Mingrui DingWeifan XuGaofeng PeiPilong Li...
475-492页查看更多>>摘要：Biomolecular condensation,driven by multivalency,serves as a fundamental mechanism within cells,facilitating the formation of distinct compartments,including membraneless organelles that play essential roles in various cellular processes.Perturbations in the delicate equilibrium of condensation,whether resulting in gain or loss of phase separation,have robustly been associated with cellular dysfunction and physiological disorders.As ongoing research endeavors wholeheartedly embrace this newly acknowledged principle,a transformative shift is occurring in our comprehension of disease.Consequently,significant strides have been made in unraveling the profound relevance and potential causal connections between abnormal phase separation and various diseases.This com-prehensive review presents compelling recent evidence that highlight the intricate associations between aberrant phase separation and neurodegenerative diseases,cancers,and infectious diseases.Additionally,we provide a suc-cinct summary of current efforts and propose innovative solutions for the development of potential therapeutics to combat the pathological consequences attributed to aberrant phase separation.
Chuanle WangYan HuangYue YangRuofei Li...
493-511页查看更多>>摘要：Telomeres are specialized structures at the ends of linear chromosomes that protect genome stability.The telomeric repeat-containing RNA(TERRA)that is transcribed from subtelomeric regions can invade into double-stranded DNA regions and form RNA:DNA hybrid-containing structure called R-loop.In tumor cells,R-loop formation is closely linked to gene expression and the alternative lengthening of telomeres(ALT)path-way.Dysregulated R-loops can cause stalled replication forks and telomere instability.However,how R-loops are recognized and regulated,particularly at telomeres,is not well understood.We discovered that ILF3 selec-tively associates with telomeric R-loops and safeguards telomeres from abnormal homologous recombination.Knocking out ILF3 results in excessive R-loops at telomeres and triggers telomeric DNA damage responses.In addition,ILF3 deficiency disrupts telomere homeostasis and causes abnormalities in the ALT pathway.Using the proximity-dependent biotin identification(BioID)technology,we mapped the ILF3 interactome and discovered that ILF3 could interact with several DNA/RNA helicases,including DHX9.Importantly,ILF3 may aid in the res-olution of telomeric R-loops through its interaction with DHX9.Our findings suggest that ILF3 may function as a reader of telomeric R-loops,helping to prevent abnormal homologous recombination and maintain telomere homeostasis.
Kai-Hui ZhangFei-Fei ZhangZhi-Ling ZhangKe-Fei Fang...
512-529页查看更多>>摘要：Polycystic ovary syndrome(PCOS)is the leading cause of anovulatory infertility.Inadequate understanding of the ovulation drivers hinders PCOS intervention.Herein,we report that follicle stimulating hormone(FSH)controls follicular fluid(FF)glutamine levels to determine ovulation.Murine ovulation starts from FF-exposing granulosa cell(GC)apoptosis.FF glutamine,which decreases in pre-ovulation porcine FF,elevates in PCOS patients FF.High-glutamine chow to elevate FF glutamine inhibits mouse GC apoptosis and induces hormonal,metabolic,and mor-phologic PCOS traits.Mechanistically,follicle-development-driving FSH promotes GC glutamine synthesis to elevate FF glutamine,which maintain follicle wall integrity by inhibiting GC apoptosis through inactivating ASK1-JNK apop-totic pathway.FSH and glutamine inhibit the rapture of cultured murine follicles.Glutamine removal or ASK1-JNK pathway activation with metformin or AT-101 reversed PCOS traits in PCOS models that are induced with either glutamine or EsR1-KO.These suggest that glutamine,FSH,and ASK1-JNK pathway are targetable to alleviate PCOS.
Tao ChenYiliang XuXiaocui XuJianzhang Wang...
530-546页查看更多>>摘要：Adenomyosis is a poorly understood gynecological disorder lacking effective treatments.Controversy persists regarding"invagination"and"metaplasia"theories.The endometrial-myometrial junction(EMJ)connects the endo-metrium and myometrium and is important for diagnosing and classifying adenomyosis,but its in-depth study is just beginning.Using single-cell RNA sequencing and spatial profiling,we mapped transcriptional alterations across eutopic endometrium,lesions,and EMJ.Within lesions,we identified unique epithelial(LGR5+)and inva-sive stromal(PKIB+)subpopulations,along with WFDC1+progenitor cells,supporting a complex interplay between"invagination"and"metaplasia"theories of pathogenesis.Further,we observed endothelial cell heterogeneity and abnormal angiogenic signaling involving vascular endothelial growth factor and angiopoietin pathways.Cell-cell communication differed markedly between ectopic and eutopic endometrium,with aberrant signaling in lesions involving pleiotrophin,TWEAK,and WNT cascades.This study reveals unique stem cell-like and invasive cell sub-populations within adenomyosis lesions identified,dysfunctional signaling,and EMJ abnormalities critical to devel-oping precise diagnostic and therapeutic strategies.
Fumiaki ItoHanjing YangZ.Hong ZhouXiaojiang S.Chen...
547-552页
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