目的探讨低密度脂蛋白受体相关蛋白2(low-density lipoprotein receptor-related protein 2,LRP2)基因rs2544390单核苷酸多态性与高尿酸血症的相关性。方法选取2024年6—12月北京市顺义区医院受试者198例,采用iPLEX基因分型技术,对高尿...目的探讨低密度脂蛋白受体相关蛋白2(low-density lipoprotein receptor-related protein 2,LRP2)基因rs2544390单核苷酸多态性与高尿酸血症的相关性。方法选取2024年6—12月北京市顺义区医院受试者198例,采用iPLEX基因分型技术,对高尿酸血症患者134例和健康对照者64例的rs2544390基因位点进行分型,分析不同基因型与高尿酸血症易感性的关系。结果高尿酸血症组的每周进食豆类食物的次数和运动的次数少于正常对照组(P<0.01);高密度脂蛋白(high-density lipoprotein,HDL)水平低于正常对照组(P<0.001),而血肌酐(serum creatinine,SCr)和天冬氨酸转氨酶(aspartate aminotransferase,AST)水平高于正常对照组(P<0.001);高尿酸血症组TT占比(82.1%)显著高于对照组(65.6%);3种基因型(TT、TC、CC)在高尿酸血症组与正常对照组的分布存在显著差异(χ^(2)=6.593,P=0.037);采用显性遗传模型(TT vs.TC+CC)分析时,2组突变等位基因携带者占比的差异更为显著(χ^(2)=6.583,P=0.010);Logistic回归分析发生高尿酸血症的相关因素,单因素分析结果显示:体重指数(body mass index,BMI)、吸烟、进食内脏、SCr以及rs2544390基因型多态性与高尿酸血症的风险显著相关(P<0.05);而运动次数、HDL与高尿酸血症的发病风险呈显著负相关(P<0.05);多因素分析结果显示:BMI升高、进食内脏、高甘油三酯、SCr升高、rs2544390风险基因型与高尿酸血症的风险显著相关(P<0.05);运动次数增加、高密度脂蛋白升高是高尿酸血症的独立保护因素(P<0.05)。结论rs2544390基因多态性与高尿酸血症的发生密切相关,为高尿酸血症的独立危险因素,基因与环境因素的协同效应是疾病发生发展的关键环节。展开更多
Recently,Tian et al.published a research paper with significant breakthroughs in Cell[1].The study found that targeting the signalling pathways named Serpine2-lowdensity lipoprotein receptor-related protein 1(Lrp1)and...Recently,Tian et al.published a research paper with significant breakthroughs in Cell[1].The study found that targeting the signalling pathways named Serpine2-lowdensity lipoprotein receptor-related protein 1(Lrp1)and ectonucleoside triphosphate diphosphohydrolase 1(CD39)-adenosine A_(3)receptor(A_(3)AR)is a promising strategy for the treatment of vascular dementia.The Serpine2-Lrp1 signalling pathway primarily exerts its therapeutic effects on myelin regeneration by regulating the differentiation of oligodendrocyte precursor cells.Serpine2 is a secretory serine protease inhibitor regulates proteolytic homeostasis.It may also bind to cell surface receptors such as Lrp1 to directly activate signalling pathways.As a transmembrane glycoprotein receptor,Lrpl mediates the endocytic clearance of ligands.展开更多
Low-density lipoprotein receptor-related protein 1(LRP1)is a multifunctional endocytic receptor whose dysfunction is linked to developmental dysplasia of the hip,osteoporosis and osteoarthritis.Our work addresses the ...Low-density lipoprotein receptor-related protein 1(LRP1)is a multifunctional endocytic receptor whose dysfunction is linked to developmental dysplasia of the hip,osteoporosis and osteoarthritis.Our work addresses the critical question of how these skeletal pathologies emerge.Here,we show the abundant expression of LRP1 in skeletal progenitor cells at mouse embryonic stage E10.5 and onwards,especially in the perichondrium,the stem cell layer surrounding developing limbs essential for bone formation.Lrp1 deficiency in these stem cells causes joint fusion,malformation of cartilage/bone template and markedly delayed or lack of primary ossification.展开更多
Loss-of-function variants of low-density lipoprotein receptor-related protein 5(LRP5)can lead to reduced bone formation,culminating in diminished bone mass.Our previous study reported transcription factor osterix(SP7)...Loss-of-function variants of low-density lipoprotein receptor-related protein 5(LRP5)can lead to reduced bone formation,culminating in diminished bone mass.Our previous study reported transcription factor osterix(SP7)-binding sites on the LRP5 promoter and its pivotal role in upregulating LRP5 expression during implant osseointegration.However,the potential role of SP7 in ameliorating LRP5-dependent osteoporosis remained unknown.In this study,we used mice with a conditional knockout(c KO)of LRP5 in mature osteoblasts,which presented decreased osteogenesis.The in vitro experimental results showed that SP7 could promote LRP5 expression,thereby upregulating the osteogenic markers such as alkaline phosphatase(ALP),Runt-related transcription factor 2(Runx2),andβ-catenin(P<0.05).For the in vivo experiment,the SP7 overexpression virus was injected into a bone defect model of LRP5 c KO mice,resulting in increased bone mineral density(BMD)(P<0.001)and volumetric density(bone volume(BV)/total volume(TV))(P<0.001),and decreased trabecular separation(Tb.Sp)(P<0.05).These data suggested that SP7 could ameliorate bone defect healing in LRP5 c KO mice.Our study provides new insights into potential therapeutic opportunities for ameliorating LRP5-dependent osteoporosis.展开更多
Streptococcus suis serotype 2(SS2)is a zoonotic pathogen that can cause acute infection,such as septicemia in pigs and streptococcal toxic shock-like syndrome(STSLS)in humans,indicating that SS2 can evade innate immun...Streptococcus suis serotype 2(SS2)is a zoonotic pathogen that can cause acute infection,such as septicemia in pigs and streptococcal toxic shock-like syndrome(STSLS)in humans,indicating that SS2 can evade innate immunity.Macrophages perform essential antimicrobial functions in the innate immune system by engulfing and killing pathogens.Previously,a dna K mutant strain that showed impaired phagocytosis resistance ability was screened from the transposon mutant library of SS2,but the specific mechanism is unclear.In this study,we further demonstrated that DnaK was required for SS2 to be antiphagocytosed by macrophages and survive in adverse environments.A mouse challenge experiment indicated that DnaK promoted bacteremia and systemic dissemination of SS2,enhancing bacterial pathogenicity.Western blot and immunofluorescence results indicated that DnaK could be secreted by SS2 and was able to enter RAW264.7 macrophages.Then,the endocytic receptor LRP1 regulated by DnaK was identified through RNA sequencing(RNA-Seq).We found that DnaK decreased both the mRNA and protein levels of LRP1.Knockdown of the LRP1β-chain(LRP1β)significantly decreased the phagocytosis rate of the SS2 strain ZY05719,suggesting that LRP1 is a phagocytic receptor of SS2.Furthermore,inhibitor treatment assays revealed that DnaK decreased LRP1 protein levels through the transcription factor PPARγand the ubiquitin-proteasome system.In summary,DnaK contributes to the phagocytosis resistance of SS2 by decreasing LRP1 protein levels in macrophages,providing new insights into the antiphagocytosis mechanisms of SS2 and helping to understand its pathogenesis.展开更多
Early and accurate cancer diagnosis through medical imaging is crucial for guiding treatment and enhancing patient survival.However,many state-of-the-art deep learning(DL)methods remain opaque and lack clinical interp...Early and accurate cancer diagnosis through medical imaging is crucial for guiding treatment and enhancing patient survival.However,many state-of-the-art deep learning(DL)methods remain opaque and lack clinical interpretability.This paper presents an explainable artificial intelligence(XAI)framework that combines a fine-tuned Visual Geometry Group 16-layer network(VGG16)convolutional neural network with layer-wise relevance propagation(LRP)to deliver high-performance classification and transparent decision support.This approach is evaluated on the publicly available Kaggle kidney cancer imaging dataset,which comprises labeled cancerous and noncancerous kidney scans.The proposed model achieved 98.75%overall accuracy,with precision,recall,and F1-score each exceeding 98%on an independent test set.Crucially,LRP-derived heatmaps consistently localize anatomically and pathologically significant regions such as tumor margins in agreement with established clinical criteria.The proposed framework enhances clinician trust by delivering pixel-level justifications alongside state-of-the-art predictive performance.It facilitates informed decision-making,thereby addressing a key barrier to the clinical adoption of DL in oncology.展开更多
Diagnosing dental disorders using routine photographs can significantly reduce chair-side workload and expand access to care.However,most AI-based image analysis systems suffer from limited interpretability and are tr...Diagnosing dental disorders using routine photographs can significantly reduce chair-side workload and expand access to care.However,most AI-based image analysis systems suffer from limited interpretability and are trained on class-imbalanced datasets.In this study,we developed a balanced,transformer-based pipeline to detect three common dental disorders:tooth discoloration,calculus,and hypodontia,from standard color images.After applying a color-standardized preprocessing pipeline and performing stratified data splitting,the proposed vision transformer model was fine-tuned and subsequently evaluated using standard classification benchmarks.The model achieved an impressive accuracy of 98.94%,with precision,recall and F1 scores all greater than or equal to 98%for the three classes.To ensure interpretability,three complementary saliency methods,attention roll-out,layer-wise relevance propagation,and LIME,verified that predictions rely on clinically meaningful cues such as stained enamel,supragingival deposits,and edentulous gaps.The proposed method addresses class imbalance through dataset balancing,enhances interpretability using multiple explanation methods,and demonstrates the effectiveness of transformers over CNNs in dental imaging.This method offers a transparent,real-time screening tool suitable for both clinical and tele-dentistry frameworks,providing accessible,clarity-guided care pathways.展开更多
基金support from the Sichuan Science and Technology Program(2024JDHJ0043 and 2025YFHZ0121).
文摘Recently,Tian et al.published a research paper with significant breakthroughs in Cell[1].The study found that targeting the signalling pathways named Serpine2-lowdensity lipoprotein receptor-related protein 1(Lrp1)and ectonucleoside triphosphate diphosphohydrolase 1(CD39)-adenosine A_(3)receptor(A_(3)AR)is a promising strategy for the treatment of vascular dementia.The Serpine2-Lrp1 signalling pathway primarily exerts its therapeutic effects on myelin regeneration by regulating the differentiation of oligodendrocyte precursor cells.Serpine2 is a secretory serine protease inhibitor regulates proteolytic homeostasis.It may also bind to cell surface receptors such as Lrp1 to directly activate signalling pathways.As a transmembrane glycoprotein receptor,Lrpl mediates the endocytic clearance of ligands.
基金The Andor dragonfly Spinning Disk microscope in the CCI was funded by the BBSRC(BB/R01390X/1)This work was supported by the ministry of education of the Kingdom of Saudi Arabia(to M.Alhashmi)+6 种基金Libyan Ministry of Higher Education and Scientific Research and ECMage(to A.M.E.Gremida)Qatar National Research Fund(to N.A.Al-Maslamani)European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement(860635 to M.Antonaci and A.Kerr)BBSRC Grants(BB/T00715X/1 to S.K.Maharana and G.N.WheelerBB/X000907/1 to D.A.Turner)Versus Arthritis Career Development Fellowship(21447 to K.Yamamoto)Versus Arthritis Bridging Fellowship(23137 to K.Yamamoto).
文摘Low-density lipoprotein receptor-related protein 1(LRP1)is a multifunctional endocytic receptor whose dysfunction is linked to developmental dysplasia of the hip,osteoporosis and osteoarthritis.Our work addresses the critical question of how these skeletal pathologies emerge.Here,we show the abundant expression of LRP1 in skeletal progenitor cells at mouse embryonic stage E10.5 and onwards,especially in the perichondrium,the stem cell layer surrounding developing limbs essential for bone formation.Lrp1 deficiency in these stem cells causes joint fusion,malformation of cartilage/bone template and markedly delayed or lack of primary ossification.
文摘Loss-of-function variants of low-density lipoprotein receptor-related protein 5(LRP5)can lead to reduced bone formation,culminating in diminished bone mass.Our previous study reported transcription factor osterix(SP7)-binding sites on the LRP5 promoter and its pivotal role in upregulating LRP5 expression during implant osseointegration.However,the potential role of SP7 in ameliorating LRP5-dependent osteoporosis remained unknown.In this study,we used mice with a conditional knockout(c KO)of LRP5 in mature osteoblasts,which presented decreased osteogenesis.The in vitro experimental results showed that SP7 could promote LRP5 expression,thereby upregulating the osteogenic markers such as alkaline phosphatase(ALP),Runt-related transcription factor 2(Runx2),andβ-catenin(P<0.05).For the in vivo experiment,the SP7 overexpression virus was injected into a bone defect model of LRP5 c KO mice,resulting in increased bone mineral density(BMD)(P<0.001)and volumetric density(bone volume(BV)/total volume(TV))(P<0.001),and decreased trabecular separation(Tb.Sp)(P<0.05).These data suggested that SP7 could ameliorate bone defect healing in LRP5 c KO mice.Our study provides new insights into potential therapeutic opportunities for ameliorating LRP5-dependent osteoporosis.
文摘目的 本研究拟通过体外实验研究槲皮素(Quercetin,QCT)与AC16心肌细胞增殖的关系,探析QCT阻止AC16心肌细胞增殖作用与Wnt/β-catenin信号通路的关系。方法 选用不同浓度QCT对AC16细胞进行干预,使用倒置显微镜拍照观察法、台盼蓝计数法和CCK-8法检测QCT对AC16细胞增殖的影响。Western blot检测QCT对磷酸化-β-连环蛋白(Phosphorylated β-catenin,p-β-catenin)、细胞性骨髓瘤样癌基因(c-Myc)、β-连环蛋白(β-catenin)、低密度脂蛋白受体相关蛋白5(Low density lipoprotein receptor-related protein 5,LRP5)和低密度脂蛋白受体相关蛋白6(Low density lipoprotein receptor-related protein 6,LRP6)表达的影响。台盼蓝计数法检测过表达β-catenin ΔN、LRP5和LRP6基因后研究QCT对细胞增殖的影响以及沉默LRP5和LRP6基因后研究QCT对细胞增殖的影响。结果 与对照组比,QCT使得AC16细胞活细胞数下降,抑制增殖率,且具有浓度依赖性。条件摸索显示10和20μmol/L的QCT会导致AC16细胞中p-β-catenin蛋白修饰水平显著增加(P<0.05),c-Myc、β-catenin、LRP5和LRP6蛋白表达水平显著下调(P<0.05),因此后续实验选择10μmol/L的QCT作为干预浓度。而AC16细胞中过表达β-catenin ΔN、LRP5和LRP6基因,与单独给药组相比,过表达相关基因后10μmol/L的QCT引起的细胞增殖抑制现象被有效逆转(P<0.05)。另外,沉默LRP5和LRP6再联合10μmol/L的QCT干预,AC16细胞的增殖抑制并未产生协同现象(P>0.05)。结论 QCT可以通过下调LRP5/6表达以抑制Wnt/β-catenin信号通路从而发挥其阻止AC16心肌细胞增殖的作用。
基金funded by the National Key Research and Development Program of China(2021YFD1800400)the National Natural Science Foundation of China(32373018)+2 种基金Jiangsu Agriculture Science and Technology Innovation Fund,China(CX(23)1029)the Excellent Research Innovation Team in Universities in Anhui Province,China(2022AH010088)the Shennong Scholar Project of Anhui Agricultural University,China(rc392101)。
文摘Streptococcus suis serotype 2(SS2)is a zoonotic pathogen that can cause acute infection,such as septicemia in pigs and streptococcal toxic shock-like syndrome(STSLS)in humans,indicating that SS2 can evade innate immunity.Macrophages perform essential antimicrobial functions in the innate immune system by engulfing and killing pathogens.Previously,a dna K mutant strain that showed impaired phagocytosis resistance ability was screened from the transposon mutant library of SS2,but the specific mechanism is unclear.In this study,we further demonstrated that DnaK was required for SS2 to be antiphagocytosed by macrophages and survive in adverse environments.A mouse challenge experiment indicated that DnaK promoted bacteremia and systemic dissemination of SS2,enhancing bacterial pathogenicity.Western blot and immunofluorescence results indicated that DnaK could be secreted by SS2 and was able to enter RAW264.7 macrophages.Then,the endocytic receptor LRP1 regulated by DnaK was identified through RNA sequencing(RNA-Seq).We found that DnaK decreased both the mRNA and protein levels of LRP1.Knockdown of the LRP1β-chain(LRP1β)significantly decreased the phagocytosis rate of the SS2 strain ZY05719,suggesting that LRP1 is a phagocytic receptor of SS2.Furthermore,inhibitor treatment assays revealed that DnaK decreased LRP1 protein levels through the transcription factor PPARγand the ubiquitin-proteasome system.In summary,DnaK contributes to the phagocytosis resistance of SS2 by decreasing LRP1 protein levels in macrophages,providing new insights into the antiphagocytosis mechanisms of SS2 and helping to understand its pathogenesis.
基金supported through the Ongoing Research Funding Program(ORF-2025-498),King Saud University,Riyadh,Saudi Arabia.
文摘Early and accurate cancer diagnosis through medical imaging is crucial for guiding treatment and enhancing patient survival.However,many state-of-the-art deep learning(DL)methods remain opaque and lack clinical interpretability.This paper presents an explainable artificial intelligence(XAI)framework that combines a fine-tuned Visual Geometry Group 16-layer network(VGG16)convolutional neural network with layer-wise relevance propagation(LRP)to deliver high-performance classification and transparent decision support.This approach is evaluated on the publicly available Kaggle kidney cancer imaging dataset,which comprises labeled cancerous and noncancerous kidney scans.The proposed model achieved 98.75%overall accuracy,with precision,recall,and F1-score each exceeding 98%on an independent test set.Crucially,LRP-derived heatmaps consistently localize anatomically and pathologically significant regions such as tumor margins in agreement with established clinical criteria.The proposed framework enhances clinician trust by delivering pixel-level justifications alongside state-of-the-art predictive performance.It facilitates informed decision-making,thereby addressing a key barrier to the clinical adoption of DL in oncology.
文摘Diagnosing dental disorders using routine photographs can significantly reduce chair-side workload and expand access to care.However,most AI-based image analysis systems suffer from limited interpretability and are trained on class-imbalanced datasets.In this study,we developed a balanced,transformer-based pipeline to detect three common dental disorders:tooth discoloration,calculus,and hypodontia,from standard color images.After applying a color-standardized preprocessing pipeline and performing stratified data splitting,the proposed vision transformer model was fine-tuned and subsequently evaluated using standard classification benchmarks.The model achieved an impressive accuracy of 98.94%,with precision,recall and F1 scores all greater than or equal to 98%for the three classes.To ensure interpretability,three complementary saliency methods,attention roll-out,layer-wise relevance propagation,and LIME,verified that predictions rely on clinically meaningful cues such as stained enamel,supragingival deposits,and edentulous gaps.The proposed method addresses class imbalance through dataset balancing,enhances interpretability using multiple explanation methods,and demonstrates the effectiveness of transformers over CNNs in dental imaging.This method offers a transparent,real-time screening tool suitable for both clinical and tele-dentistry frameworks,providing accessible,clarity-guided care pathways.
