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中国科学:生命科学（英文版）
中国科学:生命科学（英文版）

周光召

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中国科学:生命科学（英文版）/Journal Science China(Life Sciences)CSCDCSTPCDSCI
查看更多>>《中国科学》是中国科学院主办、中国科学杂志社出版的自然科学专业性学术刊物。《中国科学》任务是反映中国自然科学各学科中的最新科研成果，以促进国内外的学术交流。《中国科学》以论文形式报道中国基础研究和应用研究方面具有创造性的、高水平的和有重要意义的科研成果。在国际学术界，《中国科学》作为代表中国最高水平的学术刊物也受到高度重视。国际上最具有权威的检索刊物SCI，多年来一直收录《中国科学》的论文。1999年《中国科学》夺得国家期刊奖的第一名。
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    Inhibition mechanisms of CRISPR-Cas9 by AcrⅡA25.1 and AcrⅡA32

    Jianlin ZhengYuwei ZhuTengjin HuangWenbo Gao...
    1781-1791页
    查看更多>>摘要：In the ongoing arms race between bacteria and bacteriophages,bacteriophages have evolved anti-CRISPR proteins to counteract bacterial CRISPR-Cas systems.Recently,AcrⅡA25.1 and AcrⅡA32 have been found to effectively inhibit the activity of SpyCas9 both in bacterial and human cells.However,their molecular mechanisms remain elusive.Here,we report the cryo-electron microscopy structures of ternary complexes formed by AcrⅡA25.1 and AcrⅡA32 bound to SpyCas9-sgRNA.Using structural analysis and biochemical experiments,we revealed that AcrⅡA25.1 and AcrⅡA32 recognize a novel,previously-unidentified anti-CRISPR binding site on SpyCas9.We found that both AcrⅡA25.1 and AcrⅡA32 directly interact with the WED domain,where they spatially obstruct conformational changes of the WED and PI domains,thereby inhibiting SpyCas9 from recognizing protospacer adjacent motif(PAM)and unwinding double-stranded DNA.In addition,they may inhibit nuclease activity by blocking the dynamic conformational changes of the SpyCas9 surveillance complex.In summary,our data elucidate the inhibition mechanisms of two new anti-CRISPR proteins,provide new strategies for the modulation of SpyCas9 activity,and expand our understanding of the diversity of anti-CRISPR protein inhibition mechanisms.
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    Biomolecular condensates and disease pathogenesis

    Ke RuanGe BaiYanshan FangDan Li...
    1792-1832页
    查看更多>>摘要：Biomolecular condensates or membraneless organelles(MLOs)formed by liquid-liquid phase separation(LLPS)divide intracellular spaces into discrete compartments for specific functions.Dysregulation of LLPS or aberrant phase transition that disturbs the formation or material states of MLOs is closely correlated with neurodegeneration,tumorigenesis,and many other pathological processes.Herein,we summarize the recent progress in development of methods to monitor phase separation and we discuss the biogenesis and function of MLOs formed through phase separation.We then present emerging proof-of-concept examples regarding the disruption of phase separation homeostasis in a diverse array of clinical conditions including neurodegenerative disorders,hearing loss,cancers,and immunological diseases.Finally,we describe the emerging discovery of chemical modulators of phase separation.
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    Permafrost carbon cycle and its dynamics on the Tibetan Plateau

    Leiyi ChenGuibiao YangYuxuan BaiJinfeng Chang...
    1833-1848页
    查看更多>>摘要：Our knowledge on permafrost carbon(C)cycle is crucial for understanding its feedback to climate warming and developing nature-based solutions for mitigating climate change.To understand the characteristics of permafrost C cycle on the Tibetan Plateau,the largest alpine permafrost region around the world,we summarized recent advances including the stocks and fluxes of permafrost C and their responses to thawing,and depicted permafrost C dynamics within this century.We find that this alpine permafrost region stores approximately 14.1 Pg(1 Pg=1015 g)of soil organic C(SOC)in the top 3 m.Both substantial gaseous emissions and lateral C transport occur across this permafrost region.Moreover,the mobilization of frozen C is expedited by permafrost thaw,especially by the formation of thermokarst landscapes,which could release significant amounts of C into the atmosphere and surrounding water bodies.This alpine permafrost region nevertheless remains an important C sink,and its capacity to sequester C will continue to increase by 2100.For future perspectives,we would suggest developing long-term in situ observation networks of C stocks and fluxes with improved temporal and spatial coverage,and exploring the mechanisms underlying the response of ecosystem C cycle to permafrost thaw.In addition,it is essential to improve the projection of permafrost C dynamics through in-depth model-data fusion on the Tibetan Plateau.
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    Ononin inhibits triple-negative breast cancer lung metastasis by targeting the EGFR-mediated PI3K/Akt/mTOR pathway

    Kumar GanesanCong XuJianming WuBing Du...
    1849-1866页
    查看更多>>摘要：The spreading of cancer cells from the primary tumor site to other parts of the body,known as metastasis,is the leading cause of cancer recurrence and mortality in patients with triple-negative breast cancer(TNBC).Overexpression of epidermal growth factor receptor(EGFR)is observed in approximately 70％of TNBC patients.EGFR is crucial for promoting tumor metastasis and associated with poor prognosis.Therefore,it is vital to identify effective therapeutic strategies targeting EGFR inhibition.Ononin,an isoflavonoid found in various plants,such as clover and soybeans,has been shown to have anticancer properties in several cancers.In the present study,we aimed to investigate the effects of ononin on TNBC lung metastasis and the associated molecular pathways.We used various assays,including cell viability,colony formation,Transwell,wound healing,ELISA,Western blotting,and staining techniques,to achieve this objective.The results demonstrated that ononin effectively suppressed cellular proliferation and induced apoptosis,as evidenced by the cell viability assay,colony formation assay,and expression of apoptosis markers,and reduced the metastatic capabilities of TNBC cells.These effects were achieved through the direct suppression of cell adhesion,invasiveness and motility.Furthermore,in TNBC xenograft lung metastatic models,ononin treatment significantly reduced tumor growth and lung metastasis.Additionally,ononin reversed the epithelial-mesenchymal transition(EMT)by downregulating the expression of EMT markers and matrix metalloproteinases,as confirmed by Western blot analysis.Further-more,ononin treatment reduced EGFR phosphorylation and suppressed the PI3K,Akt,and mTOR signaling pathways,which was further confirmed using EGFR agonists or inhibitors.Importantly,ononin treatment did not exert any toxic effects on liver or kidney function.In conclusion,our findings suggest that ononin is a safe and potentially therapeutic treatment for TNBC metastasis that targets the EGFR-mediated PI3K/Akt/mTOR pathway.Further studies are warranted to validate its efficacy and explore its potential clinical applications.
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    The p38/MAPK pathway as a therapeutic target to prevent therapeutic escape of breast cancer stem cells

    Weixiao YanXiaotong WangWenjing WangQi Guo...
    1867-1880页
    查看更多>>摘要：Cancer stem cells(CSCs)play an important role in metastasis development,tumor recurrence,and treatment resistance,and are essential for the eradication of cancer.Currently,therapies fail to eradicate CSCs due to their therapeutic stress-induced cellular escape,which leads to enhanced aggressive behaviors compared with CSCs that have never been treated.However,the underlying mechanisms regulating the therapeutic escape remain unknown.To this end,we established a model to isolate the therapeutic escaped CSCs(TSCSCs)from breast CSCs and performed the transcription profile to reveal the mechanism.Mechanistically,we demonstrated that the behavior of therapeutic escape was regulated through the p38/MAPK signaling pathway,resulting in TSCSCs exhibiting enhanced motility and metastasis.Notably,blocking the p38/MAPK signaling pathway effectively reduced motility and metastasis ability both in vitro and in vivo,which were further supported by downregulated motility-related genes and epithelial-mesenchymal transition(EMT)-related proteins vimentin and N-cadherin.The obtained findings reveal the p38/MAPK pathway as a potential therapeutic target for TSCSCs and would provide profound implications for cancer therapy.
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    CircZFR promotes colorectal cancer progression via stabilizing BCLAF1 and regulating the miR-3127-5p/RTKN2 axis

    Jiaxin ChenHuijuan WangJianbin XuEngeng Chen...
    1881-1898页
    查看更多>>摘要：Aberrant expression of circular RNAs(circRNAs)is frequently linked to colorectal cancer(CRC).Here,we identified circZFR as a promising biomarker for CRC diagnosis and prognosis,CircZFR was upregulated in CRC tissues and serum exosomes and its level was linked to cancer incidence,advanced-stages,and metastasis.In both in vitro and in vivo settings,circZFR promoted the growth and spread while suppressing apoptosis of CRC.Exosomes with circZFR overexpression promoted the proliferation and migration of cocultured CRC cells.Mechanistically,epithelial splicing regulatory protein 1(ESRP1)in CRC cells may enhance the production of circZFR.BCL2-associated transcription factor 1(BCLAF1)bound to circZFR,which prevented its ubiquitinated degradation.Additionally,circZFR sponged miR-3127-5p to boost rhotekin 2(RTKN2)expression.Our TCP1-CD-QDs nanocarrier was able to carry and deliver circZFR siRNA(si-circZFR)to the vasculature of CRC tissues and cells,which inhibited the growth of tumors in patient-derived xenograft(PDX)models.Taken together,our results show that circZFR is an oncogenic circRNA,which promotes the development and spread of CRC in a BCLAF1 and miR-3127-5p-dependent manner.CircZFR is a possible serum biopsy marker for the diagnosis and a desirable target for further treatment of CRC.
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    TBC1D1 is an energy-responsive polarization regulator of macrophages via governing ROS production in obesity

    Qi WangPing RongWen ZhangXinyu Yang...
    1899-1914页
    查看更多>>摘要：Energy status is linked to the production of reactive oxygen species(ROS)in macrophages,which is elevated in obesity.However,it is unclear how ROS production is upregulated in macrophages in response to energy overload for mediating the development of obesity.Here,we show that the Rab-GTPase activating protein(RabGAP)TBC1D1,a substrate of the energy sensor AMP-activated protein kinase(AMPK),is a critical regulator of macrophage ROS production and consequent adipose inflammation for obesity development.TBC1D1 deletion decreases,whereas an energy overload-mimetic non-phosphorylatable TBC1D1S231A mutation increases,ROS production and Ml-like polarization in macrophages.Mechanistically,TBC1D1 and its downstream target Rab8a form an energy-responsive complex with NOX2 for ROS generation.Transplantation of TBC1D1S231A bone marrow aggravates diet-induced obesity whereas treatment with an ultra-stable TtSOD for removal of ROS selectively in macrophages alleviates both TBC1D1S231A mutation-and diet-induced obesity.Our findings therefore have implications for drug discovery to combat obesity.
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    Deamidation enables pathogenic SMAD6 variants to activate the BMP signaling pathway

    Ling LiLei LuZiqi XiaoJingyi Lv...
    1915-1927页
    查看更多>>摘要：The BMP signaling pathway plays a crucial role in regulating early embryonic development and tissue homeostasis.SMAD6 encodes a negative regulator of BMP,and rare variants of SMAD6 are recurrently found in individuals with birth defects.However,we observed that a subset of rare pathogenic variants of SMAD6 consistently exhibited positive regulatory effects instead of the initial negative effects on the BMP signaling pathway.We sought to determine whether these SMAD6 variants have common pathogenic mechanisms.Here,we showed that pathogenic SMAD6 variants accompanying this functional reversal exhibit similar increases in deamidation.Mechanistically,increased deamidation of SMAD6 variants promotes the accumulation of the BMP receptor BMPR1A and the formation of new complexes,both of which lead to BMP signaling pathway activation.Specifically,two residues,N262 and N404,in SMAD6 were identified as the crucial sites of deamidation,which was catalyzed primarily by glutamine-fructose-6-phosphate transaminase 2(GFPT2).Additionally,treatment of cells harboring SMAD6 variants with a deamidase inhibitor restored the inhibitory effect of SMAD6 on the BMP signaling pathway.Conversely,when wild-type SMAD6 was manually simulated to mimic the deamidated state,the reversed function of activating BMP signaling was reproduced.Taken together,these findings show that deamidation of SMAD6 plays a crucial role in the functional reversal of BMP signaling activity,which can be induced by a subset of various SMAD6 variants.Our study reveals a common pathogenic mechanism shared by these variants and provides a potential strategy for preventing birth defects through deamidation regulation,which might prevent the off-target effects of gene editing.
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    Early-onset and later-onset cancer:trends,risk factors,and prevention in Northern China

    Tong LiuChen-An LiuQing-Song ZhangQi Zhang...
    1928-1940页
    查看更多>>摘要：The characteristics of early-onset(onset age＜50 years)and later-onset(onset age ≥ 50 years)cancers differ significantly.Identifying novel risk factors for both types of cancer is crucial for increasing awareness of cancer prevention and for reducing its burden.This study aimed to analyze the trends in incidence and risk factors for early-onset and late-onset cancers.We conducted a prospective study by drawing data from the Kailuan Study.This study included 6,741 participants with cancer(624 with early-onset cancer and 6,117 with later-onset cancer)and 6,780 matched controls among the 186,249 participants who underwent Kailuan health examinations from 2006 to 2019.The primary outcomes were cancer incidence rates,and associated risk factors for early-and later-onset cancer.Weighted Cox regression was used to calculate hazard ratios and 95％confidence intervals of each exposure factor for early-and later-onset cancer by cancer type.Population-attributable risk proportions were used to estimate the number of cases that could be prevented by eliminating a risk factor from the population.Except for liver cancer,incidence rates for nearly all types of cancer increased during the study period.Smoking,alcohol consumption,lipid metabolism disorders,hypertension,diabetes mellitus,fatty liver,and inflammation were associated with a significantly increased risk of cancer at multiple sites,but risk factors for cancer incidence differed by site.Smoking,alcohol consumption,inflammation,and hypertension were the major contributors to preventable cancer.The incidence of several different types of cancer,including early-onset cancer,is increasing in northeastern China.Differences in risk factors between early-onset and later-onset malignancies may con-tribute to the divergence in the observed changes in incidence trends between these two specific types of cancer.
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    Identification of LRRC46 as a novel candidate gene for high myopia

    Lingxi JiangChao DaiYao WeiBo Zhao...
    1941-1956页
    查看更多>>摘要：High myopia(HM)is the primary cause of blindness,with the microstructural organization and composition of collagenous fibers in the cornea and sclera playing a crucial role in the biomechanical behavior of these tissues.In a previously reported myopic linkage region,MYP5(17q21-22),a potential candidate gene,LRRC46(c.C235T,p.Q79X),was identified in a large Han Chinese pedigree.LRRC46 is expressed in various eye tissues in humans and mice,including the retina,cornea,and sclera.In subsequent cell experiments,the mutation(c.C235T)decreased the expression of LRRC46 protein in human corneal epithelial cells(HCE-T).Further investigation revealed that Lrrc46-/-mice(KO)exhibited a classical myopia phenotype.The thickness of the cornea and sclera in KO mice became thinner and more pronounced with age,the activity of limbal stem cells decreased,and microstructural changes were observed in the fibroblasts of the sclera and cornea.We performed RNA-seq on scleral and corneal tissues of KO and normal control wild-type(WT)mice,which indicated a significant downregulation of the collagen synthesis-related pathway(extracellular matrix,ECM)in KO mice.Subsequent in vitro studies further indicated that LRRC46,a member of the important LRR protein family,primarily affected the formation of collagens.This study suggested that LRRC46 is a novel candidate gene for HM,influencing collagen protein Ⅷ(Col8a1)formation in the eye and gradually altering the biomechanical structure of the cornea and sclera,thereby promoting the occurrence and development of HM.
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