Molecular mechanisms underlying roles of long non-coding RNA small nucleolar RNA host gene 16 in digestive system cancers

This editorial reviews the molecular mechanisms underlying the roles of the long non-coding RNA(lncRNA)small nucleolar RNA host gene 16(SNHG16)in digestive system cancers based on two recent studies on lncRNAs in digestive system tumors.The first study,by Zhao et al,explored how hBD-1 affects colon cancer,via the lncRNA TCONS_00014506,by inhibiting mTOR and promoting autophagy.The second one,by Li et al,identified the lncRNA prion protein testis specific(PRNT)as a factor in oxaliplatin resistance by sponging ZNF184 to regulate HIPK2 and influence colorectal cancer progression and chemoresistance,suggesting PRNT as a potential therapeutic target for colorectal cancer.Both of these two articles discuss the mechanisms by which lncRNAs contribute to the development and progression of digestive system cancers.As a recent research hotspot,SNHG16 is a typical lncRNA that has been extensively studied for its association with digestive system cancers.The prevailing hypothesis is that SNHG16 participates in the development and progression of digestive system tumors by acting as a competing endogenous RNA,interacting with other proteins,regulating various genes,and affecting downstream target molecules.This review systematically examines the recently reported biological functions,related molecular mechanisms,and potential clinical significance of SNHG16 in various digestive system cancers,and explores the relationship between SNHG16 and digestive system cancers.The findings suggest that SNHG16 may serve as a potential biomarker and therapeutic target for human digestive system cancers.

Evaluation of intermittent-distributed-generation hosting capability of a distribution system with integrated energy-storage systems

The penetration rate of distributed generation is gradually increasing in the distribution system concerned.This is creating new problems and challenges in the planning and operation of the system.The intermittency and variability of power outputs from numerous distributed renewable generators could significantly jeopardize the secure operation of the distribution system.Therefore,it is necessary to assess the hosting capability for intermittent distributed generation by a distribution system considering operational constraints.This is the subject of this study.An assessment model considering the uncertainty of generation outputs from distributed generators is presented for this purpose.It involves different types of regulation or control functions using on-load tap-changers(OLTCs),reactive power compensation devices,energy storage systems,and the reactive power support of the distributed generators employed.A robust optimization model is then attained It is solved by Bertsimas robust counterpart through GUROBI solver.Finally,the feasibility and efficiency of the proposed method are demonstrated by a modified IEEE 33-bus distribution system.In addition,the effects of the aforementioned regulation or control functions on the enhancement of the hosting capability for intermittent distributed generation are examined.

Towards system genetics analysis of head and neck squamous cell carcinoma using the mouse model,cellular platform,and clinical human data

Head and neck squamous cell cancer(HNSCC)is a leading global malignancy.Every year,More than 830000 people are diagnosed with HNSCC globally,with more than 430000 fatalities.HNSCC is a deadly diverse malignancy with many tumor locations and biological characteristics.It originates from the squamous epithelium of the oral cavity,oropharynx,nasopharynx,larynx,and hypopharynx.The most frequently impacted regions are the tongue and larynx.Previous investigations have demonstrated the critical role of host genetic susceptibility in the progression of HNSCC.Despite the advances in our knowledge,the improved survival rate of HNSCC patients over the last 40 years has been limited.Failure to identify the molecular origins of development of HNSCC and the genetic basis of the disease and its biological heterogeneity impedes the development of new therapeutic methods.These results indicate a need to identify more genetic factors underlying this complex disease,which can be better used in early detection and prevention strategies.The lack of reliable animal models to investigate the underlying molecular processes is one of the most significant barriers to understanding HNSCC tumors.In this report,we explore and discuss potential research prospects utilizing the Collaborative Cross mouse model and crossing it to mice carrying single or double knockout genes(e.g.Smad 4 and P53 genes)to identify genetic factors affecting the development of this complex disease using genome-wide association studies,epigenetics,micro RNA,long noncoding RNA,lnc RNA,histone modifications,methylation,phosphorylation,and proteomics.

A Proposed Architecture for Local-Host and AWS with Multiagent System

Cloud computing has become one of the leading technologies in the world today.The benefits of cloud computing affect end users directly.There are several cloud computing frameworks,and each has ways of monitoring and providing resources.Cloud computing eliminates customer requirements such as expensive system configuration and massive infrastructure while improving dependability and scalability.From the user’s perspective,cloud computing makes it easy to upload multiagents and operate on different web services.In this paper,the authors used a restful web service and an agent system to discuss,deployments,and analysis of load performance parameters like memory use,cen-tral processing unit(CPU)utilization,network latency,etc.,both on localhost and an Amazon Web Service Elastic Cloud Computing(AWS-EC2)server.The Java Agent Development Environment(JADE)tool has been used to propose an archi-tecture and conduct a comparative study on both local and remote servers.JADE is an open-source tool for maintaining applications on AWS infrastructure.The focus of the study should be to reduce the complexity and time of load perfor-mance parameters by using an agent system on a cloud server instead of establish-ing a massive infrastructure on a local system,even for a small application.

Carbon-based interface engineering and architecture design for high-performance lithium metal anodes

Metallic lithium(Li)is considered the“Holy Grail”anode material for the nextgeneration of Li batteries with high energy density owing to the extraordinary theoretical specific capacity and the lowest negative electrochemical potential.However,owing to inhomogeneous Li-ion flux,Li anodes undergo uncontrollable Li deposition,leading to limited power output and practical applications.Carbon materials and their composites with controllable structures and properties have received extensive attention to guide the homogeneous growth of Li to achieve high-performance Li anodes.In this review,the correlation between the behavior of Li anode and the properties of carbon materials is proposed.Subsequently,we review emerging strategies for rationally designing high-performance Li anodes with carbon materials,including interface engineering(stabilizing solid electrolyte interphase layer and other functionalized interfacial layer)and architecture design of host carbon(constructing three-dimension structure,preparing hollow structure,introducing lithiophilic sites,optimizing geometric effects,and compositing with Li).Based on the insights,some prospects on critical challenges and possible future research directions in this field are concluded.It is anticipated that further innovative works on the fundamental chemistry and theoretical research of Li anodes are needed.

Stable immobilization of lithium polysulfides using three-dimensional ordered mesoporous Mn_(2)O_(3) as the host material in lithium-sulfur batteries

Lithium-sulfur batteries(LSBs)have drawn significant attention owing to their high theoretical discharge capacity and energy density.However,the dissolution of long-chain polysulfides into the electrolyte during the charge and discharge process(“shuttle effect”)results in fast capacity fading and inferior electrochemical performance.In this study,Mn_(2)O_(3)with an ordered mesoporous structure(OM-Mn_(2)O_(3))was designed as a cathode host for LSBs via KIT-6 hard templating,to effectively inhibit the polysulfide shuttle effect.OM-Mn_(2)O_(3)offers numerous pores to confine sulfur and tightly anchor the dissolved polysulfides through the combined effects of strong polar-polar interactions,polysulfides,and sulfur chain catenation.The OM-Mn_(2)O_(3)/S composite electrode delivered a discharge capacity of 561 mAh g^(-1) after 250 cycles at 0.5 C owing to the excellent performance of OM-Mn_(2)O_(3).Furthermore,it retained a discharge capacity of 628mA h g^(-1) even at a rate of 2 C,which was significantly higher than that of a pristine sulfur electrode(206mA h g^(-1)).These findings provide a prospective strategy for designing cathode materials for high-performance LSBs.

Myotis bat STING attenuates aging-related inflammation in female mice

Bats,notable as the only flying mammals,serve as natural reservoir hosts for various highly pathogenic viruses in humans(e.g.,SARS-CoV and Ebola virus).Furthermore,bats exhibit an unparalleled longevity among mammals relative to their size,particularly the Myotis bats,which can live up to 40 years.However,the mechanisms underlying these distinctive traits remain incompletely understood.In our prior research,we demonstrated that bats exhibit dampened STING-interferon activation,potentially conferring upon them the capacity to mitigate virus-or aging-induced inflammation.To substantiate this hypothesis,we established the first in vivo bat-mouse model for aging studies by integrating Myotis davidii bat STING(MdSTING)into the mouse genome.We monitored the genotypes of these mice and performed a longitudinal comparative transcriptomic analysis on MdSTING and wild-type mice over a 3-year aging process.Blood transcriptomic analysis indicated a reduction in aging-related inflammation in female MdSTING mice,as evidenced by significantly lower levels of pro-inflammatory cytokines and chemokines,immunopathology,and neutrophil recruitment in aged female MdSTING mice compared to aged wild-type mice in vivo.These results indicated that MdSTING knock-in attenuates the aging-related inflammatory response and may also improve the healthspan in mice in a sex-dependent manner.Although the underlying mechanism awaits further study,this research has critical implications for bat longevity research,potentially contributing to our comprehension of healthy aging in humans.

Synergizing 3D-printed structure and sodiophilic interface enables highly efficient sodium metal anodes

Sodium(Na)metal batteries have gained increasing attention more recently,owing to their high energy densities and cost efficiencies,but are severely handicapped by the unsatisfactory Coulombic efficiency(CE)and cycling stability stemming from dendrite growth on Na anodes.In this study,we developed a strategy of direct ink writing(DIW)3D printing combined with electroless deposition to construct a hierarchical Cu grid coated with a dense nanoscale Ag interfacial layer as the host material for Na plating.The sodiophilic Ag interface contributes to a fall in the Na nucleation energy,hence enabling uniform Na deposition on each 3D-printed filament.The constructed 3D-printed structure can effectively moderate the electric-field distribution and lower the local current density for relieving Na inhomogeneous growth,as confirmed by finite element simulation and Na plating/stripping morphology evolution results.In particular,the unique 3D structure also promotes the lateral growth of Na,thus the volume change of Na metal was accommodated to stabilize the solid electrolyte interphase(SEI).As a result,the CE of the half-cell can reach 99.9%at the current density of 1 m A/cm^(2)after 300 cycles and the full-cell exhibits outstanding electrochemical performance(capacity retention of 91.0%after 500 cycles at 2 C).

Two intestinal microbiota-derived metabolites, deoxycholic acid and butyrate, synergize to enhance host defense peptide synthesis and alleviate necrotic enteritis

Background Necrotic enteritis(NE)is a major enteric disease in poultry,yet effective mitigation strategies remain elusive.Deoxycholic acid(DCA)and butyrate,two major metabolites derived from the intestinal microbiota,have independently been shown to induce host defense peptide(HDP)synthesis.However,the potential synergy between these two compounds remains unexplored.Methods To investigate the possible synergistic effect between DCA and butyrate in regulating HDP synthesis and barrier function,we treated chicken HD11 macrophage cells and jejunal explants with DCA and sodium butyrate(NaB),either individually or in combination,for 24 h.Subsequently,we performed RNA isolation and reverse transcrip-tion-quantitative PCR to analyze HDP genes as well as the major genes associated with barrier function.To further determine the synergy between DCA and NaB in enhancing NE resistance,we conducted two independent trials with Cobb broiler chicks.In each trial,the diet was supplemented with DCA or NaB on the day-of-hatch,followed by NE induction through sequential challenges with Eimeria maxima and Clostridium perfringens on d 10 and 14,respectively.We recorded animal mortality after infection and assessed intestinal lesions on d 17.The impact of DCA and NaB on the microbiota in the ileum and cecum was evaluated through bacterial 16S rRNA gene sequencing.Results We found that the combination of DCA and NaB synergistically induced multiple HDP genes in both chicken HD11 cells and jejunal explants.Additionally,the gene for claudin-1,a major tight junction protein,also exhibited synergistic induction in response to DCA and NaB.Furthermore,dietary supplementation with a combination of 0.75 g/kg DCA and 1 g/kg NaB led to a significant improvement in animal survival and a reduction in intestinal lesions compared to either compound alone in a chicken model of NE.Notably,the cecal microbiota of NE-infected chickens showed a marked decrease in SCFA-producing bacteria such as Bacteroides,Faecalibacterium,and Cuneatibacter,with lactobacilli becoming the most dominant species.However,supplementation with DCA and NaB largely restored the intestinal microbiota to healthy levels.Conclusions DCA synergizes with NaB to induce HDP and claudin-1 expression and enhance NE resistance,with potential for further development as cost-effective antibiotic alternatives.

Hatching and development of maize cyst nematode Heterodera zeae infecting different plant hosts

The occurrence, distribution, and rapid molecular detection technology of Heterodera zeae Koshy et al. 1971, have been reported in China. We explored the biological characteristics of H. zeae sampled in Henan Province, China to understand its interaction with plants. Cysts and second-stage juveniles(J2s) were identified under an optical and scanning electron microscope, internal transcribed spacer(ITS) phylogenetic tree, and sequence characterized amplified region(SCAR)-PCR analyses. The optimum hatching temperatures of H. zeae were 30°C and 28°C, with cumulative hatching rates of 16.5 and 16.1%, respectively, at 30 days post-hatching(dph). The hatching rate of H. zeae eggs was improved by 20-and 50-time maize soil leachate and root juice, and 10-time root exudates. The hatching rate in 10-time root exudates was the highest(25.9%). The 10-time root exudates of maize and millet produced the highest hatching rate at 30 dph(25.9 and 22.9%, respectively), followed by wheat(19.9%), barley(18.3%), and rice(17.6%). Heterodera zeae developed faster in maize than in other crops. Fourth-stage juveniles(J4s) were detected in maize roots 8 days post-inoculation(dpi) at 28°C but not in other crops. Combined with hatching tests, the Huang–Huai–Hai summer maize region and the south and central-southwest mountainous maize areas are highly suitable for H. zeae in China. This is the first systematically study of the hatching and infection characteristics on different plant hosts of corn cyst nematode H. zeae in temperate regions. This study laid a theoretical foundation for the rapid spread and high environmental adaptability of corn cyst nematode.

Driving inward growth of lithium metal in hollow microcapsule hosts by heteroatom‐controlled nucleation

The application of Li metal anodes in rechargeable batteries is impeded by safety issues arising from the severe volume changes and formation of dendritic Li deposits.Three‐dimensional hollow carbon is receiving increasing attention as a host material capable of accommodating Li metal inside its cavity;however,uncontrollable and nonuniform deposition of Li remains a challenge.In this study,we synthesize metal–organic framework‐derived carbon microcapsules with heteroatom clusters(Zn and Ag)on the capsule walls and it is demonstrated that Ag‐assisted nucleation of Li metal alters the outward‐to‐inward growth in the microcapsule host.Zn‐incorporated microcapsules are prepared via chemical etching of zeolitic imidazole framework‐8 polyhedra and are subsequently decorated with Ag by a galvanic displacement reaction between Ag^(+) and metallic Zn.Galvanically introduced Ag significantly reduces the energy barrier and increases the reaction rate for Li nucleation in the microcapsule host upon Li plating.Through combined electrochemical,microstructural,and computational studies,we verify the beneficial role of Ag‐assisted Li nucleation in facilitating inward growth inside the cavity of the microcapsule host and,in turn,enhancing electrochemical performance.This study provides new insights into the design of reversible host materials for practical Li metal batteries.

NbN quantum dots anchored hollow carbon nanorods as efficient polysulfide immobilizer and lithium stabilizer for Li-S full batteries

The shuttle effect of lithium polysulfides(LiPSs)and uncontrollable lithium dendrite growth seriously hinder the practical application of lithium-sulfur(Li-S)batteries.To simultaneously address such issues,monodispersed Nb N quantum dots anchored on nitrogen-doped hollow carbon nanorods(NbN@NHCR)are elaborately developed as efficient Li PSs immobilizer and Li stabilizer for high-performance Li-S full batteries.Density functional theory(DFT)calculations and experimental characterizations demonstrate that the sulfiphilic and lithiophilic NbN@NHCR hybrid can not only efficiently immobilize the soluble Li PSs and facilitate diffusion-conversion kinetics for alleviating the shuttling effect,but also homogenize the distribution of Li+ions and regulate uniform Li deposition for suppressing Li-dendrite growth.As a result,the assembled Li-S full batteries(NbN@NHCR-S||Nb N@NHCR-Li)deliver excellent long-term cycling stability with a low decay rate of 0.031%per cycle over 1000 cycles at high rate of 2 C.Even at a high S loading of 5.8 mg cm^(-2)and a low electrolyte/sulfur ratio of 5.2μL mg^(-1),a large areal capacity of 6.2 mA h cm^(-2)can be achieved in Li-S pouch cell at 0.1 C.This study provides a new perspective via designing a dual-functional sulfiphilic and lithiophilic hybrid to address serious issues of the shuttle effect of S cathode and dendrite growth of Li anode.

Large-scale interplant exchange of macromolecules between soybean and dodder under nutrient stresses

Parasitic plants and their hosts communicate through haustorial connections.Nutrient deficiency is a common stress for plants,yet little is known about whether and how host plants and parasites communicate during adaptation to such nutrient stresses.In this study,we used transcriptomics and proteomics to analyze how soybean(Glycine max)and its parasitizing dodder(Cuscuta australis)respond to nitrate and phosphate deficiency(-N and-P).After-N and-P treatment,the soybean and dodder plants exhibited substantial changes of transcriptome and proteome,although soybean plants showed very few transcriptional responses to-P and dodder did not show any transcriptional changes to either-N or-P.Importantly,large-scale interplant transport of mRNAs and proteins was detected.Although the mobile mRNAs only comprised at most 0.2%of the transcriptomes,the foreign mobile proteins could reach 6.8%of the total proteins,suggesting that proteins may be the major forms of interplant communications.Furthermore,the interplant mobility of macromolecules was specifically affected by the nutrient regimes and the transport of these macromolecules was very likely independently regulated.This study provides new insight into the communication between host plants and parasites under stress conditions.

Turnip mosaic virus pathogenesis and host resistance mechanisms in Brassica

Turnip mosaic virus(TuMV)is a devastating potyvirus pathogen that infects a wide variety of both cultivated and wild Brassicaceae plants.We urgently need more information and understanding of TuMV pathogenesis and the host responses involved in disease development in cruciferous crops.TuMV displays great versatility in viral pathogenesis,especially in its replication and intercellular movement.Moreover,in the coevolutionary arms races between TuMV and its hosts,the virus has evolved to co-opt host factors to facilitate its infection and counter host defense responses.This review mainly focuses on recent advances in understanding the viral factors that contribute to the TuMV infection cycle and the host resistance mechanism in Brassica.Finally,we propose some future research directions on TuMV pathogenesis and control strategies to design durable TuMV-resistant Brassica crops.

Role of short-chain fatty acids in host physiology

Short-chain fatty acids(SCFAs)are major metabolites produced by the gut microbiota through the fermentation of dietary fiber,and they have garnered significant attention due to their close association with host health.As important mediators between the gut microbiota and the host,SCFAs serve as energy substrates for intestinal epithelial cells and maintain homeostasis in host immune and energy metabolism by influencing host epigenetics,activating G protein-coupled receptors,and inhibiting pathogenic microbial infections.This review provides a comprehensive summary of SCFAs synthesis and metabolism and offering an overview of the latest research progress on their roles in protecting gut health,enhancing energy metabolism,mitigating diseases such as cancer,obesity,and diabetes,modulating the gut-brain axis and gut-l ung axis,and promoting bone health.

Viologen-based host–guest supramolecule with tunable intramolecular/intermolecular electron transfer chromism and dynamic fluorescence

Viologen,as a type of strong electron acceptor,is prone to undergo electron transfer(ET)and change color under external stimuli.However,due to the easy aggrega-tion of viologen molecules,they usually suffer from poorfluorescence emission in the condensed phase.Herein,a new viologen derivative of VioCl_(2)⋅2Cl(1^(2+)⋅2Cl)was designed and synthesized,in which thefluorescence was enhanced by intro-ducing Me-β-CD to weaken the interactions between viologen molecules.Then a viologen-based host-guest supramolecule of 1^(2+)@Me-β-CD was obtained by elec-trostatic interactions.Photo-/chemo-responded guest 1^(2+)supplies 1^(2+)@Me-β-CD,a green and dark purple caused by intramolecular and intermolecular ET.Further-more,1^(2+)@Me-β-CD displays an additional thermal responsive purple color.The triple chromic behaviors all exhibit excellent reversibility and cycling stability.As expected,1^(2+)@Me-β-CD exhibits strong photoluminescence(PL)in solid-liquid dual states,presenting an improved quantum yield(Φ)from 1^(2+)(Φ_(s)=0.37%,Φ_(1)= 16.74%)to=1^(2+)@Me-β-CD(Φ_(s)= 10.45%,Φ_(1)= 25.86%),and thefluores-=cence intensity can be dynamically modulated by light,heat,and acid/base vapors.The multi-responsive chromism and tunablefluorescence of 1^(2+)@Me-β-CD allow for potential applications in information security and smart windows.

Isolation of a feline-derived feline panleukopenia virus with an A300P substitution in the VP2 protein and confrmation of its pathogenicity in dogs

Feline panleukopenia virus(FPV)is a single-stranded DNA virus that can infect cats and cause feline panleukopenia,which is a highly contagious and fatal disease in felines.The sequence of FPV is highly variable,and mutations in the amino acids of its capsid protein play crucial roles in altering viral virulence,immunogenicity,host selection,and other abilities.In this study,the epidemiology of FPV was studied using 746 gastrointestinal swab samples derived from cats that presented gastrointestinal symptoms specifcally,diarrhea or vomiting during the period spanning from 2018 to 2022.The overall prevalence of FPV-positive patients among these samples was determined to be 45.4%.Capsid(virion)protein 2(VP2)gene of each FPV-positive sample was sequenced and amplifed,yielding 65 VP2 sequences.Among them,six VP2 gene sequences were detected in the majority of the samples test positive for FPV,and these positive samples originated from a diverse range of geographical locations.These isolates were named FPV-6,FPV-10,FPV-15,FPV-251,FPV-271 and FPV-S2.Additionally,the substitution of Ala300Pro(A300P)in VP2 was detected for the frst time in feline-derived FPV(FPV-251).FPV-251 isolate,with this substitution in VP2 protein,exhibited stable proliferative capacity in Madin-Darby canine kidney(MDCK)cells and A72 cells.FPV-271 was selected as the FPV control isolate due to its single amino acid diference from VP2 protein of FPV-251 at position 300(FPV-271 has alanine,while FPV-251 has proline).After oral infection,both FPV-251 and FPV-271 isolates caused feline panleukopenia,which is characterized by clinical signs of enterocolitis.However,FPV-251 can infect dogs through the oral route and cause gastrointestinal(GI)symptoms with lesions in the intestine and mesenteric lymph nodes(MLNs)of infected dogs.This is the frst report on the presence of an A300P substitution in VP2 protein of feline-derived FPV.Additionally,FPV isolate with a substitution of A300P at VP2 protein demonstrated efcient replication capabilities in canine cell lines and the ability to infect dogs.

Allergen degradation of bee pollen by lactic acid bacteria fermentation and its alleviatory effects on allergic reactions in BALB/c mice

Food allergy as a global health problem threatens food industry.Bee pollen(BP)is a typical food with allergenic potentials,although it performs various nutritional/pharmacological functions to humans.In this study,lactic acid bacteria(LAB)were used to ferment Brassica napus BP for alleviating its allergenicity.Four novel allergens(glutaredoxin,oleosin-B2,catalase and lipase)were identified with significant decreases in LAB-fermented BP(FBP)than natural BP by proteomics.Meanwhile,metabolomics analysis showed significant increases of 28 characteristic oligopeptides and amino acids in FBP versus BP,indicating the degradation of LAB on allergens.Moreover,FBP showed alleviatory effects in BALB/c mice,which relieved pathological symptoms and lowered production of allergic mediators.Microbial high-throughput sequencing analysis showed that FBP could regulate gut microbiota and metabolism to strengthen immunity,which were closely correlated with the alleviation of allergic reactivity.These findings could contribute to the development and utilization of hypoallergenic BP products.

Understanding host-graft crosstalk for predicting the outcome of stem cell transplantation

Mesenchymal stromal cells(MSCs)hold great promise for tissue regeneration in debilitating disorders.Despite reported improvements,the short-term outcomes of MSC transplantation,which is possibly linked to poor cell survival,demand extensive investigation.Disease-associated stress microenvironments further complicate outcomes.This debate underscores the need for a deeper understanding of the phenotypes of transplanted MSCs and their environment-induced fluctuations.Additionally,questions arise about how to predict,track,and comprehend cell fate post-transplantation.In vivo cellular imaging has emerged as a critical requirement for both short-and long-term safety and efficacy studies.However,translating preclinical imaging methods to clinical settings remains challenging.The fate and function of transplanted cells within the host environment present intricate challenges,including MSC engraftment,variability,and inconsistencies between preclinical and clinical data.The study explored the impact of high glucose concentrations on MSC survival in diabetic environments,emphasizing mitochondrial factors.Preserving these factors may enhance MSC survival,suggesting potential strategies involving genetic modification,biomaterials,and nanoparticles.Understanding stressors in diabetic patients is crucial for predicting the effects of MSC-based therapies.These multifaceted challenges call for a holistic approach involving the incorporation of large-scale data,computational disease modeling,and possibly artificial intelligence to enable deterministic insights.

Roles of host proteases in the entry of SARS-CoV-2

The spike protein(S)of SARS-CoV-2 is responsible for viral attachment and entry,thus a major factor for host suscep-tibility,tissue tropism,virulence and pathogenicity.The S is divided with S1 and S2 region,and the S1 contains the receptor-binding domain(RBD),while the S2 contains the hydrophobic fusion domain for the entry into the host cell.Numerous host proteases have been implicated in the activation of SARS-CoV-2 S through various c leavage sites.In this article,we review host proteases including furin,trypsin,transmembrane protease serine 2(TMPRSS2)and cathepsins in the activation of SARS-CoV-2 S.Many betacoronaviruses including SARS-CoV-2 have polybasic residues at the S1/S2 site which is subjected to the cleavage by furin.The S1/S2 cleavage facilitates more assessable RBD to the receptor ACE2,and the binding triggers further conformational changes and exposure of the S2'site to proteases such as type Il transmembrane serine proteases(TTPRs)including TMPRSS2.In the presence of TMPRSS2 on the target cells,SARS-CoV-2 can utilize a direct entry route by fusion of the viral envelope to the cellular membrane.In the absence of TMPRSS2,SARS-CoV-2 enter target cells via endosomes where multiple cathepsins cleave the S for the successful entry.Additional host proteases involved in the cleavage of the S were discussed.This article also includes roles of 3C-like protease inhibitors which have inhibitory activity against cathepsin L in the entry of SARS-CoV-2,and discussed the dual roles of such inhibitors in virus replication.