Traditional Chinese medicine(TCM)has shown remarkable potential for treating liver fibrosis.In this study,to identify novel TCMs with antifibrotic properties,we used a technique called high-throughput sequencing-based...Traditional Chinese medicine(TCM)has shown remarkable potential for treating liver fibrosis.In this study,to identify novel TCMs with antifibrotic properties,we used a technique called high-throughput sequencing-based high-throughput screening(HTS2),which is based on RNA-mediated oligonucleotide annealing,selection,and ligation followed by sequencing.This technology achieved parallel and quantitative analysis of gene expression in response to thousands of drug treatments[1].展开更多
科学数据银行(Science Data Bank)于2022年4月18日正式发布共享社会经济路径(SSPs)人口和经济格点化数据库(gridded datasets for population and economy under Shared Socioeconomic Pathways)。该数据集是在多个国际和国内项目支持下...科学数据银行(Science Data Bank)于2022年4月18日正式发布共享社会经济路径(SSPs)人口和经济格点化数据库(gridded datasets for population and economy under Shared Socioeconomic Pathways)。该数据集是在多个国际和国内项目支持下,经过十余年的研究和探索制作而成。数据集包含SSP1~SSP5情景下2020-2100年全球、“一带一路”沿线国家和中国城市和农村的人口和GDP逐年格点预估数据,分辨率为0.5°×0.5°。展开更多
Objective:To evaluate the efficacy and safety of QL1206(a denosumab biosimilar to Xgeva■)in breast cancer patients with bone metastasis(BM)through subgroup analysis of a randomized,double-blind phaseⅢtrial(No.NCT045...Objective:To evaluate the efficacy and safety of QL1206(a denosumab biosimilar to Xgeva■)in breast cancer patients with bone metastasis(BM)through subgroup analysis of a randomized,double-blind phaseⅢtrial(No.NCT04550949).Methods:This subgroup analysis included patients with BM from breast cancer enrolled in a phaseⅢtrial.Patients were randomized(1:1)to receive either three cycles of QL1206 or denosumab(120 mg subcutaneously every 4 weeks).Subsequently,they received 10 cycles of QL1206(120 mg)over 40 weeks,followed by a 20-week safety follow-up.The primary endpoint was the percentage changes from baseline to week 13 in urinary Ntelopeptide corrected for creatinine(u NTx/Cr).Results:The breast cancer cohort consisted of 311 patients.Vertebral involvement(66.4%)was the most prevalent BM site at enrollment,while 27.7%of patients presented with≥3 metastatic bone lesions.At week 13,QL1206 demonstrated a median u NTx/Cr reduction of-69.9%(range:-98.1%-568.0%)vs.-74.3%(range:-97.7%-386.3%)for denosumab.The analysis of covariance revealed comparable least-square means for log-transformed changes:-1.416[95%confidence interval(95%CI):-1.736 to-1.096]vs.-1.501(95%CI:-1.824 to-1.178),yielding an between-group difference of 0.085(90%CI:-0.062-0.232;P=0.343).After a 53-week treatment period,83.6%achieved bone density improvement/disease stabilization.Safety profiles were comparable between groups.Conclusions:QL1206 demonstrated similar efficacy and safety to the reference denosumab in patients with BM from breast cancer,supporting QL1206 as a new option for management of BM from breast cancer.展开更多
Identification of natural substances with antioxidant properties is ongoing research for addressing issues related to oxidative stress especially attributed to environmental effects.Our previous study demonstrated tha...Identification of natural substances with antioxidant properties is ongoing research for addressing issues related to oxidative stress especially attributed to environmental effects.Our previous study demonstrated that Lateolabrax japonicus peptides(LPH),rich in Glu,Gly,and hydrophobic amino acids,exhibited remarkable antioxidant activity in vitro,with though its action mechanism yet to be revealed.Therefore,to assess the in vivo antioxidative properties of LPH,we employed H_(2)O_(2) to generate oxidative stress in Drosophila melanogaster model.Results indicated that LPH significantly prolonged the lifespan of Drosophila subjected to oxidative stress mostly mediated via LPH’s enhancement of the antioxidant defense system and intestinal functions.Antioxidant effects were manifested by a decrease in malondialdehyde(MDA)levels,elevated superoxide dismutase(SOD),catalase(CAT),and glutathione peroxidase(GSH-Px)activities,decreased levels of reactive oxygen species(ROS)in intestinal epithelial cells,and the preservation of intestinal length.LPH effectively controlled the excessive proliferation and differentiation of oxidative stress-induced Drosophila intestinal stem cells.At the gene level,LPH upregulated the expression of antioxidant-related Nrf2 genes while concurrently downregulated mTOR expression level.Furthermore,high-throughput 16S rDNA sequencing revealed that the addition of LPH significantly influenced the diversity and abundance of the intestinal microbiota in H_(2)O_(2)-induced Drosophila.These findings provide a deeper understanding of the antioxidative mechanism of LPH,suggesting its potential applications in food industry and to be assessed using other in vivo oxidative stress models.展开更多
BACKGROUND Current drugs primarily target inflammation control but do not reverse tissue remodeling changes for asthma.Human mesenchymal stem cells are known for their anti-inflammatory and tissue remodeling capabilit...BACKGROUND Current drugs primarily target inflammation control but do not reverse tissue remodeling changes for asthma.Human mesenchymal stem cells are known for their anti-inflammatory and tissue remodeling capabilities.However,limited research has explored the therapeutic impact of varying doses and frequencies of human umbilical cord blood-derived mesenchymal stem cells(HUC-MSCs)on established airway remodeling in experimental asthma.AIM To explore and optimize the dosage and administration frequency of HUC-MSCs in experimental models of ovalbumin(OVA)-induced asthma.METHODS BALB/c mice underwent sensitization and were challenged using OVA.Control animals were administered a saline solution following the same protocol.HUC-MSCs were identified using flow cytometry.HUC-MSCs at incremental dosages(1×105,2×105,4×105)were injected via tail veins on day 30(the second after the final stimulation).After comparing each group and determining the optimal dose,supplement the optimal dose twice on day 30 and day 33(the second and fifth day after the final stimulation).Bronchoalveolar lavage fluid(BALF)and serum were harvested for analysis of concentrations of interleukin-4(IL-4),IL-13,immunoglobulin E and interferon-gamma(IFN-γ)by enzyme-linked immunosorbent assay.Pharmacology of airways and lung functions were also evaluated to identify the optimal group.RESULTS The study shows that HUC-MSC transplantation ameliorates OVA-induced asthma by significantly reducing airway inflammation and obstruction in preclinical models.This effect is associated with decreased Th2 cytokines IL-4 and IL-13,and increased Th1 cytokine IFN-γ.The optimal dose of 2×105 cells/mouse was identified as the most effective in reducing local asthmatic airway inflammation and changing levels of IL-4,IL-13,and IFN-γin serum and BALF compared to other single doses of HUC-MSC.Multiple treatments with the medium dose(2×105 cells)of HUC-MSCs on days 30 and 33 yield the best pathological and lung function outcomes.However,double treatments do not reduce IL-4 and IL-13 expression or enhance IFN-γproduction in serum or BALF more effectively than a single medium dose.CONCLUSION HUC-MSCs effectively regulate pro-inflammatory mediators in serum and BALF,modulating airway remodeling and lung function.In this acute mouse asthma model,a single dosage of 2×105 is optimal,with more significant effects of decreasing airway obstruction requiring repeated administration.展开更多
Multiple nucleotide variants(MNVs)are frequently misannotated as separate single-nucleotide variants(SNVs)by widely utilized variant-calling pipelines,presenting substantial challenges in genetic testing and research....Multiple nucleotide variants(MNVs)are frequently misannotated as separate single-nucleotide variants(SNVs)by widely utilized variant-calling pipelines,presenting substantial challenges in genetic testing and research.The role of MNVs in genetic diagnosis remains inadequately characterized,particularly within large disease cohorts.In this study,we comprehensively investigate codon-level MNVs(cMNVs)across 157 hearing loss(HL)-related genes in 11,467 HL cases and 7258 controls from the Chinese Deafness Gene Consortium(CDGC)cohort.A total of 116 cMNVs are identified,occurring in 29.07%of HL cases.Among them,56.03%of cMNVs exhibit functional consequences distinct from constituent SNVs.Moreover,amino acid substitutions exclusive to cMNVs cause more substantial physicochemical disruptions than those associated with SNVs.Notably,51 cMNVs show pathogenicity classifications that diverge from at least one constituent SNV,impacting genetic interpretation in 145 cases.Pathogenicity interpretation of cMNV facilitates definitive genetic diagnoses in eight HL cases that would otherwise have been subject to misdiagnoses or missed diagnoses.These findings provide critical insights into the genomic characteristics,functional impacts,and diagnostic implications of cMNVs,underscoring their clinical significance in genetic diagnosis and emphasizing the necessity for comprehensive and accurate detection and interpretation of cMNVs in genetic testing and research.展开更多
The reconstruction of demographic history using ancient and modern genomic resources reveals extensive interactions and admixture between ancient nomadic pastoralists and the social organizations of the Chinese Centra...The reconstruction of demographic history using ancient and modern genomic resources reveals extensive interactions and admixture between ancient nomadic pastoralists and the social organizations of the Chinese Central Plain.However,the extent to which Y-chromosome genetic legacies from nomadic emperor-related ancestral lineages influence the Chinese paternal gene pool remains unclear.Here,we genotype 2717 ethnolinguistically diverse samples belonging to C2a lineages,perform whole-genome sequencing on 997 representative samples,and integrate these data with ancient genomic sequences.We reconstruct the evolutionary histories of Northern Zhou-,Qing emperor-,and pastoralist-related lineages to assess their genetic impact on modern Chinese populations.This reassembled fine-scale Ychromosome phylogeny identifies deep divergence and five Neolithic expansion events contributing differently to the formation of northern Chinese populations.Phylogeographic modeling indicates that the nomadic empires of the Northern Zhou and Qing dynasties genetically originated from the Mongolian Plateau.Phylogenetic topology and shared haplotype patterns show that three upstream ancestors of Northern Zhou(C2a1a1b1a2a1b-FGC28857),Donghu tribe(C2a1a1b1-F1756),and Qing(C2a1a3a2-F10283)emperor-related lineages expanded during the middle Neolithic,contributing significantly to genetic flow between ancient northeastern Asians and modern East Asians.Notably,this study reveals limited direct contributions of Emperor Wu of Northern Zhou’s lineages to modern East Asians.展开更多
High-power laser melting deposition stands as a viable solution for the high-quality and efficient manufacturing of large-sized titani-um alloy components.This article explores how laser influences the quality of depo...High-power laser melting deposition stands as a viable solution for the high-quality and efficient manufacturing of large-sized titani-um alloy components.This article explores how laser influences the quality of deposited layers when operating within a laser power range of 3-8 kW,and a H-shaped TC4 component with half-meter high was successfully fabricated by the laser melting deposition technology with a power of 5 kW,exhibiting a well-formed surface.In addition,the microstructure and properties of deposited TC4 components were examined.The as-deposited component is mainly composed of coarse columnar crystals.However,the distribu-tion and size of grains are particularly uneven with a range of 1-5 mm in length.The deposited TC4 is made up of lots of basketweave structure and a bit Widmanstatten structures at the grain boundaries.What’s more,lath-shapedαphase and a small amount ofβphase can be found in the grain.There is no significant disparity in grain size along the height direction;however,the heat accumula-tion resulting from deposition leads to a reduced length-to-width ratio ofα-laths in the bottom region.The tensile performance of samples from the top area marginally surpasses that of the bottom,and the tensile performance in the vertical direction is marginally better than that in the horizontal direction.According to the prevailing GB/T 38915-2020 and HB 5432-89 standards,the tensile properties of the fabricated components,sampled from various regions and directions,exceed those of forgings.The direction of sampling has weak influence on impact energy;however,fatigue crack propagation experiments indicate that cracks are more pre-valent and propagate at a slightly faster rate in horizontally-oriented specimens,a phenomenon attributed to the combined effects of grain morphology and microstructure.展开更多
文摘Traditional Chinese medicine(TCM)has shown remarkable potential for treating liver fibrosis.In this study,to identify novel TCMs with antifibrotic properties,we used a technique called high-throughput sequencing-based high-throughput screening(HTS2),which is based on RNA-mediated oligonucleotide annealing,selection,and ligation followed by sequencing.This technology achieved parallel and quantitative analysis of gene expression in response to thousands of drug treatments[1].
文摘科学数据银行(Science Data Bank)于2022年4月18日正式发布共享社会经济路径(SSPs)人口和经济格点化数据库(gridded datasets for population and economy under Shared Socioeconomic Pathways)。该数据集是在多个国际和国内项目支持下,经过十余年的研究和探索制作而成。数据集包含SSP1~SSP5情景下2020-2100年全球、“一带一路”沿线国家和中国城市和农村的人口和GDP逐年格点预估数据,分辨率为0.5°×0.5°。
文摘Objective:To evaluate the efficacy and safety of QL1206(a denosumab biosimilar to Xgeva■)in breast cancer patients with bone metastasis(BM)through subgroup analysis of a randomized,double-blind phaseⅢtrial(No.NCT04550949).Methods:This subgroup analysis included patients with BM from breast cancer enrolled in a phaseⅢtrial.Patients were randomized(1:1)to receive either three cycles of QL1206 or denosumab(120 mg subcutaneously every 4 weeks).Subsequently,they received 10 cycles of QL1206(120 mg)over 40 weeks,followed by a 20-week safety follow-up.The primary endpoint was the percentage changes from baseline to week 13 in urinary Ntelopeptide corrected for creatinine(u NTx/Cr).Results:The breast cancer cohort consisted of 311 patients.Vertebral involvement(66.4%)was the most prevalent BM site at enrollment,while 27.7%of patients presented with≥3 metastatic bone lesions.At week 13,QL1206 demonstrated a median u NTx/Cr reduction of-69.9%(range:-98.1%-568.0%)vs.-74.3%(range:-97.7%-386.3%)for denosumab.The analysis of covariance revealed comparable least-square means for log-transformed changes:-1.416[95%confidence interval(95%CI):-1.736 to-1.096]vs.-1.501(95%CI:-1.824 to-1.178),yielding an between-group difference of 0.085(90%CI:-0.062-0.232;P=0.343).After a 53-week treatment period,83.6%achieved bone density improvement/disease stabilization.Safety profiles were comparable between groups.Conclusions:QL1206 demonstrated similar efficacy and safety to the reference denosumab in patients with BM from breast cancer,supporting QL1206 as a new option for management of BM from breast cancer.
基金supported by National Key R&D Program of China(2023YFD2100205)Fuzhou Science&Technology Project,China(2022-Y-0022022-P-023).
文摘Identification of natural substances with antioxidant properties is ongoing research for addressing issues related to oxidative stress especially attributed to environmental effects.Our previous study demonstrated that Lateolabrax japonicus peptides(LPH),rich in Glu,Gly,and hydrophobic amino acids,exhibited remarkable antioxidant activity in vitro,with though its action mechanism yet to be revealed.Therefore,to assess the in vivo antioxidative properties of LPH,we employed H_(2)O_(2) to generate oxidative stress in Drosophila melanogaster model.Results indicated that LPH significantly prolonged the lifespan of Drosophila subjected to oxidative stress mostly mediated via LPH’s enhancement of the antioxidant defense system and intestinal functions.Antioxidant effects were manifested by a decrease in malondialdehyde(MDA)levels,elevated superoxide dismutase(SOD),catalase(CAT),and glutathione peroxidase(GSH-Px)activities,decreased levels of reactive oxygen species(ROS)in intestinal epithelial cells,and the preservation of intestinal length.LPH effectively controlled the excessive proliferation and differentiation of oxidative stress-induced Drosophila intestinal stem cells.At the gene level,LPH upregulated the expression of antioxidant-related Nrf2 genes while concurrently downregulated mTOR expression level.Furthermore,high-throughput 16S rDNA sequencing revealed that the addition of LPH significantly influenced the diversity and abundance of the intestinal microbiota in H_(2)O_(2)-induced Drosophila.These findings provide a deeper understanding of the antioxidative mechanism of LPH,suggesting its potential applications in food industry and to be assessed using other in vivo oxidative stress models.
基金Supported by the Joint Innovation Project Funds of Huaqiao University,No.2022YX001。
文摘BACKGROUND Current drugs primarily target inflammation control but do not reverse tissue remodeling changes for asthma.Human mesenchymal stem cells are known for their anti-inflammatory and tissue remodeling capabilities.However,limited research has explored the therapeutic impact of varying doses and frequencies of human umbilical cord blood-derived mesenchymal stem cells(HUC-MSCs)on established airway remodeling in experimental asthma.AIM To explore and optimize the dosage and administration frequency of HUC-MSCs in experimental models of ovalbumin(OVA)-induced asthma.METHODS BALB/c mice underwent sensitization and were challenged using OVA.Control animals were administered a saline solution following the same protocol.HUC-MSCs were identified using flow cytometry.HUC-MSCs at incremental dosages(1×105,2×105,4×105)were injected via tail veins on day 30(the second after the final stimulation).After comparing each group and determining the optimal dose,supplement the optimal dose twice on day 30 and day 33(the second and fifth day after the final stimulation).Bronchoalveolar lavage fluid(BALF)and serum were harvested for analysis of concentrations of interleukin-4(IL-4),IL-13,immunoglobulin E and interferon-gamma(IFN-γ)by enzyme-linked immunosorbent assay.Pharmacology of airways and lung functions were also evaluated to identify the optimal group.RESULTS The study shows that HUC-MSC transplantation ameliorates OVA-induced asthma by significantly reducing airway inflammation and obstruction in preclinical models.This effect is associated with decreased Th2 cytokines IL-4 and IL-13,and increased Th1 cytokine IFN-γ.The optimal dose of 2×105 cells/mouse was identified as the most effective in reducing local asthmatic airway inflammation and changing levels of IL-4,IL-13,and IFN-γin serum and BALF compared to other single doses of HUC-MSC.Multiple treatments with the medium dose(2×105 cells)of HUC-MSCs on days 30 and 33 yield the best pathological and lung function outcomes.However,double treatments do not reduce IL-4 and IL-13 expression or enhance IFN-γproduction in serum or BALF more effectively than a single medium dose.CONCLUSION HUC-MSCs effectively regulate pro-inflammatory mediators in serum and BALF,modulating airway remodeling and lung function.In this acute mouse asthma model,a single dosage of 2×105 is optimal,with more significant effects of decreasing airway obstruction requiring repeated administration.
基金supported by the Key Project of the National Natural Science Foundation of China(82030030)the National Natural Science Foundation of China(82171836)+1 种基金the Science and Technology Department of Sichuan Province(2024NSFSC0648)the 1·3·5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYJC20002).
文摘Multiple nucleotide variants(MNVs)are frequently misannotated as separate single-nucleotide variants(SNVs)by widely utilized variant-calling pipelines,presenting substantial challenges in genetic testing and research.The role of MNVs in genetic diagnosis remains inadequately characterized,particularly within large disease cohorts.In this study,we comprehensively investigate codon-level MNVs(cMNVs)across 157 hearing loss(HL)-related genes in 11,467 HL cases and 7258 controls from the Chinese Deafness Gene Consortium(CDGC)cohort.A total of 116 cMNVs are identified,occurring in 29.07%of HL cases.Among them,56.03%of cMNVs exhibit functional consequences distinct from constituent SNVs.Moreover,amino acid substitutions exclusive to cMNVs cause more substantial physicochemical disruptions than those associated with SNVs.Notably,51 cMNVs show pathogenicity classifications that diverge from at least one constituent SNV,impacting genetic interpretation in 145 cases.Pathogenicity interpretation of cMNV facilitates definitive genetic diagnoses in eight HL cases that would otherwise have been subject to misdiagnoses or missed diagnoses.These findings provide critical insights into the genomic characteristics,functional impacts,and diagnostic implications of cMNVs,underscoring their clinical significance in genetic diagnosis and emphasizing the necessity for comprehensive and accurate detection and interpretation of cMNVs in genetic testing and research.
基金the financial support received from the National Natural Science Foundation of China(82202078)the National Social Science Foundation of China(23&ZD203)+4 种基金support for G.H.includes National Natural Science Foundation of China(82402203)the Open Project of the Key Laboratory of Forensic Genetics of the Ministry of Public Security(2022FGKFKT05)the Center for Archaeological Science of Sichuan University(23SASA01)the 1‧3‧5 Project for Disciplines of Excellence at West China Hospital,Sichuan University(ZYJC20002)the Sichuan Science and Technology Program(2024NSFSC1518).
文摘The reconstruction of demographic history using ancient and modern genomic resources reveals extensive interactions and admixture between ancient nomadic pastoralists and the social organizations of the Chinese Central Plain.However,the extent to which Y-chromosome genetic legacies from nomadic emperor-related ancestral lineages influence the Chinese paternal gene pool remains unclear.Here,we genotype 2717 ethnolinguistically diverse samples belonging to C2a lineages,perform whole-genome sequencing on 997 representative samples,and integrate these data with ancient genomic sequences.We reconstruct the evolutionary histories of Northern Zhou-,Qing emperor-,and pastoralist-related lineages to assess their genetic impact on modern Chinese populations.This reassembled fine-scale Ychromosome phylogeny identifies deep divergence and five Neolithic expansion events contributing differently to the formation of northern Chinese populations.Phylogeographic modeling indicates that the nomadic empires of the Northern Zhou and Qing dynasties genetically originated from the Mongolian Plateau.Phylogenetic topology and shared haplotype patterns show that three upstream ancestors of Northern Zhou(C2a1a1b1a2a1b-FGC28857),Donghu tribe(C2a1a1b1-F1756),and Qing(C2a1a3a2-F10283)emperor-related lineages expanded during the middle Neolithic,contributing significantly to genetic flow between ancient northeastern Asians and modern East Asians.Notably,this study reveals limited direct contributions of Emperor Wu of Northern Zhou’s lineages to modern East Asians.
基金supported by National Key Research and Development Program Project(2022YFB4602300)National Natural Science Foundation Sponsored Project(52205419)Major Science and Technology Projects in Sichuan Province(2023ZDZX0003).
文摘High-power laser melting deposition stands as a viable solution for the high-quality and efficient manufacturing of large-sized titani-um alloy components.This article explores how laser influences the quality of deposited layers when operating within a laser power range of 3-8 kW,and a H-shaped TC4 component with half-meter high was successfully fabricated by the laser melting deposition technology with a power of 5 kW,exhibiting a well-formed surface.In addition,the microstructure and properties of deposited TC4 components were examined.The as-deposited component is mainly composed of coarse columnar crystals.However,the distribu-tion and size of grains are particularly uneven with a range of 1-5 mm in length.The deposited TC4 is made up of lots of basketweave structure and a bit Widmanstatten structures at the grain boundaries.What’s more,lath-shapedαphase and a small amount ofβphase can be found in the grain.There is no significant disparity in grain size along the height direction;however,the heat accumula-tion resulting from deposition leads to a reduced length-to-width ratio ofα-laths in the bottom region.The tensile performance of samples from the top area marginally surpasses that of the bottom,and the tensile performance in the vertical direction is marginally better than that in the horizontal direction.According to the prevailing GB/T 38915-2020 and HB 5432-89 standards,the tensile properties of the fabricated components,sampled from various regions and directions,exceed those of forgings.The direction of sampling has weak influence on impact energy;however,fatigue crack propagation experiments indicate that cracks are more pre-valent and propagate at a slightly faster rate in horizontally-oriented specimens,a phenomenon attributed to the combined effects of grain morphology and microstructure.
