To enhance the anesthetic efficacy of propofol while mitigating its systemic toxicity and irreversible developmental neurotoxicity, we developed a strategy leveraging the neuroprotective effects of baicalin in combina...To enhance the anesthetic efficacy of propofol while mitigating its systemic toxicity and irreversible developmental neurotoxicity, we developed a strategy leveraging the neuroprotective effects of baicalin in combination with propofol anesthesia via baicalinbased nanocomposites. High propofol-loaded porous Baicalin-Fe(Ⅲ) infinite coordination polymer@propofol nanocomposites were synthesized, wherein baicalin coordinates with Fe3+ ions to form porous nanoparticles that encapsulate propofol within a core-shell structure. These nanocomposites exhibited an average diameter of 92.3 ± 10.2 nm and a pore volume of 0.322 cm^(3)/g, achieving ultra-high propofol loading(~62%) with no detectable leakage over 100 d, attributed to their large surface area and strong molecular interactions.When combined with focused ultrasound(FUS) and microbubbles, the effective dose(ED_(50))of propofol decreased from 10 to 4.3 mg/kg, doubling the duration of anesthesia and extending the therapeutic window by 200%. Importantly, the therapeutic index improved1.66-fold while vital physiological parameters remained stable. Histological analyses revealed an 80% reduction in neuronal injury compared to free propofol, and behavioral tests demonstrated significant enhancements in motor and cognitive performance, alongside recovery from propofol-induced irreversible developmental neurotoxicity, indicating effective neuroprotection. Collectively, this baicalin-propofol nanocomposite, coupled with FUS-mediated delivery, represents a promising approach for safe and long-term anesthesia in clinical applications.展开更多
α-Chiral amides are common in pharmaceuticals,agrochemicals,natural products,and peptides,prompting the need for new synthetic methods.Here,we introduce a nickel-catalyzed asymmetric reductive amidation method to syn...α-Chiral amides are common in pharmaceuticals,agrochemicals,natural products,and peptides,prompting the need for new synthetic methods.Here,we introduce a nickel-catalyzed asymmetric reductive amidation method to synthesizeα-chiral amides from benzyl ammonium salts and isocyanates.The key to success is using a chiral 2,2-bipyridine ligand(-)-Ph-SBpy,enabling high yield(up to 95%)and enantiomeric ratio(up to 98:2 er)under mild conditions.Addition of phenol prevents isocyanate polymerization by reversibly forming a carbamate intermediate,enhancing selectivity and efficiency.The synthetic utility is showcased through transformations of the enantioenriched amides,and the mechanism and enantioselectivity are supported by experimental and computational studies.展开更多
Gelatin/Alginate hydrogels were engineered for bioplotting in tissue engineering.One major drawback of hydrogel scaffolds is the lack of adequate mechanical properties.In this study,using a bioplotter,we constructed t...Gelatin/Alginate hydrogels were engineered for bioplotting in tissue engineering.One major drawback of hydrogel scaffolds is the lack of adequate mechanical properties.In this study,using a bioplotter,we constructed the scaffolds with different pore architectures by deposition of gelatin/alginate hydrogels layerby-layer.The scaffolds with different crosslinking degree were obtained by post-crosslinking methods.Their physicochemical properties,as well as cell viability,were assessed.Different crosslinking methods had little influence on scaffold architecture,porosity,pore size and distribution.By contrast,the water absorption ability,degradation rate and mechanical properties of the scaffolds were dramatically affected by treatment with various concentrations of crosslinking agent(glutaraldehyde).The crosslinking process using glutaraldehyde markedly improved the stability and mechanical strength of the hydrogel scaf-folds.Besides the post-processing methods,the pore architecture can also evidently affect the mechanical properties of the scaffolds.The crosslinked gelatin/alginate scaffolds showed a good potential to encap-sulate cells or drugs.展开更多
Tantalum(Ta) as a new type of medical metal is now utilized in several orthopedic applications due to its excellent fracture toughness and workability,high corrosion resistance,good biocompatibility and X-ray visibili...Tantalum(Ta) as a new type of medical metal is now utilized in several orthopedic applications due to its excellent fracture toughness and workability,high corrosion resistance,good biocompatibility and X-ray visibility,but it lacks bioactivity.Therefore,pure Ta was hydrothermally calcified in CaHPO4 solution at 120-200℃ here for bioactive surface modification.Scanning electron microscopy(SEM),energy-dispersive X-ray spectroscopy(EDX),X-ray photoelectron spectroscopy(XPS),X-ray diffraction(XRD) and Raman spectroscopy analyses show that thin tantalum oxide film with a few calcium phosphate precipitates is formed at the surface after the treatment at 200℃.The hydrothermally treated sample has good hydrophilicity and corrosion resistance evidenced by the water contact angle measurement and the potentiodynamic polarization test,respectively,and it can induce the formation of apatite layer after soaked in the simulated body fluid for 1 week.The present method would be applicable for bioactive surface modification of tantalum implants with irregular shapes and even porous structure.展开更多
Runt-related transcription factor 1(Runx1)plays a key role in cartilage formation,but its function in articular cartilage formation is unclear.We generated non-inducible and inducible Runx1-deficient mice(Runx1^(f/f)C...Runt-related transcription factor 1(Runx1)plays a key role in cartilage formation,but its function in articular cartilage formation is unclear.We generated non-inducible and inducible Runx1-deficient mice(Runx1^(f/f)Col2α1-Cre and Runx1^(f/f)Col2α1-CreER mice)and found that chondrocyte-specific Runx1-deficient mice developed a spontaneous osteoarthritis(OA)-like phenotype and showed exacerbated articular cartilage destruction under OA,characterized by articular cartilage degradation and cartilage ossification,with decreased Col2α1 expression and increased Mmp13 and Adamts5 expression.RNA-sequencing analysis of hip articular cartilage from the Runx1^(f/f)Col2α1-Cre mice compared to that from wild-type mice and subsequent validation analyses demonstrated that Runx1 is a central regulator in multiple signaling pathways,converging signals of the Hippo/Yap,TGFβ/Smad,and Wnt/β-catenin pathways into a complex network to regulate the expression of downstream genes,thereby controlling a series of osteoarthritic pathological processes.RNA-sequencing analysis of mutant knee joints showed that Runx1’s role in signaling pathways in articular cartilage is different from that in whole knee joints,indicating that Runx1 regulation is tissue-specific.Histopathologic analysis confirmed that Runx1 deficiency decreased the levels of YAP and p-Smad2/3 and increased the levels of activeβ-catenin.Overexpression of Runx1 dramatically increased YAP expression in chondrocytes.Adeno-associated virus-mediated Runx1 overexpression in the knee joints of osteoarthritic mice showed the protective effect of Runx1 on articular cartilage damaged in OA.Our results notably showed that Runx1 is a central regulator of articular cartilage homeostasis by orchestrating the YAP,TGFβ,and Wnt signaling pathways in the formation of articular cartilage and OA,and targeting Runx1 and its downstream genes may facilitate the design of novel therapeutic approaches for OA.展开更多
Neural regeneration was once considered to be impossible, especially in the central nervous system where neural regeneration comprise the generation of new neurons, glia, axons, myelin, and synapses. Until recently, n...Neural regeneration was once considered to be impossible, especially in the central nervous system where neural regeneration comprise the generation of new neurons, glia, axons, myelin, and synapses. Until recently, neural stem cells/neural progenitor cells (NSCs/NPCs) were identified from various areas of brain and brought hopes to the neural repair and regeneration. Tissue engineering has revolutionized the current neural regeneration technology and it has become a pioneering interdisciplinary field in the areas of biomedical research. Polyhydoxyalkanoate (PHA) as one of biodegradable material has been successfully used as tissue engineering materials. It has also been applied in nerve tissue engineering due to the high biocompatibility and low cytotoxicity. Over the past 10 years, different kinds of modification strategies have been undertaken to improve the properties of PHA to fit the requirements from various fields. Several members of PHA family have been attempted for neural regeneration. This article reviewed the recent modification strategies for improving the properties of PHA and highlighted the pioneer applications in neural regeneration.展开更多
Bioactive scaffolds with interconnected porous structures are essential for guiding cell growth and new bone formation. In this work, we successfully fabricated three-dimensional （3D） porous β-tricalcium phosphate...Bioactive scaffolds with interconnected porous structures are essential for guiding cell growth and new bone formation. In this work, we successfully fabricated three-dimensional （3D） porous β-tricalcium phosphate （β-TCP）/calcium silicate （CS） composite scaffolds with different ratios by 3D printing technique and further investigated the physiochemical properties, in vitro apatite mineralization properties and degradability of porous β-TCP/CS scaffolds. Moreover, a series of in vitro cell experiments including the attachment, proliferation and osteogenic differentiation of mouse bone marrow stromal cells were conducted to testify their biological performances. The results showed that 3D printed β-TCP/CS scaffolds possessed of controllable internal porous structures and external shape. Furthermore, the introduction of CS decreased the shrinkage of scaffolds and improved the in vitro apatite formation activity and degradation rate. Meanwhile, compared with pure β- TCP scaffold, the β-TCP/CS composite scaffolds were more conducive to promote cell adhesion, spread and osteogenesis differentiation. However, when the content of CS was increased to 45%, the ions dissolution rate of the composite scaffolds was so high that leaded to the increase in pH value, which inhibited the proliferation of cells. Our results suggested that the introduction of appropriate CS into β-TCP bioceramic is an effective strategy to prepare bioactive 3D printed bioceramic scaffolds for hard tissue regeneration.展开更多
Cells in vivo are in a three-dimensional(3D)complicated microenvironment composed of various biological,physical and chemical cues.Although it is well accepted that biological and chemical cues can significantly influ...Cells in vivo are in a three-dimensional(3D)complicated microenvironment composed of various biological,physical and chemical cues.Although it is well accepted that biological and chemical cues can significantly influence cell functions,more and more evidence has also shown that physical cues are also vital.Using today’s micro and nanoscale technologies,creating synthetic but native-like conditions are the prerequisites for understanding cell behaviors.Most research has been carried out on artificial two-dimensional(2D)substrates.However,recent studies showed that cells respond and behave differently in these 2D settings compared to in 3D intricate microenvironment.Therefore,innovative 3D in vitro cellular models with precisely patterned multiple types of cells are needed for re-creating distinct niches and in vitro cell modeling under well-defined and reproducible conditions.In this talk,I will present the 3D nano and microscale tissue engineering methods we are developing for engineering cell spatiotemporal mechanical microenvironment.展开更多
Rhesus monkey models of Parkinson＇s disease were induced by injection of N-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine. Neural firings were recorded using microelectrodes placed in the interna segment of the globus p...Rhesus monkey models of Parkinson＇s disease were induced by injection of N-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine. Neural firings were recorded using microelectrodes placed in the interna segment of the globus pallidus. The wavelets and power spectra show gradual power reduction during the disease process along with increased firing rates in the Parkinson＇s disease state. Singular values of coefficients decreased considerably during tremor-related activity as well as in the Parkinson＇s disease state compared with normal signals, revealing that higher-frequency components weaken when Parkinson＇s disease occurs. We speculate that the death of neurons could be reflected by irregular frequency spike trains, and that wavelet packet decomposition can effectively detect the degradation of neurons and the loss of information transmission in the neural circuitry.展开更多
Temporal interference(TI)is a form of stimulation that epitomizes an innovative and non-invasive approach for profound neuromodulation of the brain,a technique that has been validated in mice.Yet,the thin cranial bone...Temporal interference(TI)is a form of stimulation that epitomizes an innovative and non-invasive approach for profound neuromodulation of the brain,a technique that has been validated in mice.Yet,the thin cranial bone structure of mice has a marginal influence on the effect of the TI technique and may not effectively showcase its effectiveness in larger animals.Based on this,we carried out TI stimulation experiments on rats.Following the TI intervention,analysis of electrophysiological data and immunofluorescence staining indicated the generation of a stimulation focus within the nucleus accumbens(depth,8.5 mm)in rats.Our findings affirm the viability of the TI methodology in the presence of thick cranial bones,furnishing efficacious parameters for profound stimulation with TI administered under such conditions.This experiment not only sheds light on the intervention effects of TI deep in the brain but also furnishes robust evidence in support of its prospective clinical utility.展开更多
Three-dimensional(3D)single molecule localization microscopy(SMLM)plays an important role in biomedical applications,but its data processing is very complicated.Deep learning is a potential tool to solve this problem....Three-dimensional(3D)single molecule localization microscopy(SMLM)plays an important role in biomedical applications,but its data processing is very complicated.Deep learning is a potential tool to solve this problem.As the state of art 3D super-resolution localization algorithm based on deep learning,FD-DeepLoc algorithm reported recently still has a gap with the expected goal of online image processing,even though it has greatly improved the data processing throughput.In this paper,a new algorithm Lite-FD-DeepLoc is developed on the basis of FD-DeepLoc algorithm to meet the online image processing requirements of 3D SMLM.This new algorithm uses the feature compression method to reduce the parameters of the model,and combines it with pipeline programming to accelerate the inference process of the deep learning model.The simulated data processing results show that the image processing speed of Lite-FD-DeepLoc is about twice as fast as that of FD-DeepLoc with a slight decrease in localization accuracy,which can realize real-time processing of 256×256 pixels size images.The results of biological experimental data processing imply that Lite-FD-DeepLoc can successfully analyze the data based on astigmatism and saddle point engineering,and the global resolution of the reconstructed image is equivalent to or even better than FD-DeepLoc algorithm.展开更多
Effective treatment of intervertebral disc degeneration with biomaterials remains a challenge,owing to the difficulty in simultaneously overcoming oxidative stress and its associated cascades in the nucleus pulposus m...Effective treatment of intervertebral disc degeneration with biomaterials remains a challenge,owing to the difficulty in simultaneously overcoming oxidative stress and its associated cascades in the nucleus pulposus microenvironment,which includes cellular senescence,apoptosis,inflammation,and extracellular matrix(ECM)degradation.To address these issues,a multifunctional hydrogel(HG-QNT)loaded with transforming growth factorβ1(TGFβ1)and quercetin-based nanoparticles(QUNPs)is developed through borate ester bonding and Schiffbase reaction-induced crosslinking.Specifically,QUNPs fabricated via coordination and hydrophobic interactions endow the hydrogel with extraordinary antioxidative properties.Benefiting from the multi-dynamic crosslinking,the hydrogel achieves self-healing,mechanical stability,and pH-responsive release of QUNPs and TGFβ1.The HG-QNT hydrogel is demonstrated to enhance the proliferation of encapsulated nucleus pulposus cells,thereby providing an ideal platform for cell transplantation.The cooperative antioxidation of QUNPs and the hydrogel carrier renders HG-QNT effective in mitigating oxidative stress,resulting in the suppression of cellular senescence,mitochondrial dysfunction,apoptosis,excessive inflammation,and abnormal catabolism.Afterwards,TGFβ1 and QUNPs act in synergy with the hydrogel to restore the anabolic/catabolic balance by enhancing ECM synthesis.Overall,the strategy orchestrating multiple modulation by HG-QNT hydrogel shows great potential for application in intervertebral disc regeneration.展开更多
Characterization of the distribution and accurate counting of RNA molecules in the context of tissues is necessary to understand their complexity and heterogeneity.Single-molecule fluorescence in situ hybridization re...Characterization of the distribution and accurate counting of RNA molecules in the context of tissues is necessary to understand their complexity and heterogeneity.Single-molecule fluorescence in situ hybridization reveals the abundance and distribution of RNA and resolves different cell types in complex tissues.Especially,off-target binding and nonspecific adsorption of probes are prone to producing nonspecific amplification.Herein,we present highly de-noising amplified imaging,which leverages a sitespecific cleavage-amplifying design to achieve accurate counting of RNA in tissues.Our method avoids adding probe as primer,decreases nonspecific spots of single cells from 7 to nearly zero,and enables RNA imaging in uncleared tissue sections with nearly zero noise.We demonstrate the efficacy of this method on various thickness of mouse tissue sections.We envision this approach will serve as a tool to revealing the information content from patient samples for biomedical purpose.展开更多
AIM:To use two-sample Mendelian randomization(MR)method to study uveitis causal association with wet age-related macular degeneration(wAMD)risk from the genetic level.METHODS:Two-sample MR analysis was used to assess ...AIM:To use two-sample Mendelian randomization(MR)method to study uveitis causal association with wet age-related macular degeneration(wAMD)risk from the genetic level.METHODS:Two-sample MR analysis was used to assess the causal role of uveitis on wAMD risk,using the 8 genetic variants associated strongly with uveitis as instrumental variables.Besides,eight MR methods[inverse variance weighted(IVW),weighted median,MR-Egger regression,weighted mode,simple mode,robust adjusted profile score(RAPS),contamination inverse-variance weighted method,and debiased inverse-variance weighted method]were used to get the whole causal estimate for multiple instrumental single nucleotide polymorphism(SNPs).The MR analysis was based on Europeans.RESULTS:Uveitis was related to a higher risk of wAMD[odds ratio(OR):1.08,95%confidence interval(CI)1.03–1.12;P=1.03×10^(-3)]with the IVW method.No heterogeneity and directional pleiotropy were detected.On the contrary,no significant results were detected in reverse MR analysis.CONCLUSION:Uveitis is related to an increased risk of wAMD.Due to the high blindness rate of wAMD,understanding and controlling the risk factors of AMD is of great significance for reducing its incidence and early diagnosis and treatment.展开更多
Magnetic resonance imaging(MRI)is a powerful tool for diagnosing and monitoring brain diseases,but its low sensitivity can hinder early detection.To address this challenge,we utilized chemical exchange saturation tran...Magnetic resonance imaging(MRI)is a powerful tool for diagnosing and monitoring brain diseases,but its low sensitivity can hinder early detection.To address this challenge,we utilized chemical exchange saturation transfer(CEST)MRI,which greatly enhances sensitivity for detecting low-concentration compounds.In this study,we developed a CEST contrast agent based on a recombinant adeno-associated viruses(rAAVs)encoding the protamine-1(PRM1)MRI reporter gene.CEST MRI revealed that PRM1 contrast agent effectively highlighted caudate putamen region after injection of the rAAVs into the mouse brain,clearly distinguishing it from the surrounding tissue,with no observable damage.This method provides a sensitive,metal-free CEST contrast agent for in vivo brain cell detection,demonstrating potential for both diagnostic and therapeutic applications in brain diseases.展开更多
Neuroinflammation plays an important role in the occurrence and development of neurological diseases.In addition to microglia,the role of astrocytes in neuroinflammation has gradually attracted attention.Photobiomodul...Neuroinflammation plays an important role in the occurrence and development of neurological diseases.In addition to microglia,the role of astrocytes in neuroinflammation has gradually attracted attention.Photobiomodulation(PBM),as a non-invasive treatment,has been shown potential to alleviate inflammation of microglia or astrocytes.In this study,the spatiotemporal regulation and molecular mechanism of PBM on astrocytes were deeply explored by analyzing the effects and genomics at different time points.The results showed that PBM significantly attenuated the upregulation of inflammatory factors and mitochondrial dysfunction in astrocytes under LPS stimulation for 4 h and 24 h.RNA-seq analysis showed that the JAK-STAT pathway played an important role in the early stage of both LPS-induced astrocytic neuroin-flammation and PBM-alleviated astrocytic neuroinflammation.Under PBM treatment,Stat5a translocation to the nucleus and upregulated Socs3 expression were observed in LPS-treated astrocytes,which may inhibit the overactivation of the JAK-STAT inflammatory signaling pathway and thus alleviate astrocyte inflammation.Taken together,this study provides new insight into the molecular mechanism of the potential application of PBM in the treatment of neuroinflammation.展开更多
Male sexual behaviors,including mounting,intromission,and ejaculation,are not only critical for reproduction but also serve as a model for understanding how the brain orchestrates sequential motor and motivational pro...Male sexual behaviors,including mounting,intromission,and ejaculation,are not only critical for reproduction but also serve as a model for understanding how the brain orchestrates sequential motor and motivational processes.While previous studies have identified key brain regions involved in sexual behaviors,such as the medial preoptic area(MPOA)and the nucleus accumbens(NAc)[14],the neural mechanisms governing the transitions between different phases of male sexual behavior remain poorly understood.展开更多
Melanoma Differentiation-Associated gene 5(MDA5)serves as a pattern recognition receptor(PRR)that identifies pathogen-associated molecular patterns(PAMPs),making it instrumental in antiviral defense.However,its non-ca...Melanoma Differentiation-Associated gene 5(MDA5)serves as a pattern recognition receptor(PRR)that identifies pathogen-associated molecular patterns(PAMPs),making it instrumental in antiviral defense.However,its non-canonical role in adaptive immunity,particularly in regulating B-cell immune functions,is poorly characterized.Here,we demonstrate that MDA5 is critical for the marginal zone(MZ)B-cell differentiation,B-cell receptor(BCR)signal transduction,and cytoskeletal dynamics.We determined that the MDA5-NF-κB-DNM1 axis governs actin polymerization and that this impairment in Mda5 knockout(KO)B cells can be rescued by the treatment with the dynamin1(DNM1)activator Bis-T-23.Furthermore,MDA5 deficiency induces metabolic perturbations in B cells,characterized by a reduced extracellular acidification rate(ECAR)and oxygen consumption rate(OCR),excessive reactive oxygen species(ROS)accumulation,and increased mitochondrial fission.Notably,taurine levels are decreased in Mda5 KO B cells,and in vitro taurine supplementation rescues impaired BCR signaling.Finally,MDA5-deficient mice exhibit a blunted humoral immune response.Overall,this study reveals the key functions and molecular mechanisms of MDA5 in B-cell differentiation,BCR signaling,and the humoral immune response.展开更多
Atrial fibrillation(AF) has been considered as a growing epidemiological problem in the world,with a substantial impact on morbidity and mortality.Ambulatory electrocardiography(e.g.,Holter) monitoring is commonly use...Atrial fibrillation(AF) has been considered as a growing epidemiological problem in the world,with a substantial impact on morbidity and mortality.Ambulatory electrocardiography(e.g.,Holter) monitoring is commonly used for AF diagnosis and therapy and the automated detection of AF is of great significance due to the vast amount of information provided.This study presents a combined method to achieve high accuracy in AF detection.Firstly,we detected the suspected transitions between AF and sinus rhythm using the delta RR interval distribution difference curve,which were then classified by a combination analysis of P wave and RR interval.The MIT-BIH AF database was used for algorithm validation and a high sensitivity and a high specificity(98.2% and 97.5%,respectively) were achieved.Further,we developed a dataset of 24-h paroxysmal AF Holter recordings(n=45) to evaluate the performance in clinical practice,which yielded satisfactory accuracy(sensitivity=96.3%,specificity=96.8%).展开更多
基金funded by the National Natural Science Foundation of China (No. 82271572)The Clinical Research Award of the First Affiliated Hospital of Xi'an Jiaotong University (No. XJTU1AF2021CRF-008) and (No. XTJU1AF-CRF2023-025)。
文摘To enhance the anesthetic efficacy of propofol while mitigating its systemic toxicity and irreversible developmental neurotoxicity, we developed a strategy leveraging the neuroprotective effects of baicalin in combination with propofol anesthesia via baicalinbased nanocomposites. High propofol-loaded porous Baicalin-Fe(Ⅲ) infinite coordination polymer@propofol nanocomposites were synthesized, wherein baicalin coordinates with Fe3+ ions to form porous nanoparticles that encapsulate propofol within a core-shell structure. These nanocomposites exhibited an average diameter of 92.3 ± 10.2 nm and a pore volume of 0.322 cm^(3)/g, achieving ultra-high propofol loading(~62%) with no detectable leakage over 100 d, attributed to their large surface area and strong molecular interactions.When combined with focused ultrasound(FUS) and microbubbles, the effective dose(ED_(50))of propofol decreased from 10 to 4.3 mg/kg, doubling the duration of anesthesia and extending the therapeutic window by 200%. Importantly, the therapeutic index improved1.66-fold while vital physiological parameters remained stable. Histological analyses revealed an 80% reduction in neuronal injury compared to free propofol, and behavioral tests demonstrated significant enhancements in motor and cognitive performance, alongside recovery from propofol-induced irreversible developmental neurotoxicity, indicating effective neuroprotection. Collectively, this baicalin-propofol nanocomposite, coupled with FUS-mediated delivery, represents a promising approach for safe and long-term anesthesia in clinical applications.
基金the National Natural Science Foundation of China(Nos.22150410339,W2432012,22301233 and 22171218)the Ministry of Science and Technology China(No.wgxz2022188)。
文摘α-Chiral amides are common in pharmaceuticals,agrochemicals,natural products,and peptides,prompting the need for new synthetic methods.Here,we introduce a nickel-catalyzed asymmetric reductive amidation method to synthesizeα-chiral amides from benzyl ammonium salts and isocyanates.The key to success is using a chiral 2,2-bipyridine ligand(-)-Ph-SBpy,enabling high yield(up to 95%)and enantiomeric ratio(up to 98:2 er)under mild conditions.Addition of phenol prevents isocyanate polymerization by reversibly forming a carbamate intermediate,enhancing selectivity and efficiency.The synthetic utility is showcased through transformations of the enantioenriched amides,and the mechanism and enantioselectivity are supported by experimental and computational studies.
基金supported by the National Basic Research Program of China(“973 Program”,No.2012CB619100)the National Natural Science Foundation of China(Grant No.51372085)+1 种基金the Guangdong–Hongkong Common Technology Bidding Project(No.2013B010136003)the Postdoctoral Science Foundation of China(No.2013M542172)
文摘Gelatin/Alginate hydrogels were engineered for bioplotting in tissue engineering.One major drawback of hydrogel scaffolds is the lack of adequate mechanical properties.In this study,using a bioplotter,we constructed the scaffolds with different pore architectures by deposition of gelatin/alginate hydrogels layerby-layer.The scaffolds with different crosslinking degree were obtained by post-crosslinking methods.Their physicochemical properties,as well as cell viability,were assessed.Different crosslinking methods had little influence on scaffold architecture,porosity,pore size and distribution.By contrast,the water absorption ability,degradation rate and mechanical properties of the scaffolds were dramatically affected by treatment with various concentrations of crosslinking agent(glutaraldehyde).The crosslinking process using glutaraldehyde markedly improved the stability and mechanical strength of the hydrogel scaf-folds.Besides the post-processing methods,the pore architecture can also evidently affect the mechanical properties of the scaffolds.The crosslinked gelatin/alginate scaffolds showed a good potential to encap-sulate cells or drugs.
基金financially supported by the Industry-University-Research Collaboration Program of Ronggui District,Shunde City(No.201701)the High Efficiency Medical Devices Engineering and Technology Research Center of Guangdong Province(No.2018110100310005409)。
文摘Tantalum(Ta) as a new type of medical metal is now utilized in several orthopedic applications due to its excellent fracture toughness and workability,high corrosion resistance,good biocompatibility and X-ray visibility,but it lacks bioactivity.Therefore,pure Ta was hydrothermally calcified in CaHPO4 solution at 120-200℃ here for bioactive surface modification.Scanning electron microscopy(SEM),energy-dispersive X-ray spectroscopy(EDX),X-ray photoelectron spectroscopy(XPS),X-ray diffraction(XRD) and Raman spectroscopy analyses show that thin tantalum oxide film with a few calcium phosphate precipitates is formed at the surface after the treatment at 200℃.The hydrothermally treated sample has good hydrophilicity and corrosion resistance evidenced by the water contact angle measurement and the potentiodynamic polarization test,respectively,and it can induce the formation of apatite layer after soaked in the simulated body fluid for 1 week.The present method would be applicable for bioactive surface modification of tantalum implants with irregular shapes and even porous structure.
基金supported by the National Institutes of Health[AR-070135 and AG-056438 to W.C.,and AR-075735 and AR-074954 to Y.P.L].Y.Z.(201706290105)and T.Z.(201406920028)were sponsored by the China Scholarship Council.
文摘Runt-related transcription factor 1(Runx1)plays a key role in cartilage formation,but its function in articular cartilage formation is unclear.We generated non-inducible and inducible Runx1-deficient mice(Runx1^(f/f)Col2α1-Cre and Runx1^(f/f)Col2α1-CreER mice)and found that chondrocyte-specific Runx1-deficient mice developed a spontaneous osteoarthritis(OA)-like phenotype and showed exacerbated articular cartilage destruction under OA,characterized by articular cartilage degradation and cartilage ossification,with decreased Col2α1 expression and increased Mmp13 and Adamts5 expression.RNA-sequencing analysis of hip articular cartilage from the Runx1^(f/f)Col2α1-Cre mice compared to that from wild-type mice and subsequent validation analyses demonstrated that Runx1 is a central regulator in multiple signaling pathways,converging signals of the Hippo/Yap,TGFβ/Smad,and Wnt/β-catenin pathways into a complex network to regulate the expression of downstream genes,thereby controlling a series of osteoarthritic pathological processes.RNA-sequencing analysis of mutant knee joints showed that Runx1’s role in signaling pathways in articular cartilage is different from that in whole knee joints,indicating that Runx1 regulation is tissue-specific.Histopathologic analysis confirmed that Runx1 deficiency decreased the levels of YAP and p-Smad2/3 and increased the levels of activeβ-catenin.Overexpression of Runx1 dramatically increased YAP expression in chondrocytes.Adeno-associated virus-mediated Runx1 overexpression in the knee joints of osteoarthritic mice showed the protective effect of Runx1 on articular cartilage damaged in OA.Our results notably showed that Runx1 is a central regulator of articular cartilage homeostasis by orchestrating the YAP,TGFβ,and Wnt signaling pathways in the formation of articular cartilage and OA,and targeting Runx1 and its downstream genes may facilitate the design of novel therapeutic approaches for OA.
文摘Neural regeneration was once considered to be impossible, especially in the central nervous system where neural regeneration comprise the generation of new neurons, glia, axons, myelin, and synapses. Until recently, neural stem cells/neural progenitor cells (NSCs/NPCs) were identified from various areas of brain and brought hopes to the neural repair and regeneration. Tissue engineering has revolutionized the current neural regeneration technology and it has become a pioneering interdisciplinary field in the areas of biomedical research. Polyhydoxyalkanoate (PHA) as one of biodegradable material has been successfully used as tissue engineering materials. It has also been applied in nerve tissue engineering due to the high biocompatibility and low cytotoxicity. Over the past 10 years, different kinds of modification strategies have been undertaken to improve the properties of PHA to fit the requirements from various fields. Several members of PHA family have been attempted for neural regeneration. This article reviewed the recent modification strategies for improving the properties of PHA and highlighted the pioneer applications in neural regeneration.
文摘Bioactive scaffolds with interconnected porous structures are essential for guiding cell growth and new bone formation. In this work, we successfully fabricated three-dimensional （3D） porous β-tricalcium phosphate （β-TCP）/calcium silicate （CS） composite scaffolds with different ratios by 3D printing technique and further investigated the physiochemical properties, in vitro apatite mineralization properties and degradability of porous β-TCP/CS scaffolds. Moreover, a series of in vitro cell experiments including the attachment, proliferation and osteogenic differentiation of mouse bone marrow stromal cells were conducted to testify their biological performances. The results showed that 3D printed β-TCP/CS scaffolds possessed of controllable internal porous structures and external shape. Furthermore, the introduction of CS decreased the shrinkage of scaffolds and improved the in vitro apatite formation activity and degradation rate. Meanwhile, compared with pure β- TCP scaffold, the β-TCP/CS composite scaffolds were more conducive to promote cell adhesion, spread and osteogenesis differentiation. However, when the content of CS was increased to 45%, the ions dissolution rate of the composite scaffolds was so high that leaded to the increase in pH value, which inhibited the proliferation of cells. Our results suggested that the introduction of appropriate CS into β-TCP bioceramic is an effective strategy to prepare bioactive 3D printed bioceramic scaffolds for hard tissue regeneration.
文摘Cells in vivo are in a three-dimensional(3D)complicated microenvironment composed of various biological,physical and chemical cues.Although it is well accepted that biological and chemical cues can significantly influence cell functions,more and more evidence has also shown that physical cues are also vital.Using today’s micro and nanoscale technologies,creating synthetic but native-like conditions are the prerequisites for understanding cell behaviors.Most research has been carried out on artificial two-dimensional(2D)substrates.However,recent studies showed that cells respond and behave differently in these 2D settings compared to in 3D intricate microenvironment.Therefore,innovative 3D in vitro cellular models with precisely patterned multiple types of cells are needed for re-creating distinct niches and in vitro cell modeling under well-defined and reproducible conditions.In this talk,I will present the 3D nano and microscale tissue engineering methods we are developing for engineering cell spatiotemporal mechanical microenvironment.
基金supported in part by a grant from the National Natural Science Foundation of China,No. 81071150,10872156the National High Technology Research and Development Program of China (863 Program),No.2006AA04Z370
文摘Rhesus monkey models of Parkinson＇s disease were induced by injection of N-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine. Neural firings were recorded using microelectrodes placed in the interna segment of the globus pallidus. The wavelets and power spectra show gradual power reduction during the disease process along with increased firing rates in the Parkinson＇s disease state. Singular values of coefficients decreased considerably during tremor-related activity as well as in the Parkinson＇s disease state compared with normal signals, revealing that higher-frequency components weaken when Parkinson＇s disease occurs. We speculate that the death of neurons could be reflected by irregular frequency spike trains, and that wavelet packet decomposition can effectively detect the degradation of neurons and the loss of information transmission in the neural circuitry.
基金supported by the National Key Research and Development Program Project(2021YFC2400203)the Shaanxi Province Key Research and Development Program Project(2023-YBSF-120)+1 种基金the Shandong Provincial Natural Science Foundation(ZR2024QF287)the National Natural Science Foundation of China(31972907).
文摘Temporal interference(TI)is a form of stimulation that epitomizes an innovative and non-invasive approach for profound neuromodulation of the brain,a technique that has been validated in mice.Yet,the thin cranial bone structure of mice has a marginal influence on the effect of the TI technique and may not effectively showcase its effectiveness in larger animals.Based on this,we carried out TI stimulation experiments on rats.Following the TI intervention,analysis of electrophysiological data and immunofluorescence staining indicated the generation of a stimulation focus within the nucleus accumbens(depth,8.5 mm)in rats.Our findings affirm the viability of the TI methodology in the presence of thick cranial bones,furnishing efficacious parameters for profound stimulation with TI administered under such conditions.This experiment not only sheds light on the intervention effects of TI deep in the brain but also furnishes robust evidence in support of its prospective clinical utility.
基金supported by the Start-up Fund from Hainan University(No.KYQD(ZR)-20077)。
文摘Three-dimensional(3D)single molecule localization microscopy(SMLM)plays an important role in biomedical applications,but its data processing is very complicated.Deep learning is a potential tool to solve this problem.As the state of art 3D super-resolution localization algorithm based on deep learning,FD-DeepLoc algorithm reported recently still has a gap with the expected goal of online image processing,even though it has greatly improved the data processing throughput.In this paper,a new algorithm Lite-FD-DeepLoc is developed on the basis of FD-DeepLoc algorithm to meet the online image processing requirements of 3D SMLM.This new algorithm uses the feature compression method to reduce the parameters of the model,and combines it with pipeline programming to accelerate the inference process of the deep learning model.The simulated data processing results show that the image processing speed of Lite-FD-DeepLoc is about twice as fast as that of FD-DeepLoc with a slight decrease in localization accuracy,which can realize real-time processing of 256×256 pixels size images.The results of biological experimental data processing imply that Lite-FD-DeepLoc can successfully analyze the data based on astigmatism and saddle point engineering,and the global resolution of the reconstructed image is equivalent to or even better than FD-DeepLoc algorithm.
基金supported by the National Natural Science Foun-dation of China(Grant No.52073103,52272276,51873069,and 52373128)Beijing Municipal Health Commission(BMHC-2021-6,BJRITO-RDP-2024)Beijing Municipal Public Welfare Devel-opment and Reform Pilot Project for Medical Research Institutes(JYY2023-11,JYY2023-8).
文摘Effective treatment of intervertebral disc degeneration with biomaterials remains a challenge,owing to the difficulty in simultaneously overcoming oxidative stress and its associated cascades in the nucleus pulposus microenvironment,which includes cellular senescence,apoptosis,inflammation,and extracellular matrix(ECM)degradation.To address these issues,a multifunctional hydrogel(HG-QNT)loaded with transforming growth factorβ1(TGFβ1)and quercetin-based nanoparticles(QUNPs)is developed through borate ester bonding and Schiffbase reaction-induced crosslinking.Specifically,QUNPs fabricated via coordination and hydrophobic interactions endow the hydrogel with extraordinary antioxidative properties.Benefiting from the multi-dynamic crosslinking,the hydrogel achieves self-healing,mechanical stability,and pH-responsive release of QUNPs and TGFβ1.The HG-QNT hydrogel is demonstrated to enhance the proliferation of encapsulated nucleus pulposus cells,thereby providing an ideal platform for cell transplantation.The cooperative antioxidation of QUNPs and the hydrogel carrier renders HG-QNT effective in mitigating oxidative stress,resulting in the suppression of cellular senescence,mitochondrial dysfunction,apoptosis,excessive inflammation,and abnormal catabolism.Afterwards,TGFβ1 and QUNPs act in synergy with the hydrogel to restore the anabolic/catabolic balance by enhancing ECM synthesis.Overall,the strategy orchestrating multiple modulation by HG-QNT hydrogel shows great potential for application in intervertebral disc regeneration.
基金supported by the National Natural Science Foundation of China(Nos.22125404,92068118,21874105)the Natural Science Basic Research Program of Shaanxi Province(Nos.2023-JCJQ-13,2020JQ-021)the Innovation Capability Support Program of Shaanxi Province(No.2023-CX-TD-62)。
文摘Characterization of the distribution and accurate counting of RNA molecules in the context of tissues is necessary to understand their complexity and heterogeneity.Single-molecule fluorescence in situ hybridization reveals the abundance and distribution of RNA and resolves different cell types in complex tissues.Especially,off-target binding and nonspecific adsorption of probes are prone to producing nonspecific amplification.Herein,we present highly de-noising amplified imaging,which leverages a sitespecific cleavage-amplifying design to achieve accurate counting of RNA in tissues.Our method avoids adding probe as primer,decreases nonspecific spots of single cells from 7 to nearly zero,and enables RNA imaging in uncleared tissue sections with nearly zero noise.We demonstrate the efficacy of this method on various thickness of mouse tissue sections.We envision this approach will serve as a tool to revealing the information content from patient samples for biomedical purpose.
基金Supported by the National Natural Science Foundation of China(No.82201163)Natural Science Foundation Youth Foundation of Shaanxi Province(No.2023-JC-QN-0861)Shaanxi Province Key Research and Development Program(No.2021SF-332).
文摘AIM:To use two-sample Mendelian randomization(MR)method to study uveitis causal association with wet age-related macular degeneration(wAMD)risk from the genetic level.METHODS:Two-sample MR analysis was used to assess the causal role of uveitis on wAMD risk,using the 8 genetic variants associated strongly with uveitis as instrumental variables.Besides,eight MR methods[inverse variance weighted(IVW),weighted median,MR-Egger regression,weighted mode,simple mode,robust adjusted profile score(RAPS),contamination inverse-variance weighted method,and debiased inverse-variance weighted method]were used to get the whole causal estimate for multiple instrumental single nucleotide polymorphism(SNPs).The MR analysis was based on Europeans.RESULTS:Uveitis was related to a higher risk of wAMD[odds ratio(OR):1.08,95%confidence interval(CI)1.03–1.12;P=1.03×10^(-3)]with the IVW method.No heterogeneity and directional pleiotropy were detected.On the contrary,no significant results were detected in reverse MR analysis.CONCLUSION:Uveitis is related to an increased risk of wAMD.Due to the high blindness rate of wAMD,understanding and controlling the risk factors of AMD is of great significance for reducing its incidence and early diagnosis and treatment.
基金financially supported by the National Natural Science Foundation of China(82127802,22374157)Strategic Priority Research Program,CAS(XDB0540000,XDC0170000)CAS Youth Interdisciplinary Team(JCTD-2022-13).In addition,Xin Zhou acknowledges the support from the Tencent Foundation through the XPLORER PRIZE.
文摘Magnetic resonance imaging(MRI)is a powerful tool for diagnosing and monitoring brain diseases,but its low sensitivity can hinder early detection.To address this challenge,we utilized chemical exchange saturation transfer(CEST)MRI,which greatly enhances sensitivity for detecting low-concentration compounds.In this study,we developed a CEST contrast agent based on a recombinant adeno-associated viruses(rAAVs)encoding the protamine-1(PRM1)MRI reporter gene.CEST MRI revealed that PRM1 contrast agent effectively highlighted caudate putamen region after injection of the rAAVs into the mouse brain,clearly distinguishing it from the surrounding tissue,with no observable damage.This method provides a sensitive,metal-free CEST contrast agent for in vivo brain cell detection,demonstrating potential for both diagnostic and therapeutic applications in brain diseases.
基金funded in part by the STI2030-Major Projects(2022ZD0212200)Hainan Province Key Area R&D Program(KJRC2023C30)+1 种基金Project of Collaborative Innovation Center of One Health(XTCX2022JKB02)Sanya Yazhou Bay Science and Technology City(SKJC-JYRC-2024-38).
文摘Neuroinflammation plays an important role in the occurrence and development of neurological diseases.In addition to microglia,the role of astrocytes in neuroinflammation has gradually attracted attention.Photobiomodulation(PBM),as a non-invasive treatment,has been shown potential to alleviate inflammation of microglia or astrocytes.In this study,the spatiotemporal regulation and molecular mechanism of PBM on astrocytes were deeply explored by analyzing the effects and genomics at different time points.The results showed that PBM significantly attenuated the upregulation of inflammatory factors and mitochondrial dysfunction in astrocytes under LPS stimulation for 4 h and 24 h.RNA-seq analysis showed that the JAK-STAT pathway played an important role in the early stage of both LPS-induced astrocytic neuroin-flammation and PBM-alleviated astrocytic neuroinflammation.Under PBM treatment,Stat5a translocation to the nucleus and upregulated Socs3 expression were observed in LPS-treated astrocytes,which may inhibit the overactivation of the JAK-STAT inflammatory signaling pathway and thus alleviate astrocyte inflammation.Taken together,this study provides new insight into the molecular mechanism of the potential application of PBM in the treatment of neuroinflammation.
基金supported by the National Natural Science Foundation of China(32525031,32500896,32571210,and 32171233)the China Postdoctoral Science Foundation(2025M772776 and BX20250148)+2 种基金the Sanqin Talent Special Support Program(2024STD04)the Natural Science Foundation of Shandong Province of China(ZR2025MS1180)the Natural Science Foundation of Shaanxi Province of China(2019JC-07,2021TD-37,2023-ZDLSF-23,and 2024JC-YBMS-146).
文摘Male sexual behaviors,including mounting,intromission,and ejaculation,are not only critical for reproduction but also serve as a model for understanding how the brain orchestrates sequential motor and motivational processes.While previous studies have identified key brain regions involved in sexual behaviors,such as the medial preoptic area(MPOA)and the nucleus accumbens(NAc)[14],the neural mechanisms governing the transitions between different phases of male sexual behavior remain poorly understood.
基金supported by the National Natural Science Foundation of China(82371784,32311530061)the National Key Research and Development Program of China(2023YFC2507900,2023YFC2706300)+2 种基金R&D Program of Guangzhou Laboratory(SRPG22-006)State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases(2024ZZ10014)the Hubei Provincial Natural Science Foundation of China(Grant number:2024AFB634).
文摘Melanoma Differentiation-Associated gene 5(MDA5)serves as a pattern recognition receptor(PRR)that identifies pathogen-associated molecular patterns(PAMPs),making it instrumental in antiviral defense.However,its non-canonical role in adaptive immunity,particularly in regulating B-cell immune functions,is poorly characterized.Here,we demonstrate that MDA5 is critical for the marginal zone(MZ)B-cell differentiation,B-cell receptor(BCR)signal transduction,and cytoskeletal dynamics.We determined that the MDA5-NF-κB-DNM1 axis governs actin polymerization and that this impairment in Mda5 knockout(KO)B cells can be rescued by the treatment with the dynamin1(DNM1)activator Bis-T-23.Furthermore,MDA5 deficiency induces metabolic perturbations in B cells,characterized by a reduced extracellular acidification rate(ECAR)and oxygen consumption rate(OCR),excessive reactive oxygen species(ROS)accumulation,and increased mitochondrial fission.Notably,taurine levels are decreased in Mda5 KO B cells,and in vitro taurine supplementation rescues impaired BCR signaling.Finally,MDA5-deficient mice exhibit a blunted humoral immune response.Overall,this study reveals the key functions and molecular mechanisms of MDA5 in B-cell differentiation,BCR signaling,and the humoral immune response.
文摘Atrial fibrillation(AF) has been considered as a growing epidemiological problem in the world,with a substantial impact on morbidity and mortality.Ambulatory electrocardiography(e.g.,Holter) monitoring is commonly used for AF diagnosis and therapy and the automated detection of AF is of great significance due to the vast amount of information provided.This study presents a combined method to achieve high accuracy in AF detection.Firstly,we detected the suspected transitions between AF and sinus rhythm using the delta RR interval distribution difference curve,which were then classified by a combination analysis of P wave and RR interval.The MIT-BIH AF database was used for algorithm validation and a high sensitivity and a high specificity(98.2% and 97.5%,respectively) were achieved.Further,we developed a dataset of 24-h paroxysmal AF Holter recordings(n=45) to evaluate the performance in clinical practice,which yielded satisfactory accuracy(sensitivity=96.3%,specificity=96.8%).
