Numerous c-mesenchymal-epithelial transition(c-MET)inhibitors have been reported as potential anticancer agents.However,most fail to enter clinical trials owing to poor efficacy or drug resistance.To date,the scaffold...Numerous c-mesenchymal-epithelial transition(c-MET)inhibitors have been reported as potential anticancer agents.However,most fail to enter clinical trials owing to poor efficacy or drug resistance.To date,the scaffold-based chemical space of small-molecule c-MET inhibitors has not been analyzed.In this study,we constructed the largest c-MET dataset,which included 2,278 molecules with different struc-tures,by inhibiting the half maximal inhibitory concentration(IC_(50))of kinase activity.No significant differences in drug-like properties were observed between active molecules(1,228)and inactive mol-ecules(1,050),including chemical space coverage,physicochemical properties,and absorption,distri-bution,metabolism,excretion,and toxicity(ADMET)profiles.The higher chemical diversity of the active molecules was downscaled using t-distributed stochastic neighbor embedding(t-SNE)high-dimensional data.Further clustering and chemical space networks(CSNs)analyses revealed commonly used scaffolds for c-MET inhibitors,such as M5,M7,and M8.Activity cliffs and structural alerts were used to reveal“dead ends”and“safe bets”for c-MET,as well as dominant structural fragments consisting of pyr-idazinones,triazoles,and pyrazines.Finally,the decision tree model precisely indicated the key structural features required to constitute active c-MET inhibitor molecules,including at least three aromatic het-erocycles,five aromatic nitrogen atoms,and eight nitrogeneoxygen atoms.Overall,our analyses revealed potential structure-activity relationship(SAR)patterns for c-MET inhibitors,which can inform the screening of new compounds and guide future optimization efforts.展开更多
Silver ion(Ag^(+))is a highly toxic metal ion,and its monitoring in water or food resources has become extraordinarily necessary within the scope of human health.In the light of the fact of Ag^(+)-induced folding stru...Silver ion(Ag^(+))is a highly toxic metal ion,and its monitoring in water or food resources has become extraordinarily necessary within the scope of human health.In the light of the fact of Ag^(+)-induced folding structure of specific peptides,an unlabeled and highselectivity Ag^(+)assay is presented by means of intrinsic fluorescence of peptides.Under the quenching effect of gold nanoparticles(AuNPs),characteristic fluorescence of peptides could be considerably reduced by rapid modification.Along with the Ag adding,the fluorescence signals of peptide-AuNPs are largely enhanced by the behavior between peptides and Agt.This is basically involving the formation of 4-coordinated complexes,generating the changes of peptides in structure and fluorescence properties.Under this circumstance,the adverse influence of plenty of interfering ions is suppressed,including the toxic Hg^(2+),Pb^(2+).The results highlight that Ag ions could be selectively recognized as low as 2.4 nmol/L with a linear range of 5 to 800 nmol/L.In comparison with other programs,the given approach declares simplicity,sensitivity,and superior selectivity.Furthermore,the biosensor excels in the practical application in water samples(e.g.,lake,tap and drinking water)owing to its non-interference and on-site rapid determination.展开更多
With the development of education and technology,the construction of research public platforms has emerged as a critical initiative for many universities and top-tier public hospitals.The core and most fundamental fun...With the development of education and technology,the construction of research public platforms has emerged as a critical initiative for many universities and top-tier public hospitals.The core and most fundamental function of a basic public platform is to aggregate large instruments and specific resources,providing open services for instrumental analysis and sample testing.Optimized management and high-quality,efficient services are essential for such platforms.This article elucidates the construction of a research public platform in West China Hospital,focusing on the adoption of hierarchical management and precise services.The core of the hierarchical management lies in building a multi-level service platform composed of routine support platforms,advanced technology platforms,and specially qualification platforms,while establishing a talent hierarchy that differentiates between core and routine positions.This structure is designed to accurately meet the diverse needs of users and enhance resource efficiency.By implementing user access control with differentiated permissions for internal and external users and a dynamic credit-based review system,the laboratory can ensure safe and efficient operations.The four service modes—instrument usage,in-lab experiments,sample testing,and collaborative projects—are precisely aligned with various research scenarios.Proactive engagement with grant-funded projects,customized services for research groups,and a multidimensional training system further strengthen the platform's support for major scientific research tasks.Through systematic management and service innovation,this model achieves efficient integration and sustainable development of platform resources,providing a valuable reference for the construction of public platforms in similar medical institutions.展开更多
The features of additive manufacturing(AM)have made commercially pure titanium(CP-Ti)an attractive candidate material for biomedical implants.However,achieving high strength and ductility is challenging because of the...The features of additive manufacturing(AM)have made commercially pure titanium(CP-Ti)an attractive candidate material for biomedical implants.However,achieving high strength and ductility is challenging because of the columnar structures and fine martensite formation.This study investigated the effect of carbon nanotubes(CNTs)addition on the microstructure and mechanical properties of grade 1 CP-Ti(Gr-1)during the laser powder bed fusion(L-PBF)process.A minute amount of 0.2%mass fraction(wt%)CNTs addition resulted in a high yield strength of approximately 700 MPa and exceptional ductility of 25.7%.Therein,a portion of the CNTs dissolved in the matrix as solute atoms,contributing to solution strengthening,while others were transformed into Ti C_(x)through an in situ reaction with the Ti matrix.Furthermore,the addition of CNTs resulted in the formation of a larger fraction of equiaxed grains and increased the activity of basal and prismatic slip systems.Hence,Gr-1 with CNTs exhibited significantly increased ductility while maintaining a high strength comparable to that of Gr-1 without CNTs.The insights gained from this study provide a novel approach for designing strong and ductile Ti alloys for AM.展开更多
A comprehensive understanding of the molecular details at spatial levels within heterogeneous cardiac tissue in heart failure(HF)is paramount for enhancing our knowledge of the pathophysiology of HF and pinpointing po...A comprehensive understanding of the molecular details at spatial levels within heterogeneous cardiac tissue in heart failure(HF)is paramount for enhancing our knowledge of the pathophysiology of HF and pinpointing potential therapeutic targets.Here,we present an analytical strategy for the deep discovery of heterogeneous metabolism and drug response in the heart tissue of rats with HF using airflow-assisted desorption electrospray ionization mass spectrometry imaging(AFADESI-MSI)coupled with bulk RNAsequencing.Spatial metabolomics illustrated pronounced metabolic heterogeneity between the infarct(I),infarct margin(IM),and non-infarct(NI)areas of heart tissue in HF.Integrated transcriptomics showed that increased mRNA expression of ATP citrate lyase disrupted the tricarboxylic acid(TCA)cycle in the NI area.Impairment of the carnitine shuttle system led to a significant accumulation of carnitines,suggesting potential abnormalities in fatty acid(FA)oxidation.Coupling on-tissue chemical derivatization with AFADESI-MSI enabled us to confirm the occurrence of incomplete oxidation of FAs in the NI area.Additionally,we observed a heterogeneous drug response between the anti-HF medications valsartan and Qishen Yiqi Dripping Pills(QDP).Valsartan exhibited a more pronounced effect on metabolic regulation in the I area,whereas QDP exerted stronger regulatory effects on metabolism in the NI area.Utilizing this method,four potential therapeutic targets were identified in HF:CPT1A,PDHB,ACLY,and BCAT2,which were preliminarily validated by western blotting.Overall,integrating spatial metabolomics with transcriptomics facilitates comprehensive analyses that link differential metabolites and genes,enabling a more precise characterization of metabolic changes in heart injury microareas and providing effective methods for elucidating molecular mechanisms and identifying potential therapeutic targets for HF.展开更多
Developing novel building blocks with predictable side-chain orientations and minimal intramolecular interactions is essential for peptide-based self-assembling materials.Traditional structures likeα-helices andβ-sh...Developing novel building blocks with predictable side-chain orientations and minimal intramolecular interactions is essential for peptide-based self-assembling materials.Traditional structures likeα-helices andβ-sheets rely on such interactions for stability,limiting control over exposed interacting moieties.Here,we reported a novel,frame-like peptide scaffold that maintains exceptional stability without intramolecular interactions.This structure exposes its backbone and orients side chains for hierarchical self-assembly into micron-scale cubes.By introducing mutations at specific sites,we controlled packing orientations,offering new options for tunable self-assembly.Our scaffold provides a versatile platform for designing advanced peptide materials,with applications in nanotechnology and biomaterials.展开更多
Being widespread across the globe,severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)keeps evolving and generating new variants and continuously poses threat to public health,especially to the population with ...Being widespread across the globe,severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)keeps evolving and generating new variants and continuously poses threat to public health,especially to the population with chronic comorbidities.Diabetes mellitus is one of high-risk factors for severe outcome of coronavirus disease 2019(COVID-19).Establishment of animal models that parallel the clinical and pathological features of COVID-19 complicated with diabetes is thus highly essential.Here,in this study,we constructed leptin receptor gene knockout hamsters with the phenotype of diabetes mellitus(db/db),and revealed that the diabetic hamsters were more susceptible to SARS-CoV-2 and its variants than wild-type hamsters.SARS-CoV-2 and its variants induced a stronger immune cytokine response in the lungs of diabetic hamsters than in wild-type hamsters.Comparative histopathology analyses also showed that infection of SARS-CoV-2 and the variants caused more severe lung tissue injury in diabetic hamsters,and may induce serious complications such as diabetic kidney disease and cardiac lesions.Our findings demonstrated that despite the decreased respiratory pathogenicity,the SARS-CoV-2 variants were still capable of impairing other organs such as kidney and heart in diabetic hamsters,suggesting that the risk of evolving SARS-CoV-2 variants to diabetic patients should never be neglected.This hamster model may help better understand the pathogenesis mechanism of severe COVID-19 in patients with diabetes.It will also aid in development and testing of effective therapeutics and prophylactic treatments against SARS-CoV-2 variants among these high-risk populations.展开更多
Although per-and polyfluoroalkyl substances(PFAS)have been frequently linked to cardiovascular and renal disease separately,evidence remains scarce regarding their systematic effect.Therefore,we recruited 546 newly di...Although per-and polyfluoroalkyl substances(PFAS)have been frequently linked to cardiovascular and renal disease separately,evidence remains scarce regarding their systematic effect.Therefore,we recruited 546 newly diagnosed acute coronary syndrome(ACS)patients and detected seven myocardial enzymes and six kidney function biomarkers.Twelve PFASwere also assessedwith ultra-high-performance liquid chromatography-tandem mass spectrometry.Generalized linear model and restricted cubic spline model were applied to single pollutant analysis.Quantile g-computation was used for mixture analysis.Network model was utilized to identify central and bridge nodes of pollutants and phenotypes.In the present study,perfluorohexane sulfonic acid was positively associated with uric acid(UA)(β=0.04,95%confidence interval(CI):0.01,0.07),and perfluorobutanoic acid was negatively associated with estimated glomerular filtration rate(β=-0.04,95%CI:-0.07,-0.01)but positively associated with UA(β=0.03,95%CI:0.01,0.06).In mixture analysis,each quantile increase in the PFAS mixture was significantly associated with UA(β=0.08,95%CI:0.04,0.11).Network analysis revealed that perfluorooctanoate,UA,and myoglobin were denoted as bridge nodes,and the first principal component of lactate dehydrogenase and creatine kinase-myocardial band was identified as the node with the highest strength and expected influence.This study investigates the systematic impact of PFAS exposure through cardiorenal interaction network,which highlights that PFAS may serve as an upstream approach in UA-modulated cardiorenal network to affect cardiorenal system comprehensively.展开更多
Widely used spin-coated nickle oxide (NiOx) based perovskite solar cells often suffer from severe interfacial reactions between the NiOxand adjacent perovskite layers due to surface defect states,which inherently impa...Widely used spin-coated nickle oxide (NiOx) based perovskite solar cells often suffer from severe interfacial reactions between the NiOxand adjacent perovskite layers due to surface defect states,which inherently impair device performance in a long-term view,even with surface molecule passivation.In this study,we developed high-quality magnetron-sputtered NiOxthin films through detailed process optimization,and compared systematically sputtered and spin-coated NiOxthin film surfaces from materials to devices.These sputtered NiOxfilms exhibit improved crystallinity,smoother surfaces,and significantly reduced Ni3+or Ni vacancies compared to their spin-coated counterparts.Consequently,the interface between the perovskite and sputtered NiOxfilm shows a substantially reduced density of defect states.Perovskite solar cells (PSCs) fabricated with our optimally sputtered NiOxfilms achieved a high power conversion efficiency (PCE) of up to 19.93%and demonstrated enhanced stability,maintaining 86.2% efficiency during 500 h of maximum power point tracking under one standard sun illumination.Moreover,with the surface modification using (4-(2,7-dibromo-9,9-dimethylacridin-10(9H)-yl)butyl)p hosphonic acid (DMAcPA),the device PCE was further promoted to 23.07%,which is the highest value reported for sputtered NiOxbased PSCs so far.展开更多
Objective:Sheep are commonly used as large animal pre-clinical models for inves-tigating cardiovascular therapies,interventions,anatomy and physiology.Further,novel small diameter vascular grafts are frequently tested...Objective:Sheep are commonly used as large animal pre-clinical models for inves-tigating cardiovascular therapies,interventions,anatomy and physiology.Further,novel small diameter vascular grafts are frequently tested via implantation into sheep carotid arteries(CAs).This is because,unlike humans,acute occlusion of one or both sheep CAs is not associated with morbidity or mortality and thus provides safer experimental testing,with reduced ethical constraints,animal numbers and costs.However,to date there has been no evidence regarding sheep tolerance of femoral artery(FA)occlusion.Methods:In this study,seven sheep underwent CA graft surgery,with digital subtrac-tion angiography(DSA)of the CAs performed every 2 months via femoral access,for a total of 8 months.Four months into the study,the left FA of two sheep became inac-cessible due to a suspected FA occlusion.Thus,femoral angiography was performed,followed by FA dissection,FA histology and retrospective analysis of both veterinar-ian animal monitoring and pain scores.Results:FA angiography and histology confirmed complete left FA occlusion in two sheep.Retrospective animal monitoring demonstrated sheep with occluded FAs did not display increased pain scores or deleterious effects on their gait or wellbeing.Conclusion:Our data shows that sheep tolerate FA occlusion with no symptoms,similar to their cerebral circulation,making them an appropriate model for assessing small diameter femoral graft interposition studies and testing other cardiovascular interventions.展开更多
Calcium influx into neurons triggers neuronal death during cerebral ischemia/reperfusion injury.Various calcium channels are involved in cerebral ischemia/reperfusion injury.Cav3.2 channel is a main subtype of T-type ...Calcium influx into neurons triggers neuronal death during cerebral ischemia/reperfusion injury.Various calcium channels are involved in cerebral ischemia/reperfusion injury.Cav3.2 channel is a main subtype of T-type calcium channels.T-type calcium channel blockers,such as pimozide and mibefradil,have been shown to prevent cerebral ischemia/reperfusion injury-induced brain injury.However,the role of Cav3.2 channels in cerebral ischemia/reperfusion injury remains unclear.Here,in vitro and in vivo models of cerebral ischemia/reperfusion injury were established using middle cerebral artery occlusion in mice and high glucose hypoxia/reoxygenation exposure in primary hippocampal neurons.The results showed that Cav3.2 expression was significantly upregulated in injured hippocampal tissue and primary hippocampal neurons.We further established a Cav3.2 gene-knockout mouse model of cerebral ischemia/reperfusion injury.Cav3.2 knockout markedly reduced infarct volume and brain water content,and alleviated neurological dysfunction after cerebral ischemia/reperfusion injury.Additionally,Cav3.2 knockout attenuated cerebral ischemia/reperfusion injury-induced oxidative stress,inflammatory response,and neuronal apoptosis.In the hippocampus of Cav3.2-knockout mice,calcineurin overexpression offset the beneficial effect of Cav3.2 knockout after cerebral ischemia/reperfusion injury.These findings suggest that the neuroprotective function of Cav3.2 knockout is mediated by calcineurin/nuclear factor of activated T cells 3 signaling.Findings from this study suggest that Cav3.2 could be a promising target for treatment of cerebral ischemia/reperfusion injury.展开更多
Background Cell metabolism plays a pivotal role in tumor progression,and targeting cancer metabolism might effectively kill cancer cells.We aimed to investigate the role of hexokinases in prostate cancer(PCa)and ident...Background Cell metabolism plays a pivotal role in tumor progression,and targeting cancer metabolism might effectively kill cancer cells.We aimed to investigate the role of hexokinases in prostate cancer(PCa)and identify a crucial target for PCa treatment.Methods The Cancer Genome Atlas(TCGA)database,online tools and clinical samples were used to assess the expression and prognostic role of ADP-dependent glucokinase(ADPGK)in PCa.The effect of ADPGK expression on PCa cell malignant phenotypes was validated in vitro and in vivo.Quantitative proteomics,metabolomics,and extracellular acidification rate(ECAR)and oxygen consumption rate(OCR)tests were performed to evaluate the impact of ADPGK on PCa metabolism.The underlying mechanisms were explored through ADPGK overexpression and knockdown,co-immunoprecipitation(Co-IP),ECAR analysis and cell counting kit-8(CCK-8)assays.Results ADPGK was the only glucokinase that was both upregulated and predicted worse overall survival(OS)in prostate adenocarcinoma(PRAD).Clinical sample analysis demonstrated that ADPGK was markedly upregulated in PCa tissues vs.non-PCa tissues.High ADPGK expression indicates worse survival outcomes,and ADPGK serves as an independent factor of biochemical recurrence.In vitro and in vivo experiments showed that ADPGK overexpression promoted PCa cell proliferation and migration,and ADPGK inhibition suppressed malignant phenotypes.Metabolomics,proteomics,and ECAR and OCR tests revealed that ADPGK significantly accelerated glycolysis in PCa.Mechanistically,ADPGK binds aldolase C(ALDOC)to promote glycolysis via AMP-activated protein kinase(AMPK)phosphorylation.ALDOC was positively correlated with ADPGK,and high ALDOC expression was associated with worse survival outcomes in PCa.Conclusions In summary,ADPGK is a driving factor in PCa progression,and its high expression contributes to a poor prognosis in PCa patients.ADPGK accelerates PCa glycolysis and progression by activating ALDOC-AMPK signaling,suggesting that ADPGK might be an effective target and marker for PCa treatment and prognosis evaluation.展开更多
Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the uterus.Angiogenesis is a major pathophysiology in endometriosis.Our previous studies have demonstrated that the pr...Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the uterus.Angiogenesis is a major pathophysiology in endometriosis.Our previous studies have demonstrated that the prodrug of epigallocatechin gallate(ProEGCG)exhibits superior anti-endometriotic and anti-angiogenic effects compared to epigallocatechin gallate(EGCG).However,their direct binding targets and underlying mechanisms for the differential effects remain unknown.In this study,we demonstrated that oral ProEGCG can be effective in preventing and treating endometriosis.Additionally,1D and 2D Proteome Integral Solubility Alteration assay-based chemical proteomics identified metadherin(MTDH)and PX domain containing serine/threonine kinase-like(PXK)as novel binding targets of EGCG and ProEGCG,respectively.Computational simulation and BioLayer interferometry were used to confirm their binding affinity.Our results showed that MTDH-EGCG inhibited protein kinase B(Akt)-mediated angiogenesis,while PXK-ProEGCG inhibited epidermal growth factor(EGF)-mediated angiogenesis via the EGF/hypoxia-inducible factor(HIF-1a)/vascular endothelial growth factor(VEGF)pathway.In vitro and in vivo knockdown assays and microvascular network imaging further confirmed the involvement of these signaling pathways.Moreover,our study demonstrated that ProEGCG has superior therapeutic effects than EGCG by targeting distinct signal transduction pathways and may act as a novel antiangiogenic therapy for endometriosis.展开更多
Synthetic biology provides unprecedented opportunities to tackle critical issues including climate change and sustainable development by constructing microbial cell factories to produce industrially valuable biochemic...Synthetic biology provides unprecedented opportunities to tackle critical issues including climate change and sustainable development by constructing microbial cell factories to produce industrially valuable biochemicals,biofuels,and biomaterials using renewable biomass resources[1],where strain screening for specific metabolic traits is a critical step.Rapid,accurate,and simultaneous quantification of multiple metabolites is critical for multi-perspective strain performance evaluation and strain screening,and a generalized method or platform will also reduce method development time to speed up the screening process.展开更多
The overdiagnosis of prostate cancer(PCa)caused by nonspecific elevation serum prostate-specific antigen(PSA)and the overtreatment of indolent PCa have become a global problem that needs to be solved urgently.We aimed...The overdiagnosis of prostate cancer(PCa)caused by nonspecific elevation serum prostate-specific antigen(PSA)and the overtreatment of indolent PCa have become a global problem that needs to be solved urgently.We aimed to construct a prediction model and provide a risk stratification system to reduce unnecessary biopsies.In this retrospective study,clinical data of 1807 patients from three Chinese hospitals were used.The final model was built using stepwise logistic regression analysis.The apparent performance of the model was assessed by receiver operating characteristic curves,calibration plots,and decision curve analysis.Finally,a risk stratification system of clinically significant prostate cancer(csPCa)was created,and diagnosis-free survival analyses were performed.Following multivariable screening and evaluation of the diagnostic performances,a final diagnostic model comprised of the PSA density and Prostate Imaging-Reporting and Data System(PI-RADS)score was established.Model validation in the development cohort and two external cohorts showed excellent discrimination and calibration.Finally,we created a risk stratification system using risk thresholds of 0.05 and 0.60 as the cut-off values.The follow-up results indicated that the diagnosis-free survival rate for csPCa at 12 months and 24 months postoperatively was 99.7%and 99.4%,respectively,for patients with a risk threshold below O.05 after the initial negative prostate biopsy,which was significantly better than patients with higher risk.Our diagnostic model and risk stratification system can achieve a personalized risk calculation of csPCa.It provides a standardized tool for Chinese patients and physicians when considering thenecessity of prostatebiopsy.展开更多
Background:Ginkgo flavone aglycones(GA),a Ginkgo(Ginkgo biloba)extract,has been proven to have good biological activity in atherosclerosis(AS)treatment.Moreover,its active compounds and the corresponding mechanism for...Background:Ginkgo flavone aglycones(GA),a Ginkgo(Ginkgo biloba)extract,has been proven to have good biological activity in atherosclerosis(AS)treatment.Moreover,its active compounds and the corresponding mechanism for the treatment of AS remain unclear.Methods:To evaluate and identify the potential pharmacological mechanisms of GA in AS treatment,the program Cytoscape was used to generate network mappings of the GA-AS-potential target gene.GO and KEGG enrichment analyses were performed to further investigate the potential mechanism of AS and the pharmacological properties of GA.A molecular docking approach was utilized to determine the GA components that interact with Akt.In vitro experiments were carried out to identify the anti-atherosclerotic effects of GA by targeting Akt.Results:Network pharmacological research determined that the active components of GA(quercetin,kaempferol,and isorhamnetin)correlated with AS target genes such as AKT1,EGFR,SRC,ESR1,PTGS2,MMP9,KDR,GSK3B,APP,and MMP2,respectively.GO enrichment and KEGG analysis showed that PI3K-Akt signaling may play an important role in GA treatment.Molecular docking experiments indicated that quercetin,kaempferol,and isorhamnetin integrate into the binding pockets of the most potentially beneficial GA-AS target protein(Akt).Consequently,cell experiments were conducted to support the anti-atherosclerotic activity of GA on AS by inhibiting the phosphorylation of AKT1 and its downstream signaling molecules,which regulated the proliferation of HASMCs.Conclusion:Our results detailed GA's active ingredients,potential targets,and molecular basis against AS.GA may exert anti-atherosclerotic effects by suppressing Akt phosphorylation and inhibiting the proliferation of HASMCs.It also proposed a viable approach to determining the scientific foundation and therapeutic mechanism of Chinese herbal medicine extracts in disease therapy.展开更多
The three-phase Enriched Environment(EE)paradigm has been shown to promote post-stroke functional improvement,but the neuronal mechanisms are still unclear.In this study,we applied a multimodal neuroimaging protocol c...The three-phase Enriched Environment(EE)paradigm has been shown to promote post-stroke functional improvement,but the neuronal mechanisms are still unclear.In this study,we applied a multimodal neuroimaging protocol combining magnetic resonance imaging(MRI)and positron emission tomography(PET)to examine the effects of post-ischemic EE treatment on structural and functional neuroplasticity in the bilateral sensorimotor cortex.Rats were subjected to permanent middle cerebral artery occlusion.The motor function of the rats was examined using the DigiGait test.MRI was applied to investigate the EE-induced structural modifications of the bilateral sensorimotor cortex.[^(18)F]-fluorodeoxyglucose PET was used to detect glucose metabolism.Blood oxygen level-dependent(BOLD)-functional MRI(fMRI)was used to identify the regional brain activity and functional connectivity(FC).In addition,the expression of neuroplasticity-related signaling pathways including neurotrophic factors(BDNF/CREB),axonal guidance proteins(Robo1/Slit2),and axonal growth-inhibitory proteins(NogoA/NgR)as well as downstream proteins(RhoA/ROCK)in the bilateral sensorimotor cortex were measured by Western blots.Our results showed the three-phase EE improved the walking ability.Structural T2 mapping imaging and diffusion tensor imaging demonstrated that EE benefited structure integrity in the bilateral sensorimotor cortex.PET-MRI fused images showed improved glucose metabolism in the corresponding regions after EE intervention.Specifically,the BOLD-based amplitude of low-frequency fluctuations showed that EE increased spontaneous activity in the bilateral motor cortex and ipsilateral sensory cortex.In addition,FC results showed increased sensorimotor connectivity in the ipsilateral hemisphere and increased interhemispheric motor cortical connectivity and motor cortical-thalamic connectivity following EE intervention.In addition,a strong correlation was found between increased functional connectivity and improved motor performance of limbs.Specifically,EE regulated the expression of neuroplasticity-related signaling,involving BDNF/CREB,Slit2/Robo1,as well as the axonal growth–inhibitory pathways Nogo-A/Nogo receptor and RhoA/ROCK in the bilateral sensorimotor cortex.Our results indicated that the three-phase enriched environment paradigm enhances neuronal plasticity of the bilateral sensorimotor cortex and consequently ameliorates post-stroke gait deficits.These findings might provide some new clues for the development of EE and thus facilitate the clinical translation of EE.展开更多
The combination of nucleic acid and small-molecule drugs in tumor treatment holds significant promise;however,the precise delivery and controlled release of drugs within the cytoplasm encounter substantial obstacles,i...The combination of nucleic acid and small-molecule drugs in tumor treatment holds significant promise;however,the precise delivery and controlled release of drugs within the cytoplasm encounter substantial obstacles,impeding the advancement of formulations.To surmount the challenges associated with precise drug delivery and controlled release,we have developed a multi-level p H-responsive co-loaded drug lipid nanoplatform.This platform first employs cyclic cell-penetrating peptides to exert a multi-level pH response,thereby enhancing the uptake efficiency of tumor cells and endow the nanosystem with effective endosomal/lysosomal escape.Subsequently,small interferring RNA(siRNA)complexes are formed by compacting siRNA with stearic acid octahistidine,which is capable of responding to the lysosome-tocytoplasm pH gradient and facilitate siRNA release.The siRNA complexes and docetaxel are simultaneously encapsulated into liposomes,thereby creating a lipid nanoplatform capable of co-delivering nucleic acid and small-molecule drugs.The efficacy of this platform has been validated through both in vitro and in vivo experiments,affirming its significant potential for practical applications in the co-delivery of nucleic acids and small-molecule drugs.展开更多
FL-Online(http://fanlab.ac.cn) is an out-of-box modern web service featuring a user-friendly interface and simplified parameters, providing academic users with access to a series of online programs for biomolecular cr...FL-Online(http://fanlab.ac.cn) is an out-of-box modern web service featuring a user-friendly interface and simplified parameters, providing academic users with access to a series of online programs for biomolecular crystallography, including SAPI-online, OASIS-online, C-IPCAS-online and a series of upcoming software releases. Meanwhile, it is a highly scalable and maintainable web application framework that provides a powerful and flexible solution for academic web development needs. All the codes are open-source under MIT licenses in GitHub.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.:82173699 and 32200531)Shanghai Jiao Tong University Trans-Med Awards Research,China(STAR Project No.:20230101)Shanghai Science and Technol-ogy Commission,China(Grant No.:23DZ2290600).
文摘Numerous c-mesenchymal-epithelial transition(c-MET)inhibitors have been reported as potential anticancer agents.However,most fail to enter clinical trials owing to poor efficacy or drug resistance.To date,the scaffold-based chemical space of small-molecule c-MET inhibitors has not been analyzed.In this study,we constructed the largest c-MET dataset,which included 2,278 molecules with different struc-tures,by inhibiting the half maximal inhibitory concentration(IC_(50))of kinase activity.No significant differences in drug-like properties were observed between active molecules(1,228)and inactive mol-ecules(1,050),including chemical space coverage,physicochemical properties,and absorption,distri-bution,metabolism,excretion,and toxicity(ADMET)profiles.The higher chemical diversity of the active molecules was downscaled using t-distributed stochastic neighbor embedding(t-SNE)high-dimensional data.Further clustering and chemical space networks(CSNs)analyses revealed commonly used scaffolds for c-MET inhibitors,such as M5,M7,and M8.Activity cliffs and structural alerts were used to reveal“dead ends”and“safe bets”for c-MET,as well as dominant structural fragments consisting of pyr-idazinones,triazoles,and pyrazines.Finally,the decision tree model precisely indicated the key structural features required to constitute active c-MET inhibitor molecules,including at least three aromatic het-erocycles,five aromatic nitrogen atoms,and eight nitrogeneoxygen atoms.Overall,our analyses revealed potential structure-activity relationship(SAR)patterns for c-MET inhibitors,which can inform the screening of new compounds and guide future optimization efforts.
基金Supported by the National Natural Science Foundation of China(21775114,21874102)。
文摘Silver ion(Ag^(+))is a highly toxic metal ion,and its monitoring in water or food resources has become extraordinarily necessary within the scope of human health.In the light of the fact of Ag^(+)-induced folding structure of specific peptides,an unlabeled and highselectivity Ag^(+)assay is presented by means of intrinsic fluorescence of peptides.Under the quenching effect of gold nanoparticles(AuNPs),characteristic fluorescence of peptides could be considerably reduced by rapid modification.Along with the Ag adding,the fluorescence signals of peptide-AuNPs are largely enhanced by the behavior between peptides and Agt.This is basically involving the formation of 4-coordinated complexes,generating the changes of peptides in structure and fluorescence properties.Under this circumstance,the adverse influence of plenty of interfering ions is suppressed,including the toxic Hg^(2+),Pb^(2+).The results highlight that Ag ions could be selectively recognized as low as 2.4 nmol/L with a linear range of 5 to 800 nmol/L.In comparison with other programs,the given approach declares simplicity,sensitivity,and superior selectivity.Furthermore,the biosensor excels in the practical application in water samples(e.g.,lake,tap and drinking water)owing to its non-interference and on-site rapid determination.
基金supported by Sichuan University AI-Driven In-novative Experimental Technology Research Project(SCU2025047).
文摘With the development of education and technology,the construction of research public platforms has emerged as a critical initiative for many universities and top-tier public hospitals.The core and most fundamental function of a basic public platform is to aggregate large instruments and specific resources,providing open services for instrumental analysis and sample testing.Optimized management and high-quality,efficient services are essential for such platforms.This article elucidates the construction of a research public platform in West China Hospital,focusing on the adoption of hierarchical management and precise services.The core of the hierarchical management lies in building a multi-level service platform composed of routine support platforms,advanced technology platforms,and specially qualification platforms,while establishing a talent hierarchy that differentiates between core and routine positions.This structure is designed to accurately meet the diverse needs of users and enhance resource efficiency.By implementing user access control with differentiated permissions for internal and external users and a dynamic credit-based review system,the laboratory can ensure safe and efficient operations.The four service modes—instrument usage,in-lab experiments,sample testing,and collaborative projects—are precisely aligned with various research scenarios.Proactive engagement with grant-funded projects,customized services for research groups,and a multidimensional training system further strengthen the platform's support for major scientific research tasks.Through systematic management and service innovation,this model achieves efficient integration and sustainable development of platform resources,providing a valuable reference for the construction of public platforms in similar medical institutions.
基金financially supported by the National Key Research and Development Project of the Ministry of Science and Technology of China(No.2022YFB4601000)the Fundamental Research Funds for the Central Universities(No.2042023kf0103)the Ministry of Trade,Industry and Energy,Korea(No.20013095)。
文摘The features of additive manufacturing(AM)have made commercially pure titanium(CP-Ti)an attractive candidate material for biomedical implants.However,achieving high strength and ductility is challenging because of the columnar structures and fine martensite formation.This study investigated the effect of carbon nanotubes(CNTs)addition on the microstructure and mechanical properties of grade 1 CP-Ti(Gr-1)during the laser powder bed fusion(L-PBF)process.A minute amount of 0.2%mass fraction(wt%)CNTs addition resulted in a high yield strength of approximately 700 MPa and exceptional ductility of 25.7%.Therein,a portion of the CNTs dissolved in the matrix as solute atoms,contributing to solution strengthening,while others were transformed into Ti C_(x)through an in situ reaction with the Ti matrix.Furthermore,the addition of CNTs resulted in the formation of a larger fraction of equiaxed grains and increased the activity of basal and prismatic slip systems.Hence,Gr-1 with CNTs exhibited significantly increased ductility while maintaining a high strength comparable to that of Gr-1 without CNTs.The insights gained from this study provide a novel approach for designing strong and ductile Ti alloys for AM.
基金supported by the National Natural Science Foundation of China(No.82374158)National Science and Technology Major Project(No.2018ZX09711001-002-004)+1 种基金the Jiangxi University of Chinese Medicine Science and Technology Innovation Team Development Program(No.CXTD22007)the Medical and Health Technology Innovation Project(No.2022-I2M-1-020).
文摘A comprehensive understanding of the molecular details at spatial levels within heterogeneous cardiac tissue in heart failure(HF)is paramount for enhancing our knowledge of the pathophysiology of HF and pinpointing potential therapeutic targets.Here,we present an analytical strategy for the deep discovery of heterogeneous metabolism and drug response in the heart tissue of rats with HF using airflow-assisted desorption electrospray ionization mass spectrometry imaging(AFADESI-MSI)coupled with bulk RNAsequencing.Spatial metabolomics illustrated pronounced metabolic heterogeneity between the infarct(I),infarct margin(IM),and non-infarct(NI)areas of heart tissue in HF.Integrated transcriptomics showed that increased mRNA expression of ATP citrate lyase disrupted the tricarboxylic acid(TCA)cycle in the NI area.Impairment of the carnitine shuttle system led to a significant accumulation of carnitines,suggesting potential abnormalities in fatty acid(FA)oxidation.Coupling on-tissue chemical derivatization with AFADESI-MSI enabled us to confirm the occurrence of incomplete oxidation of FAs in the NI area.Additionally,we observed a heterogeneous drug response between the anti-HF medications valsartan and Qishen Yiqi Dripping Pills(QDP).Valsartan exhibited a more pronounced effect on metabolic regulation in the I area,whereas QDP exerted stronger regulatory effects on metabolism in the NI area.Utilizing this method,four potential therapeutic targets were identified in HF:CPT1A,PDHB,ACLY,and BCAT2,which were preliminarily validated by western blotting.Overall,integrating spatial metabolomics with transcriptomics facilitates comprehensive analyses that link differential metabolites and genes,enabling a more precise characterization of metabolic changes in heart injury microareas and providing effective methods for elucidating molecular mechanisms and identifying potential therapeutic targets for HF.
基金supported by the National Basic Research Program of China 973 Program(Nos.2021YFA0910803,2021YFC2103900)the National Natural Science Foundation of China(No.21977011)+4 种基金the Natural Science Foundation of Guangdong Province(Nos.2022A1515010996 and 2020A1515011544)the Shenzhen Science and Technology Innovation Committee(Nos.RCJC20200714114433053,JCYJ20180507181527112 and JCYJ20200109140406047)the Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions(No.2019SHIBS0004)the Shenzhen Fundamental Research Program(No.GXWD20201231165807007–20200827170132001)Tian Fu Jin Cheng Laboratory(Advanced Medical Center)Group Racing Project(No.TFJC2023010008)。
文摘Developing novel building blocks with predictable side-chain orientations and minimal intramolecular interactions is essential for peptide-based self-assembling materials.Traditional structures likeα-helices andβ-sheets rely on such interactions for stability,limiting control over exposed interacting moieties.Here,we reported a novel,frame-like peptide scaffold that maintains exceptional stability without intramolecular interactions.This structure exposes its backbone and orients side chains for hierarchical self-assembly into micron-scale cubes.By introducing mutations at specific sites,we controlled packing orientations,offering new options for tunable self-assembly.Our scaffold provides a versatile platform for designing advanced peptide materials,with applications in nanotechnology and biomaterials.
基金supported by the National Natural Science Foundation of Jiangsu Province(BE20197310 to J-M.L.)the National Key R&D Program of China(2021YFF0702500 to J-M.L.and A-M.S.,and the Start-up Funding of Scientific Researches for Postdoc in Guangzhou,Guangdong Province to H-F.L.).
文摘Being widespread across the globe,severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)keeps evolving and generating new variants and continuously poses threat to public health,especially to the population with chronic comorbidities.Diabetes mellitus is one of high-risk factors for severe outcome of coronavirus disease 2019(COVID-19).Establishment of animal models that parallel the clinical and pathological features of COVID-19 complicated with diabetes is thus highly essential.Here,in this study,we constructed leptin receptor gene knockout hamsters with the phenotype of diabetes mellitus(db/db),and revealed that the diabetic hamsters were more susceptible to SARS-CoV-2 and its variants than wild-type hamsters.SARS-CoV-2 and its variants induced a stronger immune cytokine response in the lungs of diabetic hamsters than in wild-type hamsters.Comparative histopathology analyses also showed that infection of SARS-CoV-2 and the variants caused more severe lung tissue injury in diabetic hamsters,and may induce serious complications such as diabetic kidney disease and cardiac lesions.Our findings demonstrated that despite the decreased respiratory pathogenicity,the SARS-CoV-2 variants were still capable of impairing other organs such as kidney and heart in diabetic hamsters,suggesting that the risk of evolving SARS-CoV-2 variants to diabetic patients should never be neglected.This hamster model may help better understand the pathogenesis mechanism of severe COVID-19 in patients with diabetes.It will also aid in development and testing of effective therapeutics and prophylactic treatments against SARS-CoV-2 variants among these high-risk populations.
基金supported by the China Postdoctoral Science Foundation(Nos.2023M730317 and 2023T160066)the Fundamental Research Funds for the Central Universities(No.3332023042)+3 种基金the Open Project of Hebei Key Laboratory of Environment and Human Health(No.202301)the Programs of the National Natural Science Foundation of China(No.21976050)the Science and Technology Program of Hebei Province(No.21377779D)the Natural Science Foundation of Hebei Province,China(No.B2020206008).
文摘Although per-and polyfluoroalkyl substances(PFAS)have been frequently linked to cardiovascular and renal disease separately,evidence remains scarce regarding their systematic effect.Therefore,we recruited 546 newly diagnosed acute coronary syndrome(ACS)patients and detected seven myocardial enzymes and six kidney function biomarkers.Twelve PFASwere also assessedwith ultra-high-performance liquid chromatography-tandem mass spectrometry.Generalized linear model and restricted cubic spline model were applied to single pollutant analysis.Quantile g-computation was used for mixture analysis.Network model was utilized to identify central and bridge nodes of pollutants and phenotypes.In the present study,perfluorohexane sulfonic acid was positively associated with uric acid(UA)(β=0.04,95%confidence interval(CI):0.01,0.07),and perfluorobutanoic acid was negatively associated with estimated glomerular filtration rate(β=-0.04,95%CI:-0.07,-0.01)but positively associated with UA(β=0.03,95%CI:0.01,0.06).In mixture analysis,each quantile increase in the PFAS mixture was significantly associated with UA(β=0.08,95%CI:0.04,0.11).Network analysis revealed that perfluorooctanoate,UA,and myoglobin were denoted as bridge nodes,and the first principal component of lactate dehydrogenase and creatine kinase-myocardial band was identified as the node with the highest strength and expected influence.This study investigates the systematic impact of PFAS exposure through cardiorenal interaction network,which highlights that PFAS may serve as an upstream approach in UA-modulated cardiorenal network to affect cardiorenal system comprehensively.
基金National Natural Science Foundation of China (NSFC)(52273266, U2001216)Shenzhen Science and Technology Innovation Committee (20231121102401001)+2 种基金Shenzhen Key Laboratory Project (ZDSYS201602261933302)GuangdongHong Kong-Macao Joint Laboratory on Micro-Nano Manufacturing Technology (2021LSYS004)SUSTech high level special funds (G03050K002)。
文摘Widely used spin-coated nickle oxide (NiOx) based perovskite solar cells often suffer from severe interfacial reactions between the NiOxand adjacent perovskite layers due to surface defect states,which inherently impair device performance in a long-term view,even with surface molecule passivation.In this study,we developed high-quality magnetron-sputtered NiOxthin films through detailed process optimization,and compared systematically sputtered and spin-coated NiOxthin film surfaces from materials to devices.These sputtered NiOxfilms exhibit improved crystallinity,smoother surfaces,and significantly reduced Ni3+or Ni vacancies compared to their spin-coated counterparts.Consequently,the interface between the perovskite and sputtered NiOxfilm shows a substantially reduced density of defect states.Perovskite solar cells (PSCs) fabricated with our optimally sputtered NiOxfilms achieved a high power conversion efficiency (PCE) of up to 19.93%and demonstrated enhanced stability,maintaining 86.2% efficiency during 500 h of maximum power point tracking under one standard sun illumination.Moreover,with the surface modification using (4-(2,7-dibromo-9,9-dimethylacridin-10(9H)-yl)butyl)p hosphonic acid (DMAcPA),the device PCE was further promoted to 23.07%,which is the highest value reported for sputtered NiOxbased PSCs so far.
基金funded by R.D.H.,P.B.,A.S.W. and Z.W,Heart Foundation Vanguard Grant#107321funded by contributions from The Baird Institute for applied Heart and Lung Research.
文摘Objective:Sheep are commonly used as large animal pre-clinical models for inves-tigating cardiovascular therapies,interventions,anatomy and physiology.Further,novel small diameter vascular grafts are frequently tested via implantation into sheep carotid arteries(CAs).This is because,unlike humans,acute occlusion of one or both sheep CAs is not associated with morbidity or mortality and thus provides safer experimental testing,with reduced ethical constraints,animal numbers and costs.However,to date there has been no evidence regarding sheep tolerance of femoral artery(FA)occlusion.Methods:In this study,seven sheep underwent CA graft surgery,with digital subtrac-tion angiography(DSA)of the CAs performed every 2 months via femoral access,for a total of 8 months.Four months into the study,the left FA of two sheep became inac-cessible due to a suspected FA occlusion.Thus,femoral angiography was performed,followed by FA dissection,FA histology and retrospective analysis of both veterinar-ian animal monitoring and pain scores.Results:FA angiography and histology confirmed complete left FA occlusion in two sheep.Retrospective animal monitoring demonstrated sheep with occluded FAs did not display increased pain scores or deleterious effects on their gait or wellbeing.Conclusion:Our data shows that sheep tolerate FA occlusion with no symptoms,similar to their cerebral circulation,making them an appropriate model for assessing small diameter femoral graft interposition studies and testing other cardiovascular interventions.
基金supported by the Natural Science Foundation of Anhui Province of China,No.2208085Y32Scientific Research Plan Project of Anhui Province of China,No.2022AH020076the Chen Xiao-Ping Foundation for the Development of Science and Technology of Hubei Province,No.CXPJJH12000005-07-115(all to CT).
文摘Calcium influx into neurons triggers neuronal death during cerebral ischemia/reperfusion injury.Various calcium channels are involved in cerebral ischemia/reperfusion injury.Cav3.2 channel is a main subtype of T-type calcium channels.T-type calcium channel blockers,such as pimozide and mibefradil,have been shown to prevent cerebral ischemia/reperfusion injury-induced brain injury.However,the role of Cav3.2 channels in cerebral ischemia/reperfusion injury remains unclear.Here,in vitro and in vivo models of cerebral ischemia/reperfusion injury were established using middle cerebral artery occlusion in mice and high glucose hypoxia/reoxygenation exposure in primary hippocampal neurons.The results showed that Cav3.2 expression was significantly upregulated in injured hippocampal tissue and primary hippocampal neurons.We further established a Cav3.2 gene-knockout mouse model of cerebral ischemia/reperfusion injury.Cav3.2 knockout markedly reduced infarct volume and brain water content,and alleviated neurological dysfunction after cerebral ischemia/reperfusion injury.Additionally,Cav3.2 knockout attenuated cerebral ischemia/reperfusion injury-induced oxidative stress,inflammatory response,and neuronal apoptosis.In the hippocampus of Cav3.2-knockout mice,calcineurin overexpression offset the beneficial effect of Cav3.2 knockout after cerebral ischemia/reperfusion injury.These findings suggest that the neuroprotective function of Cav3.2 knockout is mediated by calcineurin/nuclear factor of activated T cells 3 signaling.Findings from this study suggest that Cav3.2 could be a promising target for treatment of cerebral ischemia/reperfusion injury.
基金National Key R&D Plan(2023YFC3403200)National Natural Science Foundation of China(82070784,81702536,81974099 and 82170785)+4 种基金Science&Technology Department of Sichuan Province,China(2022JDRC0040,21GJHZ0246)Young Investigator Award of Sichuan University 2017(2017SCU04A17)Sichuan University-Panzhihua Science and Technology Cooperation Special Fund(2020CDPZH-4)China Postdoctoral Science Foundation(2021M692306)Post-Doctor Research Project of West China Hospital of Sichuan University(2021HXBH025).
文摘Background Cell metabolism plays a pivotal role in tumor progression,and targeting cancer metabolism might effectively kill cancer cells.We aimed to investigate the role of hexokinases in prostate cancer(PCa)and identify a crucial target for PCa treatment.Methods The Cancer Genome Atlas(TCGA)database,online tools and clinical samples were used to assess the expression and prognostic role of ADP-dependent glucokinase(ADPGK)in PCa.The effect of ADPGK expression on PCa cell malignant phenotypes was validated in vitro and in vivo.Quantitative proteomics,metabolomics,and extracellular acidification rate(ECAR)and oxygen consumption rate(OCR)tests were performed to evaluate the impact of ADPGK on PCa metabolism.The underlying mechanisms were explored through ADPGK overexpression and knockdown,co-immunoprecipitation(Co-IP),ECAR analysis and cell counting kit-8(CCK-8)assays.Results ADPGK was the only glucokinase that was both upregulated and predicted worse overall survival(OS)in prostate adenocarcinoma(PRAD).Clinical sample analysis demonstrated that ADPGK was markedly upregulated in PCa tissues vs.non-PCa tissues.High ADPGK expression indicates worse survival outcomes,and ADPGK serves as an independent factor of biochemical recurrence.In vitro and in vivo experiments showed that ADPGK overexpression promoted PCa cell proliferation and migration,and ADPGK inhibition suppressed malignant phenotypes.Metabolomics,proteomics,and ECAR and OCR tests revealed that ADPGK significantly accelerated glycolysis in PCa.Mechanistically,ADPGK binds aldolase C(ALDOC)to promote glycolysis via AMP-activated protein kinase(AMPK)phosphorylation.ALDOC was positively correlated with ADPGK,and high ALDOC expression was associated with worse survival outcomes in PCa.Conclusions In summary,ADPGK is a driving factor in PCa progression,and its high expression contributes to a poor prognosis in PCa patients.ADPGK accelerates PCa glycolysis and progression by activating ALDOC-AMPK signaling,suggesting that ADPGK might be an effective target and marker for PCa treatment and prognosis evaluation.
基金supported by the GRF RGC&CRF,Hong Kong(Grant Nos.:475012 and C5045-20 EF)HMRF,Hong Kong(Grant No.:03141386)+3 种基金ITF,Hong Kong(Grant No.:ITS/209/12)UGC Direct Grant 2011,2012,2021.032HKOG Trust Fund 2011,2014,2019the National Natural Science Foundation of China(Grant Nos.:81974225 and 82201823)。
文摘Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the uterus.Angiogenesis is a major pathophysiology in endometriosis.Our previous studies have demonstrated that the prodrug of epigallocatechin gallate(ProEGCG)exhibits superior anti-endometriotic and anti-angiogenic effects compared to epigallocatechin gallate(EGCG).However,their direct binding targets and underlying mechanisms for the differential effects remain unknown.In this study,we demonstrated that oral ProEGCG can be effective in preventing and treating endometriosis.Additionally,1D and 2D Proteome Integral Solubility Alteration assay-based chemical proteomics identified metadherin(MTDH)and PX domain containing serine/threonine kinase-like(PXK)as novel binding targets of EGCG and ProEGCG,respectively.Computational simulation and BioLayer interferometry were used to confirm their binding affinity.Our results showed that MTDH-EGCG inhibited protein kinase B(Akt)-mediated angiogenesis,while PXK-ProEGCG inhibited epidermal growth factor(EGF)-mediated angiogenesis via the EGF/hypoxia-inducible factor(HIF-1a)/vascular endothelial growth factor(VEGF)pathway.In vitro and in vivo knockdown assays and microvascular network imaging further confirmed the involvement of these signaling pathways.Moreover,our study demonstrated that ProEGCG has superior therapeutic effects than EGCG by targeting distinct signal transduction pathways and may act as a novel antiangiogenic therapy for endometriosis.
基金supported by the National Key Research and Development Program of China(Grant No.:2023YFA0913900)the Tianjin Synthetic Biotechnology Innovation Capacity Improvement Project,China(Grant Nos.:TSBICIP-PTJS-003 and TSBICIP-CXRC-073).
文摘Synthetic biology provides unprecedented opportunities to tackle critical issues including climate change and sustainable development by constructing microbial cell factories to produce industrially valuable biochemicals,biofuels,and biomaterials using renewable biomass resources[1],where strain screening for specific metabolic traits is a critical step.Rapid,accurate,and simultaneous quantification of multiple metabolites is critical for multi-perspective strain performance evaluation and strain screening,and a generalized method or platform will also reduce method development time to speed up the screening process.
基金This study was supported by the Key Research and Development Program of Anhui Province(No.202204295107020003)the National Natural Science Foundation of Anhui Province(No.2108085MH293)+1 种基金the Distinguished Young Scholars Fund of Anhui Province(No.2022AH020078)the Key health Project of Anhui Province(AHWJ2022a037).
文摘The overdiagnosis of prostate cancer(PCa)caused by nonspecific elevation serum prostate-specific antigen(PSA)and the overtreatment of indolent PCa have become a global problem that needs to be solved urgently.We aimed to construct a prediction model and provide a risk stratification system to reduce unnecessary biopsies.In this retrospective study,clinical data of 1807 patients from three Chinese hospitals were used.The final model was built using stepwise logistic regression analysis.The apparent performance of the model was assessed by receiver operating characteristic curves,calibration plots,and decision curve analysis.Finally,a risk stratification system of clinically significant prostate cancer(csPCa)was created,and diagnosis-free survival analyses were performed.Following multivariable screening and evaluation of the diagnostic performances,a final diagnostic model comprised of the PSA density and Prostate Imaging-Reporting and Data System(PI-RADS)score was established.Model validation in the development cohort and two external cohorts showed excellent discrimination and calibration.Finally,we created a risk stratification system using risk thresholds of 0.05 and 0.60 as the cut-off values.The follow-up results indicated that the diagnosis-free survival rate for csPCa at 12 months and 24 months postoperatively was 99.7%and 99.4%,respectively,for patients with a risk threshold below O.05 after the initial negative prostate biopsy,which was significantly better than patients with higher risk.Our diagnostic model and risk stratification system can achieve a personalized risk calculation of csPCa.It provides a standardized tool for Chinese patients and physicians when considering thenecessity of prostatebiopsy.
基金supported by the Science and Technology Foundation of Basic Research Program of Guizhou Province([2023]General 371,[2020]1Y381)the Administration of Traditional Chinese Medicine of Guizhou Province(QZYY-2018-130)+3 种基金the project of Key Laboratory of Basic Pharmacology of Ministry of Education,Zunyi Medicial University(No.qianjiaoheKYzi[2022]395)the Cultivation Plan of the NSFC(National Natural Science Foundation of China)of the affiliated hospital of Guizhou Medical University(GYFYNSFC-2021-55,GYFYNSFC-2021-56)the Cultivation Plan of the NSFC(National Natural Science Foundation of China)of Guizhou Medical University(21NSFCP13)the Science and Technology Foundation of Health Commission of Guizhou Province(gzwkj 2022-221).
文摘Background:Ginkgo flavone aglycones(GA),a Ginkgo(Ginkgo biloba)extract,has been proven to have good biological activity in atherosclerosis(AS)treatment.Moreover,its active compounds and the corresponding mechanism for the treatment of AS remain unclear.Methods:To evaluate and identify the potential pharmacological mechanisms of GA in AS treatment,the program Cytoscape was used to generate network mappings of the GA-AS-potential target gene.GO and KEGG enrichment analyses were performed to further investigate the potential mechanism of AS and the pharmacological properties of GA.A molecular docking approach was utilized to determine the GA components that interact with Akt.In vitro experiments were carried out to identify the anti-atherosclerotic effects of GA by targeting Akt.Results:Network pharmacological research determined that the active components of GA(quercetin,kaempferol,and isorhamnetin)correlated with AS target genes such as AKT1,EGFR,SRC,ESR1,PTGS2,MMP9,KDR,GSK3B,APP,and MMP2,respectively.GO enrichment and KEGG analysis showed that PI3K-Akt signaling may play an important role in GA treatment.Molecular docking experiments indicated that quercetin,kaempferol,and isorhamnetin integrate into the binding pockets of the most potentially beneficial GA-AS target protein(Akt).Consequently,cell experiments were conducted to support the anti-atherosclerotic activity of GA on AS by inhibiting the phosphorylation of AKT1 and its downstream signaling molecules,which regulated the proliferation of HASMCs.Conclusion:Our results detailed GA's active ingredients,potential targets,and molecular basis against AS.GA may exert anti-atherosclerotic effects by suppressing Akt phosphorylation and inhibiting the proliferation of HASMCs.It also proposed a viable approach to determining the scientific foundation and therapeutic mechanism of Chinese herbal medicine extracts in disease therapy.
基金supported by the National Natural Science Foundation of China(82174471).
文摘The three-phase Enriched Environment(EE)paradigm has been shown to promote post-stroke functional improvement,but the neuronal mechanisms are still unclear.In this study,we applied a multimodal neuroimaging protocol combining magnetic resonance imaging(MRI)and positron emission tomography(PET)to examine the effects of post-ischemic EE treatment on structural and functional neuroplasticity in the bilateral sensorimotor cortex.Rats were subjected to permanent middle cerebral artery occlusion.The motor function of the rats was examined using the DigiGait test.MRI was applied to investigate the EE-induced structural modifications of the bilateral sensorimotor cortex.[^(18)F]-fluorodeoxyglucose PET was used to detect glucose metabolism.Blood oxygen level-dependent(BOLD)-functional MRI(fMRI)was used to identify the regional brain activity and functional connectivity(FC).In addition,the expression of neuroplasticity-related signaling pathways including neurotrophic factors(BDNF/CREB),axonal guidance proteins(Robo1/Slit2),and axonal growth-inhibitory proteins(NogoA/NgR)as well as downstream proteins(RhoA/ROCK)in the bilateral sensorimotor cortex were measured by Western blots.Our results showed the three-phase EE improved the walking ability.Structural T2 mapping imaging and diffusion tensor imaging demonstrated that EE benefited structure integrity in the bilateral sensorimotor cortex.PET-MRI fused images showed improved glucose metabolism in the corresponding regions after EE intervention.Specifically,the BOLD-based amplitude of low-frequency fluctuations showed that EE increased spontaneous activity in the bilateral motor cortex and ipsilateral sensory cortex.In addition,FC results showed increased sensorimotor connectivity in the ipsilateral hemisphere and increased interhemispheric motor cortical connectivity and motor cortical-thalamic connectivity following EE intervention.In addition,a strong correlation was found between increased functional connectivity and improved motor performance of limbs.Specifically,EE regulated the expression of neuroplasticity-related signaling,involving BDNF/CREB,Slit2/Robo1,as well as the axonal growth–inhibitory pathways Nogo-A/Nogo receptor and RhoA/ROCK in the bilateral sensorimotor cortex.Our results indicated that the three-phase enriched environment paradigm enhances neuronal plasticity of the bilateral sensorimotor cortex and consequently ameliorates post-stroke gait deficits.These findings might provide some new clues for the development of EE and thus facilitate the clinical translation of EE.
基金supported by the grants from the National Natural Science Foundation of China(Nos.81973251 and 81302725)Hebei Province Funding Project for Introduced Overseas Personnel(Nos.C20230351 and C20220345)+3 种基金Key Research and Development Program of Hebei Province(No.22372701D)Hebei Province Natural Science Fund(No.H2020206610)Hebei Provincial Health Commission Government-Funded Clinical Medicine Talent Program(No.ZF2024048)Hebei Medical University Undergraduate Innovative Experiment Program(No.USIP2023008)。
文摘The combination of nucleic acid and small-molecule drugs in tumor treatment holds significant promise;however,the precise delivery and controlled release of drugs within the cytoplasm encounter substantial obstacles,impeding the advancement of formulations.To surmount the challenges associated with precise drug delivery and controlled release,we have developed a multi-level p H-responsive co-loaded drug lipid nanoplatform.This platform first employs cyclic cell-penetrating peptides to exert a multi-level pH response,thereby enhancing the uptake efficiency of tumor cells and endow the nanosystem with effective endosomal/lysosomal escape.Subsequently,small interferring RNA(siRNA)complexes are formed by compacting siRNA with stearic acid octahistidine,which is capable of responding to the lysosome-tocytoplasm pH gradient and facilitate siRNA release.The siRNA complexes and docetaxel are simultaneously encapsulated into liposomes,thereby creating a lipid nanoplatform capable of co-delivering nucleic acid and small-molecule drugs.The efficacy of this platform has been validated through both in vitro and in vivo experiments,affirming its significant potential for practical applications in the co-delivery of nucleic acids and small-molecule drugs.
基金Project supported by the National Natural Science Foundation of China(Grant Nos.32371280 and T2350011)。
文摘FL-Online(http://fanlab.ac.cn) is an out-of-box modern web service featuring a user-friendly interface and simplified parameters, providing academic users with access to a series of online programs for biomolecular crystallography, including SAPI-online, OASIS-online, C-IPCAS-online and a series of upcoming software releases. Meanwhile, it is a highly scalable and maintainable web application framework that provides a powerful and flexible solution for academic web development needs. All the codes are open-source under MIT licenses in GitHub.
