broad application prospects in automotive, aerospace,weapons, digital products and so on. The compound casting has the characteristics of low cost, easy to achieve metallurgical combination and suitable for the preparation of complex bimetallic parts. However, bimetallic joint strength is low due to differences of physical properties between Al and Mg, oxide film on metallic surface and interfacial Al-Mg IMCs, which is closely related to the interfacial microstructure and properties. Therefore, how to control the interface of the bimetal to achieve performance enhancement is the focus and difficulty in this field. At present, there are mainly the following strengthening methods. First, the “zincate galvanizing” and “electrolytic polishing+anodic oxidation” technology were exert on the surface of Al alloy to remove and break the oxide film, which improved the wettability between Al and Mg. Second, the undesirable Al-Mg IMCs were reduce or elimination by adding the interlayers(Zn, Ni and Ni-Cu). Thirdly, the evolution process of interfacial microstructure was changed and fine strengthening phases were formed by adding Si element to Al alloy or rare earth element to Mg alloy. Fourthly, mechanical vibration and ultrasonic vibration were applied in the process of the filling and solidification to refine and homogenize the interfacial structure. Finally, some other methods, including secondary rolling, thermal modification, heat treatment and constructing exterior 3D morphology, also can be used to regulate the interfacial microstructure and compositions. The above strengthening methods can be used alone or in combination to achieve bimetallic strengthening. Finally, the future development direction of the Mg/Al bimetal is prospected, which provides some new ideas for the development and application of the Mg/Al bimetal.

Aquatic Medicine Knowledge Graph Completion Based on Hybrid Convolution

Aquatic medicine knowledge graph is an effective means to realize intelligent aquaculture.Graph completion technology is key to improving the quality of knowledge graph construction.However,the difficulty of semantic discrimination among similar entities and inconspicuous semantic features result in low accuracy when completing aquatic medicine knowledge graph with complex relationships.In this study,an aquatic medicine knowledge graph completion method(TransH+HConvAM)is proposed.Firstly,TransH is applied to split the vector plane between entities and relations,ameliorating the poor completion effect caused by low semantic resolution of entities.Then,hybrid convolution is introduced to obtain the global interaction of triples based on the complete interaction between head/tail entities and relations,which improves the semantic features of triples and enhances the completion effect of complex relationships in the graph.Experiments are conducted to verify the performance of the proposed method.The MR,MRR and Hit@10 of the TransH+HConvAM are found to be 674,0.339,and 0.361,respectively.This study shows that the model effectively overcomes the poor completion effect of complex relationships and improves the construction quality of the aquatic medicine knowledge graph,providing technical support for intelligent aquaculture.

Alignment efficient image-sentence retrieval considering transferable cross-modal representation learning

Traditional image-sentence cross-modal retrieval methods usually aim to learn consistent representations of heterogeneous modalities,thereby to search similar instances in one modality according to the query from another modality in result.The basic assumption behind these methods is that parallel multi-modal data(i.e.,different modalities of the same example are aligned)can be obtained in prior.In other words,the image-sentence cross-modal retrieval task is a supervised task with the alignments as ground-truths.However,in many real-world applications,it is difficult to realign a large amount of parallel data for new scenarios due to the substantial labor costs,leading the non-parallel multi-modal data and existing methods cannot be used directly.On the other hand,there actually exists auxiliary parallel multi-modal data with similar semantics,which can assist the non-parallel data to learn the consistent representations.Therefore,in this paper,we aim at“Alignment Efficient Image-Sentence Retrieval”(AEIR),which recurs to the auxiliary parallel image-sentence data as the source domain data,and takes the non-parallel data as the target domain data.Unlike single-modal transfer learning,AEIR learns consistent image-sentence cross-modal representations of target domain by transferring the alignments of existing parallel data.Specifically,AEIR learns the image-sentence consistent representations in source domain with parallel data,while transferring the alignment knowledge across domains by jointly optimizing a novel designed cross-domain cross-modal metric learning based constraint with intra-modal domain adversarial loss.Consequently,we can effectively learn the consistent representations for target domain considering both the structure and semantic transfer.Furthermore,extensive experiments on different transfer scenarios validate that AEIR can achieve better retrieval results comparing with the baselines.

Improving mechanical properties of AZ91D magnesium/A356 aluminum bimetal prepared by compound casting via a high velocity oxygen fuel sprayed Ni coating

In this paper,a Ni coating was deposited on the surface of the A356 aluminum alloy by high velocity oxygen fuel spraying to improve the performance of the AZ91D magnesium/A356 aluminum bimetal prepared by a compound casting.The effects of the Ni coating as well as its thickness on microstructure and mechanical properties of the AZ91D/A356 bimetal were systematically researched for the first time.Results demonstrated that the Ni coating and its thickness had a significant effect on the interfacial phase compositions and mechanical properties of the AZ91D/A356 bimetal.The 10μm’s Ni coating cannot prevent the generation of the Al-Mg intermetallic compounds(IMCs)at the interface zone of the AZ91D/A356 bimetal,while the Ni coating with the thickness of 45μm and 190μm can avoid the formation of the Al-Mg IMCs.When the Ni coating was 45μm,the Ni coating disappeared and transformed into Mg-Mg_(2)Ni eutectic structures+Ni_(2)Mg_(3)Al particles at the interface zone.With a thickness of 190μm’s Ni coating,part of the Ni coating remained and the interface layer was composed of the Mg-Mg_(2)Ni eutectic structures+Ni_(2)Mg_(3)Al particles,Mg_(2)Ni layer,Ni solid solution(SS)layer,Al_(3)Ni_(2) layer,Al_(3)Ni layer and sporadic Al_(3)Ni+Al-Al_(3)Ni eutectic structures from AZ91D side to A356 side in sequence.The interface layer consisting of the Mg-Ni and Al-Ni IMCs obtained with the Ni coating had an obvious lower hardness than the Al-Mg IMCs.The shear strength of the AZ91D/A356 bimetal with a Ni coating of 45μm thickness enhanced 41.4%in comparison with that of the bimetal without Ni coating,and the fracture of the bimetal with 45μm’s Ni coating occurred between the Mg matrix and the interface layer with a mixture of brittle fracture and ductile fracture.

Effect of vibration on interfacial microstructure and mechanical properties of Mg/Al bimetal prepared by a novel compound casting

In this work,a vibration was applied in the preparation of the Mg/Al bimetal by a novel compound casting in order to improve the mechanical properties of the Mg/Al bimetal,and the effect of the vibration on the interfacial microstructure and mechanical properties of the Mg/Al bimetal was investigated.The results indicated that the vibration had a significant effect on the interfacial microstructure and mechanical properties of the Mg/Al bimetal,but it did not change the phase compositions of the interface,which was composed of layerⅠ(Al3Mg2+Mg2Si),layerⅡ(Al_(12)Mg_(17)+Mg_(2)Si)and layerⅢ(Al_(12)Mg_(17)/δ-Mg).Without vibration,the Mg_(2)Si phase with a needle-like morphology mainly aggregated in the layerⅡof the interface.After the application of the vibration,the SEM and EBSD analysis results showed that the Mg_(2)Si and Al3Mg2phases in the interface were obviously refined,and the distribution of the Mg_(2)Si became more uniform,due to the strong forced convection of the molten metal resulting from the vibration.The TEM analysis indicated that the interface between the A_(l3)Mg_(2) and Mg_(2)Si phases was non-coherent,suggesting the Mg_(2)Si particles cannot act as a heterogeneous nucleation base during the solidification process of the interface.Compared to the Mg/Al bimetal without vibration,the shear strength of the Mg/Al bimetal with vibration increased by about 50%from 31.7 MPa on average to 47.5 MPa,and the hardness of the layer I of the interface increased,and the hardness of the layerⅢdecreased.The fracture surface transformed from a flat fracture morphology without vibration to an irregular zigzag fracture morphology.

An improved constant volume cycle model for performance analysis and shape design of PDRE nozzle

An improved constant volume cycle （CVC） model is developed to analyze the nozzle effects on the thrust and specific impulse of pulse detonation rocket engine （PDRE）. Theoretically, this model shows that the thrust coefficient/specific impulse of PDRE is a function of the nozzle contraction/expansion ratio and the operating frequency. The relationship between the nozzle contraction ratio and the operation frequency is obtained by introducing the duty ratio, by which the key problem in the theoretical design can be solved. Therefore, the performance of PDRE can be accessed to guide the preliminary shape design of nozzle conveniently and quickly. The higher the operating frequency of PDRE is, the smaller the nozzle contraction ratio should be. Besides, the lower the ambient pressure is, the larger the expansion ratio of the nozzle should be. When the ambient pressure is 1.013 × 105 Pa, the optimal expansion ratio will be less than 2.26. When the ambient pressure is reduced to vacuum, the extremum of the optimal thrust coefficient is 2.236 9, and the extremum of the specific impulse is 321.01 s. The results of the improved model are verified by numerical simulation.

Effect of Hyperconjugation on Photovoltaic Performance in Pseduo-2D Perylene Diimide Derivatives

Theπ-πinteraction is acknowledged as the predominant factor to determine the molecular packing in organic photovoltaic materials,while other non-covalent intermolecular interactions especially theσ-πhyperconjugation are often ignored.Herein,a perylene diimide(PDI)derivative named FIDT-PDI is designed and synthesized to shed light into the effect of hyperconjugation on the molecular packing and further the photovoltaic performance.Dynamic NMR and 2D NOE NMR demonstrate the formation of intermolecularσ-πhyperconjugation between the C—H bond of the PDI moiety in one molecule and the phenyl sidechain in another molecule of FIDT-PDI.Benefiting from theσ-πhyperconjugation,FIDT-PDI with twisted backbone reversely exhibits more ordered packing and stronger crystallinity compared with another PDI derivative FIDTT-PDI which has better planarity,consequently achieving superior PCE and higher carrier mobility.This contribution is the first paradigm to unravel the structure-property relationship betweenσ-πhyper-conjugation of conjugated materials and corresponding photovoltaic performance.

PBX/Knotted 1 homeobox-2(PKNOX2)is a novel regulator of myocardial fibrosis

Much effort has been made to uncover the cellular heterogeneities of human hearts by single-nucleus RNA sequencing.However,the cardiac transcriptional regulation networks have not been systematically described because of the limitations in detecting transcription factors.In this study,we optimized a pipeline for isolating nuclei and conducting single-nucleus RNA sequencing targeted to detect a higher number of cell signal genes and an optimal number of transcription factors.With this unbiased protocol,we characterized the cellular composition of healthy human hearts and investigated the transcriptional regulation networks involved in determining the cellular identities and functions of the main cardiac cell subtypes.Particularly in fibroblasts,a novel regulator,PKNOX2,was identified as being associated with physiological fibroblast activation in healthy hearts.To validate the roles of these transcription factors in maintaining homeostasis,we used single-nucleus RNA-sequencing analysis of transplanted failing hearts focusing on fibroblast remodelling.The trajectory analysis suggested that PKNOX2 was abnormally decreased from fibroblast activation to pathological myofibroblast formation.Both gain-and loss-of-function in vitro experiments demonstrated the inhibitory role of PKNOX2 in pathological fibrosis remodelling.Moreover,fibroblast-specific overexpression and knockout of PKNOX2 in a heart failure mouse model induced by transverse aortic constriction surgery significantly improved and aggravated myocardial fibrosis,respectively.In summary,this study established a high-quality pipeline for single-nucleus RNA-sequencing analysis of heart muscle.With this optimized protocol,we described the transcriptional regulation networks of the main cardiac cell subtypes and identified PKNOX2 as a novel regulator in suppressing fibrosis and a potential therapeutic target for future translational studies.

Effects of dietary protein level on nutrients digestibility and reproductive performance of female mink(Neovison vison)during gestation

The objective of this study was to determine whether nutrient digestibility and reproductive performance of pregnant mink(Neovison vison) were affected by different dietary protein levels. One hundred and twenty female mink were randomly assigned to four groups, receiving diets of fresh material with different protein levels. The dietary protein levels,expressed as percentage of dry matter(DM),were 32,36, 40 and 44% respectively. These values corresponded to average 320, 360, 400 and 440 g protein/kg DM, respectively. Results were as follows. All of crude protein digestibility, nitrogen(N) intake, N retention increased along with dietary protein level increasing. Low protein level(32%) significantly reduced the above indicators(P < 0.05). DM digestibility and ether extract digestibility were not affected by dietary protein level. Results of mated females, barren females, kids per litter, live born kids per mated female, birth survival rate, and birth weight showed that mink achieved optimal reproductive performance when dietary protein level was 36%. In conclusion, dietary protein was anticipated to significantly influence some nutrients' utilization. Adopting the appropriate dietary protein level allow better reproduction performance. The most preferable reproductive performance was achieved when diet contained 275.5 g digestible protein per kg DM for female mink in gestation.

Effects of dry dietary protein on digestibility, nitrogen-balance and growth performance of young male mink

The experiment was to study the nutrient digestibility and metabolism performance of male minks,which were fed different protein level diets during growth period. Effects of protein quantity on growth and development of minks and feed conversion ratio(FCR) were also investigated. Sixty healthy male minks of 45 d were randomly allocated into six groups with ten replicates, which was one sable for each replicate. The minks in six groups were fed diets in which protein levels were 28, 30,32, 34, 36 and 38%,respectively. The six groups were denoted as P28, P30, P32, P34, P36 and P38. After 2 wk, all minks were weighed, average daily gains(ADG) were calculated, and the digestibility values of nutrients were determined. The results indicated that digestibility of calcium, nitrogen of fence, nitrogen deposition, net protein utilization(NPU), and biological value of protein(BV) were similar(P > 0.05), however, nitrogen intake greatly varied among groups(P < 0.01). Compared with group P28, groups of P34, P36 and P38 showed significant difference(P < 0.01) in ADG and FCR. In conclusion, it was recommended that adding34% protein to mink diet would optimize production parameters including ADG, digestibility of nutrition,and FCR, and negative result was observed when diet protein was lower than 28%.

Effect of La on microstructure,mechanical properties and fracture behavior of Al/Mg bimetallic interface manufactured by compound casting

To improve the Al/Mg bimetallic interface,La was added into the Al/Mg bimetallic interface manufactured by a compound casting process.The effect of La addition on the microstructure,mechanical properties and fracture behavior of the Al/Mg bimetallic interface and the formation mechanism of the interface were studied in detail.Al_(11)La_(3),Al_(8)Mn_(4)La,Al_(20)Ti_(2)La,and other rare earth precipitates(RE precipitates)preferentially precipitated at the interface with La addition,while the number of the Al_(11)La_(3)and Al_(8)Mn_(4)La located in eutectic structure area(E area)gradually increased and aggregated in the interface with the increase of the La content.Besides,the matrix structure in different areas of the Al/Mg interface changed in different degrees,and the eutectic structure and primaryγ(Mg_(17)Al_(12))dendrites in the E area were refned,but the intermetallic compounds area(IMC area)had no obvious change.With the addition of the La,the interface was strengthened under the comprehensive effect of refnement strengthening and precipitation strengthening from the E area.When the La content increased to 1.0%,the shear strength of the Al/Mg bimetal reached the maximum of 51.54 MPa,which was 30.95%higher than the group without La addition.However,with the further increase of the La content,the large area aggregation of the Al_(11)La_(3)and Al_(8)Mn_(4)La occurred in the interface,leading to the separation of the matrix structure of the E area and the decrease of the shear strength of the Al/Mg interface.

Generation of high-quality electron beams by ionization injection in a single acceleration stage

Ionization-induced electron injection in laser wakefield accelerators, which was recently proposed to lower the laser intensity threshold for electron trapping into the wake wave, has the drawback of generating electron beams with large and continuous energy spreads, severely limiting their future applications. Complex target designs based on separating the electron trapping and acceleration stages were proposed as the only way for getting small energy-spread electron beams. Here, based on the self-truncated ionization-injection concept which requires the use of unmatched laser–plasma parameters and by using tens of TW laser pulses focused onto a gas jet of helium mixed with low concentrations of nitrogen, we demonstrate single-stage laser wakefield acceleration of multi-hundred MeV electron bunches with energy spreads of a few percent. The experimental results are verified by PIC simulations.

Relativistic correction to the dissociation temperature of B_(c) mesons in a hot medium

By solving two body Dirac equations with potentials at finite temperature,we calculate the dissociation temperature T_(d) of B_(c) mesons in quark-gluon plasma.It is found that T_(d) becomes higher with the relativistic correction than the T_(d) from the Schrodinger equation.Both the short range interaction and the constant term of the potential at the long-range scale have a contribution to the shift of T_(d),while the spin interaction is negligible.

P21-activated kinase 1 (PAK1)-mediated cytoskeleton rearrangement promotes SARS-CoV-2 entry and ACE2 autophagic degradation

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the causative agent of coronavirus disease 2019(COVID-19),has had a significant impact on healthcare systems and economies worldwide.The continuous emergence of new viral strains presents a major challenge in the development of effective antiviral agents.Strategies that possess broad-spectrum antiviral activities are desirable to control SARS-CoV-2 infection.ACE2,an angiotensin-containing enzyme that prevents the overactivation of the renin angiotensin system,is the receptor for SARS-CoV-2.ACE2 interacts with the spike protein and facilitates viral attachment and entry into host cells.Yet,SARS-CoV-2 infection also promotes ACE2 degradation.Whether restoring ACE2 surface expression has an impact on SARS-CoV-2 infection is yet to be determined.Here,we show that the ACE2-spike complex is endocytosed and degraded via autophagy in a manner that depends on clathrin-mediated endocytosis and PAK1-mediated cytoskeleton rearrangement.In contrast,free cellular spike protein is selectively cleaved into S1 and s2 subunits in a lysosomal-dependent manner.Importantly,we show that the pan-PAK inhibitor FRAX-486 restores ACE2 surface expression and suppresses infection by different SARS-CoV-2 strains.FRAX-486-treated Syrian hamsters exhibit significantly decreased lung viral load and alleviated pulmonary inflammation compared with untreated hamsters.In summary,our findings have identified novel pathways regulating viral entry,as well as therapeutic targets and candidate compounds for controlling the emerging strains of SARS-CoV-2 infection.