来自用户 孤舟蓑笠翁 的文献。
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孤舟蓑笠翁 (2025-06-19 21:20):
#paper 【doi】10.1016/j.cell.2025.05.035;【发表年份】2025年;【期刊】Cell;【标题】Digital reconstruction of full embryos during early mouse organogenesis。【内容总结】这篇研究旨在构建小鼠胚胎早期器官发生的单细胞分辨率3D图谱,通过结合Stereo-seq空间转录组技术和细胞分割方法,对E7.5-E8.0阶段的6个小鼠胚胎进行高通量分析(获得104,343个细胞),开发了SEU-3D可视化平台实现3D“数字胚胎”重建;研究发现胚胎-胚外交界处存在“原基决定区(PDZ)”,该区域通过协调跨胚层信号(如BMP、Wnt)驱动心脏原基形成,同时绘制了中胚层(如心脏祖细胞空间亚群)和内胚层(如原肠管发育轨迹)的细胞图谱,揭示了器官发生早期的空间信号网络机制。
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孤舟蓑笠翁 (2025-06-19 20:37):
#paper 【doi】10.1038/s41591-025-03563-4;【发表年份】2025年;【期刊】Nature Medicine;【标题】Social disadvantage accelerates aging。【内容总结】这项研究的目标是调查社会劣势(比如低教育水平或贫困)是否会加速人体衰老过程,他们用了四个大型人群队列的数据(包括UK Biobank、芬兰公共部门研究等),测量了参与者的社会劣势指标(如教育和成人社会经济地位),并分析血浆蛋白质(用SomaScan平台检测了7000多种蛋白)和83种年龄相关疾病(如糖尿病、心脏病)的关系,主要方法包括队列研究设计、时间事件分析(Cox比例风险模型评估疾病风险)、中介分析(量化蛋白质的介导效应)和GO通路富集分析。简单来说,他们发现社会劣势的人更容易得66种衰老相关疾病(风险增加1.2-1.5倍),14种特定蛋白质(如S100A12、CRP和DNAJB9)部分介导了这一关联(最高达39%),这些蛋白质激活了NF-kB和IL-8炎症通路,表明社会劣势通过加速免疫衰老来促进疾病发生。
Abstract:
Abstract Social disadvantage, like advanced age, is a risk factor for a broad range of health conditions; however, whether it influences the aging process remains unclear. Here, using a multicohort … >>>
Abstract Social disadvantage, like advanced age, is a risk factor for a broad range of health conditions; however, whether it influences the aging process remains unclear. Here, using a multicohort approach, we investigated the associations of social disadvantage with age-related plasma proteins and age-related diseases. We found proteomic signatures of accelerated immune aging and 14 specific age-related proteins linked to social disadvantage during both early and later life. Individuals experiencing social disadvantage had an increased risk of 66 age-related diseases, with up to 39% of these associations mediated by the 14 age-related proteins (for example, DNAJB9, F2, HSPA1A, BGN). The main enriched pathway involved the upregulation of the pro-inflammatory regulator NF-κB24 and its downstream factor interleukin-8. Our findings support the hypothesis that social disadvantage throughout the life course may accelerate aging, a biological mechanism that could explain why social stratification plays such a fundamental role in determining human health. <<<
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孤舟蓑笠翁 (2025-06-19 20:25):
#paper 【doi】10.1038/s41586-025-09083-y;【发表年份】2025年;【期刊】Nature;【标题】Single-cell transcriptomic and chromatin dynamics of the human brain in PTSD。【内容总结】这篇论文想弄清楚创伤后应激障碍(PTSD)如何改变大脑细胞的分子工作机制,帮助理解为什么患者会有长期症状。他们用了单核RNA测序和单核ATAC测序来分析超过200万个来自111个人类大脑前额叶皮层的细胞核,比较了PTSD患者、重度抑郁症(MDD)患者和健康对照组的差异,还结合了空间转录组学技术验证结果。主要方法包括:细胞类型聚类找不同脑细胞、差异基因分析看哪些基因表达变了、基因本体论分析看功能变化、细胞间通讯分析测信号传递、以及整合遗传数据找风险基因。结果发现PTSD会让抑制性神经元、内皮细胞和小胶质细胞的基因表达出问题,比如内皮细胞中应激相关基因FKBP5明显升高,SST神经元信号输出减少导致脑细胞沟通变差;还鉴定出ELFN1等风险基因的调控机制,这些变化在糖皮质激素信号和神经炎症通路中特别突出,而和抑郁症相比,PTSD有独特的分子特征比如微胶质细胞活动更低。简而言之,研究用前沿技术扫描PTSD大脑细胞,发现特定细胞的功能紊乱是症状持续的关键,并锁定了几个潜在治疗靶点。
IF:50.500Q1 Nature, 2025-6-18. DOI: 10.1038/s41586-025-09083-y PMID: 40533550
Abstract:
Post-traumatic stress disorder (PTSD) is a polygenic disorder occurring after extreme trauma exposure. Recent studies have begun to detail the molecular biology of PTSD. However, given the array of PTSD-perturbed … >>>
Post-traumatic stress disorder (PTSD) is a polygenic disorder occurring after extreme trauma exposure. Recent studies have begun to detail the molecular biology of PTSD. However, given the array of PTSD-perturbed molecular pathways identified so far, it is implausible that a single cell type is responsible. Here we profile the molecular responses in over two million nuclei from the dorsolateral prefrontal cortex of 111 human brains, collected post-mortem from individuals with and without PTSD and major depressive disorder. We identify neuronal and non-neuronal cell-type clusters, gene expression changes and transcriptional regulators, and map the epigenomic regulome of PTSD in a cell-type-specific manner. Our analysis revealed PTSD-associated gene alterations in inhibitory neurons, endothelial cells and microglia and uncovered genes and pathways associated with glucocorticoid signalling, GABAergic transmission and neuroinflammation. We further validated these findings using cell-type-specific spatial transcriptomics, confirming disruption of key genes such as SST and FKBP5. By integrating genetic, transcriptomic and epigenetic data, we uncovered the regulatory mechanisms of credible variants that disrupt PTSD genes, including ELFN1, MAD1L1 and KCNIP4, in a cell-type-specific context. Together, these findings provide a comprehensive characterization of the cell-specific molecular regulatory mechanisms that underlie the persisting effects of traumatic stress response on the human prefrontal cortex. <<<
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孤舟蓑笠翁 (2025-06-17 22:27):
#paper 【doi】10.1038/s41591-025-03592-z;【发表年份】2025;【期刊】Nature Medicine;【标题】Single-cell profiling of the human endometrium in polycystic ovary syndrome。【内容总结】通俗地说,这项研究想搞清楚为什么患有多囊卵巢综合征(PCOS)的女性子宫内膜容易出问题(比如着床失败、流产风险高),以及药物二甲双胍是否有效。他们用了先进的单细胞测序技术,详细分析了27名超重/肥胖且有胰岛素抵抗的PCOS女性和对照组女性的子宫内膜细胞组成和基因活动,并在部分PCOS女性用药(二甲双胍或生活方式干预)16周后再次分析。具体来说,研究发现PCOS女性的子宫内膜里上皮细胞变多了,而间质和免疫细胞变少了,并且许多控制细胞粘附、细胞外基质和整合素信号的关键基因(如ITGA2, ITGA3)在特定的上皮细胞亚群(如SOX9+LGR5+、AR+细胞)中变得不正常,这些异常与子宫内膜癌和着床失败有关。重要的是,用二甲双胍治疗16周后,这些异常的基因表达在多个关键细胞类型中(特别是上皮细胞和免疫细胞)得到了明显的改善,甚至部分恢复了,而生活方式干预效果相对较弱。这揭示了PCOS子宫内膜在细胞层面上的具体变化机制,并表明二甲双胍能通过调节这些细胞特异性的异常来帮助恢复子宫内膜健康。
Abstract:
Abstract Polycystic ovary syndrome (PCOS) has a negative effect on the receptivity of the endometrium to embryo implantation and increases the risk of miscarriage and endometrial cancer. The cellular and … >>>
Abstract Polycystic ovary syndrome (PCOS) has a negative effect on the receptivity of the endometrium to embryo implantation and increases the risk of miscarriage and endometrial cancer. The cellular and molecular heterogeneity of the endometrium in women with PCOS has not been well studied. Our study presents a comprehensive cellular atlas of the endometrium during the proliferative phase in women with PCOS characterized by overweight and obesity, hyperandrogenism and insulin resistance compared with controls of similar age, weight and body mass index. Analysis of 247,791 isolated endometrial nuclei from 27 biopsies (5 controls and 12 PCOS cases at baseline and 7 after 16 weeks of metformin and 3 after lifestyle intervention) revealed cell-type-specific disease signatures and variations in cellular composition and localization. Samples taken after 16 weeks of metformin treatment and lifestyle management showed extensive recovery of disease-specific endometrial signatures. We linked the specific role of each cell type to clinical features such as hyperandrogenism and insulin resistance, and specific cell types to risk of endometrial and metabolic disease. In addition, potential therapeutic targets such as integrin inhibitors were identified and the role of metformin in restoring endometrial health in patients with PCOS was highlighted. Our findings lay the groundwork to significantly advance the understanding of PCOS-specific endometrial dysfunction for future targeted therapies. <<<
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孤舟蓑笠翁 (2025-06-16 22:13):
#paper 【doi】10.1038/s41591-025-03653-3;【发表年份】2025年;【期刊】Nature Medicine;【标题】Effect of felzartamab on the molecular phenotype of antibody-mediated rejection in kidney transplant biopsies。【内容总结】本研究目标是探索新药felzartamab如何改善肾移植后常见问题——抗体排斥反应(ABMR)的分子变化,通过一项小规模临床试验:20名患者被分成两组(10人用felzartamab,10人用安慰剂),研究者用基因检测工具分析他们肾活检样本在治疗前、24周(治疗结束)和52周(停药后)的数据,结果发现,felzartamab在治疗期间有效降低了排斥相关基因(如干扰素诱导基因和自然杀伤细胞基因)的表达,平均减少47%和28%,但停药后8成患者反弹;同时,药物意外减轻了肾组织损伤标志物(如IRRAT30和IRITD3等)的长期表达,且未引发有害的T细胞反应,表明短期治疗虽不能完全阻止排斥复发,但可能保护肾脏功能。
Abstract:
Abstract A recent randomized controlled trial demonstrated that treatment with anti-CD38 monoclonal antibody felzartamab suppressed antibody-mediated rejection (ABMR) in kidney transplant patients but with recurrence after treatment in some patients. … >>>
Abstract A recent randomized controlled trial demonstrated that treatment with anti-CD38 monoclonal antibody felzartamab suppressed antibody-mediated rejection (ABMR) in kidney transplant patients but with recurrence after treatment in some patients. Here we examined the molecular effects of 6 months of felzartamab treatment on biopsies from the trial using genome-wide microarray analysis, comparing pretreatment, end-of-treatment (week 24) and posttreatment (week 52) biopsies from ten patients treated with felzartamab and ten patients in the placebo group. Felzartamab reduced molecular ABMR activity scores in all nine patients with baseline ABMR activity, selectively suppressing interferon gamma-inducible and natural killer cell transcripts, with minimal effect on ABMR stage-related endothelial transcripts. Suppression was often incomplete when ABMR activity was intense, and molecular recurrence was nearly universal by week 52. However, we also found that felzartamab had parenchymal benefits at week 52, slowing the trajectories of molecular injury scores beyond the treatment period, suggesting that suppression of ABMR activity could potentially slow future progression to kidney failure. These data provide preliminary molecular insights into the effects of CD38-directed treatment for ABMR, which have the potential to inform future therapeutic strategies. <<<
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孤舟蓑笠翁 (2025-06-16 21:14):
#paper 【doi】10.1038/s41591-025-03570-5;【发表年份】2025年;【期刊】Nature Medicine;【标题】Optimal dietary patterns for healthy aging。【内容总结】这项研究的目标是找出能最好促进健康老龄化的饮食模式,因为全球人口老龄化加剧,许多人面临慢性病和功能衰退的风险,而饮食是预防疾病和维持生活质量的关键因素。简单来说,研究者使用了美国两大长期队列研究的数据——护士健康研究和健康专业人员随访研究,从1986年到2016年追踪了105,015名参与者,分析了八种健康饮食模式(如替代健康饮食指数AHEI、地中海饮食aMED、DASH饮食等)和超加工食品摄入与健康老龄化的关系;健康老龄化定义为活到70岁时无11种主要慢性病、认知功能完好、身体功能正常和心理健康良好。具体地,结果显示,坚持这些健康饮食模式的人有显著更高的健康老龄化几率,其中AHEI饮食效果最强(最高依从组比最低组的几率高出86%),而超加工食品则会降低几率;食物方面,多吃水果、蔬菜、全谷物、坚果、豆类和低脂乳制品有益,但反式脂肪、钠、含糖饮料和红肉或加工肉有害,这些发现在男女中都成立,尤其对女性、吸烟者和体重较高者更明显。
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孤舟蓑笠翁 (2025-06-15 09:44):
#paper 【doi】10.1038/s41591-025-03562-5;【发表年份】2025年;【期刊】Nature Medicine;【标题】Prospective, multicenter validation of a platform for rapid molecular profiling of central nervous system tumors。【内容总结】研究人员想开发一个又快又准的方法来诊断脑肿瘤,因为现有技术太慢太贵,尤其在全球资源有限的地方不好用,所以他们搞了个叫Rapid-CNS2的新工具,结合纳米孔测序和自适应采样技术,能在手术中30分钟内给出肿瘤的大致分类和基因拷贝数信息,24小时内提供完整的分子报告,包括突变、融合和甲基化数据,还搭配了一个叫MNP-Flex的智能分类器处理甲基化信息;他们在多个医院测试了301个肿瘤样本,结果超级好——甲基化家族分类准确率92.9%,基因突变检测与常规方法91.67%一致,拷贝数分析与金标准完全匹配,MNP-Flex更牛,家族和子类准确率分别达99.6%和99.2%,术中测试15分钟就搞定83%的样本,整体诊断时间从几周缩到40小时,让医生能更快制定个性化治疗方案。
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孤舟蓑笠翁 (2025-06-13 20:26):
#paper 【doi】10.1038/s41591-025-03692-w;【发表年份】2025年;【期刊】Nature Medicine;【标题】T and B cell responses against Epstein-Barr virus in primary sclerosing cholangitis。该研究简略地探讨了EB病毒(EBV)与原发性硬化性胆管炎(PSC)的免疫关联,发现PSC患者的T/B细胞对EBV反应异常增强。具体通过比较504名PSC患者和904名健康人的T细胞受体(TCR)测序,鉴定出1008个PSC相关克隆型,其中多数靶向EBV抗原(如BZLF1和EBNA3),且受PSC风险HLA等位基因(如HLA-B*08:01)限制;通过噬菌体免疫沉淀测序(PhIP-seq)分析120名PSC和202名健康人血清,显示PSC患者抗EBV抗体反应显著升高(尤其靶向BMRF1等裂解期蛋白);从PSC肝脏浸润B细胞提取的单克隆抗体也证实靶向EBV抗原(如BFRF3);最后通过超116万人电子病历分析,发现传染性单核细胞增多症(EBV引起)患者患PSC风险比健康人高12倍(95% CI: 6.3-22.9),远高于其他免疫疾病(如克罗恩病),表明EBV感染与PSC发病存在强流行病学关联,提示EBV再激活可能在PSC病理中起关键作用。
Abstract:
Abstract Primary sclerosing cholangitis (PSC) is an idiopathic, progressive and incurable liver disease. Here, we aimed for systematic analyses of adaptive immune responses in PSC. By profiling the T cell … >>>
Abstract Primary sclerosing cholangitis (PSC) is an idiopathic, progressive and incurable liver disease. Here, we aimed for systematic analyses of adaptive immune responses in PSC. By profiling the T cell repertoires of 504 individuals with PSC and 904 healthy controls, we identified 1,008 clonotypes associated with PSC. A substantial fraction of these clonotypes was restricted to known PSC human leukocyte antigen susceptibility alleles and known to target Epstein–Barr virus (EBV) epitopes. We further utilized phage-immunoprecipitation sequencing to determine antibody epitope repertoires of 120 individuals with PSC and 202 healthy controls, which showed a higher burden of anti-EBV responses in PSC than controls. EBV-specific monoclonal antibodies isolated from B cells in PSC livers corroborated convergent B and T cell responses against EBV. By analyzing electronic health records of >116 million people, we identified an association between infectious mononucleosis and PSC (odds ratio, 12; 95% confidence interval, 6.3–22.9), suggesting a link between EBV and PSC. <<<
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孤舟蓑笠翁 (2025-06-12 11:26):
#paper 【doi】10.1016/j.cell.2025.05.019;【发表年份】2025年;【期刊】Cell;【标题】MT-125 inhibits non-muscle myosin IIA and IIB and prolongs survival in glioblastoma。这项研究的目标是开发一种新药MT-125来治疗致命的胶质母细胞瘤(GBM),因为GBM是最具侵袭性的脑肿瘤,当前的治疗效果有限,而MT-125通过特异性地抑制非肌肉肌球蛋白IIA和IIB(NMIIA和NMIIB),这两种蛋白在肿瘤细胞运动、分裂和信号传递中起关键作用,从而阻断肿瘤生长。在方法上,研究人员首先设计了MT-125作为已知抑制剂blebbistatin的衍生物,通过生化实验验证它对NMIIA和NMIIB的高选择性(如抑制常数测定),并评估了其药代动力学、脑渗透性和安全性(包括动物毒性测试);在体外实验中,测试了MT-125对GBM细胞侵袭、细胞分裂的影响(如Transwell入侵实验和细胞核多核化分析),以及它如何增加活性氧(ROS)水平和诱导铁死亡;在体内实验中,使用小鼠GBM模型(包括基因工程模型和患者来源的异种移植模型),给予MT-125单药或与放疗或激酶抑制剂(如sunitinib或paxalisib)联合治疗,监测生存期和肿瘤变化。结果显示,MT-125有效抑制肿瘤细胞侵袭和细胞分裂,导致多核化(如48小时后12%-25%细胞出现多核),并增加ROS和铁死亡,显著延长小鼠生存期(如单药治疗使中位生存期提高);更详细地,MT-125表现出良好的安全性和治疗指数(如耐受剂量高达30 mg/kg),与放疗结合时通过ROS机制增强DNA损伤和细胞死亡,与PDGFR抑制剂sunitinib或mTOR抑制剂联合时产生强协同效应,在动物模型中生存期翻倍,部分小鼠实现长期缓解,这为GBM治疗提供了新的临床策略。
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孤舟蓑笠翁 (2025-05-30 22:24):
#paper 【doi】10.1038/s41586-025-09053-4;【发表年份】2025年;【期刊】Nature;【标题】Cross-tissue multicellular coordination and its rewiring in cancer。这篇论文研究了人体组织中不同细胞类型如何协同工作维持健康,以及这种协同在癌症中如何被破坏。科学家们整合了35种健康组织和29种癌症类型的单细胞数据,开发了CoVarNet计算工具,发现了12种跨组织的"细胞模块"(CMs)——这些是经常一起出现的细胞组合。比如在脾脏中,某些免疫细胞模块会随着年龄增长而改变;在乳腺中,特定成纤维细胞模块与绝经相关。更惊人的是,癌症会破坏健康组织的细胞模块,同时形成新的、促进肿瘤生长的模块。通过分析这些模块,研究者还找到了可能用于癌症早期诊断的分子标志物。简单来说,这项工作就像绘制了一幅"细胞社交网络"地图,展示了健康时细胞如何团队合作,而癌症时这些团队如何重组——这为理解疾病机制和开发新疗法提供了重要线索。
IF:50.500Q1 Nature, 2025-May-28. DOI: 10.1038/s41586-025-09053-4 PMID: 40437094
Abstract:
The multicellular coordination that underlies tissue homeostasis and disease progression is of fundamental interest. However, how diverse cell types are organized within tissue niches for cohesive functioning remains largely unknown. … >>>
The multicellular coordination that underlies tissue homeostasis and disease progression is of fundamental interest. However, how diverse cell types are organized within tissue niches for cohesive functioning remains largely unknown. Here we systematically characterized cross-tissue coordinated cellular modules in healthy tissues, uncovering their spatiotemporal dynamics and phenotypic associations, and examined their rewiring in cancer. We first compiled a comprehensive single-cell transcriptomic atlas from 35 human tissues, revealing substantial inter-tissue variability in cellular composition. By leveraging covariance in cellular abundance, we identified 12 cellular modules with distinct cellular compositions, tissue prevalences and spatial organizations, and demonstrated coordinated intercellular communication within cellular modules using in situ spatial and in vivo perturbation data. Among them, two immune cellular modules in the spleen showed contrasting chronological dynamics with ageing. Analysis of multicellular changes in the breast revealed a menopausal trajectory associated with fibroblast dynamics. Furthermore, interrogation across cancer types uncovered simultaneous rewiring of two types of multicellular ecosystem during tumour progression, including the loss of tissue-specific healthy organization and the emergence of a convergent cancerous ecosystem. These findings reveal fundamental organizing principles of multicellular ecosystems in health and cancer, laying a foundation for further investigations into tissue-level functional coordination across diverse contexts. <<<
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孤舟蓑笠翁 (2025-04-05 09:05):
#paper 【doi】10.1038/s41586-025-08732-6;【发表年份】2025年;【期刊】Nature;【标题】VDAC2 loss elicits tumour destruction and inflammation for cancer therapy。本研究发现,电压依赖性阴离子通道2(VDAC2)在肿瘤免疫逃逸中起关键作用。研究者利用CRISPR–Cas9基因筛选技术,发现VDAC2是免疫信号依赖的检查点,限制了干扰素-γ(IFNγ)介导的肿瘤破坏和肿瘤微环境的炎症重编程。研究中,靶向肿瘤细胞中的VDAC2能够增强IFNγ诱导的细胞死亡和cGAS–STING信号通路的激活,显著改善抗肿瘤效果和免疫治疗反应。通过全基因组遗传互作筛选,研究者确定BAK是VDAC2缺失诱导效应的介质。机制上,IFNγ刺激增加了BIM、BID和BAK的表达,而VDAC2的缺失则导致IFNγ诱导的BAK激活失控,进而引发线粒体损伤。随后,线粒体DNA异常释放到细胞质中,触发了cGAS–STING信号通路和I型干扰素反应的强烈激活。重要的是,共同缺失STING信号通路组分会削弱肿瘤细胞中VDAC2耗竭的治疗效果,这表明靶向VDAC2整合了CD8+ T细胞和IFNγ介导的适应性免疫与肿瘤内源性类固有免疫反应。研究结果揭示了VDAC2作为一个双重作用靶点,能够克服肿瘤免疫逃逸,并强调了协同破坏和炎症化肿瘤以实现有效癌症免疫治疗的重要性。
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孤舟蓑笠翁 (2025-04-03 20:39):
#paper 【doi】10.1016/j.cell.2025.03.018;【发表年份】2025年;【期刊】Cell;【标题】A single-cell atlas reveals immune heterogeneity in anti-PD-1-treated non-small cell lung cancer。本研究的目标是探究非小细胞肺癌(NSCLC)患者在接受抗PD-1治疗后的免疫微环境异质性,以了解不同患者对治疗反应的差异。研究者们通过单细胞RNA测序(scRNA-seq)和T细胞受体测序(scTCR-seq)分析了234名接受新辅助化疗联合抗PD-1治疗的NSCLC患者的肿瘤样本。研究发现,这些患者可以分为五种不同的肿瘤免疫微环境(TIME)亚型,这些亚型与主要病理反应(MPR)率相关。具体来说,NK细胞、记忆B细胞和耗竭前体T细胞与MPR相关,而非MPR患者则表现出更高的CCR8+ Tregs水平。此外,T细胞克隆扩增特征分析揭示了非MPR患者中的异质性,表现为Tex相关细胞和CCR8+ Tregs的不同扩增程度。研究还发现,耗竭前体T细胞(Texp细胞)的比例与无复发生存期相关,能够识别出尽管未达到MPR但复发风险降低的患者亚组。这项研究提供了对化疗免疫治疗反应的TIME异质性分析,为NSCLC管理提供了新的见解。
IF:45.500Q1 Cell, 2025-May-29. DOI: 10.1016/j.cell.2025.03.018 PMID: 40147443
Abstract:
Anti-PD-(L)1 treatment is standard for non-small cell lung cancer (NSCLC), but patients show variable responses to the same regimen. The tumor immune microenvironment (TIME) is associated with immunotherapy response, yet … >>>
Anti-PD-(L)1 treatment is standard for non-small cell lung cancer (NSCLC), but patients show variable responses to the same regimen. The tumor immune microenvironment (TIME) is associated with immunotherapy response, yet the heterogeneous underlying therapeutic outcomes remain underexplored. We applied single-cell RNA and TCR sequencing (scRNA/TCR-seq) to analyze surgical tumor samples from 234 NSCLC patients post-neoadjuvant chemo-immunotherapy. Analyses revealed five distinct TIME subtypes with varying major pathological response (MPR) rates. MPR patients had elevated levels of FGFBP2 NK/NK-like T cells, memory B cells, or effector T cells, while non-MPR patients showed higher CCR8 Tregs. T cell clonal expansion analyses unveiled heterogeneity in non-MPR patients, marked by varying expansions of Tex-relevant cells and CCR8 Tregs. Precursor exhausted T cells (Texp cells) correlated with recurrence-free survival, identifying a patient subgroup with reduced recurrence risk despite lack of MPR. Our study dissects TIME heterogeneity in response to chemoimmunotherapy, offering insights for NSCLC management. <<<
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孤舟蓑笠翁 (2025-03-05 21:45):
#paper 【doi】10.1038/s41586-024-07954-4;【发表年份】2024年;【期刊】Nature;【标题】Temporal recording of mammalian development and precancer。该研究旨在突破传统细胞事件追踪技术的局限性,通过开发基于CRISPR的单细胞分子钟平台,实现哺乳动物发育和肿瘤起源的精准时空记录。研究者利用自突变CRISPR条形码技术,在单细胞水平同步捕获基因表达和遗传变异信息,系统解析了小鼠胚胎器官形成过程中细胞增殖、分化和克隆动态,揭示出肠道发育中未被识别的新型祖细胞群体及其功能特征。进一步将此技术应用于人类结直肠癌前病变样本(包含116个息肉的转录组和418个息肉的突变组数据),首次证实约15-30%的腺瘤起源于多个独立正常干细胞,挑战了传统单克隆致癌假说,为癌症早期起源机制研究提供了多维证据支持。
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孤舟蓑笠翁 (2025-03-02 17:41):
#paper doi:10.1038/s41587-024-02248-6;发表年份:2024;期刊:Nature Biotechnology;标题:High-throughput discovery of MHC class I- and II-restricted T cell epitopes using synthetic cellular circuits。传统抗原检测技术依赖人类原代T细胞,只能识别少数MHC类型(如人类MHC I类),且无法高效分析低亲和力抗原或跨物种(如小鼠)模型。为了解决这些问题,本研究开发了名为TCR-MAP的新技术,其核心是通过基因工程改造Jurkat细胞(一种实验室常用的T细胞系),使其携带特定T细胞受体(TCR)和一个名为Sortase A的酶;当TCR识别到抗原呈递细胞(如病毒感染的细胞或肿瘤细胞)表面的抗原肽-MHC复合物时,Sortase A会被激活,并在靶细胞表面打上生物素“标记”,随后通过磁珠富集这些标记细胞并测序解析抗原。实验证明,该技术能同时兼容人类和小鼠的MHC I/II类抗原,成功识别了CMV病毒抗原、肿瘤抗原(如CTAG1B)以及自身免疫疾病相关抗原(如心脏中的CKMT2),检测灵敏度达到微摩尔级(可发现极微量的抗原),且无需依赖不稳定的原代T细胞。这一平台为病毒逃逸研究、肿瘤疫苗开发和自身免疫病机制解析提供了高效工具,未来还可扩展至脂类等非蛋白抗原的检测。
Abstract:
AbstractAntigen discovery technologies have largely focused on major histocompatibility complex (MHC) class I-restricted human T cell receptors (TCRs), leaving methods for MHC class II-restricted and mouse TCR reactivities relatively undeveloped. … >>>
AbstractAntigen discovery technologies have largely focused on major histocompatibility complex (MHC) class I-restricted human T cell receptors (TCRs), leaving methods for MHC class II-restricted and mouse TCR reactivities relatively undeveloped. Here we present TCR mapping of antigenic peptides (TCR-MAP), an antigen discovery method that uses a synthetic TCR-stimulated circuit in immortalized T cells to activate sortase-mediated tagging of engineered antigen-presenting cells (APCs) expressing processed peptides on MHCs. Live, tagged APCs can be directly purified for deconvolution by sequencing, enabling TCRs with unknown specificity to be queried against barcoded peptide libraries in a pooled screening context. TCR-MAP accurately captures self-reactivities or viral reactivities with high throughput and sensitivity for both MHC class I-restricted and class II-restricted TCRs. We elucidate problematic cross-reactivities of clinical TCRs targeting the cancer/testis melanoma-associated antigen A3 and discover targets of myocarditis-inciting autoreactive T cells in mice. TCR-MAP has the potential to accelerate T cell antigen discovery efforts in the context of cancer, infectious disease and autoimmunity. <<<
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孤舟蓑笠翁 (2025-02-28 21:55):
#paper 10.1038/s41586-025-08622-x. 2025. Nature. Comparative characterization of human accelerated regions in neurons. 这项研究通过比较人类和黑猩猩诱导多能干细胞(iPS细胞)诱导的兴奋性神经元中的HARs,揭示了HARs在人类大脑进化中的潜在作用。研究发现,HAR202在人类神经元中通过改变多个转录因子的结合亲和力来降低NPAS3的表达,而在黑猩猩神经元中,HAR202的同源区域则增强了NPAS3的表达。此外,2xHAR.319在人类神经元中特异性地增强了PUM2的表达,这对于维持iPS细胞的多能性和神经元分化至关重要。敲除2xHAR.319会导致PUM2表达下降,影响细胞的自我更新和分化能力。最后,HAR26;2xHAR.178在人类神经元中通过增强SOCS2的表达来促进神经突起的生长,而在黑猩猩神经元中,这一区域的同源区域则没有这种作用。这些发现为理解HARs在人类大脑进化中的作用提供了新的见解。
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孤舟蓑笠翁 (2025-01-31 23:36):
#paper 10.1186/s12967-023-04576-8。2023。Harnessing large language models (LLMs) for candidate gene prioritization and selection。该论文探讨了用大语言模型以知识驱动的方式对组学数据得到的一大堆基因进行解读、筛选,从而加速获得临床见解的可行性。结果发现OpenAI的GPT-4和Anthropic的Claude表现最佳。我的一个重要收获是发现对于目前的大语言模型的有效使用不是自己原来想的简单的提问就可以的,而是貌似应该是像完成一个项目分解为小的任务,然后逐步推进、整合额外信息,最后得出结论。这提醒我要想用好目前的大语言模型,需要学习如何提问。
Abstract:
AbstractBackgroundFeature selection is a critical step for translating advances afforded by systems-scale molecular profiling into actionable clinical insights. While data-driven methods are commonly utilized for selecting candidate genes, knowledge-driven methods … >>>
AbstractBackgroundFeature selection is a critical step for translating advances afforded by systems-scale molecular profiling into actionable clinical insights. While data-driven methods are commonly utilized for selecting candidate genes, knowledge-driven methods must contend with the challenge of efficiently sifting through extensive volumes of biomedical information. This work aimed to assess the utility of large language models (LLMs) for knowledge-driven gene prioritization and selection.MethodsIn this proof of concept, we focused on 11 blood transcriptional modules associated with an Erythroid cells signature. We evaluated four leading LLMs across multiple tasks. Next, we established a workflow leveraging LLMs. The steps consisted of: (1) Selecting one of the 11 modules; (2) Identifying functional convergences among constituent genes using the LLMs; (3) Scoring candidate genes across six criteria capturing the gene’s biological and clinical relevance; (4) Prioritizing candidate genes and summarizing justifications; (5) Fact-checking justifications and identifying supporting references; (6) Selecting a top candidate gene based on validated scoring justifications; and (7) Factoring in transcriptome profiling data to finalize the selection of the top candidate gene.ResultsOf the four LLMs evaluated, OpenAI's GPT-4 and Anthropic's Claude demonstrated the best performance and were chosen for the implementation of the candidate gene prioritization and selection workflow. This workflow was run in parallel for each of the 11 erythroid cell modules by participants in a data mining workshop. Module M9.2 served as an illustrative use case. The 30 candidate genes forming this module were assessed, and the top five scoring genes were identified as BCL2L1, ALAS2, SLC4A1, CA1, and FECH. Researchers carefully fact-checked the summarized scoring justifications, after which the LLMs were prompted to select a top candidate based on this information. GPT-4 initially chose BCL2L1, while Claude selected ALAS2. When transcriptional profiling data from three reference datasets were provided for additional context, GPT-4 revised its initial choice to ALAS2, whereas Claude reaffirmed its original selection for this module.ConclusionsTaken together, our findings highlight the ability of LLMs to prioritize candidate genes with minimal human intervention. This suggests the potential of this technology to boost productivity, especially for tasks that require leveraging extensive biomedical knowledge. <<<
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孤舟蓑笠翁 (2025-01-01 01:23):
#paper DOI: 10.1038/s41467-024-52615-9. Nature Communications, 2024. The estrogen response in fibroblasts promotes ovarian metastases of gastric cancer. 这篇论文探索了女性胃癌往卵巢的转移在绝经前高发的机制。主要利用单细胞转录组技术,作者发现绝经前女性的雌激素和雌激素受体(ER)水平较高,而雌激素在卵巢转移中起到了关键的促进作用。具体来说,卵巢成纤维细胞表达高水平的ER,并且在雌激素的刺激下,这些成纤维细胞分泌Midkine(MDK),而MDK通过与低密度脂蛋白受体相关蛋白1(LRP1)结合,促进胃癌细胞的迁移和侵袭,从而增强了卵巢转移的能力。
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孤舟蓑笠翁 (2024-05-31 22:29):
#paper doi: 10.1038/s41587-021-01033-z. Differential abundance testing on single-cell data using k-nearest neighbor graphs. 这个研究跳出了对细胞分群的框架,而是从一个细胞的邻居入手,比较组间的细胞比例差异
IF:33.100Q1 Nature biotechnology, 2022-02. DOI: 10.1038/s41587-021-01033-z PMID: 34594043 PMCID:PMC7617075
Abstract:
Current computational workflows for comparative analyses of single-cell datasets typically use discrete clusters as input when testing for differential abundance among experimental conditions. However, clusters do not always provide the … >>>
Current computational workflows for comparative analyses of single-cell datasets typically use discrete clusters as input when testing for differential abundance among experimental conditions. However, clusters do not always provide the appropriate resolution and cannot capture continuous trajectories. Here we present Milo, a scalable statistical framework that performs differential abundance testing by assigning cells to partially overlapping neighborhoods on a k-nearest neighbor graph. Using simulations and single-cell RNA sequencing (scRNA-seq) data, we show that Milo can identify perturbations that are obscured by discretizing cells into clusters, that it maintains false discovery rate control across batch effects and that it outperforms alternative differential abundance testing strategies. Milo identifies the decline of a fate-biased epithelial precursor in the aging mouse thymus and identifies perturbations to multiple lineages in human cirrhotic liver. As Milo is based on a cell-cell similarity structure, it might also be applicable to single-cell data other than scRNA-seq. Milo is provided as an open-source R software package at https://github.com/MarioniLab/miloR . <<<
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19.
孤舟蓑笠翁 (2024-04-30 22:44):
#paper doi:10.1101/2024.03.18.585576,bioRxiv,2024-03-19。Single-cell genomics and regulatory networks for 388 human brains。这个研究首次在人群规模对人脑前额叶区域进行了单细胞核转录组、染色质可及性测序,然后在细胞类型的精度对基因调控网络、细胞通讯网络等方面进行了生理和病理条件下的探究。研究结果可以在项目(brainSCOPE)的官网获取。官网:http://brainscope.psychencode.org。该研究用了388个人的脑。其中333个是该研究产生的,55个是外来的;健康个体有182个,其余有精神分裂症、双相障碍(抑郁狂躁型忧郁症)、自闭症或老年痴呆。388个个体有snRNA-seq数据。59个个体有snATAC-seq数据,其中40个的是snMultiome(对同一个细胞既测转录组又测ATAC)。质控后共280万个细胞核(注释到了28种细胞)。【研究角度及部分主要发现】1,对每种细胞找cis-eQTL和cis调控元件。2,构建细胞类型特异性的基因调控网络和细胞间通信网络,并展示这些网络在衰老和神经精神疾病中的变异。3,探究每种细胞的占比、基因表达、表观遗传和年龄、老年痴呆的关联。用基因表达量构建预测年龄的摸型。发现有6种细胞的转录组有很强的预测能力。4,在每种细胞里构建摸型,用遗传变异预测对细胞、组织的基因表达的影响。模拟基因序列的干绕对基因表达、表型(包括疾病倾向)等下游的影响。【研究的不足或未来研究方向】 1,RNA表达量不能代替蛋白表达量。这在某些脑区尤其突出。2,人去世后的脑组织和活人的脑组织有区别。3,研究更多脑区,以及发育、衰老中的脑区或者类器官。4,整合更多类型的数据,比如成像数据,用于提升预测表型的能力。【应用前景】1,为理解神经精神疾病的分子机制提供了新的视角,有助于发现新的治疗方法。2,通过整合模型(LNCTP),可以从基因型数据中预测个体的细胞类型特异性功能基因表达,为精准医疗提供工具。3,研究结果可用于优先考虑潜在的药物靶点,并模拟特定基因的表达变化,以预测其对疾病表型的潜在影响。4,该研究创建的brainSCOPE资源库可供其他研究者使用,以进一步探索大脑的分子结构和功能。总体而言,这项研究通过大规模的单细胞分析,为理解人类大脑的复杂性、疾病机制和潜在的治疗干预提供了宝贵的资源和新的洞见。
Abstract:
Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet, little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly … >>>
Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet, little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multi-omics datasets into a resource comprising >2.8M nuclei from the prefrontal cortex across 388 individuals. For 28 cell types, we assessed population-level variation in expression and chromatin across gene families and drug targets. We identified >550K cell-type-specific regulatory elements and >1.4M single-cell expression-quantitative-trait loci, which we used to build cell-type regulatory and cell-to-cell communication networks. These networks manifest cellular changes in aging and neuropsychiatric disorders. We further constructed an integrative model accurately imputing single-cell expression and simulating perturbations; the model prioritized ~250 disease-risk genes and drug targets with associated cell types. <<<
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孤舟蓑笠翁 (2022-07-31 08:58):
#paper doi:10.1016/j.ccell.2015.09.018 Cancer Cell, 2015, RNA-Seq of Tumor-Educated Platelets Enables Blood-Based Pan-Cancer, Multiclass, and Molecular Pathway Cancer Diagnostics. 发现血小板携带的mRNA可以预测(准确率96%)是否患癌,并且可以进一步预测(准确率74%)原发组织。
IF:48.800Q1 Cancer cell, 2015-Nov-09. DOI: 10.1016/j.ccell.2015.09.018 PMID: 26525104 PMCID:PMC4644263
Abstract:
Tumor-educated blood platelets (TEPs) are implicated as central players in the systemic and local responses to tumor growth, thereby altering their RNA profile. We determined the diagnostic potential of TEPs … >>>
Tumor-educated blood platelets (TEPs) are implicated as central players in the systemic and local responses to tumor growth, thereby altering their RNA profile. We determined the diagnostic potential of TEPs by mRNA sequencing of 283 platelet samples. We distinguished 228 patients with localized and metastasized tumors from 55 healthy individuals with 96% accuracy. Across six different tumor types, the location of the primary tumor was correctly identified with 71% accuracy. Also, MET or HER2-positive, and mutant KRAS, EGFR, or PIK3CA tumors were accurately distinguished using surrogate TEP mRNA profiles. Our results indicate that blood platelets provide a valuable platform for pan-cancer, multiclass cancer, and companion diagnostics, possibly enabling clinical advances in blood-based "liquid biopsies". <<<
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