Magnolol,a compound extracted from Magnolia officinalis,demonstrates potential efficacy in addressing metabolic dysfunction and cardiovascular diseases.Its biological activities encompass anti-inflammatory,antioxidant...Magnolol,a compound extracted from Magnolia officinalis,demonstrates potential efficacy in addressing metabolic dysfunction and cardiovascular diseases.Its biological activities encompass anti-inflammatory,antioxidant,anticoagulant,and anti-diabetic effects.Growth/differentiation factor-15(GDF-15),a member of the transforming growth factorβsuperfamily,is considered a potential therapeutic target for metabolic disorders.This study investigated the impact of magnolol on GDF-15 production and its underlying mechanism.The research examined the pharmacological effect of magnolol on GDF-15 expression in vitro and in vivo,and determined the involvement of endoplasmic reticulum(ER)stress signaling in this process.Luciferase reporter assays,chromatin immunoprecipitation,and in vitro DNA binding assays were employed to examine the regulation of GDF-15 by activating transcription factor 4(ATF4),CCAAT enhancer binding proteinγ(CEBPG),and CCCTC-binding factor(CTCF).The study also investigated the effect of magnolol and ATF4 on the activity of a putative enhancer located in the intron of the GDF-15 gene,as well as the influence of single nucleotide polymorphisms(SNPs)on magnolol and ATF4-induced transcription activity.Results demonstrated that magnolol triggers GDF-15 production in endothelial cells(ECs),hepatoma cell line G2(HepG2)and hepatoma cell line 3B(Hep3B)cell lines,and primary mouse hepatocytes.The cooperative binding of ATF4 and CEBPG upstream of the GDF-15 gene or the E1944285 enhancer located in the intron led to full-power transcription of the GDF-15 gene.SNP alleles were found to impact the magnolol and ATF4-induced transcription activity of GDF-15.In high-fat diet ApoE^(-/-)mice,administration of magnolol induced GDF-15 production and partially suppressed appetite through GDF-15.These findings suggest that magnolol regulates GDF-15 expression through priming of promoter and enhancer activity,indicating its potential as a drug for the treatment of metabolic disorders.展开更多
Chloride ions(Cl^(-))have been shown to impact the long-lasting nature of reinforced concrete.However,Cl^(-)that are already bound inside the concrete will not lead to the deterioration of the concrete’s characterist...Chloride ions(Cl^(-))have been shown to impact the long-lasting nature of reinforced concrete.However,Cl^(-)that are already bound inside the concrete will not lead to the deterioration of the concrete’s characteristics.The composition of the cement-based material,including the type of cement and auxiliary materials,greatly influences the ability of the material to bind Cl^(-),and varied components result in varying binding beha-vior of the Cl^(-).Simultaneously,the Cl^(-)binding process in concrete is influenced by both the internal and exterior surroundings,as well as the curing practices.These factors impact the hydration process of the cement and the internal pore structure of the concrete.Currently,mathematical theories and molecular dynamics simulations have increasingly been employed as the prevalent methods for examining the binding behaviors of Cl^(-)in concrete.These techniques are extensively utilized for predicting the lifespan and conducting microscopic studies of reinforced concrete in Cl^(-)settings.This work proposes recommendations for future research based on a summary of experimental and simulation investigations on Cl^(-)binding.Which will offer theoretical guidance for studying the binding of Cl^(-)in cement-based materials.展开更多
Objective Junctophilin-2(JPH2)is an essential structural protein that maintains junctional membrane complexes(JMCs)in cardiomyocytes by tethering the plasma membrane to the sarcoplasmic reticulum,thereby facilitating ...Objective Junctophilin-2(JPH2)is an essential structural protein that maintains junctional membrane complexes(JMCs)in cardiomyocytes by tethering the plasma membrane to the sarcoplasmic reticulum,thereby facilitating excitationcontraction(E-C)coupling.Mutations in JPH2 have been associated with hypertrophic cardiomyopathy(HCM),but the molecular mechanisms governing its membrane-binding properties and the functional relevance of its membrane occupation and recognition nexus(MORN)repeat motifs remain incompletely understood.This study aimed to elucidate the structural basis of JPH2 membrane association and its implications for HCM pathogenesis.Methods A recombinant N-terminal fragment of mouse JPH2(residues 1-440),encompassing the MORN repeats and an adjacent helical region,was purified under near-physiological buffer conditions.X-ray crystallography was employed to determine the structure of the JPH2 MORN-Helix domain.Sequence conservation analysis across species and junctophilin isoforms was performed to assess the evolutionary conservation of key structural features.Functional membrane-binding assays were conducted using liposome co-sedimentation and cell-based localization studies in COS7 and HeLa cells.In addition,site-directed mutagenesis targeting positively charged residues and known HCM-associated mutations,including R347C,was used to evaluate their effects on membrane interaction and subcellular localization.Results The crystal structure of the mouse JPH2 MORN-Helix domain was resolved at 2.6Å,revealing a compact,elongated architecture consisting of multiple tandem MORN motifs arranged in a curved configuration,forming a continuous hydrophobic core stabilized by alternating aromatic residues.A C-terminalα-helix further reinforced structural integrity.Conservation analysis identified the inner groove of the MORN array as a highly conserved surface,suggesting its role as a protein-binding interface.A flexible linker segment enriched in positively charged residues,located adjacent to the MORN motifs,was found to mediate direct electrostatic interactions with negatively charged phospholipid membranes.Functional assays demonstrated that mutation of these basic residues impaired membrane association,while the HCM-linked R347C mutation completely abolished membrane localization in cellular assays,despite preserving the overall MORN-Helix fold in structural modeling.Conclusion This study provides structural insight into the membrane-binding mechanism of the cardiomyocyte-specific protein JPH2,highlighting the dual roles of its MORN-Helix domain in membrane anchoring and protein interactions.The findings clarify the structural basis for membrane targeting via a positively charged linker and demonstrate that disruption of this interaction—such as that caused by the R347C mutation—likely contributes to HCM pathogenesis.These results not only enhance current understanding of JPH2 function in cardiac E-C coupling but also offer a structural framework for future investigations into the assembly and regulation of JMCs in both physiological and disease contexts.展开更多
BACKGROUND Pancreatic surgery has markedly evolved during the past several years with the development of minimally invasive techniques such as laparoscopy.pancreaticojejunostomy(PJ),also known as pancreatoenterostomy,...BACKGROUND Pancreatic surgery has markedly evolved during the past several years with the development of minimally invasive techniques such as laparoscopy.pancreaticojejunostomy(PJ),also known as pancreatoenterostomy,is a critical step in surgical reconstruction after pancreatic resection.However,the laparoscopic performance of PJ presents additional technical challenges,especially in achieving a secure anastomosis while preserving the integrity of pancreatic tissue.AIM To evaluate the effectiveness and safety of binding and interlocking PJ(BIPJ)as a novel technique in laparoscopic pancreatic surgery.METHODS Data of patients who underwent laparoscopic pancreatic surgery from 2018 to 2023 were obtained from the hepatobiliary and pancreatic surgery database of the Second Affiliated Hospital of Zhejiang University School of Medicine and retrospectively analyzed.According to the different PJ methods used during surgery,the patients were divided into two groups:The BIPJ group and the ductto-mucosa PJ(DMPJ)group.RESULTS BIPJ was performed in 33 patients,and DMPJ was performed in 34 patients.The operative time was significantly shorter in the BIPJ group(median,340 minutes;interquartile range,310-350)than in the DMPJ group(median,388 minutes;interquartile range,341-464)(P=0.004).No significant differences were found between the DMPJ and BIPJ groups in terms of the rates of pancreatic fistula,intra-abdominal hemorrhage,intra-abdominal abscess,postoperative biliary fistula,reoperation,or postoperative hospital stay.CONCLUSION The suitability of laparoscopic PJ for all pancreatic textures,ability to perform full laparoscopy,shorter operation time,and comparable safety with traditional PJ make BIPJ a promising option for both surgeons and patients.展开更多
Background Post-weaning diarrhea(PWD)in piglets,often caused by F4^(+)enterotoxigenic Escherichia coli(ETEC),poses significant challenges in pig production.Traditional solutions like antibiotics and zinc oxide face in...Background Post-weaning diarrhea(PWD)in piglets,often caused by F4^(+)enterotoxigenic Escherichia coli(ETEC),poses significant challenges in pig production.Traditional solutions like antibiotics and zinc oxide face increasing restrictions due to growing concerns over antibiotic resistance and environmental sustainability.This study investigates the application of bivalent heavy chain variable domain(V_(H)H)constructs(BL1.2 and BL2.2)targeting ETEC virulence factors,administered in feed to mitigate ETEC-induced PWD in weaned piglets.Results The supplementation of BL1.2 and BL2.2 in both mash and pelleted feed significantly reduced the diarrhea incidence and fecal shedding of F4^(+)ETEC in challenged piglets.Pelleted feed containing V_(H)H constructs helped to preserve gut barrier integrity by maintaining levels of the tight junction protein occludin in the small intestine.Additionally,the constructs maintained blood granulocyte counts at a similar level to the non-challenged control group,including neutrophils,and ameliorated the acute phase protein response after challenge.Notably,even at low feed intake immediately after weaning,V_(H)H constructs helped maintain piglet health by mitigating ETEC-induced inflammation and the resulting diarrhea.Conclusions Our findings demonstrated that using V_(H)H constructs as feed additives could serve as an effective strategy to help manage ETEC-associated PWD,by reducing F4^(+)ETEC gut colonization and supporting gut barrier function of weaned piglets.The high stability of these V_(H)H constructs supports their incorporation into industrial feed manufacturing processes,offering a more sustainable preventive strategy compared to traditional antimicrobial interventions,which could contribute to sustainable farming practices.展开更多
Dear Editor,The pandemic of coronavirus disease 2019(COVID-19)caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),continues despite extensive efforts to control viral transmission.Meanwhile,the emerg...Dear Editor,The pandemic of coronavirus disease 2019(COVID-19)caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),continues despite extensive efforts to control viral transmission.Meanwhile,the emergence of SARS-CoV-2 variants with antigenically divergence in viral protein dampens the efficacy of authorized vaccines,leading to the breakthrough infections in vaccinated population(Cao et al.,2021,2022;Tuekprakhon et al.,2022;Xiang et al.,2022).Moreover,diverse sarbecoviruses in bats and pangolins have been discovered and isolated(Ge et al.,2013;Xiao et al.,2020).Some of these viruses have exhibited efficient binding to human angiotensin-converting enzyme 2(hACE2)(Xiao et al.,2020;Liu et al.,2021;Temmam et al.,2022),highlighting the risk of spillover from wild animals to human.Thus,the development of pan-sarbecovirus vaccines is of high priority.展开更多
Genetic disruption of the RAS binding domain(RBD)of Phosphoinositide 3-kinase alpha(PI3Kα)impairs the growth of tumors driven by the small guanosine triphosphatase RAS in mice and does not impact PI3Kα's role in...Genetic disruption of the RAS binding domain(RBD)of Phosphoinositide 3-kinase alpha(PI3Kα)impairs the growth of tumors driven by the small guanosine triphosphatase RAS in mice and does not impact PI3Kα's role in insulin mediated control of glucose homeostasis.Selectively blocking the RAS-PI3Kαinteraction may represent a strategy for treating RAS-dependent cancers as it would avoid the toxicity associated with inhibitors of PI3Kαlipid kinase activity.We developed compounds that bind covalently to cysteine 242 in the RBD of PI3K p110αand block RAS activation of PI3Kαactivity.In mice,inhibitors slow the growth of RAS mutant tumors and Human Epidermal Growth Factor Receptor 2(HER2)overexpressing tumors,particularly when combined with other inhibitors of the RAS/Mitogen-activated protein kinase pathway,without causing hyperglycemia.Oncogenic mutations in the small guanosine triphosphatase RAS occur in 20%of human cancers,with RAS proteins activating both the mitogen-activated protein kinase(MAPK)and Phosphoinositide 3-kinase(PI3K)pathways(1-3).As each of these pathways has oncogenic potential,simultaneous activation,as occurs in mutant RAS driven cancers,generates aggressive disease.In RAS-driven cell and animal models,inhibition of both the MAPK and PI3K pathways is more efficacious than targeting the individual pathways(4);however,dose-limiting toxicities in humans prevent clinical success of this strategy.展开更多
Accurate identification of RNA-ligand binding sites is essential for elucidating RNA function and advancing structurebased drug discovery.Here,we present RLsite,a novel deep learning framework that integrates energy-,...Accurate identification of RNA-ligand binding sites is essential for elucidating RNA function and advancing structurebased drug discovery.Here,we present RLsite,a novel deep learning framework that integrates energy-,structure-and sequence-based features to predict nucleotide-level binding sites with high accuracy.RLsite leverages energy-based threedimensional representations,obtained from atomic probe interactions using a pre-trained ITScore-NL potential,and models their contextual features through a 3D convolutional neural network(3D-CNN)augmented with self-attention.In parallel,structure-based features,including network properties,Laplacian norm,and solvent-accessible surface area,together with sequence-based evolutionary constraint scores,are mapped along the RNA sequence and used as sequential descriptors.These descriptors are modeled using a bidirectional long short-term memory(BiLSTM)network enhanced with multihead self-attention.By effectively fusing these complementary modalities,RLsite achieves robust and precise binding site prediction.Extensive evaluations across four diverse RNA-ligand benchmark datasets demonstrate that RLsite consistently outperforms state-of-the-art methods in terms of precision,recall,Matthews correlation coefficient(MCC),area under the curve(AUC),and overall robustness.Notably,on a particularly challenging test set composed of RNA structures containing junctions,RLsite surpasses the second-best method by 7.3%in precision,3.4%in recall,7.5%in MCC,and 10.8%in AUC,highlighting its potential as a powerful tool for RNA-targeted molecular design.展开更多
BACKGROUND The exact mechanisms underlying diabetic nephropathy(DN)remain incompletely elucidated,prompting researchers to explore new perspectives and identify novel intervention targets in this field.AIM To explore ...BACKGROUND The exact mechanisms underlying diabetic nephropathy(DN)remain incompletely elucidated,prompting researchers to explore new perspectives and identify novel intervention targets in this field.AIM To explore the role and underlying mechanisms of farnesoid X receptor(FXR)in the development of DN by regulating endoplasmic reticulum stress(ERS)molecular chaperone binding immunoglobulin protein(BiP)expression.METHODS Bioinformatics analyses identified potential FXR-binding elements in the BiP promoter.Dual-luciferase and chromatin immunoprecipitation(ChIP)assays confirmed FXR-BiP binding sites.In vitro studies used SV40 MES 13 cells under varying glucose conditions and treatments with FXR modulators[obeticholic acid(INT-747)and guggulsterones]or BiP small interfering RNA.The expression of BiP and ERS-related proteins[protein kinase R-like endoplasmic reticulum kinase(PERK),inositol-requiring enzyme 1(IRE1),activating transcription factor 6(ATF6)]was assessed alongside cell proliferation and extracellular matrix(ECM)synthesis.In vivo studies in DN mice(db/db)examined the effects of FXR activation on renal function and morphology.RESULTS FXR bound to the target sequence in the BiP promoter region,enhancing transcriptional activity,as confirmed by ChIP experiments.FXR expression decreased in SV40 MES 13 cells stimulated with high glucose and in renal tissues of DN mice compared with control.Treatment of SV40 MES 13 cells with the FXR agonist INT-747 significantly increased intracellular BiP expression,whereas silencing the FXR gene led to the downregulation of BiP levels.In vivo administration of INT-747 significantly elevated BiP levels in renal tissues,improved renal function and fibrosis in DN mice,while inhibiting the expression of ERS-related signaling proteins PERK,IRE1,and ATF6.CONCLUSION FXR promotes BiP expression by binding to its promoter,suppressing ERS pathways,and reducing mesangial cell proliferation and ECM synthesis.These findings highlight FXR as a potential therapeutic target for diabetic glomerulosclerosis.展开更多
A switch from avian-typeα-2,3 to human-typeα-2,6 receptors is an essential element for the initiation of a pandemic from an avian influenza virus.Some H9N2 viruses exhibit a preference for binding to human-typeα-2,...A switch from avian-typeα-2,3 to human-typeα-2,6 receptors is an essential element for the initiation of a pandemic from an avian influenza virus.Some H9N2 viruses exhibit a preference for binding to human-typeα-2,6 receptors.This identifies their potential threat to public health.However,our understanding of the molecular basis for the switch of receptor preference is still limited.In this study,we employed the random forest algorithm to identify the potentially key amino acid sites within hemagglutinin(HA),which are associated with the receptor binding ability of H9N2 avian influenza virus(AIV).Subsequently,these sites were further verified by receptor binding assays.A total of 12 substitutions in the HA protein(N158D,N158S,A160 N,A160D,A160T,T163I,T163V,V190T,V190A,D193 N,D193G,and N231D)were predicted to prefer binding toα-2,6 receptors.Except for the V190T substitution,the other substitutions were demonstrated to display an affinity for preferential binding toα-2,6 receptors by receptor binding assays.Especially,the A160T substitution caused a significant upregulation of immune-response genes and an increased mortality rate in mice.Our findings provide novel insights into understanding the genetic basis of receptor preference of the H9N2 AIV.展开更多
BACKGROUND The Mac-2 binding protein glycosylated isomer(M2BPGi)is a serum marker for fibrosis that correlates with the fibrosis stages in various liver diseases.AIM To examine the M2BPGi’s threshold for staging fibr...BACKGROUND The Mac-2 binding protein glycosylated isomer(M2BPGi)is a serum marker for fibrosis that correlates with the fibrosis stages in various liver diseases.AIM To examine the M2BPGi’s threshold for staging fibrosis in patients with chronic hepatitis B(CHB),and its changes during treatment.METHODS This was a prospective,longitudinal study.A total of 348 eligible patients were recruited from the Hepatology Department,Medic Medical Center between March 2020 and December 2023.Liver enzyme tests,platelet counts,M2BPGi levels,and FibroScan were conducted at baseline and at 3-month intervals until six months post-treatment.Correlation plots of M2BPGi,FibroScan,and the other parameters were generated.Receiver operating characteristic curves were constructed for M2BPGi and the other parameters to evaluate their performance.RESULTS M2BPGi levels correlated well with FibroScan results and increased as the fibrosis stage advanced.The median M2BPGi levels at the different stages of fibrosis showed statistically significant differences.The cut-off values of M2BPGi for diagnosing significant fibrosis(F≥2),advanced fibrosis(F3),and cirrhosis(F4)were determined to be 1.08,1.4,and 1.52,respectively.In the context of fibrosis regression in CHB patients during the first 6-month of treatment,M2BPGi levels appeared to decrease before this pattern occurred in the FibroScan results.CONCLUSION M2BPGi levels were strongly correlated with FibroScan.M2BPGi can be used to assess liver fibrosis,and to serve as a tool for monitoring fibrosis regression in CHB patients undergoing treatment.展开更多
Perovskite solar cells(PSCs)are promising in the field of photovoltaics but are hindered by surface defects and stability.However,the energetic losses occurring at the interfaces between the perovskite and the charge ...Perovskite solar cells(PSCs)are promising in the field of photovoltaics but are hindered by surface defects and stability.However,the energetic losses occurring at the interfaces between the perovskite and the charge transport layers often lead to reduced power conversion efficiency(PCE).Surface treatment is an effective strategy but the passivating ligands usually bind with a single active site.The resulted dense packing of resistive passivators perpendicular to the surface is detrimental to charge transport.Here,we present a passivator that can bind to two neighboring lead(Ⅱ)ion(Pb^(2+))defect sites simultaneously with an aligned parallel mode to the perovskite surface,effectively suppressing the surface trap density and preventing the aggregation.The target device fulfills a PCE of 25.1%and maintains over 85% of the initial efficiency after 800 h of exposure to a relative humidity(RH)of 65%±5%.展开更多
Molecular recognition of bioreceptors and enzymes relies on orthogonal interactions with small molecules within their cavity. To date, Chinese scientists have developed three types of strategies for introducing active...Molecular recognition of bioreceptors and enzymes relies on orthogonal interactions with small molecules within their cavity. To date, Chinese scientists have developed three types of strategies for introducing active sites inside the cavity of macrocyclic arenes to better mimic molecular recognition of bioreceptors and enzymes.The editorial aims to enlighten scientists in this field when they develop novel macrocycles for molecular recognition, supramolecular assembly, and applications.展开更多
BACKGROUND Mac-2 binding protein glycosylation isomer(M2BPGi)serves as a marker of activated hepatic stellate cells and as such holds potential as a biomarker for liver fibrosis.In Viet Nam,metabolic dysfunction-assoc...BACKGROUND Mac-2 binding protein glycosylation isomer(M2BPGi)serves as a marker of activated hepatic stellate cells and as such holds potential as a biomarker for liver fibrosis.In Viet Nam,metabolic dysfunction-associated steatotic liver disease(MASLD)is rising in prevalence and there is an urgent need for better clinical management,particularly in early detection methods that will improve overall prognosis.AIM To examine M2BPGi cut-off values for staging liver fibrosis in patients with MASLD and risk factors associated with disease progression.METHODS A total of 301 individuals with ultrasound-confirmed or FibroScan-confirmed diagnosis of fatty liver were enrolled in the study.The participants were stratified according to fibrosis stage,measured via magnetic resonance elastography.M2-BPGi,Fibrosis-4(FIB-4)Index score,and routine parameters of liver function were assessed to statistically investigate the correlation of M2BPGi levels in various fibrosis stages and to identify risk factors associated with fibrosis severity.RESULTS M2BPGi levels positively correlated with fibrosis stages,with cut-off indexes of 0.57 for F0-1,0.68 for F2-3,and 0.78 for F4.M2BPGi levels in the F0-1 group were significantly different from those in both the F2-3 group(P=0.038)and the F4 group(P=0.0051);the F2-3 and F4 groups did not show a significant difference(P=0.39).Females exhibited significantly higher M2BPGi levels than males for all fibrosis stages,particularly in the F2-3 group(P=0.01)and F4 group(P=0.0006).In the F4(cirrhosis)group,individuals with diabetes had significantly higher M2BPGi levels than those without.M2BPGi,hemoglobin A1c,and FIB-4 score were identified as independent risk factors for greater fibrosis and cirrhosis.CONCLUSION M2BPGi levels varied significantly throughout fibrosis progression,from early MASLD to cirrhosis,with sex correlation.M2BPGi holds promise as an early biomarker for fibrosis characterization in MASLD adult patient populations.展开更多
Influenza A viruses(IAVs)are single-stranded negative-sense RNA viruses that continually challenge animal and human health.In IAV-infected cells,host RNA-binding proteins play key roles in the life cycle of IAV by dir...Influenza A viruses(IAVs)are single-stranded negative-sense RNA viruses that continually challenge animal and human health.In IAV-infected cells,host RNA-binding proteins play key roles in the life cycle of IAV by directly binding to viral RNA.Here,we examined the role of the host RNA-binding protein nucleophosmin-1(NPM1)in IAV replication.We found that,as a nucleolar phosphoprotein,NPM1 directly binds to viral RNA(vRNA)and inhibits the replication of various subtypes of IAV.NPM1 binding to vRNA competitively reduces the assembly of the viral ribonucleoprotein complex and the viral polymerase activity,thereby reducing the generation of progeny viral RNA and virions.The RNA-binding activity of NPM1,with the key residues T199,T219,T234,and T237,is essential for its anti-influenza function.Taken together,our findings demonstrate that NPM1 acts as an RNA-binding protein and interacts with IAV vRNA to suppress viral replication.展开更多
A series of potential HDACIs containing diverse Zn^(2+)-chelating hydroxamate moieties were synthesized and evaluated for their anticancer activity in vitro on HeLa,A549,and HepG2 cell lines.The A549 cell line was the...A series of potential HDACIs containing diverse Zn^(2+)-chelating hydroxamate moieties were synthesized and evaluated for their anticancer activity in vitro on HeLa,A549,and HepG2 cell lines.The A549 cell line was the most sensitive,and the most active compound,e8,exhibited an IC_(50) value of 1.68μmol/L,surpassing the positive control,SAHA(IC_(50)=4.85μmol/L).Additionally,compound e8 demonstrated lower toxicity to normal WI-38 cells compared to SAHA(IC_(50)=415.93μmol/L vs.9.09μmol/L).Furthermore,e8 efficiently induced G0/G1 phase cell cycle arrest and apoptosis in A549 cells.Molecular docking studies showed that compound e8 coordinated the Zn^(2+) cation at the enzyme’s active site and formed hydrophobic and hydrogen bonds within the hydrophobic pocket of the enzyme,resulting in stable docking with the HDAC enzyme.These studies suggested that compound e8 has the potential to be developed as a promising lead for further optimization and development of HDACIs.展开更多
Integrins are heterodimeric transmembrane receptors that mediate bidirectional interactions between the intracellular cytoskeletal array and the extracellularmatrix.These interactions are critical in tissue developmen...Integrins are heterodimeric transmembrane receptors that mediate bidirectional interactions between the intracellular cytoskeletal array and the extracellularmatrix.These interactions are critical in tissue development and function by regulating gene expression and sustaining tissue architecture.In humans,the integrin family is composed of 18 alpha(α)and 8 beta(β)subunits,constituting 24 distinctαβcombinations.Based on their structure and ligandbinding properties,only a subset of integrins,8 out of 24,recognizes the arginine-glycine-aspartate(RGD)tripeptide motif in the native ligand.One of the major RGD binding integrins is integrin alpha 8 beta 1(α8β1),a central Ras homolog gene familymemberA(RHOA)-dependentmodulator highly expressed in cells with contractile function.This review focuses on the recent advances regardingα8β1 function during organ development,with a particular interest in kidney and inner ear development.We alsodiscussα8β1’s role ininjury anddisease and its importance formesenchymal to epithelial transition during cancer development.Finally,we highlightα8β1’s importance for hearing function and its future use as a potential diagnostic and therapeutic tool for disease elimination.展开更多
BACKGROUND Mixed lineage kinase domain-like protein(MLKL)serves as a critical mediator in necroptosis,a form of regulated cell death linked to various liver diseases.This study aims to specifically investigate the rol...BACKGROUND Mixed lineage kinase domain-like protein(MLKL)serves as a critical mediator in necroptosis,a form of regulated cell death linked to various liver diseases.This study aims to specifically investigate the role of MLKL’s adenosine triphosphate(ATP)-binding pocket in facilitating necroptosis-independent pathways that may contribute to liver disease progression.By focusing on this mechanism,we seek to identify potential therapeutic targets that can modulate MLKL activity,offering new strategies for the prevention and treatment of liver-related pathologies.AIM To investigate the possibility of using the ATP-binding pocket-associated,necro-ptosis-independent MLKL pathway as a target for liver diseases.METHODS Cell death following necroptosis stimuli was evaluated using cell proliferation assays,flow cytometry,and electron microscopy in various cells.The human liver organoid system was used to evaluate whether the MLKL ATP pocket-binding inhibitor could attenuate inflammation.Additionally,alcoholic and non-alcoholic fatty liver diseases animal models were used to determine whether MLKL ATP pocket inhibitors could attenuate liver injury.RESULTS While an MLKL ATP pocket-binding inhibitor did not prevent necroptosis-induced cell death in RAW 264.7 cells,it did reduce the necroptosis-led expression of CXCL2,ICAM,and VCAM.Notably,MLKL ATP pocket inhibitor diminishes the expression of CXCL2,ICAM,and VCAM by inhibiting the IκB kinase and nuclear factor kappa-B pathways without inducing necroptosis-induced cell death in two-dimensional cell culture as well as the human-derived liver organoid system.Although MLKL ATP-binding inhibitor was ineffective in non-alcoholic fatty liver disease animal models,MLKL ATP-binding inhibitor attenuated hepatic inflammation in the alcoholic liver disease model.CONCLUSION MLKL ATP pocket-binding inhibitor exerted anti-inflammatory effects through the necroptosis-independent MLKL pathway in an animal model of alcoholic liver disease.展开更多
Corrosion of reinforcement induced by chloride invasion is extensively considered as the dominating deterioration mechanism of reinforced concrete(RC)structures,leading to serious safety hazards and tremendous economi...Corrosion of reinforcement induced by chloride invasion is extensively considered as the dominating deterioration mechanism of reinforced concrete(RC)structures,leading to serious safety hazards and tremendous economic losses.However,it still lacks well dispersive and cost-efficient nanomaterials to improve the anti-chloride-corrosion ability of RC structures.Herein,specific carbon dots(CDs)with high dispersity and low cost are deliberately designed,successfully prepared by hydrothermal processing,and then firstly applied to immensely enhance chloride binding performance of cement,thereby contributing to suppressing the corrosion of reinforcement.Specifically,the tailored CDs are composed of the carbon core with highly crystalline sp^(2)C structures and oxygen-containing groups connecting on the carbon core;The typical equilibrium test confirms that with respect to that of the blank cement paste,the chloride binding capacity of cement paste involving 0.2 wt%(by weight of cement)CDs is increased by 109% after 14-day exposure to 3 mol/L Na Cl solution;according to comprehensive analyses of phase compositions,the chloride binding mechanism of CDs-modified cement is rationally attributed to the fact that the incorporation of CDs advances the formation of calcium silicate hydrate(C-S-H)gels and Friedel's salt(Fs),thus enormously enhancing the physically adsorbed and chemically bound chloride ions of cement pastes.This work not only firstly provides a novel high-dispersity and low-cost nanomaterial toward the durability enhancement of RC structures,but also broadens the application of CDs in the field of engineering,conducing to stimulating their industrialization development.展开更多
Cellulosic materials are attracting increasing research interest because of their abundance,biocompatibility,and biodegradability,making them suitable in multiple industrial and medical applications.Functionalization ...Cellulosic materials are attracting increasing research interest because of their abundance,biocompatibility,and biodegradability,making them suitable in multiple industrial and medical applications.Functionalization of cellulose is usually required to improve or expand its properties to meet the requirements of different applications.Cellulose-binding domains(CBDs)found in various proteins have been shown to be powerful tools in the functionalization of cellulose materials.In this review,we firstly introduce the structural characteristics of commonly used CBDs belonging to carbohydrate-binding module families 1,2 and 3.Then,we summarize four main kinds of methodologies for employing CBDs to modify cellulosic materials(i.e.,CBD only,genetic fusion,non-covalent linkage and covalent linkage).Via different approaches,CBDs have been used to improve the material properties of cellulose,immobilize enzymes for biocatalysis,and design various detection tools.To achieve industrial applications,researches for lowering the production cost of CBDs,improving their performance(e.g.,stability),and expanding their application scenarios are still in need.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82171552 and 82170479)the Natural Science Foundation of Shanghai Ctiy(No.21ZR1457500)the Science and Technology Bureau of Shanghai Putuo District(No.ptkwws202102).
文摘Magnolol,a compound extracted from Magnolia officinalis,demonstrates potential efficacy in addressing metabolic dysfunction and cardiovascular diseases.Its biological activities encompass anti-inflammatory,antioxidant,anticoagulant,and anti-diabetic effects.Growth/differentiation factor-15(GDF-15),a member of the transforming growth factorβsuperfamily,is considered a potential therapeutic target for metabolic disorders.This study investigated the impact of magnolol on GDF-15 production and its underlying mechanism.The research examined the pharmacological effect of magnolol on GDF-15 expression in vitro and in vivo,and determined the involvement of endoplasmic reticulum(ER)stress signaling in this process.Luciferase reporter assays,chromatin immunoprecipitation,and in vitro DNA binding assays were employed to examine the regulation of GDF-15 by activating transcription factor 4(ATF4),CCAAT enhancer binding proteinγ(CEBPG),and CCCTC-binding factor(CTCF).The study also investigated the effect of magnolol and ATF4 on the activity of a putative enhancer located in the intron of the GDF-15 gene,as well as the influence of single nucleotide polymorphisms(SNPs)on magnolol and ATF4-induced transcription activity.Results demonstrated that magnolol triggers GDF-15 production in endothelial cells(ECs),hepatoma cell line G2(HepG2)and hepatoma cell line 3B(Hep3B)cell lines,and primary mouse hepatocytes.The cooperative binding of ATF4 and CEBPG upstream of the GDF-15 gene or the E1944285 enhancer located in the intron led to full-power transcription of the GDF-15 gene.SNP alleles were found to impact the magnolol and ATF4-induced transcription activity of GDF-15.In high-fat diet ApoE^(-/-)mice,administration of magnolol induced GDF-15 production and partially suppressed appetite through GDF-15.These findings suggest that magnolol regulates GDF-15 expression through priming of promoter and enhancer activity,indicating its potential as a drug for the treatment of metabolic disorders.
文摘Chloride ions(Cl^(-))have been shown to impact the long-lasting nature of reinforced concrete.However,Cl^(-)that are already bound inside the concrete will not lead to the deterioration of the concrete’s characteristics.The composition of the cement-based material,including the type of cement and auxiliary materials,greatly influences the ability of the material to bind Cl^(-),and varied components result in varying binding beha-vior of the Cl^(-).Simultaneously,the Cl^(-)binding process in concrete is influenced by both the internal and exterior surroundings,as well as the curing practices.These factors impact the hydration process of the cement and the internal pore structure of the concrete.Currently,mathematical theories and molecular dynamics simulations have increasingly been employed as the prevalent methods for examining the binding behaviors of Cl^(-)in concrete.These techniques are extensively utilized for predicting the lifespan and conducting microscopic studies of reinforced concrete in Cl^(-)settings.This work proposes recommendations for future research based on a summary of experimental and simulation investigations on Cl^(-)binding.Which will offer theoretical guidance for studying the binding of Cl^(-)in cement-based materials.
文摘Objective Junctophilin-2(JPH2)is an essential structural protein that maintains junctional membrane complexes(JMCs)in cardiomyocytes by tethering the plasma membrane to the sarcoplasmic reticulum,thereby facilitating excitationcontraction(E-C)coupling.Mutations in JPH2 have been associated with hypertrophic cardiomyopathy(HCM),but the molecular mechanisms governing its membrane-binding properties and the functional relevance of its membrane occupation and recognition nexus(MORN)repeat motifs remain incompletely understood.This study aimed to elucidate the structural basis of JPH2 membrane association and its implications for HCM pathogenesis.Methods A recombinant N-terminal fragment of mouse JPH2(residues 1-440),encompassing the MORN repeats and an adjacent helical region,was purified under near-physiological buffer conditions.X-ray crystallography was employed to determine the structure of the JPH2 MORN-Helix domain.Sequence conservation analysis across species and junctophilin isoforms was performed to assess the evolutionary conservation of key structural features.Functional membrane-binding assays were conducted using liposome co-sedimentation and cell-based localization studies in COS7 and HeLa cells.In addition,site-directed mutagenesis targeting positively charged residues and known HCM-associated mutations,including R347C,was used to evaluate their effects on membrane interaction and subcellular localization.Results The crystal structure of the mouse JPH2 MORN-Helix domain was resolved at 2.6Å,revealing a compact,elongated architecture consisting of multiple tandem MORN motifs arranged in a curved configuration,forming a continuous hydrophobic core stabilized by alternating aromatic residues.A C-terminalα-helix further reinforced structural integrity.Conservation analysis identified the inner groove of the MORN array as a highly conserved surface,suggesting its role as a protein-binding interface.A flexible linker segment enriched in positively charged residues,located adjacent to the MORN motifs,was found to mediate direct electrostatic interactions with negatively charged phospholipid membranes.Functional assays demonstrated that mutation of these basic residues impaired membrane association,while the HCM-linked R347C mutation completely abolished membrane localization in cellular assays,despite preserving the overall MORN-Helix fold in structural modeling.Conclusion This study provides structural insight into the membrane-binding mechanism of the cardiomyocyte-specific protein JPH2,highlighting the dual roles of its MORN-Helix domain in membrane anchoring and protein interactions.The findings clarify the structural basis for membrane targeting via a positively charged linker and demonstrate that disruption of this interaction—such as that caused by the R347C mutation—likely contributes to HCM pathogenesis.These results not only enhance current understanding of JPH2 function in cardiac E-C coupling but also offer a structural framework for future investigations into the assembly and regulation of JMCs in both physiological and disease contexts.
基金Supported by National Natural Science Foundation of China,No.82272634 and No.62233016.
文摘BACKGROUND Pancreatic surgery has markedly evolved during the past several years with the development of minimally invasive techniques such as laparoscopy.pancreaticojejunostomy(PJ),also known as pancreatoenterostomy,is a critical step in surgical reconstruction after pancreatic resection.However,the laparoscopic performance of PJ presents additional technical challenges,especially in achieving a secure anastomosis while preserving the integrity of pancreatic tissue.AIM To evaluate the effectiveness and safety of binding and interlocking PJ(BIPJ)as a novel technique in laparoscopic pancreatic surgery.METHODS Data of patients who underwent laparoscopic pancreatic surgery from 2018 to 2023 were obtained from the hepatobiliary and pancreatic surgery database of the Second Affiliated Hospital of Zhejiang University School of Medicine and retrospectively analyzed.According to the different PJ methods used during surgery,the patients were divided into two groups:The BIPJ group and the ductto-mucosa PJ(DMPJ)group.RESULTS BIPJ was performed in 33 patients,and DMPJ was performed in 34 patients.The operative time was significantly shorter in the BIPJ group(median,340 minutes;interquartile range,310-350)than in the DMPJ group(median,388 minutes;interquartile range,341-464)(P=0.004).No significant differences were found between the DMPJ and BIPJ groups in terms of the rates of pancreatic fistula,intra-abdominal hemorrhage,intra-abdominal abscess,postoperative biliary fistula,reoperation,or postoperative hospital stay.CONCLUSION The suitability of laparoscopic PJ for all pancreatic textures,ability to perform full laparoscopy,shorter operation time,and comparable safety with traditional PJ make BIPJ a promising option for both surgeons and patients.
基金financially supported by the Green Development and Demonstration Programme(GUDP)(case number 34009-19-1585)。
文摘Background Post-weaning diarrhea(PWD)in piglets,often caused by F4^(+)enterotoxigenic Escherichia coli(ETEC),poses significant challenges in pig production.Traditional solutions like antibiotics and zinc oxide face increasing restrictions due to growing concerns over antibiotic resistance and environmental sustainability.This study investigates the application of bivalent heavy chain variable domain(V_(H)H)constructs(BL1.2 and BL2.2)targeting ETEC virulence factors,administered in feed to mitigate ETEC-induced PWD in weaned piglets.Results The supplementation of BL1.2 and BL2.2 in both mash and pelleted feed significantly reduced the diarrhea incidence and fecal shedding of F4^(+)ETEC in challenged piglets.Pelleted feed containing V_(H)H constructs helped to preserve gut barrier integrity by maintaining levels of the tight junction protein occludin in the small intestine.Additionally,the constructs maintained blood granulocyte counts at a similar level to the non-challenged control group,including neutrophils,and ameliorated the acute phase protein response after challenge.Notably,even at low feed intake immediately after weaning,V_(H)H constructs helped maintain piglet health by mitigating ETEC-induced inflammation and the resulting diarrhea.Conclusions Our findings demonstrated that using V_(H)H constructs as feed additives could serve as an effective strategy to help manage ETEC-associated PWD,by reducing F4^(+)ETEC gut colonization and supporting gut barrier function of weaned piglets.The high stability of these V_(H)H constructs supports their incorporation into industrial feed manufacturing processes,offering a more sustainable preventive strategy compared to traditional antimicrobial interventions,which could contribute to sustainable farming practices.
基金supported by the National Key Research and Development Program of China(2021YFC2302400)the National Natural Science Foundation of China(82241069 and 82350801)+2 种基金supported by the National Science Fund for Distinguished Young Scholar(81925025)the Innovation Fund for Medical Sciences(2019-I2M-5-049)from the Chinese Academy of Medical Sciencessponsored by Beijing Nova Program(20240484525).
文摘Dear Editor,The pandemic of coronavirus disease 2019(COVID-19)caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),continues despite extensive efforts to control viral transmission.Meanwhile,the emergence of SARS-CoV-2 variants with antigenically divergence in viral protein dampens the efficacy of authorized vaccines,leading to the breakthrough infections in vaccinated population(Cao et al.,2021,2022;Tuekprakhon et al.,2022;Xiang et al.,2022).Moreover,diverse sarbecoviruses in bats and pangolins have been discovered and isolated(Ge et al.,2013;Xiao et al.,2020).Some of these viruses have exhibited efficient binding to human angiotensin-converting enzyme 2(hACE2)(Xiao et al.,2020;Liu et al.,2021;Temmam et al.,2022),highlighting the risk of spillover from wild animals to human.Thus,the development of pan-sarbecovirus vaccines is of high priority.
文摘Genetic disruption of the RAS binding domain(RBD)of Phosphoinositide 3-kinase alpha(PI3Kα)impairs the growth of tumors driven by the small guanosine triphosphatase RAS in mice and does not impact PI3Kα's role in insulin mediated control of glucose homeostasis.Selectively blocking the RAS-PI3Kαinteraction may represent a strategy for treating RAS-dependent cancers as it would avoid the toxicity associated with inhibitors of PI3Kαlipid kinase activity.We developed compounds that bind covalently to cysteine 242 in the RBD of PI3K p110αand block RAS activation of PI3Kαactivity.In mice,inhibitors slow the growth of RAS mutant tumors and Human Epidermal Growth Factor Receptor 2(HER2)overexpressing tumors,particularly when combined with other inhibitors of the RAS/Mitogen-activated protein kinase pathway,without causing hyperglycemia.Oncogenic mutations in the small guanosine triphosphatase RAS occur in 20%of human cancers,with RAS proteins activating both the mitogen-activated protein kinase(MAPK)and Phosphoinositide 3-kinase(PI3K)pathways(1-3).As each of these pathways has oncogenic potential,simultaneous activation,as occurs in mutant RAS driven cancers,generates aggressive disease.In RAS-driven cell and animal models,inhibition of both the MAPK and PI3K pathways is more efficacious than targeting the individual pathways(4);however,dose-limiting toxicities in humans prevent clinical success of this strategy.
基金supported by the National Natural Science Foundation of China(Grant No.12204118)the Guizhou University Talent Fund(Grant No.[2022]30).
文摘Accurate identification of RNA-ligand binding sites is essential for elucidating RNA function and advancing structurebased drug discovery.Here,we present RLsite,a novel deep learning framework that integrates energy-,structure-and sequence-based features to predict nucleotide-level binding sites with high accuracy.RLsite leverages energy-based threedimensional representations,obtained from atomic probe interactions using a pre-trained ITScore-NL potential,and models their contextual features through a 3D convolutional neural network(3D-CNN)augmented with self-attention.In parallel,structure-based features,including network properties,Laplacian norm,and solvent-accessible surface area,together with sequence-based evolutionary constraint scores,are mapped along the RNA sequence and used as sequential descriptors.These descriptors are modeled using a bidirectional long short-term memory(BiLSTM)network enhanced with multihead self-attention.By effectively fusing these complementary modalities,RLsite achieves robust and precise binding site prediction.Extensive evaluations across four diverse RNA-ligand benchmark datasets demonstrate that RLsite consistently outperforms state-of-the-art methods in terms of precision,recall,Matthews correlation coefficient(MCC),area under the curve(AUC),and overall robustness.Notably,on a particularly challenging test set composed of RNA structures containing junctions,RLsite surpasses the second-best method by 7.3%in precision,3.4%in recall,7.5%in MCC,and 10.8%in AUC,highlighting its potential as a powerful tool for RNA-targeted molecular design.
基金Supported by the Talent Launch Fund of Chongqing Medical University Affiliated University City HospitalChongqing Medical University Affiliated University City Hospital Youth Program,No.2021ZD05.
文摘BACKGROUND The exact mechanisms underlying diabetic nephropathy(DN)remain incompletely elucidated,prompting researchers to explore new perspectives and identify novel intervention targets in this field.AIM To explore the role and underlying mechanisms of farnesoid X receptor(FXR)in the development of DN by regulating endoplasmic reticulum stress(ERS)molecular chaperone binding immunoglobulin protein(BiP)expression.METHODS Bioinformatics analyses identified potential FXR-binding elements in the BiP promoter.Dual-luciferase and chromatin immunoprecipitation(ChIP)assays confirmed FXR-BiP binding sites.In vitro studies used SV40 MES 13 cells under varying glucose conditions and treatments with FXR modulators[obeticholic acid(INT-747)and guggulsterones]or BiP small interfering RNA.The expression of BiP and ERS-related proteins[protein kinase R-like endoplasmic reticulum kinase(PERK),inositol-requiring enzyme 1(IRE1),activating transcription factor 6(ATF6)]was assessed alongside cell proliferation and extracellular matrix(ECM)synthesis.In vivo studies in DN mice(db/db)examined the effects of FXR activation on renal function and morphology.RESULTS FXR bound to the target sequence in the BiP promoter region,enhancing transcriptional activity,as confirmed by ChIP experiments.FXR expression decreased in SV40 MES 13 cells stimulated with high glucose and in renal tissues of DN mice compared with control.Treatment of SV40 MES 13 cells with the FXR agonist INT-747 significantly increased intracellular BiP expression,whereas silencing the FXR gene led to the downregulation of BiP levels.In vivo administration of INT-747 significantly elevated BiP levels in renal tissues,improved renal function and fibrosis in DN mice,while inhibiting the expression of ERS-related signaling proteins PERK,IRE1,and ATF6.CONCLUSION FXR promotes BiP expression by binding to its promoter,suppressing ERS pathways,and reducing mesangial cell proliferation and ECM synthesis.These findings highlight FXR as a potential therapeutic target for diabetic glomerulosclerosis.
基金supported by the National Natural Science Foundation of China(32273037 and 32102636)the Guangdong Major Project of Basic and Applied Basic Research(2020B0301030007)+4 种基金Laboratory of Lingnan Modern Agriculture Project(NT2021007)the Guangdong Science and Technology Innovation Leading Talent Program(2019TX05N098)the 111 Center(D20008)the double first-class discipline promotion project(2023B10564003)the Department of Education of Guangdong Province(2019KZDXM004 and 2019KCXTD001).
文摘A switch from avian-typeα-2,3 to human-typeα-2,6 receptors is an essential element for the initiation of a pandemic from an avian influenza virus.Some H9N2 viruses exhibit a preference for binding to human-typeα-2,6 receptors.This identifies their potential threat to public health.However,our understanding of the molecular basis for the switch of receptor preference is still limited.In this study,we employed the random forest algorithm to identify the potentially key amino acid sites within hemagglutinin(HA),which are associated with the receptor binding ability of H9N2 avian influenza virus(AIV).Subsequently,these sites were further verified by receptor binding assays.A total of 12 substitutions in the HA protein(N158D,N158S,A160 N,A160D,A160T,T163I,T163V,V190T,V190A,D193 N,D193G,and N231D)were predicted to prefer binding toα-2,6 receptors.Except for the V190T substitution,the other substitutions were demonstrated to display an affinity for preferential binding toα-2,6 receptors by receptor binding assays.Especially,the A160T substitution caused a significant upregulation of immune-response genes and an increased mortality rate in mice.Our findings provide novel insights into understanding the genetic basis of receptor preference of the H9N2 AIV.
文摘BACKGROUND The Mac-2 binding protein glycosylated isomer(M2BPGi)is a serum marker for fibrosis that correlates with the fibrosis stages in various liver diseases.AIM To examine the M2BPGi’s threshold for staging fibrosis in patients with chronic hepatitis B(CHB),and its changes during treatment.METHODS This was a prospective,longitudinal study.A total of 348 eligible patients were recruited from the Hepatology Department,Medic Medical Center between March 2020 and December 2023.Liver enzyme tests,platelet counts,M2BPGi levels,and FibroScan were conducted at baseline and at 3-month intervals until six months post-treatment.Correlation plots of M2BPGi,FibroScan,and the other parameters were generated.Receiver operating characteristic curves were constructed for M2BPGi and the other parameters to evaluate their performance.RESULTS M2BPGi levels correlated well with FibroScan results and increased as the fibrosis stage advanced.The median M2BPGi levels at the different stages of fibrosis showed statistically significant differences.The cut-off values of M2BPGi for diagnosing significant fibrosis(F≥2),advanced fibrosis(F3),and cirrhosis(F4)were determined to be 1.08,1.4,and 1.52,respectively.In the context of fibrosis regression in CHB patients during the first 6-month of treatment,M2BPGi levels appeared to decrease before this pattern occurred in the FibroScan results.CONCLUSION M2BPGi levels were strongly correlated with FibroScan.M2BPGi can be used to assess liver fibrosis,and to serve as a tool for monitoring fibrosis regression in CHB patients undergoing treatment.
基金supported by the National Key R&D Program of China(2022YFB4200500)the Key Research and Development Plan Project of Anhui Province(2022h11020014)+3 种基金Collaborative Innovation Program of Hefei Science Center,CAS(2022HSCCIP006)the CASHIPS Director’s Fund(YZJJ201902 and YZJJZX202018)the Anhui Provincial Natural Science Foundation(2408085MB029)the Natural Science Foundation of Hebei Province of China(B2024402018)。
文摘Perovskite solar cells(PSCs)are promising in the field of photovoltaics but are hindered by surface defects and stability.However,the energetic losses occurring at the interfaces between the perovskite and the charge transport layers often lead to reduced power conversion efficiency(PCE).Surface treatment is an effective strategy but the passivating ligands usually bind with a single active site.The resulted dense packing of resistive passivators perpendicular to the surface is detrimental to charge transport.Here,we present a passivator that can bind to two neighboring lead(Ⅱ)ion(Pb^(2+))defect sites simultaneously with an aligned parallel mode to the perovskite surface,effectively suppressing the surface trap density and preventing the aggregation.The target device fulfills a PCE of 25.1%and maintains over 85% of the initial efficiency after 800 h of exposure to a relative humidity(RH)of 65%±5%.
文摘Molecular recognition of bioreceptors and enzymes relies on orthogonal interactions with small molecules within their cavity. To date, Chinese scientists have developed three types of strategies for introducing active sites inside the cavity of macrocyclic arenes to better mimic molecular recognition of bioreceptors and enzymes.The editorial aims to enlighten scientists in this field when they develop novel macrocycles for molecular recognition, supramolecular assembly, and applications.
文摘BACKGROUND Mac-2 binding protein glycosylation isomer(M2BPGi)serves as a marker of activated hepatic stellate cells and as such holds potential as a biomarker for liver fibrosis.In Viet Nam,metabolic dysfunction-associated steatotic liver disease(MASLD)is rising in prevalence and there is an urgent need for better clinical management,particularly in early detection methods that will improve overall prognosis.AIM To examine M2BPGi cut-off values for staging liver fibrosis in patients with MASLD and risk factors associated with disease progression.METHODS A total of 301 individuals with ultrasound-confirmed or FibroScan-confirmed diagnosis of fatty liver were enrolled in the study.The participants were stratified according to fibrosis stage,measured via magnetic resonance elastography.M2-BPGi,Fibrosis-4(FIB-4)Index score,and routine parameters of liver function were assessed to statistically investigate the correlation of M2BPGi levels in various fibrosis stages and to identify risk factors associated with fibrosis severity.RESULTS M2BPGi levels positively correlated with fibrosis stages,with cut-off indexes of 0.57 for F0-1,0.68 for F2-3,and 0.78 for F4.M2BPGi levels in the F0-1 group were significantly different from those in both the F2-3 group(P=0.038)and the F4 group(P=0.0051);the F2-3 and F4 groups did not show a significant difference(P=0.39).Females exhibited significantly higher M2BPGi levels than males for all fibrosis stages,particularly in the F2-3 group(P=0.01)and F4 group(P=0.0006).In the F4(cirrhosis)group,individuals with diabetes had significantly higher M2BPGi levels than those without.M2BPGi,hemoglobin A1c,and FIB-4 score were identified as independent risk factors for greater fibrosis and cirrhosis.CONCLUSION M2BPGi levels varied significantly throughout fibrosis progression,from early MASLD to cirrhosis,with sex correlation.M2BPGi holds promise as an early biomarker for fibrosis characterization in MASLD adult patient populations.
基金supported by funding from the National Natural Science Foundation of China(U23A20243 and 32272972 to QZ,32172820 to SX)the Major Science and Technology Project of Gansu Province(22ZD6NA001 to SX)+1 种基金the Youth Innovation Program(Y2023QC30)the Agricultural Science and Technology Innovation Program(CAAS-ASTIP-JBGS-20210102 to SX)of the Chinese Academy of Agricultural Sciences.
文摘Influenza A viruses(IAVs)are single-stranded negative-sense RNA viruses that continually challenge animal and human health.In IAV-infected cells,host RNA-binding proteins play key roles in the life cycle of IAV by directly binding to viral RNA.Here,we examined the role of the host RNA-binding protein nucleophosmin-1(NPM1)in IAV replication.We found that,as a nucleolar phosphoprotein,NPM1 directly binds to viral RNA(vRNA)and inhibits the replication of various subtypes of IAV.NPM1 binding to vRNA competitively reduces the assembly of the viral ribonucleoprotein complex and the viral polymerase activity,thereby reducing the generation of progeny viral RNA and virions.The RNA-binding activity of NPM1,with the key residues T199,T219,T234,and T237,is essential for its anti-influenza function.Taken together,our findings demonstrate that NPM1 acts as an RNA-binding protein and interacts with IAV vRNA to suppress viral replication.
文摘A series of potential HDACIs containing diverse Zn^(2+)-chelating hydroxamate moieties were synthesized and evaluated for their anticancer activity in vitro on HeLa,A549,and HepG2 cell lines.The A549 cell line was the most sensitive,and the most active compound,e8,exhibited an IC_(50) value of 1.68μmol/L,surpassing the positive control,SAHA(IC_(50)=4.85μmol/L).Additionally,compound e8 demonstrated lower toxicity to normal WI-38 cells compared to SAHA(IC_(50)=415.93μmol/L vs.9.09μmol/L).Furthermore,e8 efficiently induced G0/G1 phase cell cycle arrest and apoptosis in A549 cells.Molecular docking studies showed that compound e8 coordinated the Zn^(2+) cation at the enzyme’s active site and formed hydrophobic and hydrogen bonds within the hydrophobic pocket of the enzyme,resulting in stable docking with the HDAC enzyme.These studies suggested that compound e8 has the potential to be developed as a promising lead for further optimization and development of HDACIs.
基金supported by NIH-NIDCD,5R01DC21070-0,and Creighton University’s Start-up funds to MZMs.Iman Ezzat was supported by the Department of Biomedical Sciences at Creighton University and the Bellucci Foundation pre-doctoral award.
文摘Integrins are heterodimeric transmembrane receptors that mediate bidirectional interactions between the intracellular cytoskeletal array and the extracellularmatrix.These interactions are critical in tissue development and function by regulating gene expression and sustaining tissue architecture.In humans,the integrin family is composed of 18 alpha(α)and 8 beta(β)subunits,constituting 24 distinctαβcombinations.Based on their structure and ligandbinding properties,only a subset of integrins,8 out of 24,recognizes the arginine-glycine-aspartate(RGD)tripeptide motif in the native ligand.One of the major RGD binding integrins is integrin alpha 8 beta 1(α8β1),a central Ras homolog gene familymemberA(RHOA)-dependentmodulator highly expressed in cells with contractile function.This review focuses on the recent advances regardingα8β1 function during organ development,with a particular interest in kidney and inner ear development.We alsodiscussα8β1’s role ininjury anddisease and its importance formesenchymal to epithelial transition during cancer development.Finally,we highlightα8β1’s importance for hearing function and its future use as a potential diagnostic and therapeutic tool for disease elimination.
基金Supported by the National Research Foundation of Korea Grant Funded by the Korea Government,No.RS-2024-00440477the Korea Institute of Science and Technology Institutional Program,No.2E33111-24-042.
文摘BACKGROUND Mixed lineage kinase domain-like protein(MLKL)serves as a critical mediator in necroptosis,a form of regulated cell death linked to various liver diseases.This study aims to specifically investigate the role of MLKL’s adenosine triphosphate(ATP)-binding pocket in facilitating necroptosis-independent pathways that may contribute to liver disease progression.By focusing on this mechanism,we seek to identify potential therapeutic targets that can modulate MLKL activity,offering new strategies for the prevention and treatment of liver-related pathologies.AIM To investigate the possibility of using the ATP-binding pocket-associated,necro-ptosis-independent MLKL pathway as a target for liver diseases.METHODS Cell death following necroptosis stimuli was evaluated using cell proliferation assays,flow cytometry,and electron microscopy in various cells.The human liver organoid system was used to evaluate whether the MLKL ATP pocket-binding inhibitor could attenuate inflammation.Additionally,alcoholic and non-alcoholic fatty liver diseases animal models were used to determine whether MLKL ATP pocket inhibitors could attenuate liver injury.RESULTS While an MLKL ATP pocket-binding inhibitor did not prevent necroptosis-induced cell death in RAW 264.7 cells,it did reduce the necroptosis-led expression of CXCL2,ICAM,and VCAM.Notably,MLKL ATP pocket inhibitor diminishes the expression of CXCL2,ICAM,and VCAM by inhibiting the IκB kinase and nuclear factor kappa-B pathways without inducing necroptosis-induced cell death in two-dimensional cell culture as well as the human-derived liver organoid system.Although MLKL ATP-binding inhibitor was ineffective in non-alcoholic fatty liver disease animal models,MLKL ATP-binding inhibitor attenuated hepatic inflammation in the alcoholic liver disease model.CONCLUSION MLKL ATP pocket-binding inhibitor exerted anti-inflammatory effects through the necroptosis-independent MLKL pathway in an animal model of alcoholic liver disease.
基金financially supported by the National Natural Science Foundation of China-Youth Science Fund(No.52208273)the National Natural Science Foundations of ChinaNSFCShandong Joint Fund(No.U2006223)。
文摘Corrosion of reinforcement induced by chloride invasion is extensively considered as the dominating deterioration mechanism of reinforced concrete(RC)structures,leading to serious safety hazards and tremendous economic losses.However,it still lacks well dispersive and cost-efficient nanomaterials to improve the anti-chloride-corrosion ability of RC structures.Herein,specific carbon dots(CDs)with high dispersity and low cost are deliberately designed,successfully prepared by hydrothermal processing,and then firstly applied to immensely enhance chloride binding performance of cement,thereby contributing to suppressing the corrosion of reinforcement.Specifically,the tailored CDs are composed of the carbon core with highly crystalline sp^(2)C structures and oxygen-containing groups connecting on the carbon core;The typical equilibrium test confirms that with respect to that of the blank cement paste,the chloride binding capacity of cement paste involving 0.2 wt%(by weight of cement)CDs is increased by 109% after 14-day exposure to 3 mol/L Na Cl solution;according to comprehensive analyses of phase compositions,the chloride binding mechanism of CDs-modified cement is rationally attributed to the fact that the incorporation of CDs advances the formation of calcium silicate hydrate(C-S-H)gels and Friedel's salt(Fs),thus enormously enhancing the physically adsorbed and chemically bound chloride ions of cement pastes.This work not only firstly provides a novel high-dispersity and low-cost nanomaterial toward the durability enhancement of RC structures,but also broadens the application of CDs in the field of engineering,conducing to stimulating their industrialization development.
基金supported by the National Natural Science Foundation of China(32170037)and SKLMT Frontiers and Challenges Project(SKLMTFCP-2023-04).
文摘Cellulosic materials are attracting increasing research interest because of their abundance,biocompatibility,and biodegradability,making them suitable in multiple industrial and medical applications.Functionalization of cellulose is usually required to improve or expand its properties to meet the requirements of different applications.Cellulose-binding domains(CBDs)found in various proteins have been shown to be powerful tools in the functionalization of cellulose materials.In this review,we firstly introduce the structural characteristics of commonly used CBDs belonging to carbohydrate-binding module families 1,2 and 3.Then,we summarize four main kinds of methodologies for employing CBDs to modify cellulosic materials(i.e.,CBD only,genetic fusion,non-covalent linkage and covalent linkage).Via different approaches,CBDs have been used to improve the material properties of cellulose,immobilize enzymes for biocatalysis,and design various detection tools.To achieve industrial applications,researches for lowering the production cost of CBDs,improving their performance(e.g.,stability),and expanding their application scenarios are still in need.
