Using exact diagonalization of the Hamiltonian and transition matrix in the energy eigenbasis,we perform model calculations of the magnetic relaxation rate in single-molecule magnets.A careful examination of the trans...Using exact diagonalization of the Hamiltonian and transition matrix in the energy eigenbasis,we perform model calculations of the magnetic relaxation rate in single-molecule magnets.A careful examination of the transition matrix reveals that resonant tunneling does not enhance transitions between the nearly degenerate states;rather,it suppresses them.Instead,transitions from one state in the degenerate pair to neighboring states of the other are significantly enhanced.We conduct a detailed analysis of the transition rates to clearly demonstrate how resonant tunneling modulates these processes.This work provides a substantial reinterpretation of the resonant magnetic relaxation in single-molecule magnets and clearly identifies the dominant relaxation pathways.展开更多
Lanthanide-based single-molecule magnets exhibit broad magnetic hysteresis,which manifests as slow magnetic relaxation in strong magnetic fields.However,the origin of the nontrivial hysteresis behaviors remains debate...Lanthanide-based single-molecule magnets exhibit broad magnetic hysteresis,which manifests as slow magnetic relaxation in strong magnetic fields.However,the origin of the nontrivial hysteresis behaviors remains debated.Here,we propose two influential mechanisms:activation of optical-phonon-mediated direct transitions within the ground-state doublet and the resonant Raman process.These discoveries,coupled with the g-factor anisotropy,account for the observed hysteresis behaviors in the regimes of fast magnetic relaxation.Our findings complement the recognized mechanisms used to interpret the magnetic hysteresis of single-molecule magnets.展开更多
We propose a hybrid coercivity mechanism for exchange-coupled hard/soft multilayers, which incorporates elements of both the traditional nucleation and pinning mechanisms based on both threedimensional(3 D) and one-di...We propose a hybrid coercivity mechanism for exchange-coupled hard/soft multilayers, which incorporates elements of both the traditional nucleation and pinning mechanisms based on both threedimensional(3 D) and one-dimensional(1 D) micromagnetic calculations. The magnetic reversal starts with the nucleation of the domain wall near the defects or soft phases, which ends by the pinning usually in the same place. Therefore, pinning near the nucleation centers are the dominant coercivity mechanism for both exchange-coupled nanocomposites and so-called single-phased permanent magnets. Our proposed coercivity mechanism and calculated results agree very well with available experimental data,especially the recently reported high energy products achieved in NdFeB and SmCo based hard/soft multilayers. The hybrid coercivity mechanism can be readily extended to single-phased permanent magnets with defects and other magnetic systems.展开更多
Hard/soft permanent magnets have attracted a lot of attention because of their rich magnetic properties and their potential for realizing giant energy products. However, energy products obtained by scientists in exper...Hard/soft permanent magnets have attracted a lot of attention because of their rich magnetic properties and their potential for realizing giant energy products. However, energy products obtained by scientists in experiments are much smaller than the theoretical values, which has been studied by various analytical and numerical methods. The famous Stoner-Wohlfarth model(S-W model) is too simple to give the hysteresis loops whereas the intensively used variational method is too complicated to reveal the underlying mechanism in a simple form. The analytical model proposed in this paper maintains a balance between simplicity and precision, where the spins in the soft layer rotate fast and coherently with the applied field while those in the hard layer response to the applied field much slower but also coherent. An exchange coupling is provided to maintain the exchange spring which drags the spins in the hard layer to follow those in the soft layer. Similar to the more sophisticated model, the calculated hysteresis loops display three typical magnetic phases, i.e., the rigid composite magnet, the exchange spring and decoupled magnet, whereas the simple SW model can only give one single phase, i.e., the rigid composite one. In addition to the hysteresis loop, the energy product and the nucleation fields have been calculated and compared with those calculated by other methods, which justifies our model.Careful comparisons show that our calculations are in good agreement with the experimental results and other theoretical results, especially for the important coercivity value and the related mechanism.展开更多
Osteoporosis(OP),a systemic and chronic bone disease,is distinguished by low bone mass and destruction of bone microarchitecture.Ginsenoside Compound-K(CK),one of the metabolites of ginsenoside Rb1,has anti-aging,anti...Osteoporosis(OP),a systemic and chronic bone disease,is distinguished by low bone mass and destruction of bone microarchitecture.Ginsenoside Compound-K(CK),one of the metabolites of ginsenoside Rb1,has anti-aging,anti-inflammatory,anti-cancer,and hypolipidemic activities.We have demonstrated CK could promote osteogenesis and fracture healing in our previous study.However,the contribution of CK to osteoporosis has not been examined.In the present study,we investigated the effect of CK on osteoclastogenesis and ovariectomy(OVX)-induced osteoporosis.The results showed that CK inhibited receptor activator for nuclear factor-κB ligand(RANKL)-mediated osteoclast differentiation and reactive oxygen species(ROS)activity by inhibiting the phosphorylation of NF-κB p65 and oxidative stress in RAW264.7 cells.In addition,we also demonstrated that CK could inhibit bone resorption using bone marrow-derived macrophages.Furthermore,we demonstrated that CK attenuated bone loss by suppressing the activity of osteoclast and alleviating oxidative stress in vivo.Taken together,these results showed CK could inhibit osteoclastogenesis and prevent OVX-induced bone loss by inhibiting NF-κB signaling pathway.展开更多
Objective: The analgesic effect of Paeonia Lactiflora has been widely accepted in traditional Chinese medicine. But little is known about the potential mechanism. This study aims to elucidate the effective components ...Objective: The analgesic effect of Paeonia Lactiflora has been widely accepted in traditional Chinese medicine. But little is known about the potential mechanism. This study aims to elucidate the effective components and analgesic mechanism based on network pharmacology. Methods: TCMSP was screened to collect the possible active ingredients and their CAS and SMILES was searched in Pubchem and further be used for reverse molecular docking in Swiss Target Prediction database to obtain potential targets. Pain-related molecules were obtained from GeenCards database, and the predicted targets of Paeonia Lactiflora for pain treatment were selected by Wayne diagram. For mechanism analysis, the protein-protein interactions were constructed by String, the GO analysis and KEGG analysis were conducted in DAVID. Results: Through GO analysis and KEGG analysis, we found that the pain related signaling pathways mainly involved in serotonergic synapse, calcium signaling pathway, inflammatory mediator TRP channels. Using network-based systems biology and molecular docking analyses, we predicted that 11 active ingredients in Paeonia Lactiflora has the analgesic effects with 97 potential targets. PRKCA, CASP3, ALOX15, SLC6A4, PRKCG, ALOX5, PRKCB, ALOX12, EGFR, ADRB2, RYR3, RYR1, NOS2, PTAFR, PRKCQ, and PRKCD were involved in the analgesic effects of Paeonia Lactiflora. Conclusion: Paeonia Lactiflora may alleviate pain through inflammatory mediator regulation of TRP channels, Ca2+ signaling pathway and 5-HT receptor. PRKCA, PRKCB, PRKCD,PRKCQ, and PRKCG may be new targets for pain treatment.展开更多
The Jialu River in China has been seriously polluted by the direct discharge of industrial and domestic wastewater. The predominant contaminants of the Jialu River and its adjacent groundwater were recently investigat...The Jialu River in China has been seriously polluted by the direct discharge of industrial and domestic wastewater. The predominant contaminants of the Jialu River and its adjacent groundwater were recently investigated. However, the potential genotoxic impact of polluted water on human health remains to be clarified. Here, we used human–hamster hybrid（AL） cells, which are sensitive for detecting environmental mutagens. We found that the cytotoxicity and mutagenicity of the groundwater in the Jialu River basin were influenced by the infiltration of the Jialu River. Hydrological periods significantly affected the cytotoxicity, but not the mutagenic potential, of surface and groundwater. Further, the mutagenic potential of groundwater samples located 〈 1 km from the Jialu River（S（M-2） water samples） was detected earlier than that of groundwater samples located approximately 20 km from the Jialu River（SN water samples）. Because of high cytotoxicity, the mutagenic potential of water samples from the Jialu River（S（M-1） water samples） was not significantly enhanced compared with that of untreated controls. To further assess the mutagenic dispersion potential, an artificial neural network model was adopted. The results showed that the highest mutagenic potential of groundwater was observed approximately 10 km from the Jialu River. Although further investigation of mutagenic spatial dispersion is required, our data are significant for advancing our understanding of the origin, dispersion,and biological effects of water samples from polluted areas.展开更多
In order to explore the spatial distribution and variation characteristics of soil moisture in coal mining subsidence area in Mu Us sandy Land,and provide theoretical basis for the restoration of the mining area,exper...In order to explore the spatial distribution and variation characteristics of soil moisture in coal mining subsidence area in Mu Us sandy Land,and provide theoretical basis for the restoration of the mining area,experiments based on a linear sampling and classic statistical and geostatistical methods were conducted. Spatial distribution characteristics and variation of soil moisture in the typical 0 to 100 cm dune area in the subsidence area and the non-subsidence area( control) were studied. The results showed that in the typical sand dune location of nonsubsidence area( control),the probability distribution curves of soil moisture changes in all layers along vertical and horizontal directions were all normal distribution,and it was consistent with the temporal and spatial variation characteristics of soil moisture in conventional dunes in Mu Us sandy land. By contrast,two years after the coal mine collapsed,the variations of soil moisture in different layers along vertical and horizontal directions were different,and soil moisture loss was more serious than that of control dune by nearly 10% to 30%,and the standard deviation varied from 0. 54 to 1. 05,increasing by 52. 08% compared with the non-subsidence area( control). The probability of positive and negative deviation greater than 1 was over 50%,and the coefficient of variation varied from 0. 14 to 0. 28,which was 80% higher than that of nonsubsidence area( control). After collapsing,the average level of soil moisture,standard deviation,variance and variation coefficient had greatly changed,and influence of coal mining subsidence on soil moisture was the most in the middle layer( 30-70 cm),and was not obvious in the surface( 0-20 cm) and lower layer( 80-100 cm). In coal mining subsidence area,the dispersion degree of soil moisture in different layers along the vertical and horizontal direction was greatly improved,which increased spatial variation of soil moisture.展开更多
Titanium dioxide nanoparticles (TiO2 NPs) are subjected to various transformation processes (chemical,physical and biological processes) in the environment,potentially affecting their bioavailability and toxic propert...Titanium dioxide nanoparticles (TiO2 NPs) are subjected to various transformation processes (chemical,physical and biological processes) in the environment,potentially affecting their bioavailability and toxic properties.However,the size variation of TiO2 NPs during aging process and subsequent effects in mammalian cells are largely unknown.The aim of this study was to illustrate the adverse effects of TiO2 NPs in different sizes (5,15 and <100 nm) during aging process on human-hamster hybrid (AL) cells.There was an aging-time dependent enhancement of average hydrodynamic size in TiO2 NPs stock suspensions.The cytotoxicity of fresh TiO2 NPs increased in a size-dependent manner;in contrast,their genotoxicity decreased with the increasing sizes of NPs.No significant toxicity difference was observed in cells exposed to either fresh or 60 day-aged TiO2 NPs.Both Fresh and aged TiO2 NPs efficiently induced mitochondrial dysfunction and activated Caspase-3/7 in a size-dependent manner.Using mitochondrial-DNA deficient (ρ°) AL cells,we further discovered that mitochondrial dysfunction made significant contribution to the size-dependent toxicity induced by TiO2 NPs during the aging process.Taken together,our data indicated that TiO2 NPs could significantly induced the cytotoxicity and genotoxicity in an aging time-independent and size-dependent manner,which were triggered by mitochondrial dysfunction.Our study suggested the necessity to include size as an additional parameter for the cautious monitoring of TiO2 NPs disposal before entering the environment.展开更多
For more than a decade,the exfoliation of graphene and other layered materials has led to a tremendous amount of research in two-dimensional(2D)materials,among which 2D transition metal chalcogenides(TMCs)nanomaterial...For more than a decade,the exfoliation of graphene and other layered materials has led to a tremendous amount of research in two-dimensional(2D)materials,among which 2D transition metal chalcogenides(TMCs)nanomaterials have attracted much attention in a wide range of applications including photoelectric devices,lithium-ion batteries,catalysis,and energy conversion and storage owing to their unique photoelectric physical properties.With such large specific surface area,strong near-infrared(NIR)absorption and abundant chemical element composition,2D TMCs nanomaterials have become good candidates in biomedical imaging and cancer treatment.This review systematically summarizes recent progress on 2D TMCs nanomaterials,which includes their synthesis methods and applications in cancer treatment.At the end of this review,we also highlight the future prospects and challenges of 2D TMCs nanomaterials.It is expected that this work can provide the readers with a detailed overview of the synthesis of 2D TMCs and inspire more novel functional biomaterials based on 2D TMCs for cancer treatment in the future.展开更多
[Objectives]To explore the problem of"secondary desertification"caused by coal mining subsidence in sandy area and its control countermeasures.[Methods]The collapse fissure changes,vegetation displacement an...[Objectives]To explore the problem of"secondary desertification"caused by coal mining subsidence in sandy area and its control countermeasures.[Methods]The collapse fissure changes,vegetation displacement and tilt,dry sand layer and wind erosion/aeolian deposit rate of the edge,middle and basin of subsidence area were studied in detail.[Results]The width and density of fissures at the edge of subsidence area were the smallest,followed by those in the center,and the width and density of fissures in the basin of the subsidence area were the greatest,while the staggering and surface damage showed the opposite trend.The average displacement length of vegetation in the subsidence area reached 60 cm,the slope was 5.67-28.63,and the maximum wind erosion/aeolian deposit at the trunk roots was-30.52 cm/+25.41 cm,most serious at the edge of subsidence.The changes in displacement length and slope of vegetation were positively linearly correlated with the height and surface damage of collapse fissures.The thickness of dry land layer at the edge of the subsidence area reached 14 cm,4-6 cm greater than that of the control,and the thickness of dry land layer in the middle and basin of the subsidence area was both about 11 cm,1-4 cm greater than that of non-subsidence area.The wind erosion rate at the edge of the subsidence area was up to 83.34%,followed by that(52.06%)in the middle.The aeolian deposit rate in the subsidence basin was 51.84%.[Conclusions]The subsidence edge has the strongest impact on the sandy geomorphology and vegetation habitat,and is a key area for ecological restoration.It is recommended that the coal mining subsidence should be treated in a timely manner to avoid the occurrence of"secondary desertification".展开更多
The relentless emergence of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variants continues to challenge global health,as high mutation rates and complex pathogenicity obscure molecular mechanisms and im...The relentless emergence of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variants continues to challenge global health,as high mutation rates and complex pathogenicity obscure molecular mechanisms and impede clinical progress.Despite extensive research across viral evolution,structural biology,immunology,diagnostics,and therapeutics,the resulting vast and rapidly outdated literature has widened the gap between fundamental discovery and medical application.Here,we systematically mined 439,724 coronavirus disease 2019(COVID-19)publications using fine-tuned large language models to extract and distill knowledge across nine domains:antibodies,vaccines,serology,biochemistry,therapeutics,clinical presentation,risk factors,biomarkers,and diagnostics.These insights were integrated into a unified graph of 1,427,596 triples(CoVAR-KG).Covering 90%of known spike-protein variant sites,our knowledge graph forges molecular-to-clinical links that reveal how specific mutations influence antigenicity,transmissibility,and treatment response.By resolving data fragmentation,this resource accelerates target identification and streamlines hypothesis generation.Building on CoVAR-KG,we developed COVID-19 variant risk watcher(CVRW),an early-warning framework that quantifies the threat of emerging variants for real-time surveillance.Coupling the graph with retrieval-augmented GPT-4o enables rapid and in-depth comparisons of variant functionality and immune escape potential.These integrative tools furnish timely insights for vaccine design,therapeutic optimization,and pandemic preparedness,establishing a versatile platform for combating current and future viral threats.展开更多
Over the last decade,significant progress has been made in understanding the evolutionary,ecological,and metabolic significance of the gut microbiota for human health.This significant progress owes a considerable debt...Over the last decade,significant progress has been made in understanding the evolutionary,ecological,and metabolic significance of the gut microbiota for human health.This significant progress owes a considerable debt to the con-secutive publication of two seminal research papers origi-nating from pivotal research initiatives:METAgenomics of the Human Intestinal Tract(MetaHIT)(Qin et al.2010)and Human Microbiome Project(HMP)(Human Microbiome Project 2012).展开更多
Understanding the mechanisms of drug resistance inMycobacterium tuberculosis(MTB)is essential for the rapid detection of resistance and for guiding effective treatment,ultimately contributing to reducing the global bu...Understanding the mechanisms of drug resistance inMycobacterium tuberculosis(MTB)is essential for the rapid detection of resistance and for guiding effective treatment,ultimately contributing to reducing the global burden of tuberculosis(TB).Under anti-TB drugs pressure,MTB continues to accumulate resistance loci.The current repertoire of known resistance-associated mutations requires further refinement,necessitating efficient methods for the timely identification of potential resistance sites.Here,we introduce xAI-MTBDR,an explainable artificial intelligence framework designed to identify potential resistance-associated mutations and predict drug resistance in MTB.It outperforms state-of-the-art methods in predicting drug resistance for all first-line drugs,and scoring each mutation’s contribution to resistance.By leveraging public whole-genome sequencing data from nearly 40,000 MTB isolates,the framework identified 788 candidate resistance-related mutations and revealed 27 potential resistance markers,several of which are positioned closer to their respective drugs in protein structures than known resistance mutations,suggesting a potentially more direct role in mediating resistance.Furthermore,these scores enabled the framework to efficiently subgroup isolates with different resistance mechanisms and reflect varying levels of resistance.The framework serves as a valuable tool for accurate detection of drug-resistant MTB and offers new insights into its underlying mechanisms.展开更多
In gut microbial research,DNA extraction remarkably influences study outcomes and biological interpretations.Rapid advancements in the research scale and technological upgrades necessitate evaluating new methods to en...In gut microbial research,DNA extraction remarkably influences study outcomes and biological interpretations.Rapid advancements in the research scale and technological upgrades necessitate evaluating new methods to ensure reliability and precision in microbial community profiling.We systematically evaluated the performance of eight recent and commonly used extraction methods using a microbial mock community(MMC)and fecal samples from two healthy volunteers,incorporating bacterial,archaeal,and fungal constituents.Performance metrics included nucleic acid assessment,microbial profile assess-ment,and scalability for large-scale studies,leveraging shotgun metagenomics for in-depth analysis.Despite variations in DNA quantity and quality,all methods yielded sufficient DNA for shotgun metagenomic sequencing.In the MMC microbial profile assessment,the QIAamp PowerFecal pro Kit(PF)and DNeasy PowerSoil HTP kit(PS)methods exhibited higher similarity with the theoretical composition and lower variability across technical replicates compared to other methods.For fecal samples,the extraction method accounted for 21.4%of the overall microbiome variation and significantly affected the abundances of 32%of detected microbial species.Methods using mechanical lysis with small beads,such as PF and PS,demonstrated better efficiency,indicated by increased microbial diversity in extracting DNA from Gram-positive bacteria.Furthermore,the PF and PS methods are notably simple to execute and automation-friendly,though relatively costly.Our study underscores the importance of maintaining consistency in DNA extraction methods for reliable comparative metagen-omic analyses.We recommend PF and PS methods as optimal for expansive gut metagenomic research,emphasizing the critical role of mechanical lysis in DNA extraction.展开更多
The increasing consumption of fossil fuels is contributing to global resource depletion and environmental pollution.Branched-chain higher alcohols,such as isopentanol and isobutanol,have attracted significant attentio...The increasing consumption of fossil fuels is contributing to global resource depletion and environmental pollution.Branched-chain higher alcohols,such as isopentanol and isobutanol,have attracted significant attention as next-generation biofuels.Biofuel production through microbial fermentation offers a green,sustainable,and renewable alternative to chemical synthesis.While enhanced production of isopentanol has been achieved in a variety of chassis,the fermentation yield has not yet reached levels suitable for industrial-scale production.In this study,we employed a continuous perturbation tool to construct a genome-scale perturbation library,combined with an isopentanol biosensor to screen for high-yielding mutants.We identified five highyielding mutants,each exhibiting an increased glucose conversion rate and isopentanol titer.The F2 strain,in particular,achieved an isopentanol titer of 1.57±0.014 g/L and a yield of 14.04±0.251 mg/g glucose(10%glucose),surpassing the highest values reported to date in engineered Saccharomyces cerevisiae.Systematic transcriptome analysis of the isopentanol synthesis,glycolysis,glycerol metabolism,and ethanol synthesis pathways revealed that MPC,OAC1,BAT2,GUT2,PDC6,and ALD4 are linked to efficient isopentanol production.Further analysis of differentially expressed genes(DEGs)identified 17 and 12 co-expressed DEGs(co-DEGs)in all mutants and the two second-round mutants,respectively.In addition,we validated the knockout or overexpression of key co-DEGs.Our results confirmed the critical roles of HOM3 and DIP5 in isopentanol production,along with genes associated with the aerobic respiratory chain(SDH3,CYT1,COX7,ROX1,and ATG41)and cofactor balance(BNA2 and NDE1).Additionally,functional analysis of the co-DEGs revealed that MAL33 is associated with the synthesis of branched-chain higher alcohols,expanding the intracellular metabolic network and offering new possibilities for green,cost-effective biofuel production.展开更多
Ginsenosides, the main pharmacologically active natural compounds in ginseng （Panax ginseng）, are mostly the glycosylated products of protopanaxadiol （PPD） and protopanaxatriol （PPT）. No uridine diphosphate glyc...Ginsenosides, the main pharmacologically active natural compounds in ginseng （Panax ginseng）, are mostly the glycosylated products of protopanaxadiol （PPD） and protopanaxatriol （PPT）. No uridine diphosphate glycosyltransferase （UGT）, which catalyzes PPT to produce PPT-type ginsenosides, has yet been reported. Here, we show that UGTPgl, which has been demonstrated to regio-specifically glycosylate the C20-OH of PPD, also specifically glycosylates the C20-OH of PPT to produce bioactive ginsenoside FI. We report the characterization of four novel UGT genes isolated from P. ginseng, sharing high deduced amino acid identity （〉84%） with UGTPgl. We demonstrate that UGTPgl00 specifically glycosylates the C6-OH of PPT to produce bioactive ginsenoside Rhl, and UGTPgl01 catalyzes PPT to produce F1, followed by the generation of ginsenoside Rgl from FI. However, UGTPgl02 and UGTPgl03 were found to have no detectable activity on PPT. Through structural modeling and site-directed mutagenesis, we identified several key amino acids of these UGTs that may play important roles in determining their activities and substrate regio-specificities. Moreover, we constructed yeast recombinants to biosynthesize F1 and Rhl by introducing the genetically engineered PPT-producing pathway and UGTPgl or UGTPgl00. Our study reveals the possible biosynthetic pathways of PPT-type ginsenosides in Panax plants, and provides a sound manufacturing approach for bioactive PPT-type ginsenosides in yeast via synthetic biology strategies.展开更多
Variation of maternal gut microbiota may increase the risk of autism spectrum disorders(ASDs) in offspring. Animal studies have indicated that maternal gut microbiota is related to neurodevelopmental abnormalities in ...Variation of maternal gut microbiota may increase the risk of autism spectrum disorders(ASDs) in offspring. Animal studies have indicated that maternal gut microbiota is related to neurodevelopmental abnormalities in mouse offspring, while it is unclear whether there is a correlation between gut microbiota of ASD children and their mothers. We examined the relationships between gut microbiome profiles of ASD children and those of their mothers, and evaluated the clinical discriminatory power of discovered bacterial biomarkers. Gut microbiome was profiled and evaluated by 16S ribosomal RNA gene sequencing in stool samples of 59 mother–child pairs of ASD children and 30 matched mother–child pairs of healthy children. Significant differences were observed in the gut microbiome composition between ASD and healthy children in our Chinese cohort. Several unique bacterial biomarkers, such as Alcaligenaceae and Acinetobacter, were identified. Mothers of ASD children had more Proteobacteria, Alphaproteobacteria, Moraxellaceae, and Acinetobacter than mothers of healthy children. There was a clear correlation between gut microbiome profiles of children and their mothers; however, children with ASD still had unique bacterial biomarkers, such as Alcaligenaceae, Enterobacteriaceae, and Clostridium. Candidate biomarkers discovered in this study had remarkable discriminatory power. The identified patterns of mother–child gut microbiome profiles may be important for assessing risks during the early stage and planning of personalized treatment and prevention of ASD via microbiota modulation.展开更多
As a powerful paradigm,artificial intelligence(AI)is rapidly impacting every aspect of our day-to-day life and scientific research through interdisciplinary transformations.Living human organoids(LOs)have a great pote...As a powerful paradigm,artificial intelligence(AI)is rapidly impacting every aspect of our day-to-day life and scientific research through interdisciplinary transformations.Living human organoids(LOs)have a great potential for in vitro reshaping many aspects of in vivo true human organs,including organ development,disease occurrence,and drug responses.To date,AI has driven the revolutionary advances of human organoids in life science,precision medicine and pharmaceutical science in an unprecedented way.Herein,we provide a forward-looking review,the frontiers of LOs,covering the engineered construction strategies and multidisciplinary technologies for developing LOs,highlighting the cutting-edge achievements and the prospective applications of AI in LOs,particularly in biological study,disease occurrence,disease diagnosis and prediction and drug screening in preclinical assay.Moreover,we shed light on the new research trends harnessing the power of AI for LO research in the context of multidisciplinary technologies.The aim of this paper is to motivate researchers to explore organ function throughout the human life cycle,narrow the gap between in vitro microphysiological models and the real human body,accurately predict human-related responses to external stimuli(cues and drugs),accelerate the preclinical-to-clinical transformation,and ultimately enhance the health and well-being of patients.展开更多
Ginsenoside Compound K(CK)has been recognized as a major functional component that is absorbed into the systemic circulation after oral administration of ginseng.CK demonstrates diverse bioactivities.A phase I clinica...Ginsenoside Compound K(CK)has been recognized as a major functional component that is absorbed into the systemic circulation after oral administration of ginseng.CK demonstrates diverse bioactivities.A phase I clinical study indicated that CK was a potential candidate for arthritis therapy.However,a phase II clinical study was suspended because of the high cost associated with the present CK manufacturing approach,which is based on the traditional planting-extracting-biotransforming process.We previously elucidated the complete CK biosynthetic pathway and realized for the first time de novo biosynthesis of CK from glucose by engineered yeast.However,CK production was not sufficient for industrial application.Here,we systematically engineered Saccharomyces cerevisiae to achieve high titer production of CK from glucose using a previously constructed protopanaxadiol(PPD)-producing chassis,optimizing UGTPg1 expression,improving UDP-glucose biosynthesis,and tuning down UDP-glucose consumption.Our final engineered yeast strain produced CK with a titer of 5.74 g/L in fed-batch fermentation,which represents the highest CK production in microbes reported to date.Once scaled-up,this high titer de novo microbial biosynthesis platform will enable a robust and stable supply of CK,thus facilitating study and medical application of CK.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.12404085,12474122,52171188,51771127,and 52111530143)the Fund from DOE-BES(Grant No.DE-FG02-05ER46237)the Central Government Funds of Guiding Local Scientific and Technological Development for Sichuan Province,China(Grant No.2021ZYD0025)。
文摘Using exact diagonalization of the Hamiltonian and transition matrix in the energy eigenbasis,we perform model calculations of the magnetic relaxation rate in single-molecule magnets.A careful examination of the transition matrix reveals that resonant tunneling does not enhance transitions between the nearly degenerate states;rather,it suppresses them.Instead,transitions from one state in the degenerate pair to neighboring states of the other are significantly enhanced.We conduct a detailed analysis of the transition rates to clearly demonstrate how resonant tunneling modulates these processes.This work provides a substantial reinterpretation of the resonant magnetic relaxation in single-molecule magnets and clearly identifies the dominant relaxation pathways.
基金the support from the Sichuan Normal Universitysupport from the National Natural Science Foundation of China(Grant No.22375157)+1 种基金support from the National Natural Science Foundation of China(Grant Nos.12474122,52171188,51771127,and 52111530143)the Central Government Funds of Guiding Local Scientific and Technological Development for Sichuan Province(Grant No.2021ZYD0025)。
文摘Lanthanide-based single-molecule magnets exhibit broad magnetic hysteresis,which manifests as slow magnetic relaxation in strong magnetic fields.However,the origin of the nontrivial hysteresis behaviors remains debated.Here,we propose two influential mechanisms:activation of optical-phonon-mediated direct transitions within the ground-state doublet and the resonant Raman process.These discoveries,coupled with the g-factor anisotropy,account for the observed hysteresis behaviors in the regimes of fast magnetic relaxation.Our findings complement the recognized mechanisms used to interpret the magnetic hysteresis of single-molecule magnets.
基金Project supported by National Natural Science Foundation of China(51771127,51571126,51772004)
文摘We propose a hybrid coercivity mechanism for exchange-coupled hard/soft multilayers, which incorporates elements of both the traditional nucleation and pinning mechanisms based on both threedimensional(3 D) and one-dimensional(1 D) micromagnetic calculations. The magnetic reversal starts with the nucleation of the domain wall near the defects or soft phases, which ends by the pinning usually in the same place. Therefore, pinning near the nucleation centers are the dominant coercivity mechanism for both exchange-coupled nanocomposites and so-called single-phased permanent magnets. Our proposed coercivity mechanism and calculated results agree very well with available experimental data,especially the recently reported high energy products achieved in NdFeB and SmCo based hard/soft multilayers. The hybrid coercivity mechanism can be readily extended to single-phased permanent magnets with defects and other magnetic systems.
基金Project supported by National Natural Science Foundation of China(11074179,51771127,51571126,51772004)the Scientific Research Fund of Sichuan Provincial Education Department(18TD0010,16CZ0006)
文摘Hard/soft permanent magnets have attracted a lot of attention because of their rich magnetic properties and their potential for realizing giant energy products. However, energy products obtained by scientists in experiments are much smaller than the theoretical values, which has been studied by various analytical and numerical methods. The famous Stoner-Wohlfarth model(S-W model) is too simple to give the hysteresis loops whereas the intensively used variational method is too complicated to reveal the underlying mechanism in a simple form. The analytical model proposed in this paper maintains a balance between simplicity and precision, where the spins in the soft layer rotate fast and coherently with the applied field while those in the hard layer response to the applied field much slower but also coherent. An exchange coupling is provided to maintain the exchange spring which drags the spins in the hard layer to follow those in the soft layer. Similar to the more sophisticated model, the calculated hysteresis loops display three typical magnetic phases, i.e., the rigid composite magnet, the exchange spring and decoupled magnet, whereas the simple SW model can only give one single phase, i.e., the rigid composite one. In addition to the hysteresis loop, the energy product and the nucleation fields have been calculated and compared with those calculated by other methods, which justifies our model.Careful comparisons show that our calculations are in good agreement with the experimental results and other theoretical results, especially for the important coercivity value and the related mechanism.
基金the grant from National Natural Science Foundation of China(81871778)Guangdong Provincial Science and Technology Collaborative Innovation Center for Sport Science(2019B110210004)the key project of Sport Research Foundation of Guangdong Province(GDSS2022M005).
文摘Osteoporosis(OP),a systemic and chronic bone disease,is distinguished by low bone mass and destruction of bone microarchitecture.Ginsenoside Compound-K(CK),one of the metabolites of ginsenoside Rb1,has anti-aging,anti-inflammatory,anti-cancer,and hypolipidemic activities.We have demonstrated CK could promote osteogenesis and fracture healing in our previous study.However,the contribution of CK to osteoporosis has not been examined.In the present study,we investigated the effect of CK on osteoclastogenesis and ovariectomy(OVX)-induced osteoporosis.The results showed that CK inhibited receptor activator for nuclear factor-κB ligand(RANKL)-mediated osteoclast differentiation and reactive oxygen species(ROS)activity by inhibiting the phosphorylation of NF-κB p65 and oxidative stress in RAW264.7 cells.In addition,we also demonstrated that CK could inhibit bone resorption using bone marrow-derived macrophages.Furthermore,we demonstrated that CK attenuated bone loss by suppressing the activity of osteoclast and alleviating oxidative stress in vivo.Taken together,these results showed CK could inhibit osteoclastogenesis and prevent OVX-induced bone loss by inhibiting NF-κB signaling pathway.
基金the National Natural Science Foundation of China (Grant No. 81874404).
文摘Objective: The analgesic effect of Paeonia Lactiflora has been widely accepted in traditional Chinese medicine. But little is known about the potential mechanism. This study aims to elucidate the effective components and analgesic mechanism based on network pharmacology. Methods: TCMSP was screened to collect the possible active ingredients and their CAS and SMILES was searched in Pubchem and further be used for reverse molecular docking in Swiss Target Prediction database to obtain potential targets. Pain-related molecules were obtained from GeenCards database, and the predicted targets of Paeonia Lactiflora for pain treatment were selected by Wayne diagram. For mechanism analysis, the protein-protein interactions were constructed by String, the GO analysis and KEGG analysis were conducted in DAVID. Results: Through GO analysis and KEGG analysis, we found that the pain related signaling pathways mainly involved in serotonergic synapse, calcium signaling pathway, inflammatory mediator TRP channels. Using network-based systems biology and molecular docking analyses, we predicted that 11 active ingredients in Paeonia Lactiflora has the analgesic effects with 97 potential targets. PRKCA, CASP3, ALOX15, SLC6A4, PRKCG, ALOX5, PRKCB, ALOX12, EGFR, ADRB2, RYR3, RYR1, NOS2, PTAFR, PRKCQ, and PRKCD were involved in the analgesic effects of Paeonia Lactiflora. Conclusion: Paeonia Lactiflora may alleviate pain through inflammatory mediator regulation of TRP channels, Ca2+ signaling pathway and 5-HT receptor. PRKCA, PRKCB, PRKCD,PRKCQ, and PRKCG may be new targets for pain treatment.
基金supported by the CAS Strategic Priority Research Program(No.XDB14030502)the National Basic Research Program(973)of China(No.2014CB932002)+5 种基金the Natural Science Foundation of Anhui Province(No.1808085QB37)the Hi-Tech Research and Development Program(863)of China(No.2008AA062504)the National Natural Science Foundation of China(Nos.20977093,81273004,81301182,and 31470829)the Talent Research Foundation of Hefei University(No.16-17RC03)the Key Project of Natural Science Research of Anhui High Education Institutions(Nos.KJ2017A545,and KJ2017A546)the Project of Anhui Quality Engineering(No.2016msgzs060)
文摘The Jialu River in China has been seriously polluted by the direct discharge of industrial and domestic wastewater. The predominant contaminants of the Jialu River and its adjacent groundwater were recently investigated. However, the potential genotoxic impact of polluted water on human health remains to be clarified. Here, we used human–hamster hybrid（AL） cells, which are sensitive for detecting environmental mutagens. We found that the cytotoxicity and mutagenicity of the groundwater in the Jialu River basin were influenced by the infiltration of the Jialu River. Hydrological periods significantly affected the cytotoxicity, but not the mutagenic potential, of surface and groundwater. Further, the mutagenic potential of groundwater samples located 〈 1 km from the Jialu River（S（M-2） water samples） was detected earlier than that of groundwater samples located approximately 20 km from the Jialu River（SN water samples）. Because of high cytotoxicity, the mutagenic potential of water samples from the Jialu River（S（M-1） water samples） was not significantly enhanced compared with that of untreated controls. To further assess the mutagenic dispersion potential, an artificial neural network model was adopted. The results showed that the highest mutagenic potential of groundwater was observed approximately 10 km from the Jialu River. Although further investigation of mutagenic spatial dispersion is required, our data are significant for advancing our understanding of the origin, dispersion,and biological effects of water samples from polluted areas.
基金Supported by National Natural Science Foundation of China(41661062)Shaanxi Provincial Science and Technology Research and Development Plan Project(2014KJXX-21)Shaanxi Provincial Natural Science Fund Project(2014jm5126)
文摘In order to explore the spatial distribution and variation characteristics of soil moisture in coal mining subsidence area in Mu Us sandy Land,and provide theoretical basis for the restoration of the mining area,experiments based on a linear sampling and classic statistical and geostatistical methods were conducted. Spatial distribution characteristics and variation of soil moisture in the typical 0 to 100 cm dune area in the subsidence area and the non-subsidence area( control) were studied. The results showed that in the typical sand dune location of nonsubsidence area( control),the probability distribution curves of soil moisture changes in all layers along vertical and horizontal directions were all normal distribution,and it was consistent with the temporal and spatial variation characteristics of soil moisture in conventional dunes in Mu Us sandy land. By contrast,two years after the coal mine collapsed,the variations of soil moisture in different layers along vertical and horizontal directions were different,and soil moisture loss was more serious than that of control dune by nearly 10% to 30%,and the standard deviation varied from 0. 54 to 1. 05,increasing by 52. 08% compared with the non-subsidence area( control). The probability of positive and negative deviation greater than 1 was over 50%,and the coefficient of variation varied from 0. 14 to 0. 28,which was 80% higher than that of nonsubsidence area( control). After collapsing,the average level of soil moisture,standard deviation,variance and variation coefficient had greatly changed,and influence of coal mining subsidence on soil moisture was the most in the middle layer( 30-70 cm),and was not obvious in the surface( 0-20 cm) and lower layer( 80-100 cm). In coal mining subsidence area,the dispersion degree of soil moisture in different layers along the vertical and horizontal direction was greatly improved,which increased spatial variation of soil moisture.
基金supported by the Strategic Leading Science&Technology Program(B)(No.XDB14030502)the National Natural Science Foundation of China grants(Nos.21677147,91743106,21507002,21507136 and 21607157)+3 种基金the Major/Innovative Program of Development Foundation of Hefei Center for Physical Science and Technology(No.2017FXZY005)the CASHIPS Director’s Fund(No.YZJJ201704)the China Postdoctoral Science Foundation(No.2016M600477)the Anhui Province Postdoctoral Science Foundation(No.2017B161)
文摘Titanium dioxide nanoparticles (TiO2 NPs) are subjected to various transformation processes (chemical,physical and biological processes) in the environment,potentially affecting their bioavailability and toxic properties.However,the size variation of TiO2 NPs during aging process and subsequent effects in mammalian cells are largely unknown.The aim of this study was to illustrate the adverse effects of TiO2 NPs in different sizes (5,15 and <100 nm) during aging process on human-hamster hybrid (AL) cells.There was an aging-time dependent enhancement of average hydrodynamic size in TiO2 NPs stock suspensions.The cytotoxicity of fresh TiO2 NPs increased in a size-dependent manner;in contrast,their genotoxicity decreased with the increasing sizes of NPs.No significant toxicity difference was observed in cells exposed to either fresh or 60 day-aged TiO2 NPs.Both Fresh and aged TiO2 NPs efficiently induced mitochondrial dysfunction and activated Caspase-3/7 in a size-dependent manner.Using mitochondrial-DNA deficient (ρ°) AL cells,we further discovered that mitochondrial dysfunction made significant contribution to the size-dependent toxicity induced by TiO2 NPs during the aging process.Taken together,our data indicated that TiO2 NPs could significantly induced the cytotoxicity and genotoxicity in an aging time-independent and size-dependent manner,which were triggered by mitochondrial dysfunction.Our study suggested the necessity to include size as an additional parameter for the cautious monitoring of TiO2 NPs disposal before entering the environment.
基金supported by the National Natural Science Foundationof China(NSFC,Nos.21971007,21521005,51902012)Beijing Natural Science Foundation(No.2212044)the Fundamental Research Funds for the Central Universities(Nos.XK1802-6,XK1803-05)。
文摘For more than a decade,the exfoliation of graphene and other layered materials has led to a tremendous amount of research in two-dimensional(2D)materials,among which 2D transition metal chalcogenides(TMCs)nanomaterials have attracted much attention in a wide range of applications including photoelectric devices,lithium-ion batteries,catalysis,and energy conversion and storage owing to their unique photoelectric physical properties.With such large specific surface area,strong near-infrared(NIR)absorption and abundant chemical element composition,2D TMCs nanomaterials have become good candidates in biomedical imaging and cancer treatment.This review systematically summarizes recent progress on 2D TMCs nanomaterials,which includes their synthesis methods and applications in cancer treatment.At the end of this review,we also highlight the future prospects and challenges of 2D TMCs nanomaterials.It is expected that this work can provide the readers with a detailed overview of the synthesis of 2D TMCs and inspire more novel functional biomaterials based on 2D TMCs for cancer treatment in the future.
基金Key R&D Program of Shaanxi Province(2018ZDXM-GY-030)National Natural Science Foundation of China(41661062)Forestry Intellectual Property Transformation and Application Project of National Forestry and Grassland Administration of China(Zhi Zhuan 2017-7).
文摘[Objectives]To explore the problem of"secondary desertification"caused by coal mining subsidence in sandy area and its control countermeasures.[Methods]The collapse fissure changes,vegetation displacement and tilt,dry sand layer and wind erosion/aeolian deposit rate of the edge,middle and basin of subsidence area were studied in detail.[Results]The width and density of fissures at the edge of subsidence area were the smallest,followed by those in the center,and the width and density of fissures in the basin of the subsidence area were the greatest,while the staggering and surface damage showed the opposite trend.The average displacement length of vegetation in the subsidence area reached 60 cm,the slope was 5.67-28.63,and the maximum wind erosion/aeolian deposit at the trunk roots was-30.52 cm/+25.41 cm,most serious at the edge of subsidence.The changes in displacement length and slope of vegetation were positively linearly correlated with the height and surface damage of collapse fissures.The thickness of dry land layer at the edge of the subsidence area reached 14 cm,4-6 cm greater than that of the control,and the thickness of dry land layer in the middle and basin of the subsidence area was both about 11 cm,1-4 cm greater than that of non-subsidence area.The wind erosion rate at the edge of the subsidence area was up to 83.34%,followed by that(52.06%)in the middle.The aeolian deposit rate in the subsidence basin was 51.84%.[Conclusions]The subsidence edge has the strongest impact on the sandy geomorphology and vegetation habitat,and is a key area for ecological restoration.It is recommended that the coal mining subsidence should be treated in a timely manner to avoid the occurrence of"secondary desertification".
基金supported by the“Leading Goose”R&D Program of Zhejiang Province(2023C03045)National Key Research and Development Program of China(2022YFC2305200,2021YFC2301502)+2 种基金Prevention and Control of Emerging and Major Infectious Diseases-National Science and Technology Major Project(2025ZD01904000)Shanghai Science and Technology Innovation Action Plan(23JS1401500)Self-supporting Program of Guangzhou Laboratory SRPG22-007,R&D Program of Guangzhou National Laboratory(GZNL2024A01002).
文摘The relentless emergence of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variants continues to challenge global health,as high mutation rates and complex pathogenicity obscure molecular mechanisms and impede clinical progress.Despite extensive research across viral evolution,structural biology,immunology,diagnostics,and therapeutics,the resulting vast and rapidly outdated literature has widened the gap between fundamental discovery and medical application.Here,we systematically mined 439,724 coronavirus disease 2019(COVID-19)publications using fine-tuned large language models to extract and distill knowledge across nine domains:antibodies,vaccines,serology,biochemistry,therapeutics,clinical presentation,risk factors,biomarkers,and diagnostics.These insights were integrated into a unified graph of 1,427,596 triples(CoVAR-KG).Covering 90%of known spike-protein variant sites,our knowledge graph forges molecular-to-clinical links that reveal how specific mutations influence antigenicity,transmissibility,and treatment response.By resolving data fragmentation,this resource accelerates target identification and streamlines hypothesis generation.Building on CoVAR-KG,we developed COVID-19 variant risk watcher(CVRW),an early-warning framework that quantifies the threat of emerging variants for real-time surveillance.Coupling the graph with retrieval-augmented GPT-4o enables rapid and in-depth comparisons of variant functionality and immune escape potential.These integrative tools furnish timely insights for vaccine design,therapeutic optimization,and pandemic preparedness,establishing a versatile platform for combating current and future viral threats.
文摘Over the last decade,significant progress has been made in understanding the evolutionary,ecological,and metabolic significance of the gut microbiota for human health.This significant progress owes a considerable debt to the con-secutive publication of two seminal research papers origi-nating from pivotal research initiatives:METAgenomics of the Human Intestinal Tract(MetaHIT)(Qin et al.2010)and Human Microbiome Project(HMP)(Human Microbiome Project 2012).
文摘Understanding the mechanisms of drug resistance inMycobacterium tuberculosis(MTB)is essential for the rapid detection of resistance and for guiding effective treatment,ultimately contributing to reducing the global burden of tuberculosis(TB).Under anti-TB drugs pressure,MTB continues to accumulate resistance loci.The current repertoire of known resistance-associated mutations requires further refinement,necessitating efficient methods for the timely identification of potential resistance sites.Here,we introduce xAI-MTBDR,an explainable artificial intelligence framework designed to identify potential resistance-associated mutations and predict drug resistance in MTB.It outperforms state-of-the-art methods in predicting drug resistance for all first-line drugs,and scoring each mutation’s contribution to resistance.By leveraging public whole-genome sequencing data from nearly 40,000 MTB isolates,the framework identified 788 candidate resistance-related mutations and revealed 27 potential resistance markers,several of which are positioned closer to their respective drugs in protein structures than known resistance mutations,suggesting a potentially more direct role in mediating resistance.Furthermore,these scores enabled the framework to efficiently subgroup isolates with different resistance mechanisms and reflect varying levels of resistance.The framework serves as a valuable tool for accurate detection of drug-resistant MTB and offers new insights into its underlying mechanisms.
基金supported by the National Key R&D Program of China(2021YFA1301000)the Shanghai Municipal Science and Technology Major Project(Grant No.2023SHZDZX02).
文摘In gut microbial research,DNA extraction remarkably influences study outcomes and biological interpretations.Rapid advancements in the research scale and technological upgrades necessitate evaluating new methods to ensure reliability and precision in microbial community profiling.We systematically evaluated the performance of eight recent and commonly used extraction methods using a microbial mock community(MMC)and fecal samples from two healthy volunteers,incorporating bacterial,archaeal,and fungal constituents.Performance metrics included nucleic acid assessment,microbial profile assess-ment,and scalability for large-scale studies,leveraging shotgun metagenomics for in-depth analysis.Despite variations in DNA quantity and quality,all methods yielded sufficient DNA for shotgun metagenomic sequencing.In the MMC microbial profile assessment,the QIAamp PowerFecal pro Kit(PF)and DNeasy PowerSoil HTP kit(PS)methods exhibited higher similarity with the theoretical composition and lower variability across technical replicates compared to other methods.For fecal samples,the extraction method accounted for 21.4%of the overall microbiome variation and significantly affected the abundances of 32%of detected microbial species.Methods using mechanical lysis with small beads,such as PF and PS,demonstrated better efficiency,indicated by increased microbial diversity in extracting DNA from Gram-positive bacteria.Furthermore,the PF and PS methods are notably simple to execute and automation-friendly,though relatively costly.Our study underscores the importance of maintaining consistency in DNA extraction methods for reliable comparative metagen-omic analyses.We recommend PF and PS methods as optimal for expansive gut metagenomic research,emphasizing the critical role of mechanical lysis in DNA extraction.
基金supported by the National Key Research and Development Program of China(2020YFA0908300)the National Natural Science Foundation of China(32371497)the Tianjin Synthetic Biotechnology Innovation Capacity Improvement Project(TSBICIP-KJGG-021).
文摘The increasing consumption of fossil fuels is contributing to global resource depletion and environmental pollution.Branched-chain higher alcohols,such as isopentanol and isobutanol,have attracted significant attention as next-generation biofuels.Biofuel production through microbial fermentation offers a green,sustainable,and renewable alternative to chemical synthesis.While enhanced production of isopentanol has been achieved in a variety of chassis,the fermentation yield has not yet reached levels suitable for industrial-scale production.In this study,we employed a continuous perturbation tool to construct a genome-scale perturbation library,combined with an isopentanol biosensor to screen for high-yielding mutants.We identified five highyielding mutants,each exhibiting an increased glucose conversion rate and isopentanol titer.The F2 strain,in particular,achieved an isopentanol titer of 1.57±0.014 g/L and a yield of 14.04±0.251 mg/g glucose(10%glucose),surpassing the highest values reported to date in engineered Saccharomyces cerevisiae.Systematic transcriptome analysis of the isopentanol synthesis,glycolysis,glycerol metabolism,and ethanol synthesis pathways revealed that MPC,OAC1,BAT2,GUT2,PDC6,and ALD4 are linked to efficient isopentanol production.Further analysis of differentially expressed genes(DEGs)identified 17 and 12 co-expressed DEGs(co-DEGs)in all mutants and the two second-round mutants,respectively.In addition,we validated the knockout or overexpression of key co-DEGs.Our results confirmed the critical roles of HOM3 and DIP5 in isopentanol production,along with genes associated with the aerobic respiratory chain(SDH3,CYT1,COX7,ROX1,and ATG41)and cofactor balance(BNA2 and NDE1).Additionally,functional analysis of the co-DEGs revealed that MAL33 is associated with the synthesis of branched-chain higher alcohols,expanding the intracellular metabolic network and offering new possibilities for green,cost-effective biofuel production.
文摘Ginsenosides, the main pharmacologically active natural compounds in ginseng （Panax ginseng）, are mostly the glycosylated products of protopanaxadiol （PPD） and protopanaxatriol （PPT）. No uridine diphosphate glycosyltransferase （UGT）, which catalyzes PPT to produce PPT-type ginsenosides, has yet been reported. Here, we show that UGTPgl, which has been demonstrated to regio-specifically glycosylate the C20-OH of PPD, also specifically glycosylates the C20-OH of PPT to produce bioactive ginsenoside FI. We report the characterization of four novel UGT genes isolated from P. ginseng, sharing high deduced amino acid identity （〉84%） with UGTPgl. We demonstrate that UGTPgl00 specifically glycosylates the C6-OH of PPT to produce bioactive ginsenoside Rhl, and UGTPgl01 catalyzes PPT to produce F1, followed by the generation of ginsenoside Rgl from FI. However, UGTPgl02 and UGTPgl03 were found to have no detectable activity on PPT. Through structural modeling and site-directed mutagenesis, we identified several key amino acids of these UGTs that may play important roles in determining their activities and substrate regio-specificities. Moreover, we constructed yeast recombinants to biosynthesize F1 and Rhl by introducing the genetically engineered PPT-producing pathway and UGTPgl or UGTPgl00. Our study reveals the possible biosynthetic pathways of PPT-type ginsenosides in Panax plants, and provides a sound manufacturing approach for bioactive PPT-type ginsenosides in yeast via synthetic biology strategies.
基金supported by the National Natural Science Foundation of China (Grant No. 81671362)the National Natural Science Foundation of China (Grant No. 31471202)+4 种基金the Medical and Health Science and Technology Development Projects of Shandong Province (Grant No. 2015WSA01023)Shandong Provincial Key Research and Development Program (Grant No. 2018CXGC1219) to ZGthe Shandong Provincial Key Research and Development Program (Grant No. 2016YYSP009)the City of Weihai Technique Extension Project (Grant No. 2016GNS023) to LZsupported by the Taishan Scholars Program of Shandong Province (Grant No. tshw20120206), China
文摘Variation of maternal gut microbiota may increase the risk of autism spectrum disorders(ASDs) in offspring. Animal studies have indicated that maternal gut microbiota is related to neurodevelopmental abnormalities in mouse offspring, while it is unclear whether there is a correlation between gut microbiota of ASD children and their mothers. We examined the relationships between gut microbiome profiles of ASD children and those of their mothers, and evaluated the clinical discriminatory power of discovered bacterial biomarkers. Gut microbiome was profiled and evaluated by 16S ribosomal RNA gene sequencing in stool samples of 59 mother–child pairs of ASD children and 30 matched mother–child pairs of healthy children. Significant differences were observed in the gut microbiome composition between ASD and healthy children in our Chinese cohort. Several unique bacterial biomarkers, such as Alcaligenaceae and Acinetobacter, were identified. Mothers of ASD children had more Proteobacteria, Alphaproteobacteria, Moraxellaceae, and Acinetobacter than mothers of healthy children. There was a clear correlation between gut microbiome profiles of children and their mothers; however, children with ASD still had unique bacterial biomarkers, such as Alcaligenaceae, Enterobacteriaceae, and Clostridium. Candidate biomarkers discovered in this study had remarkable discriminatory power. The identified patterns of mother–child gut microbiome profiles may be important for assessing risks during the early stage and planning of personalized treatment and prevention of ASD via microbiota modulation.
基金supported by the Tianjin Synthetic Biotechnology Innovation Capacity Improvement Projects(TSBICIP-CXRC-008)Strategic Priority Research Program of the Chinese Academy of Sciences(XDC 0110300)+2 种基金Major Project of Haihe Laboratory of Synthetic Biology(E2M9560201)National Natural Science Foundation of China(32301210&31200035)the China Postdoctoral Science Foundation(No.2022M713330).
文摘As a powerful paradigm,artificial intelligence(AI)is rapidly impacting every aspect of our day-to-day life and scientific research through interdisciplinary transformations.Living human organoids(LOs)have a great potential for in vitro reshaping many aspects of in vivo true human organs,including organ development,disease occurrence,and drug responses.To date,AI has driven the revolutionary advances of human organoids in life science,precision medicine and pharmaceutical science in an unprecedented way.Herein,we provide a forward-looking review,the frontiers of LOs,covering the engineered construction strategies and multidisciplinary technologies for developing LOs,highlighting the cutting-edge achievements and the prospective applications of AI in LOs,particularly in biological study,disease occurrence,disease diagnosis and prediction and drug screening in preclinical assay.Moreover,we shed light on the new research trends harnessing the power of AI for LO research in the context of multidisciplinary technologies.The aim of this paper is to motivate researchers to explore organ function throughout the human life cycle,narrow the gap between in vitro microphysiological models and the real human body,accurately predict human-related responses to external stimuli(cues and drugs),accelerate the preclinical-to-clinical transformation,and ultimately enhance the health and well-being of patients.
基金supported by the National Key Research and Development Program of China(Grant No.2018YFA0900700)the Drug Innovation Major Project(2018ZX09711001-006-002)+3 种基金the National Natural Science Foundation of China(Nos.31901021,31921006,and 32071425)the Strategic Priority Research Program of the Chinese Academy of Sciences(Grant No.XDB27020206)the Strategic Biological Resources Service Network Plan of the Chinese Academy of Sciences(Grant No.KFJ-BRP-009)the National Key Research and Development Program of Yunnan Province(2019ZF011-1).
文摘Ginsenoside Compound K(CK)has been recognized as a major functional component that is absorbed into the systemic circulation after oral administration of ginseng.CK demonstrates diverse bioactivities.A phase I clinical study indicated that CK was a potential candidate for arthritis therapy.However,a phase II clinical study was suspended because of the high cost associated with the present CK manufacturing approach,which is based on the traditional planting-extracting-biotransforming process.We previously elucidated the complete CK biosynthetic pathway and realized for the first time de novo biosynthesis of CK from glucose by engineered yeast.However,CK production was not sufficient for industrial application.Here,we systematically engineered Saccharomyces cerevisiae to achieve high titer production of CK from glucose using a previously constructed protopanaxadiol(PPD)-producing chassis,optimizing UGTPg1 expression,improving UDP-glucose biosynthesis,and tuning down UDP-glucose consumption.Our final engineered yeast strain produced CK with a titer of 5.74 g/L in fed-batch fermentation,which represents the highest CK production in microbes reported to date.Once scaled-up,this high titer de novo microbial biosynthesis platform will enable a robust and stable supply of CK,thus facilitating study and medical application of CK.
