Drug synergistic effects refer to combinations that have a greater impact than individual drugs,which are often but sometimes harmful.Predicting synergism via computational methods like intelligence(AI)is popular,yet ...Drug synergistic effects refer to combinations that have a greater impact than individual drugs,which are often but sometimes harmful.Predicting synergism via computational methods like intelligence(AI)is popular,yet experimental validation remains challenging.DNA-programmed labeling(DPAL)is a method for target based on drug-target binding,minimizing interference from photoreactive groups and tags,which has the advantages of high sensitivity and low impact on drug activities[1–3].In the present study,we utilized the DPAL method to reveal the synergistic targets of the three main components(bufalin,cinobufagin,and resibufogenin(BCR))of cinobufacini injection with anti-hepatocarcinoma activities.展开更多
Meiosis is pivotal for sexual reproduction and fertility. Meiotic programmed DNA double-strand breaks(DSBs) initiate homologous recombination, ensuring faithful chromosome segregation and generation of gametes. Howeve...Meiosis is pivotal for sexual reproduction and fertility. Meiotic programmed DNA double-strand breaks(DSBs) initiate homologous recombination, ensuring faithful chromosome segregation and generation of gametes. However, few studies have focused on meiotic DSB formation in human reproduction.Here, we report four infertile siblings born to a consanguineous marriage, with three brothers suffering from non-obstructive azoospermia and one sister suffering from unexplained infertility with normal menstrual cycles and normal ovary sizes with follicular activity. An autosomal recessive mutation in TOP6BL was found co-segregating with infertility in this family. Investigation of one male patient revealed failure in programmed meiotic DSB formation and meiotic arrest prior to pachytene stage of prophase I.Mouse models carrying similar mutations to that in patients recapitulated the spermatogenic abnormalities of the patient. Pathogenicity of the mutation in the female patient was supported by observations in mice that meiotic programmed DSBs failed to form in mutant oocytes and oocyte maturation failure due to absence of meiotic recombination. Our study thus illustrates the phenotypical characteristics and the genotype-phenotype correlations of meiotic DSB formation failure in humans.展开更多
基金supported by the National Natural Science Foundation of China(Grant No.:82003711)Open Research Fund of Basic Medicine College(Grant No.:JCKFKT-MS-001)+2 种基金Shanghai Natural Science Foundation(Grant No.:23ZR1477600)Young Elite Scientists Sponsorship Program by CAST(Program No.:2022QNRC001)Shanghai Sailing Program(Program No.:24YF2758300).
文摘Drug synergistic effects refer to combinations that have a greater impact than individual drugs,which are often but sometimes harmful.Predicting synergism via computational methods like intelligence(AI)is popular,yet experimental validation remains challenging.DNA-programmed labeling(DPAL)is a method for target based on drug-target binding,minimizing interference from photoreactive groups and tags,which has the advantages of high sensitivity and low impact on drug activities[1–3].In the present study,we utilized the DPAL method to reveal the synergistic targets of the three main components(bufalin,cinobufagin,and resibufogenin(BCR))of cinobufacini injection with anti-hepatocarcinoma activities.
基金supported by the National Key Research and Developmental Program of China (2018YFC1003700, 2016YFC1000600, 2018YFC1003400 and 2018YFC1004700)the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB19000000)the National Natural Science Foundation of China (31890780, 31630050, 31871514 and 31771668)。
文摘Meiosis is pivotal for sexual reproduction and fertility. Meiotic programmed DNA double-strand breaks(DSBs) initiate homologous recombination, ensuring faithful chromosome segregation and generation of gametes. However, few studies have focused on meiotic DSB formation in human reproduction.Here, we report four infertile siblings born to a consanguineous marriage, with three brothers suffering from non-obstructive azoospermia and one sister suffering from unexplained infertility with normal menstrual cycles and normal ovary sizes with follicular activity. An autosomal recessive mutation in TOP6BL was found co-segregating with infertility in this family. Investigation of one male patient revealed failure in programmed meiotic DSB formation and meiotic arrest prior to pachytene stage of prophase I.Mouse models carrying similar mutations to that in patients recapitulated the spermatogenic abnormalities of the patient. Pathogenicity of the mutation in the female patient was supported by observations in mice that meiotic programmed DSBs failed to form in mutant oocytes and oocyte maturation failure due to absence of meiotic recombination. Our study thus illustrates the phenotypical characteristics and the genotype-phenotype correlations of meiotic DSB formation failure in humans.
