BACKGROUND ATP-binding cassette subfamily B member 4(ABCB4)deficiency is associated with cholestatic liver disease primarily because of missense mutations,and many variants remain unidentified.Here,we validate the pat...BACKGROUND ATP-binding cassette subfamily B member 4(ABCB4)deficiency is associated with cholestatic liver disease primarily because of missense mutations,and many variants remain unidentified.Here,we validate the pathogenicity and mechanism of ABCB4 variants in clinical and in vitro trials,hypothesizing that these variants are responsible for impaired biliary function and contribute to the development of cholestatic liver diseases.AIM To clarify the functional features and pathogenicity of ABCB4 variants.METHODS Clinical data were collected from five patients with cholestatic liver disease that was initially not detected by routine examinations.Later,whole-exome sequencing confirmed ABCB4 variants and the patients were treated from January 2017 to December 2023.Pathogenic mechanisms were analyzed using bioinformatics tools,and a cell model in vitro was established to investigate ABCB4 mRNA expression,multidrug resistance protein 3(MDR3)expression,cellular localization,and phosphatidylcholine secretion.Results were compared using Student's t-tests.RESULTS Five missense variants(c.1757T>A,c.1865G>A,c.2362C>T,c.2777C>T and c.3250C>T),one intron variant(c.537-32G>T),and one synonymous(c.C504T)variant were identified.Three of the five patients had various degrees of cholestasis,two presented with liver cirrhosis,and all had elevated gamma-glutamyl transferase.Three of the four patients who underwent a liver biopsy had bile duct dilation,and one had gallstones.Two of the four patients had normal and reduced MDR3 immunohistochemical levels.Bioinformatic analysis indicated that these variants were likely pathogenic except c.C504T variant.None of the missense variants influenced subcellular MDR3 Localization in vitro.However,the c.1865G>A variant significantly decreased ABCB4 mRNA values,and all missense variants down-regulated phosphatidylcholine secretion.CONCLUSION This study uncovered new ABCB4 variants and emphasized the pathogenic potential of specific variants.The findings from five patients provided insight into the pathogenic mechanisms underlying ABCB4-related diseases.展开更多
Toll-like receptor （TLR）-mediated inflammatory response could negatively affect bone metabolism. In this study, we determined how osteogenesis is regulated during inflammatory responses that are downstream of TLR si...Toll-like receptor （TLR）-mediated inflammatory response could negatively affect bone metabolism. In this study, we determined how osteogenesis is regulated during inflammatory responses that are downstream of TLR signaling. Human primary osteoblasts were cultured in collagen gels. Pam3CSK4 （P3C） and Escherichia coli lipopolysaccharide （EcLPS） were used as TLR2 and TLR4 ligand respectively. Porphyromonas gingivalis LPS having TLR2 activity with either TLR4 agonism （Pg1690） or TLR4 antagonism （Pg1449） and mutant E. coli LPS （LPxE/LPxF/WSK） were used. IL-lp, SH2-containing inositol phosphatase-1 （SHIP1） that has regulatory roles in osteogenesis, alkaline phosphatase and mineralization were analyzed. 3α-Aminocholestane （3AC） was used to inhibit SHIP1. Our results suggest that osteoblasts stimulated by P3C, poorly induced IL-1β but strongly upregulated SHIP1 and enhanced osteogenic mediators. On the contrary, EcLPS significantly induced IL-1β and osteogenic mediators were not induced. While Pg1690 downmodulated osteogenic mediators, Pg1449 enhanced osteogenic responses, suggesting that TLR4 signaling annuls osteogenesis even with TLR2 activity. Interestingly, mutant E. coli LPS that induces weak inflammation upregulated osteogenesis, but SHIP1 was not induced. Moreover, inhibiting SHIP1 significantly upregulated TLR2-mediated inflammatory response and downmodulated osteogenesis. In conclusion, these results suggest that induction of weak inflammatory response through TLR2 （with SHIP1 activity） and mutant TLR4 ligands could enhance osteogenesis.展开更多
为确立船舶营运过程中的风险涌现特征,需要考虑复杂系统组成因子的不确定结构问题。以复杂性系统为视角,提出了一种复杂网络不确定结构的风险功能共振分析模型。首先,利用Apriori算法对船舶系统组分进行风险分析,计算组成因子间的非线...为确立船舶营运过程中的风险涌现特征,需要考虑复杂系统组成因子的不确定结构问题。以复杂性系统为视角,提出了一种复杂网络不确定结构的风险功能共振分析模型。首先,利用Apriori算法对船舶系统组分进行风险分析,计算组成因子间的非线性交互效用,生成交互强度矩阵,从而确立船舶营运安全风险的功能共振分析模型(Functional Resonance Analysis Model,FRAM)。随后,采用图卷积网络(Graph Convolutional Network,GCN)构建系统组分网络,识别关键节点,并对因子交互关系网络结构进行重塑。最后,引入深度优先搜索(Depth First Search,DFS)算法,识别关键风险路径,计算出船舶系统组分因子的影响度。结合港口国监督(Port State Control,PSC)缺陷数据,运用前述模型对船舶营运风险进行仿真应用。应用结果表明,船舶的不安全状态受到内外部组成因子的属性影响,并存在关键共振路径关系,其中消防系统、船舶结构状态等是影响船舶不安全状态的核心节点。构建的风险功能共振分析模型能够基于不同的数据输入,自适应生成相应的风险路径依赖。基于复杂网络结构的风险功能共振模型有助于分析不确定结构复杂系统的风险涌现。展开更多
In this paper, the admittance function between seafloor undulations and vertical gravity gradient anomalies was derived. Based on this admittance function, the bathymetry model of 1 minute resolution was predicted fro...In this paper, the admittance function between seafloor undulations and vertical gravity gradient anomalies was derived. Based on this admittance function, the bathymetry model of 1 minute resolution was predicted from vertical gravity gradient anomalies and ship soundings in the experimental area from the northwest Pacific. The accuracy of the model is evaluated using ship soundings and existing models, including ETOPO1, GEBCO, DTU10 and V15.1 from SIO. The model＇s STD is 69. 481m, comparable with V15.1 which is generally believed to have the highest accuracy.展开更多
Through regulating target genes via the mechanisms of posttranscriptional cleavage or translational repression, plant miRNAs involve diverse biological processes associating with plant growth, development, and abiotic...Through regulating target genes via the mechanisms of posttranscriptional cleavage or translational repression, plant miRNAs involve diverse biological processes associating with plant growth, development, and abiotic stress responses, in this study, we functionally characterized TaMIR1119, a miRNA family member of wheat （Triticum aestivum）, in regulating the drought adaptive response of plants. TaMIR1119 putatively targets six genes categorized into the functional classes of transcriptional regulation, RNA and biochemical metabolism, trafficking, and oxidative stress defense. Upon simulated drought stress, the TaMIR1119 transcripts abundance in roots was drastically altered, showing to be upregulated gradually within a 48-h drought regime andthat the drought-induced transcripts were gradually restored along with a 48-h recovery treatment. In contrast, most miRNA target genes displayed reverse expression patterns to TaMIR1119, exhibiting a downregulated expression pattern upon drought and whose reduced transcripts were re-elevated along with a normal recovery treatment. These expression analysis results indicated that TaMIR1119 responds to drought and regulates the target genes mainly through a cleavage mechanism. Under drought stress, the tobacco lines with TaMIR1119 overexpression behaved improved phenotypes,, showing increased plant biomass, photosynthetic parameters, osmolyte accumulation, and enhanced antioxidant enzyme （AE） activities relative to wild type. Three AE genes, NtFeSOD, NtCAT1;3, and NtSOD2,1, encoding superoxide dismutase （SOD）, catalase （CAT）, and peroxidase （POD） proteins, respectively, showed upregulated expression in TaMIR1119 overexpression lines, suggesting that they are involved in the regulation of AE activities and contribution to the improved cellular reactive oxygen species （ROS） homeostasis in drought-challenged transgenic lines. Our results indicate that TaMIR1119 plays critical roles in regulating plant drought tolerance through transcriptionally regulating the target genes that modulate osmolyte accumulation, photosynthetic function, and improve cellular ROS homeostasis of plants.展开更多
AIM： To investigate those associations using data of the population-based Study of Health in Pomerania. METHODS： A study population of 3 749 residents aged 20-79 years without previously diagnosed thyroid disease wa...AIM： To investigate those associations using data of the population-based Study of Health in Pomerania. METHODS： A study population of 3 749 residents aged 20-79 years without previously diagnosed thyroid disease was available for analyses. Serum TSH was used to assess thyroid function. Cholelithiasis was defined by either a prior history of cholecystectomy or the presence of gallstones on ultrasound. Logistic regression was performed to analyze independent associations between thyroid function and cholelithiasis. RESULTS： There were 385 persons （10.3%） with low （〈0.3 mIU/L）, 3 321 persons （88.6%） with normal and 43 persons （1.2%） with high serum TSH levels （〉3 mIU/L）. The proportion of cholelithiasis among males and females was 14.4% and 25.3%, respectively. Among males, there was an independent relation between high serum TSH and cholelithiasis （OR 3.77; 95%-CI 1.06-13.41; P〈0.05）. Also among males, there was a tendency towards an elevated risk of cholelithiasis in persons with low serum TSH （OR 1.40; 95%-CI 0.96-2.02; P= 0.07）. In the female population, no such relation was identified. CONCLUSION： There is an association between thyroid and gallstone disease with a gender-specific relation between hypothyroidism and cholelithiasis.展开更多
基金Supported by the National Natural Science Foundation of China,No.81970454.
文摘BACKGROUND ATP-binding cassette subfamily B member 4(ABCB4)deficiency is associated with cholestatic liver disease primarily because of missense mutations,and many variants remain unidentified.Here,we validate the pathogenicity and mechanism of ABCB4 variants in clinical and in vitro trials,hypothesizing that these variants are responsible for impaired biliary function and contribute to the development of cholestatic liver diseases.AIM To clarify the functional features and pathogenicity of ABCB4 variants.METHODS Clinical data were collected from five patients with cholestatic liver disease that was initially not detected by routine examinations.Later,whole-exome sequencing confirmed ABCB4 variants and the patients were treated from January 2017 to December 2023.Pathogenic mechanisms were analyzed using bioinformatics tools,and a cell model in vitro was established to investigate ABCB4 mRNA expression,multidrug resistance protein 3(MDR3)expression,cellular localization,and phosphatidylcholine secretion.Results were compared using Student's t-tests.RESULTS Five missense variants(c.1757T>A,c.1865G>A,c.2362C>T,c.2777C>T and c.3250C>T),one intron variant(c.537-32G>T),and one synonymous(c.C504T)variant were identified.Three of the five patients had various degrees of cholestasis,two presented with liver cirrhosis,and all had elevated gamma-glutamyl transferase.Three of the four patients who underwent a liver biopsy had bile duct dilation,and one had gallstones.Two of the four patients had normal and reduced MDR3 immunohistochemical levels.Bioinformatic analysis indicated that these variants were likely pathogenic except c.C504T variant.None of the missense variants influenced subcellular MDR3 Localization in vitro.However,the c.1865G>A variant significantly decreased ABCB4 mRNA values,and all missense variants down-regulated phosphatidylcholine secretion.CONCLUSION This study uncovered new ABCB4 variants and emphasized the pathogenic potential of specific variants.The findings from five patients provided insight into the pathogenic mechanisms underlying ABCB4-related diseases.
基金supported by Elam M. and Georgina E.Hack Memorial Research Funds,Department of Periodontics,University of Washington,Seattle,WA,USAsupported by WVCTSI funds,West Virginia University,Morgantown,WV,USA
文摘Toll-like receptor （TLR）-mediated inflammatory response could negatively affect bone metabolism. In this study, we determined how osteogenesis is regulated during inflammatory responses that are downstream of TLR signaling. Human primary osteoblasts were cultured in collagen gels. Pam3CSK4 （P3C） and Escherichia coli lipopolysaccharide （EcLPS） were used as TLR2 and TLR4 ligand respectively. Porphyromonas gingivalis LPS having TLR2 activity with either TLR4 agonism （Pg1690） or TLR4 antagonism （Pg1449） and mutant E. coli LPS （LPxE/LPxF/WSK） were used. IL-lp, SH2-containing inositol phosphatase-1 （SHIP1） that has regulatory roles in osteogenesis, alkaline phosphatase and mineralization were analyzed. 3α-Aminocholestane （3AC） was used to inhibit SHIP1. Our results suggest that osteoblasts stimulated by P3C, poorly induced IL-1β but strongly upregulated SHIP1 and enhanced osteogenic mediators. On the contrary, EcLPS significantly induced IL-1β and osteogenic mediators were not induced. While Pg1690 downmodulated osteogenic mediators, Pg1449 enhanced osteogenic responses, suggesting that TLR4 signaling annuls osteogenesis even with TLR2 activity. Interestingly, mutant E. coli LPS that induces weak inflammation upregulated osteogenesis, but SHIP1 was not induced. Moreover, inhibiting SHIP1 significantly upregulated TLR2-mediated inflammatory response and downmodulated osteogenesis. In conclusion, these results suggest that induction of weak inflammatory response through TLR2 （with SHIP1 activity） and mutant TLR4 ligands could enhance osteogenesis.
文摘为确立船舶营运过程中的风险涌现特征,需要考虑复杂系统组成因子的不确定结构问题。以复杂性系统为视角,提出了一种复杂网络不确定结构的风险功能共振分析模型。首先,利用Apriori算法对船舶系统组分进行风险分析,计算组成因子间的非线性交互效用,生成交互强度矩阵,从而确立船舶营运安全风险的功能共振分析模型(Functional Resonance Analysis Model,FRAM)。随后,采用图卷积网络(Graph Convolutional Network,GCN)构建系统组分网络,识别关键节点,并对因子交互关系网络结构进行重塑。最后,引入深度优先搜索(Depth First Search,DFS)算法,识别关键风险路径,计算出船舶系统组分因子的影响度。结合港口国监督(Port State Control,PSC)缺陷数据,运用前述模型对船舶营运风险进行仿真应用。应用结果表明,船舶的不安全状态受到内外部组成因子的属性影响,并存在关键共振路径关系,其中消防系统、船舶结构状态等是影响船舶不安全状态的核心节点。构建的风险功能共振分析模型能够基于不同的数据输入,自适应生成相应的风险路径依赖。基于复杂网络结构的风险功能共振模型有助于分析不确定结构复杂系统的风险涌现。
文摘针对在复杂多变的海面上快速准确识别红外舰船的难题,提出了一种改进Yolov8s的红外舰船目标检测算法。首先采用轻量化网络EfficientViT(efficient vision transformer)作为主干网络,在确保精度的同时降低参数量和计算量;其次引入空间和通道重建卷积模块SCConv(spatial and channel reconstruction convolution)重构颈部网络C2f模块,减少模型参数冗余的同时,提高模型的检测精度;然后加入EMA(efficient multi-scale attention)注意力机制,提高模型的特征提取能力;最后使用WIoU(weighted intersection over union)损失函数代替CIoU(complete intersection over union)损失函数,进一步提升模型的泛化能力。实验结果表明,改进后的网络模型对比原Yolov8s网络模型,检测精度提升了2.5%,模型尺寸缩小了28%,参数量减少了31%,计算量降低了33%,在提升检测精度的同时使模型变得更加轻量化。改进后的Yolov8s网络模型在红外舰船检测任务上具有良好的性能。
基金supported by the Director Foundation of Institute of Seismology,China Earthquake Administration(IS201326125)the National Natural Science Foundation of China(41204019,41304003)
文摘In this paper, the admittance function between seafloor undulations and vertical gravity gradient anomalies was derived. Based on this admittance function, the bathymetry model of 1 minute resolution was predicted from vertical gravity gradient anomalies and ship soundings in the experimental area from the northwest Pacific. The accuracy of the model is evaluated using ship soundings and existing models, including ETOPO1, GEBCO, DTU10 and V15.1 from SIO. The model＇s STD is 69. 481m, comparable with V15.1 which is generally believed to have the highest accuracy.
基金supported by the National Natural Science Foundation of China (31371618)the Research Plan of Application Base of Hebei, China (17962901D)
文摘Through regulating target genes via the mechanisms of posttranscriptional cleavage or translational repression, plant miRNAs involve diverse biological processes associating with plant growth, development, and abiotic stress responses, in this study, we functionally characterized TaMIR1119, a miRNA family member of wheat （Triticum aestivum）, in regulating the drought adaptive response of plants. TaMIR1119 putatively targets six genes categorized into the functional classes of transcriptional regulation, RNA and biochemical metabolism, trafficking, and oxidative stress defense. Upon simulated drought stress, the TaMIR1119 transcripts abundance in roots was drastically altered, showing to be upregulated gradually within a 48-h drought regime andthat the drought-induced transcripts were gradually restored along with a 48-h recovery treatment. In contrast, most miRNA target genes displayed reverse expression patterns to TaMIR1119, exhibiting a downregulated expression pattern upon drought and whose reduced transcripts were re-elevated along with a normal recovery treatment. These expression analysis results indicated that TaMIR1119 responds to drought and regulates the target genes mainly through a cleavage mechanism. Under drought stress, the tobacco lines with TaMIR1119 overexpression behaved improved phenotypes,, showing increased plant biomass, photosynthetic parameters, osmolyte accumulation, and enhanced antioxidant enzyme （AE） activities relative to wild type. Three AE genes, NtFeSOD, NtCAT1;3, and NtSOD2,1, encoding superoxide dismutase （SOD）, catalase （CAT）, and peroxidase （POD） proteins, respectively, showed upregulated expression in TaMIR1119 overexpression lines, suggesting that they are involved in the regulation of AE activities and contribution to the improved cellular reactive oxygen species （ROS） homeostasis in drought-challenged transgenic lines. Our results indicate that TaMIR1119 plays critical roles in regulating plant drought tolerance through transcriptionally regulating the target genes that modulate osmolyte accumulation, photosynthetic function, and improve cellular ROS homeostasis of plants.
基金Supported by the German Federal Ministry for Education and Research, No. 01ZZ96030, from the Ministry for Education, Research and Cultural Affairs and the Ministry for Social Affairs of the State Mecklenburg-West Pomerania
文摘AIM： To investigate those associations using data of the population-based Study of Health in Pomerania. METHODS： A study population of 3 749 residents aged 20-79 years without previously diagnosed thyroid disease was available for analyses. Serum TSH was used to assess thyroid function. Cholelithiasis was defined by either a prior history of cholecystectomy or the presence of gallstones on ultrasound. Logistic regression was performed to analyze independent associations between thyroid function and cholelithiasis. RESULTS： There were 385 persons （10.3%） with low （〈0.3 mIU/L）, 3 321 persons （88.6%） with normal and 43 persons （1.2%） with high serum TSH levels （〉3 mIU/L）. The proportion of cholelithiasis among males and females was 14.4% and 25.3%, respectively. Among males, there was an independent relation between high serum TSH and cholelithiasis （OR 3.77; 95%-CI 1.06-13.41; P〈0.05）. Also among males, there was a tendency towards an elevated risk of cholelithiasis in persons with low serum TSH （OR 1.40; 95%-CI 0.96-2.02; P= 0.07）. In the female population, no such relation was identified. CONCLUSION： There is an association between thyroid and gallstone disease with a gender-specific relation between hypothyroidism and cholelithiasis.
