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
Loss-of-function variants in CSDE1 have been strongly linked to neuropsychiatric disorders,yet the precise role of CSDE1 in neurogenesis remains elusive.In this study,we demonstrate that knockout of Csde1 during corti...Loss-of-function variants in CSDE1 have been strongly linked to neuropsychiatric disorders,yet the precise role of CSDE1 in neurogenesis remains elusive.In this study,we demonstrate that knockout of Csde1 during cortical development in mice results in impaired neural progenitor proliferation,leading to abnormal cortical lamination and embryonic lethality.Transcriptomic analysis revealed that Csde1 upregulates the transcription of genes involved in the cell cycle network.Applying a dual thymidine-labelling approach,we further revealed prolonged cell cycle durations of neuronal progenitors in Csde1-knockout mice,with a notable extension of the G1 phase.Intersection with CLIP-seq data demonstrated that Csde1 binds to the 3′untranslated region(UTR)of mRNA transcripts encoding cell cycle genes.Particularly,we uncovered that Csde1 directly binds to the 3′UTR of mRNA transcripts encoding Cdk6,a pivotal gene in regulating the transition from the G1 to S phases of the cell cycle,thereby maintaining its stability.Collectively,this study elucidates Csde1 as a novel regulator of Cdk6,sheds new light on its critical roles in orchestrating brain development,and underscores how mutations in Csde1 may contribute to the pathogenesis of neuropsychiatric disorders.展开更多
Polyphyllin I(PPI)and polyphyllin II(PII)are the main active substances in the Paris polyphylla.However,liver toxicity of these compounds has impeded their clinical application and the potential hepatotoxicity mechani...Polyphyllin I(PPI)and polyphyllin II(PII)are the main active substances in the Paris polyphylla.However,liver toxicity of these compounds has impeded their clinical application and the potential hepatotoxicity mechanisms remain to be elucidated.In this work,we found that PPI and PII exposure could induce significant hepatotoxicity in human liver cell line L-02 and zebrafish in a dose-dependent manner.The results of the proteomic analysis in L-02 cells and transcriptome in zebrafish indicated that the hepatotoxicity of PPI and PII was associated with the cholesterol biosynthetic pathway disorders,which were alleviated by the cholesterol biosynthesis inhibitor lovastatin.Additionally,3-hydroxy-3-methy-lglutaryl CoA reductase(HMGCR)and squalene epoxidase(SQLE),the two rate-limiting enzymes in the cholesterol synthesis,selected as the potential targets,were confirmed by the molecular docking,the overexpression,and knockdown of HMGCR or SQLE with siRNA.Finally,the pull-down and surface plasmon resonance technology revealed that PPI could directly bind with SQLE but not with HMGCR.Collectively,these data demonstrated that PPI-induced hepatotoxicity resulted from the direct binding with SQLE protein and impaired the sterol-regulatory element binding protein 2/HMGCR/SQLE/lanosterol synthase pathways,thus disturbing the cholesterol biosynthesis pathway.The findings of this research can contribute to a better understanding of the key role of SQLE as a potential target in drug-induced hepatotoxicity and provide a therapeutic strategy for the prevention of drug toxic effects with similar structures in the future.展开更多
This paper investigates the influence of the deviation in freeze pipe installation on the development of the frozen wall in long cross passages by numerical simulation with ANSYS software.The study case is from the ar...This paper investigates the influence of the deviation in freeze pipe installation on the development of the frozen wall in long cross passages by numerical simulation with ANSYS software.The study case is from the artificial ground freezing project along the Fuzhou Metro Line 2 between Ziyang Station and Wuliting Station.Two freezepipe configurations,i.e.,one with perfectly aligned pipes without any deviation from design and another with randomly distributed deviation,are included for comparison.The effect of the random deviation in the freeze pipes on frozen wall interconnection time,the thickness of the frozen wall and the development of the temperature field is explored.For the characteristic section of the numerical model at a depth of 25 m,it is found that the frozen wall interconnection time under the random deviation case and no deviation case is 24 days and 18 days,respectively.The difference in the thickness of the thinnest frozen wall segment between the random deviation and no deviation cases is the largest in the early freezing stage(up to 0.75 m),which decreases with time to 0.31 m in the late freezing stage.The effects of random deviation are more significant in the early freezing stage and diminish as the freezing time increases.展开更多
Intramuscular fat(IMF)is a complex adipose tissue within skeletal muscle,appearing specially tissue heterogeneous,and the factors influencing its formation remain unclear.In conditions such as diabetes,aging,and muscl...Intramuscular fat(IMF)is a complex adipose tissue within skeletal muscle,appearing specially tissue heterogeneous,and the factors influencing its formation remain unclear.In conditions such as diabetes,aging,and muscle wasting,IMF was deposited in abnormal locations in skeletal muscle,damaged the normal physiological functions of skeletal muscle.Here,we used Longissimus dorsi muscles from pigs with different IMF contents as samples and adopted a method combining spatial transcriptome(ST)and single-nucleus RNA-seq to identify the spatial heterogeneity of IMF.ST revealed that genes involved in TGF-βsignaling pathways were specifically highly enriched in IMF.In lean pigs,IMF autocrine produces more TGF-β2,while in obese pigs,IMF received more endothelial-derived TGF-β1.In vitro experiments have proven that porcine endothelial cells in a simulated high-fat environment released more TGF-β1 than TGF-β2.Moreover,under obesity mice,the addition of TGF-βafter muscle injury abolished IMF production and slowed muscle repair,whereas TGF-βinhibition accelerated muscle repair.Our findings demonstrate that the TGF-βpathway specifically regulates these processes,suggesting it as a potential therapeutic target for managing muscle atrophy in obese patients and enhancing muscle repair while reducing IMF deposition.展开更多
Activating transcription factors, ATFs, are a group of bZIP transcription factors that act as homodimers or heterodimers with a range of other bZIP factors. In general, ATFs respond to extracellular signals, indicatin...Activating transcription factors, ATFs, are a group of bZIP transcription factors that act as homodimers or heterodimers with a range of other bZIP factors. In general, ATFs respond to extracellular signals, indicating their important roles in maintaining homeostasis. The ATF family includes ATF1, ATF2, ATF3, ATF4, ATF5, ATF6, and ATF7. Consistent with the diversity of cellular processes reported to be regulated by ATFs, the functions of ATFs are also diverse. ATFs play an important role in cell proliferation, apoptosis, differentiation and inflammation-related pathological processes. The expression and phosphorylation status of ATFs are also related to neurodegenerative diseases and polycystic kidney disease. Various miRNAs target ATFs to regulate cancer proliferation, apoptosis, autophagy, sensitivity and resistance to radiotherapy and chemotherapy. Moreover, ATFs are necessary to maintain cell redox homeostasis. Therefore, deepening our understanding of the regulation and function of ATFs will provide insights into the basic regulatory mechanisms that influence how cells integrate extracellular and intracellular signals into genomic responses through transcription factors. Under pathological conditions, especially in cancer biology and response to treatment, the characterization of ATF dysfunction is important for understanding how to therapeutically utilize ATF2 or other pathways controlled by transcription factors. In this review, we will demonstrate how ATF1, ATF2, ATF3, ATF4, ATF5, ATF6, and ATF7 function in promoting or suppressing cancer development and identify their roles in tumour immunotherapy.展开更多
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supported by STI 2030-Major Project(2021ZD0201704)the National Natural Science Foundation of China(32271141,82222025,82130043,82330035,82361138573,82160219,and 82401388)+3 种基金Hunan Provincial Grants(2023SK2084,2023RC1020,2023SK2114,2021SK1010,and 2024JJ6545)China Postdoctoral Science Foundation(2023M733969)Postdoctoral Fellowship Program of China Postdoctoral Science Foundation(GZB20230875)National Key Research and Development Program of China(2021YFA0805200)。
文摘Loss-of-function variants in CSDE1 have been strongly linked to neuropsychiatric disorders,yet the precise role of CSDE1 in neurogenesis remains elusive.In this study,we demonstrate that knockout of Csde1 during cortical development in mice results in impaired neural progenitor proliferation,leading to abnormal cortical lamination and embryonic lethality.Transcriptomic analysis revealed that Csde1 upregulates the transcription of genes involved in the cell cycle network.Applying a dual thymidine-labelling approach,we further revealed prolonged cell cycle durations of neuronal progenitors in Csde1-knockout mice,with a notable extension of the G1 phase.Intersection with CLIP-seq data demonstrated that Csde1 binds to the 3′untranslated region(UTR)of mRNA transcripts encoding cell cycle genes.Particularly,we uncovered that Csde1 directly binds to the 3′UTR of mRNA transcripts encoding Cdk6,a pivotal gene in regulating the transition from the G1 to S phases of the cell cycle,thereby maintaining its stability.Collectively,this study elucidates Csde1 as a novel regulator of Cdk6,sheds new light on its critical roles in orchestrating brain development,and underscores how mutations in Csde1 may contribute to the pathogenesis of neuropsychiatric disorders.
基金supported by the National Natural Science Foundation of China(Grant No.:82204753),the Scientific Research Staring Foundation for the New Teachers of Beijing University of Chinese Medicine(Grant No.:2020-JYB-XJSJJ-009),and Special Scientific Research for Traditional Chinese Medicine of State Administration of Traditional Chinese Medicine of China(Grant No.:201507004).The funders had no role in the study design,data collection,data analysis,interpretation,or writing of the report.
文摘Polyphyllin I(PPI)and polyphyllin II(PII)are the main active substances in the Paris polyphylla.However,liver toxicity of these compounds has impeded their clinical application and the potential hepatotoxicity mechanisms remain to be elucidated.In this work,we found that PPI and PII exposure could induce significant hepatotoxicity in human liver cell line L-02 and zebrafish in a dose-dependent manner.The results of the proteomic analysis in L-02 cells and transcriptome in zebrafish indicated that the hepatotoxicity of PPI and PII was associated with the cholesterol biosynthetic pathway disorders,which were alleviated by the cholesterol biosynthesis inhibitor lovastatin.Additionally,3-hydroxy-3-methy-lglutaryl CoA reductase(HMGCR)and squalene epoxidase(SQLE),the two rate-limiting enzymes in the cholesterol synthesis,selected as the potential targets,were confirmed by the molecular docking,the overexpression,and knockdown of HMGCR or SQLE with siRNA.Finally,the pull-down and surface plasmon resonance technology revealed that PPI could directly bind with SQLE but not with HMGCR.Collectively,these data demonstrated that PPI-induced hepatotoxicity resulted from the direct binding with SQLE protein and impaired the sterol-regulatory element binding protein 2/HMGCR/SQLE/lanosterol synthase pathways,thus disturbing the cholesterol biosynthesis pathway.The findings of this research can contribute to a better understanding of the key role of SQLE as a potential target in drug-induced hepatotoxicity and provide a therapeutic strategy for the prevention of drug toxic effects with similar structures in the future.
基金This research was supported by the project of Natural Science Foundation of Fujian Province(No.2022J01925)supported by the project of the Fuzhou Science and Technology Plan Project(2021-P-047)supported by the Open Project Program Foundation of Engineering Research Center of underground mine construction,Ministry of Education(Anhui University of Science and Technology)(No.JYBGCZX2021104).
文摘This paper investigates the influence of the deviation in freeze pipe installation on the development of the frozen wall in long cross passages by numerical simulation with ANSYS software.The study case is from the artificial ground freezing project along the Fuzhou Metro Line 2 between Ziyang Station and Wuliting Station.Two freezepipe configurations,i.e.,one with perfectly aligned pipes without any deviation from design and another with randomly distributed deviation,are included for comparison.The effect of the random deviation in the freeze pipes on frozen wall interconnection time,the thickness of the frozen wall and the development of the temperature field is explored.For the characteristic section of the numerical model at a depth of 25 m,it is found that the frozen wall interconnection time under the random deviation case and no deviation case is 24 days and 18 days,respectively.The difference in the thickness of the thinnest frozen wall segment between the random deviation and no deviation cases is the largest in the early freezing stage(up to 0.75 m),which decreases with time to 0.31 m in the late freezing stage.The effects of random deviation are more significant in the early freezing stage and diminish as the freezing time increases.
基金supported by the National Natural Science Foundation of China(323B2058)Selection and Breeding of New Local Pig Breeds and Promotion of Industrialization(2022-440000-43010101-9501)+2 种基金Selection and Breeding of Guangdong Small-ear Spotted Pig(2022-440000-4301030202-9510)China Agriculture Research System(CASR-35)the Key Scientific Research Project of Education Department of Shaanxi(22JS033).
文摘Intramuscular fat(IMF)is a complex adipose tissue within skeletal muscle,appearing specially tissue heterogeneous,and the factors influencing its formation remain unclear.In conditions such as diabetes,aging,and muscle wasting,IMF was deposited in abnormal locations in skeletal muscle,damaged the normal physiological functions of skeletal muscle.Here,we used Longissimus dorsi muscles from pigs with different IMF contents as samples and adopted a method combining spatial transcriptome(ST)and single-nucleus RNA-seq to identify the spatial heterogeneity of IMF.ST revealed that genes involved in TGF-βsignaling pathways were specifically highly enriched in IMF.In lean pigs,IMF autocrine produces more TGF-β2,while in obese pigs,IMF received more endothelial-derived TGF-β1.In vitro experiments have proven that porcine endothelial cells in a simulated high-fat environment released more TGF-β1 than TGF-β2.Moreover,under obesity mice,the addition of TGF-βafter muscle injury abolished IMF production and slowed muscle repair,whereas TGF-βinhibition accelerated muscle repair.Our findings demonstrate that the TGF-βpathway specifically regulates these processes,suggesting it as a potential therapeutic target for managing muscle atrophy in obese patients and enhancing muscle repair while reducing IMF deposition.
文摘Activating transcription factors, ATFs, are a group of bZIP transcription factors that act as homodimers or heterodimers with a range of other bZIP factors. In general, ATFs respond to extracellular signals, indicating their important roles in maintaining homeostasis. The ATF family includes ATF1, ATF2, ATF3, ATF4, ATF5, ATF6, and ATF7. Consistent with the diversity of cellular processes reported to be regulated by ATFs, the functions of ATFs are also diverse. ATFs play an important role in cell proliferation, apoptosis, differentiation and inflammation-related pathological processes. The expression and phosphorylation status of ATFs are also related to neurodegenerative diseases and polycystic kidney disease. Various miRNAs target ATFs to regulate cancer proliferation, apoptosis, autophagy, sensitivity and resistance to radiotherapy and chemotherapy. Moreover, ATFs are necessary to maintain cell redox homeostasis. Therefore, deepening our understanding of the regulation and function of ATFs will provide insights into the basic regulatory mechanisms that influence how cells integrate extracellular and intracellular signals into genomic responses through transcription factors. Under pathological conditions, especially in cancer biology and response to treatment, the characterization of ATF dysfunction is important for understanding how to therapeutically utilize ATF2 or other pathways controlled by transcription factors. In this review, we will demonstrate how ATF1, ATF2, ATF3, ATF4, ATF5, ATF6, and ATF7 function in promoting or suppressing cancer development and identify their roles in tumour immunotherapy.
