Science China Life Sciences最新文献

{"title":"CRISPR screening identifies protein methylation and ubiquitination modifications that modulate aflatoxin B₁ cytotoxicity.","authors":"Huaqiang Yang, Xi Ji, Haiwen Zhong, Xiaohui Yang, Dandan Hu, Gengyuan Cai, Zhenfang Wu","doi":"10.1007/s11427-024-2866-1","DOIUrl":"https://doi.org/10.1007/s11427-024-2866-1","url":null,"abstract":"<p><p>Aflatoxin B₁ (AFB₁) is one of the most potent mycotoxins affecting human health and animal production. To deeply understand the host-toxin interaction, we performed CRISPR screening and identified cystathionine β-synthase (CBS) as a critical host gene affecting AFB₁ cytotoxicity. Mechanistic studies revealed that CBS affects AFB₁-induced cell death by regulating the abundance of protein post-translational modifications (PTMs) in host cells. First, AFB₁ disrupted the transfer of S-adenosylmethionine (SAM) from the cytoplasm to the mitochondria, thereby reducing the intra-mitochondrial protein methylation level. Deficient intra-mitochondrial protein methylation impaired mitochondrial function and caused cell death. CBS knockout (KO) can enhance SAM generation and mobilization to restore intra-mitochondrial SAM levels by rescuing the perturbed methionine cycle after AFB₁ exposure, thereby alleviating AFB₁-induced cell death. Second, AFB₁ decreased global protein ubiquitination levels by affecting gene expression of ubiquitin-modified enzymes. CBS-KO and pharmaceutical treatment correcting gene expression of ubiquitin-modified enzymes can rescue AFB₁-induced cell death. We also investigated two PTM-regulating small molecules, SAM and PR-619, which can increase cell viability in AFB₁-exposed cells.</p>","PeriodicalId":21576,"journal":{"name":"Science China Life Sciences","volume":" ","pages":""},"PeriodicalIF":8.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Conservation medicine: a \"Unity of Nature and Man\" perspective.","authors":"Yifei Xu, Yang Li, Fuwen Wei","doi":"10.1007/s11427-024-2896-y","DOIUrl":"https://doi.org/10.1007/s11427-024-2896-y","url":null,"abstract":"","PeriodicalId":21576,"journal":{"name":"Science China Life Sciences","volume":" ","pages":""},"PeriodicalIF":8.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143754459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Two competing guilds as barometers of host health.","authors":"Haohan Ma, Kai Wang, Changtao Jiang","doi":"10.1007/s11427-025-2854-9","DOIUrl":"https://doi.org/10.1007/s11427-025-2854-9","url":null,"abstract":"","PeriodicalId":21576,"journal":{"name":"Science China Life Sciences","volume":" ","pages":""},"PeriodicalIF":8.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Does caudate lobe resection really improve the surgical outcomes of patients with hilar cholangiocarcinoma? A multicenter retrospective study.","authors":"Ran Tao, Tong Yuan, Qi Cheng, Deyu Li, Qiumeng Liu, Chang Shu, Chuang Peng, Yongjun Chen, Xiaoping Chen, Erlei Zhang, Shuai Xiang","doi":"10.1007/s11427-024-2855-x","DOIUrl":"https://doi.org/10.1007/s11427-024-2855-x","url":null,"abstract":"<p><p>In the field of hilar cholangiocarcinoma (HCCA) treatment, the value of caudate lobe resection (CLR) has not been fully elucidated. Most scholars advocate that the caudate lobe should be routinely resected. To further investigate this issue, this study aims to evaluate the impact of CLR on surgical outcomes of HCCA patients who are judged to have no obvious tumor invasion in the caudate lobe. A retrospective analysis was performed on Bismuth type II, III, or IV HCCA patients who underwent radical resection between October 2005 and April 2023 at three Chinese medical centers. Patients were divided into the CLR group and the no caudate lobe resection (No-CLR) group according to whether CLR was performed or not. Baseline and tumor characteristics as well as perioperative outcomes were compared between the two groups using propensity score matching (PSM). A total of 397 HCCA patients underwent radical resection and there were 146 patients in each group after PSM. After PSM, the mortality was similar between the two groups. However, patients in the CLR group had a higher incidence of postoperative ascites (43.8% vs 30.1%, P=0.021), liver failure (15.8% vs 6.2%, P=0.014) and intra-abdominal infection (19.2% vs 8.2%, P=0.010). The R0 rate in the CLR group was significantly higher than that in the No-CLR group (88.4% vs 76.0%, P=0.009). Nevertheless, patients undergoing CLR did not show any improvement in overall survival (OS) or recurrence-free survival (RFS). Multivariate analysis showed that CLR was not associated with improved long-term surgical outcomes. The high level of CA19-9 and lower tumor differentiation were associated with worse OS, and adjuvant therapy can significantly improve OS. Lower tumor differentiation and N2 were associated with worse RFS. In summary, there is not yet sufficient evidence to support the routine resection of the caudate lobe during surgery for HCCA. For patients without obvious tumor invasion in the caudate lobe, resection of the lobe should be carefully weighed for its benefits and risks.</p>","PeriodicalId":21576,"journal":{"name":"Science China Life Sciences","volume":" ","pages":""},"PeriodicalIF":8.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143754460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular vesicles in cancer progression: mechanisms and significance.","authors":"Ying Gao, Denghui Wei, Li Zhong, Dan Liao, Xueping Zheng, Yujie Lin, Dongmei Fang, Boyang Chang, Tiebang Kang","doi":"10.1007/s11427-024-2852-9","DOIUrl":"https://doi.org/10.1007/s11427-024-2852-9","url":null,"abstract":"<p><p>Tumor recurrence, metastasis, clinical drug resistance, and immune evasion are critical events in cancer progression, characterized by significant spatiotemporal heterogeneity and plasticity. Intercellular communication between tumor cells and other cells within the tumor microenvironment plays a pivotal role in these processes. Extracellular vesicles (EVs), heterogeneous secretory messengers carrying bioactive molecules, facilitate this cell-to-cell communication, thereby dynamically influencing cancer progression. Deciphering the mechanisms of EV formation and regulatory pathways and identifying key networks and targets in tumor metastasis, drug resistance, and immune response mediated by EVs will provide new insights into the understanding of cancer progression patterns and offer innovative strategies for cancer diagnosis and therapy.</p>","PeriodicalId":21576,"journal":{"name":"Science China Life Sciences","volume":" ","pages":""},"PeriodicalIF":8.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143721280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RIG-I-driven CDKN1A stabilization reinforces cellular senescence.","authors":"Cui Wang, Xiaoyu Jiang, Hong-Yu Li, Jianli Hu, Qianzhao Ji, Qiaoran Wang, Xiaoqian Liu, Daoyuan Huang, Kaowen Yan, Liyun Zhao, Yanling Fan, Si Wang, Shuai Ma, Juan Carlos Izpisua Belmonte, Jing Qu, Guang-Hui Liu, Weiqi Zhang","doi":"10.1007/s11427-024-2844-8","DOIUrl":"https://doi.org/10.1007/s11427-024-2844-8","url":null,"abstract":"<p><p>The innate immune signaling network follows a canonical format for signal transmission. The innate immune pathway is crucial for defense against pathogens, yet its mechanistic crosstalk with aging processes remains largely unexplored. Retinoic acid-inducible gene-I (RIG-I), a key mediator of antiviral immunity within this pathway, has an enigmatic role in stem cell senescence. Our study reveals that RIG-I levels increase in human genetic and physiological cellular aging models, and its accumulation drives cellular senescence. Conversely, CRISPR/Cas9-mediated RIG-I deletion or pharmacological inhibition in human mesenchymal stem cells (hMSCs) confers resistance to senescence. Mechanistically, RIG-I binds to endogenous mRNAs, with CDKN1A mRNA being a prominent target. Specifically, RIG-I stabilizes CDKN1A mRNA, resulting in elevated CDKN1A transcript levels and increased p21^Cip1 protein expression, which precipitates senescence. Collectively, our findings establish RIG-I as a post-transcriptional regulator of senescence and suggest potential targets for the mitigation of aging-related diseases.</p>","PeriodicalId":21576,"journal":{"name":"Science China Life Sciences","volume":" ","pages":""},"PeriodicalIF":8.0,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143711187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Developing a robust genome editing tool based on an endogenous type I-B CRISPR-Cas system in Saccharopolyspora spinosa.","authors":"Wenfang Wang, Huiyan He, Hewei Liu, Yuan Gao, Fujun Dang, Xiujuan Zhao, Shaoxin Chen, Lei Li, Yinhua Lu","doi":"10.1007/s11427-024-2869-x","DOIUrl":"https://doi.org/10.1007/s11427-024-2869-x","url":null,"abstract":"<p><p>Saccharopolyspora spinosa is an industrial rare actinomycete capable of producing important environmental-friendly biopesticides, spinosyns. However, exploitation of S. spinosa has been limited due to its genetic inaccessibility and lack of effective genome engineering tools. In this work, we characterized the activity of an endogenous type I-B CRISPR-Cas system as well as its recognized protospacer adjacent motifs (PAMs) based on bioinformatics analysis combined with a plasmid interference assay in S. spinosa. By delivering editing plasmids containing a designed miniCRISPR array (repeat+self-targeting spacer+repeat) and repair templates, we achieved 100% editing efficiency for gene deletion. Using this tool, the genetic barrier composed of the restriction-modification (RM) systems was systematically disarmed. We showed that by disarming one type I RM system (encoded by A8926_1903/1904/1905) and two type II RM systems (encoded by A8926_1725/1726 and A8926_2652/2653) simultaneously, the transformation efficiency of the replicative and integrative plasmids (pSP01 and pSI01) was increased by approximately 3.9-fold and 4.2-fold, respectively. Using the engineered strain with simultaneous knock-out of these three RM genes as the starting strain, we achieved the deletion of 75-kb spinosyns biosynthetic gene cluster (BGC) as well as gene insertion at high efficiency. Collectively, we developed a reliable and highly efficient genome editing tool based on the endogenous type I CRISPR-Cas system combined with the disarmament of the RM systems in S. spinosa. This is the first time to establish an endogenous CRISPR-Cas-based genome editing tool in the non-model industrial actinomycetes.</p>","PeriodicalId":21576,"journal":{"name":"Science China Life Sciences","volume":" ","pages":""},"PeriodicalIF":8.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143711173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cracking the chitin code: how a single pair of LysM receptors deciphers symbiosis and immunity in Marchantia.","authors":"Karen Velandia, Eloise Foo","doi":"10.1007/s11427-025-2889-x","DOIUrl":"https://doi.org/10.1007/s11427-025-2889-x","url":null,"abstract":"","PeriodicalId":21576,"journal":{"name":"Science China Life Sciences","volume":" ","pages":""},"PeriodicalIF":8.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143731527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative analysis based on CRISPR screen identifies apilimod as a potential therapeutic agent for cisplatin-induced acute kidney injury treatment.","authors":"Yunpeng Chu, Muyun Wei, Zhongyu Cao, Luan Chen, Jie Tan, Wei Bao, Fan Yang, Yingtian Zhang, Yunxiao Lin, Yutong Zhang, Shiyi Li, Cai Lv, Wei Zhou, Huihui Du, Lu Shen, Cong Huai, Zhenting Wang, Shengying Qin","doi":"10.1007/s11427-025-2874-8","DOIUrl":"https://doi.org/10.1007/s11427-025-2874-8","url":null,"abstract":"<p><p>Acute kidney injury (AKI), a life-threatening side effect of cisplatin therapy, significantly limits the drug's therapeutic potential. In this study, we conducted a genome-wide CRISPR/Cas9 knockout screen in human renal tubular epithelial cells, integrating the results with transcriptome analyses and the Connectivity Map (CMap) database. Apilimod and elacridar emerged as the top two candidates of mitigating cisplatin-induced nephrotoxicity, with apilimod demonstrating superior efficacy in drug matrix experiments. Apilimod reduced cisplatin-induced apoptosis, inflammation and reactive oxygen species (ROS) generation. Transcriptome analyses suggested that apilimod may protect against cisplatin-induced nephrotoxicity via modulating lipid metabolism. In vitro experiments revealed that apilimod significantly ameliorated cisplatin-induced lipotoxicity by enhancing lipid clearance and upregulating PGC1α-mediated fatty acid oxidation. Mechanism experiments showed that apilimod induces the nuclear translocation of TFEB through the inhibition of its target, PIKfyve, thereby enhancing PGC1α expression and ameliorating lipotoxicity. These protective effects of apilimod were simulated by siRNA-mediated PIKfyve knockdown and diminished by the PGC1α inhibitor SR-18292 and siRNA targeting TFEB, confirming the role of the PIKfyve/TFEB/PGC1α signaling axis in apilimod's renoprotective effects. In vivo, apilimod alleviated apoptosis, inflammation, and lipid accumulation in a cisplatin-induced AKI mouse model. Additionally, apilimod treatment did not compromise the antitumor effect of cisplatin in cancer cells or tumor-bearing mice. Overall, our study suggests that apilimod could be a promising therapeutic agent for the treatment of cisplatin-induced AKI and revealed its underlying molecular mechanism.</p>","PeriodicalId":21576,"journal":{"name":"Science China Life Sciences","volume":" ","pages":""},"PeriodicalIF":8.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143731534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural resistance to cancers in long-lived mammals: genomic mechanisms and experimental evidence to explain Peto's paradox.","authors":"Linxia Sun, Zhikang Xu, Mengqi Shuai, Chengxu Li, Guang Yang, Shixia Xu","doi":"10.1007/s11427-024-2838-x","DOIUrl":"https://doi.org/10.1007/s11427-024-2838-x","url":null,"abstract":"<p><p>Long-lived mammals are reported to have rare or considerably fewer instances of spontaneous tumors, suggesting they might have evolved specific or convergent mechanisms of cancer resistance to extend lifespan; however, the underlying mechanisms remain insufficiently explored. Here, we conducted comparative analysis across 60 mammalian genomes to investigate the genomic features associated with natural cancer resistance. We identified 296 strongly selected genes unique to long-lived species and associated with immune response, DNA repair, and cancer, which might contribute to cancer resistance and lifespan extension in long-lived species. Further, 229 convergent cancer-related genes were detected in the four extremely long-lived species and in-vitro assays confirmed a convergent mutation of LZTS1, shared by bowhead whales and naked mole rats, could suppress cancer development. Importantly, 16 genes were significantly related to both body weight and cancer, defined as candidate genes of Peto's paradox. Of them, the YAP1 gene, harboring the A214S mutation, was identified as a key gene that upregulated tumor suppression genes by localizing to the cytoplasm, which might prohibit cancer development in the large and long-lived cetaceans. These findings provide novel insights into the molecular mechanisms underlying natural cancer resistance in long-lived mammals and the biological basis of Peto's paradox.</p>","PeriodicalId":21576,"journal":{"name":"Science China Life Sciences","volume":" ","pages":""},"PeriodicalIF":8.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143711185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}