Alzheimer's disease(AD)is a common neurodegenerative disorder among the elderly population.There are currently no effective therapeutic drugs available,the multi-target-directed ligands(MTDLs)strategy has been con...Alzheimer's disease(AD)is a common neurodegenerative disorder among the elderly population.There are currently no effective therapeutic drugs available,the multi-target-directed ligands(MTDLs)strategy has been considered as the promising approach.Given the structural diversity of natural products,Rivastigmine's pharmacophore was integrated with diverse natural product scaffolds to construct a combinatorial compound library.This library was subsequently screened and optimized to identify a novel butyrylcholinesterase(Bu Ch E)inhibitor,compound 3c.The results showed that compound 3c exhibited favorable Bu Ch E inhibitory activity(half-maximal inhibitory concentration(IC_(50))=0.43μmol/L),potential anti-inflammatory potency,good Aβ_(1-42) aggregation inhibitory capacity and remarkable neuroprotective effects.The in vivo study exhibited that 3c significantly ameliorated AlCl_(3)-induced zebrafish AD model and scopolamine-induced memory impairment.Collectively,compound 3c was the artificial intelligence(AI)-driven promising multifunctional agent with Bu Ch E inhibition for the treatment of AD.展开更多
Coal cinder is an abundant byproduct of the extensive consumption of coal in industrial production and daily life.Making full use of the cinder is conducive to a low-carbon economy.In this study,inspired by the burnin...Coal cinder is an abundant byproduct of the extensive consumption of coal in industrial production and daily life.Making full use of the cinder is conducive to a low-carbon economy.In this study,inspired by the burning of coal,a new method for constructing a silica-based composite porous material(SiO_(2)-CPM)was developed by combusting a siloxane-modified anthracite coal gel(CSiO_(2) gel).During this process,the combustion product was directly converted into a porous material,and the calorific value of the coal remained nearly unchanged(~98%of the original calorific value was retained),demonstrating the viability of this method for energy-efficient applications.The SiO_(2)-CPM exhibited an ultra-low thermal conductivity(0.036 W/(m·K)at room temperature),outperforming conventional insulation materials(e.g.,cotton~0.05 W/(m·K)).Additionally,it showed enhanced mechanical strength(fracture stress of 41.8 kPa)compared to the powder state of the coal cinder.Experimental results indicate that the amount of siloxane,structure-directing agent,and an acidic environment were critical for mechanical enhancement.The SiO_(2)-CPM showed good dimensional stability against thermal expansion and exhibited excellent thermal insulation and fire resistance even at 900℃.Meanwhile,the SiO_(2)-CPM with complex geometry could be easily fabricated using this method owing to the excellent shaping ability of the CSiO_(2) gel.Compared to conventional methods such as sol-gel synthesis or freeze-drying,this approach for fabricating SiO_(2)-CPM is simpler and cost-effective and allows the direct utilization of coal cinder post-combustion.展开更多
Milk-derived extracellular vesicles(EVs)are promising for oral drug delivery,yet different loading methods exhibit distinct impacts on drug encapsulation and membrane integrity.This study demonstrated that sonication ...Milk-derived extracellular vesicles(EVs)are promising for oral drug delivery,yet different loading methods exhibit distinct impacts on drug encapsulation and membrane integrity.This study demonstrated that sonication method achieved high drug encapsulation in commercial milk-derived EVs(S-CM EVs),but impaired EV structure,compromising transcytosis.Incubation method(I-CM EVs)preserved EVs delivery ability,but had low drug loading.Further proteomic and transmembrane studies showed that sonication greatly damaged membrane proteins involved in trans-epithelial transportation,especially endoplasmic reticulum-Golgi pathway.To overcome this dilemma,we generated a hybrid CM EVs(H-CM EVs)by fusing I-CM EVs and S-CM EVs.H-CM EVs demonstrated comparable drug encapsulation to S-CM EVs(56.14%),significantly higher than I-CM EVs(11.92%).Importantly,H-CM EVs could maintain efficient drug delivery capability by restoring membrane fluidity,repairing damaged proteins,and enhancing enzyme resistance of SCM EVs.H-CM EVs exhibited excellent absorption characteristics with 1.85-fold higher of area under the curve and 2.50-fold higher of max plasma concentration than those of SCM EVs.On typeⅠdiabetic mice,orally delivery of insulin loaded H-CM EVs and I-CM EVs showed improved hypoglycemic effects with pharmacological availabilities of 5.15%and 5.31%,which was 1.7-fold higher than that of S-CM EVs(3.00%).This H-CM EVs platform not only achieved high drug loading and maintained functionality for effective oral delivery but also highlighted the significant translational potential for improved clinical outcomes.展开更多
Immunotherapy,particularly immune checkpoint inhibitors(ICIs)programmed death-ligand 1/programmed death-1(PD-L1/PD-1)and cytotoxic T-lymphocyte-associated antigen-4(CTLA-4),has heralded a new era of tumor treatment.Al...Immunotherapy,particularly immune checkpoint inhibitors(ICIs)programmed death-ligand 1/programmed death-1(PD-L1/PD-1)and cytotoxic T-lymphocyte-associated antigen-4(CTLA-4),has heralded a new era of tumor treatment.Although ICIs have clinical benefits,their complex heterogeneity and diverse resistance mechanisms critically limit their efficacy.Neoantigens,arising from tumor-specific alterations,offer novel targets for individualized immunotherapy,because of their high immunogenicity and tumor specificity.In the past decade,neoantigen-based tumor vaccines have been demonstrated to be a promising immunotherapy strategy to prime the tumor-specific immune response.These therapeutic vaccines include peptide vaccines,nucleic acid vaccines,and dendritic cell(DC)vaccines,and are categorized according to the neoantigen source and delivery method.In vivo,neoantigens are processed and presented by antigen-presenting cells(APCs)via the peptide-Major Histocompatibility Complex(pMHC)for T cell recognition,thereby triggering specific immune responses.Because DCs,the most potent APCs,play crucial roles in antitumor immunity,neoantigen-based DC vaccines provide a promising therapeutic strategy.A series of global clinical trials are exploring the safety,feasibility,and efficacy of neoantigen-based DC vaccines in tumors.This review focuses on current progress in clinical research on neoantigen-based DC vaccines in the treatment of solid tumors.展开更多
Surface and interface engineering plays a crucial role in modulating the properties of materials,especially two-dimensional(2D)materials.Hence,a strategy,forming heterostructures with MoS_(2),is proposed to overcome t...Surface and interface engineering plays a crucial role in modulating the properties of materials,especially two-dimensional(2D)materials.Hence,a strategy,forming heterostructures with MoS_(2),is proposed to overcome the natural agglomeration of Ti_(3)C_(2)T_(x) MXene nanosheets.Most importantly,the interactions between Ti_(3)C_(2)Tx and MoS_(2) were elaborately investigated by first-principles calculations based on density functional theory(DFT)for the first time.The calculations demonstrate that van der Waals forces dominate the interface interactions of Ti_(3)C_(2)T_(x) and MoS_(2),rendering Ti_(3)C_(2)T_(x)@MoS_(2) heterostructures favorable stability.The Ti_(3)C_(2)T_(x)@MoS_(2) heterostructure composites were synthesized through a facile one-step hydrothermal method and exhibit a 2D hierarchical structure.Furthermore,the corrosion and tribological properties of epoxy composite coatings with varying proportions of Ti_(3)C_(2)T_(x)@MoS_(2) composites were studied in detail.As a result,the epoxy composite coating with 0.1 wt.%Ti_(3)C_(2)T_(x)@MoS_(2) composites(Ti_(3)C_(2)T_(x)@MoS_(2)-0.1)exhibits excellent corrosion protection and antiwear performances.The Ti_(3)C_(2)T_(x)@MoS_(2)-0.1 keeps the largest low-frequency impedance modulus(|Z|_(0.)01 Hz)and coating resistance(R_(c))during the whole immersion period.Its wear rate is 0.09μm^(3)/(Nμm)under the load of 10 N,one half of that of pure epoxy coating(EP).This work further broadens the application of MXene-based heterostructure composites.展开更多
Exosomes,as promising vehicles,have been widely used in the research of oral drug delivery,but the generally low drug loading efficiency of exosomes seriously limits its application and transformation.In this study,we...Exosomes,as promising vehicles,have been widely used in the research of oral drug delivery,but the generally low drug loading efficiency of exosomes seriously limits its application and transformation.In this study,we systematically investigated the effects of drug loading methods and physicochemical properties(lipophilicity and molecular weight)on drug loading efficiency of milk-derived exosomes to explore the most appropriate loading conditions.Our finding revealed that the drug loading efficiency of exosomes was closely related to the drug loading method,drug lipophilicity,drug molecular weight and exosome/drug proportions.Of note,we demonstrated the universality that hydrophilic biomacromolecule drugs were the most appropriate loading drugs for milk-derived exosomes,which was attributed to the efficient loading capacity and sustained release behavior.Furthermore,milk-derived exosomes could significantly improve the transepithelial transport and oral bioavailability of model hydrophilic biomacromolecule drugs(octreotide,exendin-4 and salmon calcitonin).Collectively,our results suggested that the encapsulation of hydrophilic biomacromolecule drugs might be the most promising direction for milk exosomes as oral drug delivery vehicles.展开更多
Graphene as a lubricating additive holds great potential for industrial lubrication. However, its poor dispersity and compatibility with base oils and grease hinder maximizing performance. Here, the infuence of graphe...Graphene as a lubricating additive holds great potential for industrial lubrication. However, its poor dispersity and compatibility with base oils and grease hinder maximizing performance. Here, the infuence of graphene dispersion on the thickening efect and lubrication function is considered. A well-dispersed lubricant additive was obtained via trihexyl tetradecyl phosphonium bis(2-ethylhexyl) phosphate modifed graphene ([P_(66614)][DEHP]-G). Then lithium complex grease was prepared by saponifcation with 12-OH stearic acid, sebacic acid, and lithium hydroxide, using polyalphaolefn (PAO20) as base oil and the modifed-graphene as lubricating additive, with the original graphene as a comparison. The physicochemical properties and lubrication performance of the as-prepared greases were evaluated in detail. The results show that the as-prepared greases have high dropping point and colloidal stability. Furthermore, modifed-graphene lithium complex grease ofered the best friction reduction and anti-wear abilities, manifesting the reduction of friction coefcient and wear volume up to 18.84% and 67.34%, respectively. With base oil overfow and afux, well-dispersed [P_(66614)][DEHP]-G was readily adsorbed to the worn surfaces, resulting in the formation of a continuous and dense graphene deposition flm. The synergy of deposited graphene-flm, spilled oil, and adhesive grease greatly improves the lubrication function of grease. This research paves the way for modulating high-performance lithium complex grease to reduce the friction and wear of movable machinery.展开更多
Adolescent binge drinking leads to long-lasting disorders of the adult central nervous system,particularly aberrant hippocampal neurogenesis.In this study,we applied in vivo fluorescent tracing using NestinCreERT2::Ro...Adolescent binge drinking leads to long-lasting disorders of the adult central nervous system,particularly aberrant hippocampal neurogenesis.In this study,we applied in vivo fluorescent tracing using NestinCreERT2::Rosa26-tdTomato mice and analyzed the endogenous neurogenesis lineage progression of neural stem cells(NSCs)and dendritic spine formation of newborn neurons in the subgranular zone of the dentate gyrus.We found abnormal orientation of tamoxifen-induced tdTomato+(tdTom^(+))NSCs in adult mice 2 months after treatment with EtOH(5.0 g/kg,i.p.)for 7 consecutive days.EtOH markedly inhibited tdTom^(+)NSCs activation and hippocampal neurogenesis in mouse dentate gyrus from adolescence to adulthood.EtOH(100 mM)also significantly inhibited the proliferation to 39.2%and differentiation of primary NSCs in vitro.Adult mice exposed to EtOH also exhibited marked inhibitions in dendritic spine growth and newborn neuron maturation in the dentate gyrus,which was partially reversed by voluntary running or inhibition of the mammalian target of rapamycinenhancer of zeste homolog 2 pathway.In vivo tracing revealed that EtOH induced abnormal orientation of tdTom+NSCs and spatial misposition defects of newborn neurons,thus causing the disturbance of hippocampal neurogenesis and dendritic spine remodeling in mice.展开更多
The dysregulation of exosomal microRNAs(miRNAs)plays a crucial role in the development and progression of cancer.This study investigated the role of a newly identified serum exosomal miRNA miR-4256 in gastric cancer(G...The dysregulation of exosomal microRNAs(miRNAs)plays a crucial role in the development and progression of cancer.This study investigated the role of a newly identified serum exosomal miRNA miR-4256 in gastric cancer(GC)and the underlying mechanisms.The differentially expressed miRNAs were firstly identified in serum exosomes of GC patients and healthy individuals using next-generation sequencing and bioinformatics.Next,the expression of serum exosomal miR-4256 was analyzed in GC cells and GC tissues,and the role of miR-4256 in GC was investigated by in vitro and in vivo experiments.Then,the effect of miR-4256 on its downstream target genes HDAC5/p16^(INK4a) was studied in GC cells,and the underlying mechanisms were evaluated using dual luciferase reporter assay and Chromatin Immunoprecipitation(ChIP).Additionally,the role of the miR-4256/HDAC5/p16^(INK4a) axis in GC was studied using in vitro and in vivo experiments.Finally,the upstream regulators SMAD2/p300 that regulate miR-4256 expression and their role in GC were explored using in vitro experiments.miR-4256 was the most significantly upregulated miRNA and was overexpressed in GC cell lines and GC tissues;in vitro and in vivo results showed that miR-4256 promoted GC growth and progression.Mechanistically,miR-4256 enhanced HDAC5 expression by targeting the promoter of the HDAC5 gene in GC cells,and then restrained the expression of p16^(INK4a) through the epigenetic modulation of HDAC5 at the p16INK4a promoter.Furthermore,miR-4256 overexpression was positively regulated by the SMAD2/p300 complex in GC cells.Our data indicate that miR-4256 functions as an oncogene in GC via the SMAD2/miR-4256/HDAC5/p16^(INK4a) axis,which participates in GC progression and provides novel therapeutic and prognostic biomarkers for GC.展开更多
Shape Memory Alloy(SMA)is a typical material with memory effect,and it is widely used in many engineering fields.Based on the elastic theory and Galerkin method,a vibration system of SMA beam with rigid constraints is...Shape Memory Alloy(SMA)is a typical material with memory effect,and it is widely used in many engineering fields.Based on the elastic theory and Galerkin method,a vibration system of SMA beam with rigid constraints is proposed.The non⁃smooth transformation was employed to deal with the discontinuous position,and the original system was turned into an approximate equivalent system associated with the Dirac function.Then,using the stochastic averaging method,the drift and diffusion coefficients of the corresponding Fokker Planck Kolmogorov equation were described.Lastly,the approximate probability response of the system was formulated analytically.Meanwhile,numerical simulation was carried out to verify the effectiveness of analytical results.Furthermore,stochastic bifurcation was discussed.Results show that the stationary probability response of the system was affected by the increase of noise amplitude and restitution force,and a certain restitution value and damping could induce P⁃bifurcation.展开更多
The purpose of this study was to develop poly(amidoamine)(PAMAM)-functionalized multi-walled carbon nanotubes(MWNTs)loaded with a poorly water-soluble drug,intended to improve the drug-loading capacity,dissolution an...The purpose of this study was to develop poly(amidoamine)(PAMAM)-functionalized multi-walled carbon nanotubes(MWNTs)loaded with a poorly water-soluble drug,intended to improve the drug-loading capacity,dissolution and design a sustained release system.MWNTs were modified with a carboxyl group by acid treatment and then complex with PAMAM.PAMAM-MWNTs were investigated as a scaffold for loading the model drug,Carvedilol(CAR),using three different methods(the fusion method,the incipient wetness impregnation method,and the solvent method).The effects of different pore size,specific surface area and physical state were systematically studied using FT-IR,TGA,SEM,DSC,nitrogen adsorption,XPS and XRD.All the samples made by PAMAM-MWNTs to load the drug had a marked effect on the drug-loading capacity as well as drug dissolution,especially theⅡ-30%.展开更多
Background Kabukisyndrome(KS)is arare developmental disorder characterised by multiple congenital anomalies and intellectual disability.UTX(ubiquitously transcribed tetratricopeptide repeat,X chromosome),which encodes...Background Kabukisyndrome(KS)is arare developmental disorder characterised by multiple congenital anomalies and intellectual disability.UTX(ubiquitously transcribed tetratricopeptide repeat,X chromosome),which encodes a histone demethylase,is one of the two major pathogenic risk genes for KS.Although intellectual disability is a key phenotype of KS,the role of UTX in cognitive function remains unclear.Currently,no targeted therapies are available for KS.Aims This study aimed to investigate how UTX regulates cognition,to explore the mechanisms underlying UTX dysfunction and to identify potential molecular targets for treatment.Methods WegeneratedUTXconditional knockoutmice and found that UTX deletion downregulated calmodulin transcription by disrupting H3K27me3(trimethylated histone H3 at lysine 27)demethylation.Results UTX-knockout mice showeddecreased phosphorylation of calcium/calmodulin-dependent protein kinase I,impaired long-term potentiation and deficit in remote contextual fear memory.These effects were reversed by an Food and Drug Administration-approved drug desipramine.Conclusions Our results reveal an epigenetic mechanism underlying the important role of UTX in synaptic plasticity and cognitive function,and suggest that desipramine could be a potential treatment for KS.展开更多
The identification and optimization of mutations in nanobodies are crucial for enhancing their thera-peutic potential in disease prevention and control.However,this process is often complex and time-consuming,which li...The identification and optimization of mutations in nanobodies are crucial for enhancing their thera-peutic potential in disease prevention and control.However,this process is often complex and time-consuming,which limit its widespread application in practice.In this study,we developed a work-flow,named Evolutionary-Nanobody(EvoNB),to predict key mutation sites of nanobodies by combining protein language models(PLMs)and molecular dynamic(MD)simulations.By fine-tuning the ESM2 model on a large-scale nanobody dataset,the ability of EvoNB to capture specific sequence features of nanobodies was significantly enhanced.The fine-tuned EvoNB model demonstrated higher predictive accuracy in the conserved framework and highly variable complementarity-determining regions of nanobodies.Additionally,we selected four widely representative nanobodyeantigen complexes to verify the predicted effects of mutations.MD simulations analyzed the energy changes caused by these mu-tations to predict their impact on binding affinity to the targets.The results showed that multiple mu-tations screened by EvoNB significantly enhanced the binding affinity between nanobody and its target,further validating the potential of this workflow for designing and optimizing nanobody mutations.Additionally,sequence-based predictions are generally less dependent on structural absence,allowing them to be more easily integrated with tools for structural predictions,such as AlphaFold 3.Through mutation prediction and systematic analysis of key sites,we can quickly predict the most promising variants for experimental validation without relying on traditional evolutionary or selection processes.The EvoNB workflow provides an effective tool for the rapid optimization of nanobodies and facilitates the application of PLMs in the biomedical field.展开更多
Objective This study aimed to investigate possible serum 25-hydroxyvitamin D[25(OH)D]cutoffs for the associations between 25(OH)D and Bone turnover markers(BTMs),and how GC gene variation influences such cutoffs in Ch...Objective This study aimed to investigate possible serum 25-hydroxyvitamin D[25(OH)D]cutoffs for the associations between 25(OH)D and Bone turnover markers(BTMs),and how GC gene variation influences such cutoffs in Chinese women of childbearing age.Methods In total,1,505 non-pregnant or non-lactating women(18–45 years)were recruited from the 2015 Chinese Adult Chronic Disease and Nutrition Surveillance.Serum 25(OH)D,osteocalcin(OC),procollagen type 1 N-terminal propeptide(P1NP),β-CrossLaps of type 1 collagen containing cross-linked C-telopeptide(β-CTX),and single nucleotide polymorphisms were determined.Locally weighted regression and smoothing scatterplot and segmented regression were performed to estimate the 25(OH)D thresholds.Results The median serum 25(OH)D was 16.63(11.96–22.55)ng/mL and the prevalence of low serum 25(OH)D(<12 ng/mL)was 25.2%.Women with the lowest 25(OH)D had the highestβ-CTX.After adjustment for the confounders,25(OH)D cutoffs for OC[14.04(12.84–15.23)ng/mL],β-CTX[13.94(12.49–15.39)ng/mL],and P1NP[13.87(12.37–15.37)ng/mL]in the whole population,cutoffs for OC[12.30(10.68–13.91)ng/mL],β-CTX[12.23(10.22–14.23)ng/mL],and P1NP[11.85(10.40–13.31)ng/mL]in women with the GC rs2282679 G allele,and cutoffs for OC[12.75(11.81–13.68)ng/mL],β-CTX[13.05(11.78–14.32)ng/mL],and P1NP[12.81(11.57–14.06)ng/mL]in women with the GC rs2282679 T allele,were observed.Below these cutoffs,BTMs were negatively associated with 25(OH)D,while above these cutoffs,BTMs plateaued.Conclusion In Chinese women of childbearing age,there were thresholds effect of serum 25(OH)D concentrations on BTMs.The results indicated that serum 25(OH)D concentrations<13.87 ng/mL in this population had adverse influences on maintaining bone remodeling.BTMs were suppressed at a relatively lower serum 25(OH)D in women with the GC rs2282679 G allele compared with those with the T allele.展开更多
Heat stress,a major challenge in modern agriculture due to global warming,significantly reduces crop productivity.To mitigate its adverse effects on maize yield,it is crucial to understand the mechanisms by which heat...Heat stress,a major challenge in modern agriculture due to global warming,significantly reduces crop productivity.To mitigate its adverse effects on maize yield,it is crucial to understand the mechanisms by which heat stress impacts reproductive development.This study investigated the impact of heat stress during the 12th leaf(V12)stage,where silk development begins on grain yield formation,using heat-sensitive and heat-tolerant cultivars.Compared to pollen,silks were found to be more vulnerable to heat stress.Heat stress disrupted hormone balance and inhibited hormone signaling transduction pathways in silks,delaying silk emergence from bracts and reducing fertilization and grain yield.The heat-tolerant cultivar maintained silk growth by activating more response pathways,displaying faster hormone responses,and up-regulating hormones.Taken together,we propose that hormones play an essential role in silk development and later fertilization process.展开更多
Hydrogen energy has been recognized as “Ultimate Power Source” in the 21st century, which could be the best solution to the looming energy crisis and climate degeneration in the near future. Due to its high safety, ...Hydrogen energy has been recognized as “Ultimate Power Source” in the 21st century, which could be the best solution to the looming energy crisis and climate degeneration in the near future. Due to its high safety, low price, abundant resources and decent hydrogen storage density, magnesium based solid-state hydrogen storage materials are becoming the leading candidate for onboard hydrogen storage. However,the high operation temperature and slow reaction rate of MgH_(2), as a result of the large formation enthalpy and high reaction activation energy,respectively, are the first and most difficult problems we need to face and overcome to realize its industrialization. Herein, a state-of-the-art review on tailoring the stable thermodynamics and sluggish kinetics of hydrogen storage in MgH_(2), particularly through nanoengnieering and catalysis is presented, aiming to provide references and solutions for its promotion and application. Promising methods to overcome the challenges faced by MgH_(2)/Mg, such as bidirectional catalysts and nanoconfinement with in-situ catalysis are compared and the required improvements are discussed to stimulate further discussions and ideas in the rational design of MgH_(2)/Mg systems with ability for hydrogen release/uptake at lower temperatures and cycle stability in the near future.展开更多
基金financially supported by the China Postdoctoral Science Foundation(No.2022M712153)The National Natural Science Foundation of China(Nos.22367007 and 82304384)+1 种基金The Fundamental Research Funds for Hainan University(No.KYQD(ZR)23002)Hainan Provincial Natural Science Foundation of China(No.824RC500)。
文摘Alzheimer's disease(AD)is a common neurodegenerative disorder among the elderly population.There are currently no effective therapeutic drugs available,the multi-target-directed ligands(MTDLs)strategy has been considered as the promising approach.Given the structural diversity of natural products,Rivastigmine's pharmacophore was integrated with diverse natural product scaffolds to construct a combinatorial compound library.This library was subsequently screened and optimized to identify a novel butyrylcholinesterase(Bu Ch E)inhibitor,compound 3c.The results showed that compound 3c exhibited favorable Bu Ch E inhibitory activity(half-maximal inhibitory concentration(IC_(50))=0.43μmol/L),potential anti-inflammatory potency,good Aβ_(1-42) aggregation inhibitory capacity and remarkable neuroprotective effects.The in vivo study exhibited that 3c significantly ameliorated AlCl_(3)-induced zebrafish AD model and scopolamine-induced memory impairment.Collectively,compound 3c was the artificial intelligence(AI)-driven promising multifunctional agent with Bu Ch E inhibition for the treatment of AD.
基金supported by the National Natural Science Foundation of China(No.52573220)the National Key R&D Program of China(No.2023YFC3404201)+1 种基金the Fundamental Research Funds for the Central Universities(No.FRF-IDRY-GD24-005)the State Key Laboratory of Solid Waste Reuse for Building Materials(No.SWR-2022-009).
文摘Coal cinder is an abundant byproduct of the extensive consumption of coal in industrial production and daily life.Making full use of the cinder is conducive to a low-carbon economy.In this study,inspired by the burning of coal,a new method for constructing a silica-based composite porous material(SiO_(2)-CPM)was developed by combusting a siloxane-modified anthracite coal gel(CSiO_(2) gel).During this process,the combustion product was directly converted into a porous material,and the calorific value of the coal remained nearly unchanged(~98%of the original calorific value was retained),demonstrating the viability of this method for energy-efficient applications.The SiO_(2)-CPM exhibited an ultra-low thermal conductivity(0.036 W/(m·K)at room temperature),outperforming conventional insulation materials(e.g.,cotton~0.05 W/(m·K)).Additionally,it showed enhanced mechanical strength(fracture stress of 41.8 kPa)compared to the powder state of the coal cinder.Experimental results indicate that the amount of siloxane,structure-directing agent,and an acidic environment were critical for mechanical enhancement.The SiO_(2)-CPM showed good dimensional stability against thermal expansion and exhibited excellent thermal insulation and fire resistance even at 900℃.Meanwhile,the SiO_(2)-CPM with complex geometry could be easily fabricated using this method owing to the excellent shaping ability of the CSiO_(2) gel.Compared to conventional methods such as sol-gel synthesis or freeze-drying,this approach for fabricating SiO_(2)-CPM is simpler and cost-effective and allows the direct utilization of coal cinder post-combustion.
基金financial support from the the Regional Innovation and Development Joint Fund of National Natural Science Foundation of China(grant numbers:U22A20356)the National Key R&D Program of China(No.2021YFE0115200)the National Natural Science Foundation of China(No.81872818).
文摘Milk-derived extracellular vesicles(EVs)are promising for oral drug delivery,yet different loading methods exhibit distinct impacts on drug encapsulation and membrane integrity.This study demonstrated that sonication method achieved high drug encapsulation in commercial milk-derived EVs(S-CM EVs),but impaired EV structure,compromising transcytosis.Incubation method(I-CM EVs)preserved EVs delivery ability,but had low drug loading.Further proteomic and transmembrane studies showed that sonication greatly damaged membrane proteins involved in trans-epithelial transportation,especially endoplasmic reticulum-Golgi pathway.To overcome this dilemma,we generated a hybrid CM EVs(H-CM EVs)by fusing I-CM EVs and S-CM EVs.H-CM EVs demonstrated comparable drug encapsulation to S-CM EVs(56.14%),significantly higher than I-CM EVs(11.92%).Importantly,H-CM EVs could maintain efficient drug delivery capability by restoring membrane fluidity,repairing damaged proteins,and enhancing enzyme resistance of SCM EVs.H-CM EVs exhibited excellent absorption characteristics with 1.85-fold higher of area under the curve and 2.50-fold higher of max plasma concentration than those of SCM EVs.On typeⅠdiabetic mice,orally delivery of insulin loaded H-CM EVs and I-CM EVs showed improved hypoglycemic effects with pharmacological availabilities of 5.15%and 5.31%,which was 1.7-fold higher than that of S-CM EVs(3.00%).This H-CM EVs platform not only achieved high drug loading and maintained functionality for effective oral delivery but also highlighted the significant translational potential for improved clinical outcomes.
文摘Immunotherapy,particularly immune checkpoint inhibitors(ICIs)programmed death-ligand 1/programmed death-1(PD-L1/PD-1)and cytotoxic T-lymphocyte-associated antigen-4(CTLA-4),has heralded a new era of tumor treatment.Although ICIs have clinical benefits,their complex heterogeneity and diverse resistance mechanisms critically limit their efficacy.Neoantigens,arising from tumor-specific alterations,offer novel targets for individualized immunotherapy,because of their high immunogenicity and tumor specificity.In the past decade,neoantigen-based tumor vaccines have been demonstrated to be a promising immunotherapy strategy to prime the tumor-specific immune response.These therapeutic vaccines include peptide vaccines,nucleic acid vaccines,and dendritic cell(DC)vaccines,and are categorized according to the neoantigen source and delivery method.In vivo,neoantigens are processed and presented by antigen-presenting cells(APCs)via the peptide-Major Histocompatibility Complex(pMHC)for T cell recognition,thereby triggering specific immune responses.Because DCs,the most potent APCs,play crucial roles in antitumor immunity,neoantigen-based DC vaccines provide a promising therapeutic strategy.A series of global clinical trials are exploring the safety,feasibility,and efficacy of neoantigen-based DC vaccines in tumors.This review focuses on current progress in clinical research on neoantigen-based DC vaccines in the treatment of solid tumors.
基金financially supported by the National Natural Science Foundation of China(No.52075458)the Sichuan Science and Technology Program(No.2021JDRC0094)。
文摘Surface and interface engineering plays a crucial role in modulating the properties of materials,especially two-dimensional(2D)materials.Hence,a strategy,forming heterostructures with MoS_(2),is proposed to overcome the natural agglomeration of Ti_(3)C_(2)T_(x) MXene nanosheets.Most importantly,the interactions between Ti_(3)C_(2)Tx and MoS_(2) were elaborately investigated by first-principles calculations based on density functional theory(DFT)for the first time.The calculations demonstrate that van der Waals forces dominate the interface interactions of Ti_(3)C_(2)T_(x) and MoS_(2),rendering Ti_(3)C_(2)T_(x)@MoS_(2) heterostructures favorable stability.The Ti_(3)C_(2)T_(x)@MoS_(2) heterostructure composites were synthesized through a facile one-step hydrothermal method and exhibit a 2D hierarchical structure.Furthermore,the corrosion and tribological properties of epoxy composite coatings with varying proportions of Ti_(3)C_(2)T_(x)@MoS_(2) composites were studied in detail.As a result,the epoxy composite coating with 0.1 wt.%Ti_(3)C_(2)T_(x)@MoS_(2) composites(Ti_(3)C_(2)T_(x)@MoS_(2)-0.1)exhibits excellent corrosion protection and antiwear performances.The Ti_(3)C_(2)T_(x)@MoS_(2)-0.1 keeps the largest low-frequency impedance modulus(|Z|_(0.)01 Hz)and coating resistance(R_(c))during the whole immersion period.Its wear rate is 0.09μm^(3)/(Nμm)under the load of 10 N,one half of that of pure epoxy coating(EP).This work further broadens the application of MXene-based heterostructure composites.
基金The authors gratefully acknowledge financial support from National Natural Science Foundation of China(81872818)National Key R&D Program of China(2021YFE0115200).
文摘Exosomes,as promising vehicles,have been widely used in the research of oral drug delivery,but the generally low drug loading efficiency of exosomes seriously limits its application and transformation.In this study,we systematically investigated the effects of drug loading methods and physicochemical properties(lipophilicity and molecular weight)on drug loading efficiency of milk-derived exosomes to explore the most appropriate loading conditions.Our finding revealed that the drug loading efficiency of exosomes was closely related to the drug loading method,drug lipophilicity,drug molecular weight and exosome/drug proportions.Of note,we demonstrated the universality that hydrophilic biomacromolecule drugs were the most appropriate loading drugs for milk-derived exosomes,which was attributed to the efficient loading capacity and sustained release behavior.Furthermore,milk-derived exosomes could significantly improve the transepithelial transport and oral bioavailability of model hydrophilic biomacromolecule drugs(octreotide,exendin-4 and salmon calcitonin).Collectively,our results suggested that the encapsulation of hydrophilic biomacromolecule drugs might be the most promising direction for milk exosomes as oral drug delivery vehicles.
基金Supported by National Natural Science Foundation of China(Grant Nos.52075458 and U2141211).
文摘Graphene as a lubricating additive holds great potential for industrial lubrication. However, its poor dispersity and compatibility with base oils and grease hinder maximizing performance. Here, the infuence of graphene dispersion on the thickening efect and lubrication function is considered. A well-dispersed lubricant additive was obtained via trihexyl tetradecyl phosphonium bis(2-ethylhexyl) phosphate modifed graphene ([P_(66614)][DEHP]-G). Then lithium complex grease was prepared by saponifcation with 12-OH stearic acid, sebacic acid, and lithium hydroxide, using polyalphaolefn (PAO20) as base oil and the modifed-graphene as lubricating additive, with the original graphene as a comparison. The physicochemical properties and lubrication performance of the as-prepared greases were evaluated in detail. The results show that the as-prepared greases have high dropping point and colloidal stability. Furthermore, modifed-graphene lithium complex grease ofered the best friction reduction and anti-wear abilities, manifesting the reduction of friction coefcient and wear volume up to 18.84% and 67.34%, respectively. With base oil overfow and afux, well-dispersed [P_(66614)][DEHP]-G was readily adsorbed to the worn surfaces, resulting in the formation of a continuous and dense graphene deposition flm. The synergy of deposited graphene-flm, spilled oil, and adhesive grease greatly improves the lubrication function of grease. This research paves the way for modulating high-performance lithium complex grease to reduce the friction and wear of movable machinery.
基金supported by the National Natural Science Foundation of China,Nos.31601175(to YL),81803508(to KZ),82074056(to JY)the Natural Science Foundation of Liaoning Province of China,No.20180550335(to YL)the Scientific Research Project of Educational Commission of Liaoning Province of China,No.201610163L22(to YL)。
文摘Adolescent binge drinking leads to long-lasting disorders of the adult central nervous system,particularly aberrant hippocampal neurogenesis.In this study,we applied in vivo fluorescent tracing using NestinCreERT2::Rosa26-tdTomato mice and analyzed the endogenous neurogenesis lineage progression of neural stem cells(NSCs)and dendritic spine formation of newborn neurons in the subgranular zone of the dentate gyrus.We found abnormal orientation of tamoxifen-induced tdTomato+(tdTom^(+))NSCs in adult mice 2 months after treatment with EtOH(5.0 g/kg,i.p.)for 7 consecutive days.EtOH markedly inhibited tdTom^(+)NSCs activation and hippocampal neurogenesis in mouse dentate gyrus from adolescence to adulthood.EtOH(100 mM)also significantly inhibited the proliferation to 39.2%and differentiation of primary NSCs in vitro.Adult mice exposed to EtOH also exhibited marked inhibitions in dendritic spine growth and newborn neuron maturation in the dentate gyrus,which was partially reversed by voluntary running or inhibition of the mammalian target of rapamycinenhancer of zeste homolog 2 pathway.In vivo tracing revealed that EtOH induced abnormal orientation of tdTom+NSCs and spatial misposition defects of newborn neurons,thus causing the disturbance of hippocampal neurogenesis and dendritic spine remodeling in mice.
基金The studies involving human participants were approved by The First Affiliated Hospital of Jinan University Ethics Committee(KY-2021-095)The participants provided their written informed consent to participate in this study+1 种基金Animalinvolved experimental protocols were compliance with guidelines and licensesapproved by the Laboratory Animal Center of Jinan University(20220225-65).
文摘The dysregulation of exosomal microRNAs(miRNAs)plays a crucial role in the development and progression of cancer.This study investigated the role of a newly identified serum exosomal miRNA miR-4256 in gastric cancer(GC)and the underlying mechanisms.The differentially expressed miRNAs were firstly identified in serum exosomes of GC patients and healthy individuals using next-generation sequencing and bioinformatics.Next,the expression of serum exosomal miR-4256 was analyzed in GC cells and GC tissues,and the role of miR-4256 in GC was investigated by in vitro and in vivo experiments.Then,the effect of miR-4256 on its downstream target genes HDAC5/p16^(INK4a) was studied in GC cells,and the underlying mechanisms were evaluated using dual luciferase reporter assay and Chromatin Immunoprecipitation(ChIP).Additionally,the role of the miR-4256/HDAC5/p16^(INK4a) axis in GC was studied using in vitro and in vivo experiments.Finally,the upstream regulators SMAD2/p300 that regulate miR-4256 expression and their role in GC were explored using in vitro experiments.miR-4256 was the most significantly upregulated miRNA and was overexpressed in GC cell lines and GC tissues;in vitro and in vivo results showed that miR-4256 promoted GC growth and progression.Mechanistically,miR-4256 enhanced HDAC5 expression by targeting the promoter of the HDAC5 gene in GC cells,and then restrained the expression of p16^(INK4a) through the epigenetic modulation of HDAC5 at the p16INK4a promoter.Furthermore,miR-4256 overexpression was positively regulated by the SMAD2/p300 complex in GC cells.Our data indicate that miR-4256 functions as an oncogene in GC via the SMAD2/miR-4256/HDAC5/p16^(INK4a) axis,which participates in GC progression and provides novel therapeutic and prognostic biomarkers for GC.
基金Sponsored by the National Natural Science Foundation of China(Grant No.11302158)the Natural Science Foundation of Shaanxi Province,China(Grant No.2018JM1044)
文摘Shape Memory Alloy(SMA)is a typical material with memory effect,and it is widely used in many engineering fields.Based on the elastic theory and Galerkin method,a vibration system of SMA beam with rigid constraints is proposed.The non⁃smooth transformation was employed to deal with the discontinuous position,and the original system was turned into an approximate equivalent system associated with the Dirac function.Then,using the stochastic averaging method,the drift and diffusion coefficients of the corresponding Fokker Planck Kolmogorov equation were described.Lastly,the approximate probability response of the system was formulated analytically.Meanwhile,numerical simulation was carried out to verify the effectiveness of analytical results.Furthermore,stochastic bifurcation was discussed.Results show that the stationary probability response of the system was affected by the increase of noise amplitude and restitution force,and a certain restitution value and damping could induce P⁃bifurcation.
基金the National Basic Research Program of China(973 Program)(No.2009CB930300)National Natural Science Foundation of China(No.81273449).
文摘The purpose of this study was to develop poly(amidoamine)(PAMAM)-functionalized multi-walled carbon nanotubes(MWNTs)loaded with a poorly water-soluble drug,intended to improve the drug-loading capacity,dissolution and design a sustained release system.MWNTs were modified with a carboxyl group by acid treatment and then complex with PAMAM.PAMAM-MWNTs were investigated as a scaffold for loading the model drug,Carvedilol(CAR),using three different methods(the fusion method,the incipient wetness impregnation method,and the solvent method).The effects of different pore size,specific surface area and physical state were systematically studied using FT-IR,TGA,SEM,DSC,nitrogen adsorption,XPS and XRD.All the samples made by PAMAM-MWNTs to load the drug had a marked effect on the drug-loading capacity as well as drug dissolution,especially theⅡ-30%.
基金supported by STI2030-Major Projects(2022ZD0204900)the National Natural Science Foundation of China(NSFC)(91632103,31900732,31771157)+5 种基金the Program of Shanghai Subject Chief Scientist(17XD1401700)National Key Research and Development Program of China(2018YFE0126700)the Shanghai Education Commission Research and Innovation Program(2019-01-07-00-02-E00037)Natural Science Foundation of Chongqing cstc2021jcyjmsxmX1176,the‘111’Program of Higher Education Discipline Innovation,‘Eastern Scholar’(Shanghai Municipal Education Commission),Shanghai Municipal Commission of Science and Technology Program(21dz2210100)China Postdoctoral Science Foundation(202N1702133,2021M702137)The National Science Fund for Distinguished Young Scholars(31900732).
文摘Background Kabukisyndrome(KS)is arare developmental disorder characterised by multiple congenital anomalies and intellectual disability.UTX(ubiquitously transcribed tetratricopeptide repeat,X chromosome),which encodes a histone demethylase,is one of the two major pathogenic risk genes for KS.Although intellectual disability is a key phenotype of KS,the role of UTX in cognitive function remains unclear.Currently,no targeted therapies are available for KS.Aims This study aimed to investigate how UTX regulates cognition,to explore the mechanisms underlying UTX dysfunction and to identify potential molecular targets for treatment.Methods WegeneratedUTXconditional knockoutmice and found that UTX deletion downregulated calmodulin transcription by disrupting H3K27me3(trimethylated histone H3 at lysine 27)demethylation.Results UTX-knockout mice showeddecreased phosphorylation of calcium/calmodulin-dependent protein kinase I,impaired long-term potentiation and deficit in remote contextual fear memory.These effects were reversed by an Food and Drug Administration-approved drug desipramine.Conclusions Our results reveal an epigenetic mechanism underlying the important role of UTX in synaptic plasticity and cognitive function,and suggest that desipramine could be a potential treatment for KS.
基金supported by the National Natural Science Foundation of China(Grant Nos.:92477103,22273023,12474285 and 22373116)the National Key R&D Program of China(Grant No.:2019YFA0905200)+5 种基金Shanghai Municipal Natural Science Foundation(Grant No.:23ZR1418200)Natural Science Foundation of Chongqing,China(Grant No.:CSTB2023NSCQ-MSX0616)Shanghai Frontiers Science Center of Molecule Intelligent SynthesesShanghai Future Discipline Program(Quantum Science and Tech-nology)Shanghai Municipal Education Commission’s“Artificial Intelligence-Driven Research Paradigm Reform and Discipline Advancement Program”the Fundamental Research Funds for the Central Universities.
文摘The identification and optimization of mutations in nanobodies are crucial for enhancing their thera-peutic potential in disease prevention and control.However,this process is often complex and time-consuming,which limit its widespread application in practice.In this study,we developed a work-flow,named Evolutionary-Nanobody(EvoNB),to predict key mutation sites of nanobodies by combining protein language models(PLMs)and molecular dynamic(MD)simulations.By fine-tuning the ESM2 model on a large-scale nanobody dataset,the ability of EvoNB to capture specific sequence features of nanobodies was significantly enhanced.The fine-tuned EvoNB model demonstrated higher predictive accuracy in the conserved framework and highly variable complementarity-determining regions of nanobodies.Additionally,we selected four widely representative nanobodyeantigen complexes to verify the predicted effects of mutations.MD simulations analyzed the energy changes caused by these mu-tations to predict their impact on binding affinity to the targets.The results showed that multiple mu-tations screened by EvoNB significantly enhanced the binding affinity between nanobody and its target,further validating the potential of this workflow for designing and optimizing nanobody mutations.Additionally,sequence-based predictions are generally less dependent on structural absence,allowing them to be more easily integrated with tools for structural predictions,such as AlphaFold 3.Through mutation prediction and systematic analysis of key sites,we can quickly predict the most promising variants for experimental validation without relying on traditional evolutionary or selection processes.The EvoNB workflow provides an effective tool for the rapid optimization of nanobodies and facilitates the application of PLMs in the biomedical field.
基金funded by the National Natural Science Foundation of China(No.81872627and No.82473611)the National Financial Projects ‘Assessment and Application of Nutrients Requirement and Food Environment for Chinese Residents’(No.102393220020070000013)。
文摘Objective This study aimed to investigate possible serum 25-hydroxyvitamin D[25(OH)D]cutoffs for the associations between 25(OH)D and Bone turnover markers(BTMs),and how GC gene variation influences such cutoffs in Chinese women of childbearing age.Methods In total,1,505 non-pregnant or non-lactating women(18–45 years)were recruited from the 2015 Chinese Adult Chronic Disease and Nutrition Surveillance.Serum 25(OH)D,osteocalcin(OC),procollagen type 1 N-terminal propeptide(P1NP),β-CrossLaps of type 1 collagen containing cross-linked C-telopeptide(β-CTX),and single nucleotide polymorphisms were determined.Locally weighted regression and smoothing scatterplot and segmented regression were performed to estimate the 25(OH)D thresholds.Results The median serum 25(OH)D was 16.63(11.96–22.55)ng/mL and the prevalence of low serum 25(OH)D(<12 ng/mL)was 25.2%.Women with the lowest 25(OH)D had the highestβ-CTX.After adjustment for the confounders,25(OH)D cutoffs for OC[14.04(12.84–15.23)ng/mL],β-CTX[13.94(12.49–15.39)ng/mL],and P1NP[13.87(12.37–15.37)ng/mL]in the whole population,cutoffs for OC[12.30(10.68–13.91)ng/mL],β-CTX[12.23(10.22–14.23)ng/mL],and P1NP[11.85(10.40–13.31)ng/mL]in women with the GC rs2282679 G allele,and cutoffs for OC[12.75(11.81–13.68)ng/mL],β-CTX[13.05(11.78–14.32)ng/mL],and P1NP[12.81(11.57–14.06)ng/mL]in women with the GC rs2282679 T allele,were observed.Below these cutoffs,BTMs were negatively associated with 25(OH)D,while above these cutoffs,BTMs plateaued.Conclusion In Chinese women of childbearing age,there were thresholds effect of serum 25(OH)D concentrations on BTMs.The results indicated that serum 25(OH)D concentrations<13.87 ng/mL in this population had adverse influences on maintaining bone remodeling.BTMs were suppressed at a relatively lower serum 25(OH)D in women with the GC rs2282679 G allele compared with those with the T allele.
基金supported by the National Natural Science Foundation of China(32071959)the National Key Research and Development Program of China(2023YFD2303304)+1 种基金the Key Research and Development Program of Shandong Province(LJNY202103)the Shandong Province Key Agricultural Project for Application Technology Innovation(SDAIT02-08)to Peng Liu.
文摘Heat stress,a major challenge in modern agriculture due to global warming,significantly reduces crop productivity.To mitigate its adverse effects on maize yield,it is crucial to understand the mechanisms by which heat stress impacts reproductive development.This study investigated the impact of heat stress during the 12th leaf(V12)stage,where silk development begins on grain yield formation,using heat-sensitive and heat-tolerant cultivars.Compared to pollen,silks were found to be more vulnerable to heat stress.Heat stress disrupted hormone balance and inhibited hormone signaling transduction pathways in silks,delaying silk emergence from bracts and reducing fertilization and grain yield.The heat-tolerant cultivar maintained silk growth by activating more response pathways,displaying faster hormone responses,and up-regulating hormones.Taken together,we propose that hormones play an essential role in silk development and later fertilization process.
基金funded by Chongqing Special Key Project of Technology Innovation and Application Development(Grant No.cstc2019jscx-dxwt BX0016)Guiding Project of Scientific Research Program in Ministry of Education of Hubei Province (No. B2021025)Fundamental Research Funds for the Central Universities (2022CDJXY-010 and 2022CDJQY-013)。
文摘Hydrogen energy has been recognized as “Ultimate Power Source” in the 21st century, which could be the best solution to the looming energy crisis and climate degeneration in the near future. Due to its high safety, low price, abundant resources and decent hydrogen storage density, magnesium based solid-state hydrogen storage materials are becoming the leading candidate for onboard hydrogen storage. However,the high operation temperature and slow reaction rate of MgH_(2), as a result of the large formation enthalpy and high reaction activation energy,respectively, are the first and most difficult problems we need to face and overcome to realize its industrialization. Herein, a state-of-the-art review on tailoring the stable thermodynamics and sluggish kinetics of hydrogen storage in MgH_(2), particularly through nanoengnieering and catalysis is presented, aiming to provide references and solutions for its promotion and application. Promising methods to overcome the challenges faced by MgH_(2)/Mg, such as bidirectional catalysts and nanoconfinement with in-situ catalysis are compared and the required improvements are discussed to stimulate further discussions and ideas in the rational design of MgH_(2)/Mg systems with ability for hydrogen release/uptake at lower temperatures and cycle stability in the near future.
