Core Viewpoint - The article discusses the development of a virtual cell model called STATE by Arc Institute, which aims to predict cellular responses to various drug and genetic interventions, thereby enhancing the success rate of clinical trials and drug discovery [3][12]. Group 1: Virtual Cell Model STATE - STATE is designed to predict the responses of various cell types, including stem cells, cancer cells, and immune cells, to drugs and genetic disturbances [3][12]. - The model is trained on data from 167 million cells and over 100 million disturbance data points, covering 70 different cell lines [3][7]. - STATE consists of two interconnected modules: State Embedding (SE) and State Transition (ST), which allow for the prediction of RNA expression changes based on initial transcriptomes and disturbances [6][7]. Group 2: Performance and Advantages - STATE significantly outperforms existing computational methods, showing a 50% improvement in distinguishing disturbance effects and double the accuracy in identifying differentially expressed genes [7][9]. - The model is the first to surpass simple linear baseline models in all tests conducted [7]. - It focuses on single-cell RNA sequencing data, which is currently the only unbiased data available at scale for researchers [7]. Group 3: Data Collection and Causality - The research team compensates for the limitations of single-cell RNA sequencing data by collecting large-scale disturbance data through experiments like CRISPR gene editing [8][9]. - Disturbance data captures causal relationships between genes, providing insights into biological mechanisms that observational data cannot [8][9]. Group 4: Future Developments and Applications - The ultimate goal of the virtual cell model is to help scientists explore a vast space of combinatorial possibilities for cellular changes, which is impractical to test experimentally [12]. - The team has introduced Cell_Eval, a comprehensive evaluation framework for virtual cell modeling, focusing on biologically relevant metrics [12]. - A virtual cell challenge has been launched, offering a $100,000 prize to encourage innovation in this field [12].

撰文丨王聪 编辑丨王多鱼 排版丨水成文 接受免疫检查点阻断 （ICB） 疗法的 非小细胞肺癌 （NSCLC） 患者很少出现完全的临床响应，开发能够实现肿瘤完全消退的治疗策略是临床面临的一大挑战。 大多数患者最多只有部分临床响应，这一事实提示我们，个体肿瘤内部的免疫压力程度或敏感性并不一致。 事实上，多区域取样研究揭示了抗肿瘤免疫的广泛肿瘤内异质性，不同肿瘤区域在免疫细胞浸润程度、新抗原表达以及 T 细胞受体 （TCR） 库方面存在显著差 异。局部免疫逃逸可能会产生严重的临床后果，而且肿瘤中存在不止一处"冷肿瘤"区 （免疫细胞浸润不良） 的患者预后尤其不佳。 尽管 肿瘤由多个遗传上不同的克隆组成，但由于无法从人类癌症中分离并培养出单个亚克隆，因此，这种遗传多样性是否会影响免疫逃逸的可能性，目前仍不清 楚。 2025 年 7 月 3 日，弗朗西斯·克里克研究所、 荷兰癌症研究所、伦敦大学学院癌症研究所的研究人员在 Cancer Cell 期刊发表 了题为： Subclonal immune evasion in non-small cell lung cancer 的研究论文。 该研究利用 非小细胞肺癌 的不同肿 ...

编辑丨王多鱼 排版丨水成文 在动物基因组中，被称为 增强子 （ enhancer ） 的调控性 DNA 元件控制着特定细胞类型中基因表达的精确时空模式。然而，增强子在细胞核内的空间组织以调 控靶基因的方式，目前仍知之甚少。 2025 年 7 月 2 日 ，北京大学生物医学前沿创新中心 （ BIOPIC ） /昌平实验室 谢晓亮 院士团队在 Nature Genetics 期刊发表了题为 ： Single-cell Micro-C profiles 3D genome structures at high resolution and characterizes multi-enhancer hubs 的研究论文。 研究团队开发了 单细胞 Micro-C （scMicro-C） 技术，这种是基 于微球菌核酸酶 （ Micrococcal nuclease ） 的 3D 基因组图谱技术，能够以 高分辨率描绘 3D 基因组结构，并表征了 多增强子中心 （ multi-enhancer hub ） ，即多个增强子与基因启动子相关联，形成空间簇。 此外，该研究还观察到，在单细胞 3D 基因组结构中，具有 PES 的基因 ...

编辑丨王多鱼 排版丨水成文 "脂肪工厂"是如何运作的？ 该研究显示，尼安德特人在猎获大型动物 （马、鹿等） 后，不仅吃肉，他们还还会将富含油脂的骨头 （尤其是四肢骨） 收集起来。他们并非简单地砸骨获取骨髓，而是采用了更"高级"的工艺： 提到 尼安德特人 ，我们的印象往往是原始、粗野、智力落后于 智人 （现代人类） 的"失败者"，然而，一 项最新研究显示，这可能是一个刻板印象。 2025 年 7 月 2 日， Nature 在其官网头条报道了一项最新研究—— 尼安德特人在"脂肪工厂"中熬煮动物 骨头以获取珍贵的脂肪，这比已知的现代人类最早炼制动物脂肪的行为还要早 10 万年。 该研究以： Large-scale processing of within-bone nutrients by Neanderthals, 125,000 years ago 为 题，于 2025 年 7 月 2 日，发表在了 Science 子刊 Science Advances 上。 研究团队在德国莱比锡附近 的 Neumark-Nord 考古遗址进行发掘时，发现了一个大型的"脂肪工厂"，生 活在距今 12.5 万年前的尼安德特人， ...

Core Viewpoint - The article discusses the significance of taurine and its transporter TauT, highlighting recent research that reveals the structural and functional mechanisms of TauT, which may have implications for understanding taurine-related diseases and potential therapeutic strategies [2][9]. Group 1: Taurine and TauT Overview - Taurine is a sulfur-containing β-amino acid essential for various physiological functions, including cell stability, neurotransmission regulation, lipid metabolism, and antioxidant activity [2]. - The ability to synthesize taurine decreases with age, making external intake via TauT crucial [2]. Group 2: Recent Research Findings - A study published in Nature Communications by the Shanghai Institute of Organic Chemistry identified multiple oligomeric states of human TauT in a nanodisc environment using cryo-electron microscopy [3]. - The research revealed a novel dimerization mechanism for TauT, differing from other transporters in the SLC6 family, with cholesterol playing a role in facilitating this oligomerization [6]. Group 3: Mechanism of Substrate Recognition and Transport - The study detailed the structural dynamics of TauT in various states, elucidating its substrate specificity and transport mechanism, where the central site can bind one substrate, two Na⁺, and one Cl⁻, transitioning from an open to a closed state [7]. - Key residues Gly57 and Phe58 are critical for substrate specificity, undergoing conformational changes during substrate release [7][12]. Group 4: Implications for Health and Disease - The findings underscore the importance of lipid microenvironments in regulating TauT oligomerization and provide a structural framework for understanding TauT's function, which may aid in exploring treatment strategies for diseases related to taurine deficiency [9].

撰文丨王聪 编辑丨王多鱼 排版丨水成文 表型可塑性 （ Phenotypic plasticity ） 是驱动癌症进展、转移和治疗耐药性的显著特征。胎儿样 （ Fetal-like ） 转录程序在促进细胞的可塑性状态方面的作用 日益受到关注，但由于现有培养模型的局限性，其作用仍难以研究。 2025 年 7 月 4 日，北京大学 邓宏魁 教授、 屈默龙 副研究员、北京大学首钢医院/北京大学肿瘤医院 顾晋 教授团队 （ 熊亮 、 徐莹 、 高兆亚 为共同第一作 者 ） 在 Cell Research 期刊发表了题为 ： A patient-derived organoid model captures fetal-like plasticity in colorectal cancer 的研究论文。 该研究开发了一种 化学成分明确的患者来源的类器官系统 （ CiPDO ） ，并用该类器官系统捕捉到了 结直肠癌 的 胎儿样可塑性 状态 。 在这项最新研究中，研究团队建立了一种 化学成分明确的患者来源的类器官系统 （ CiPDO ） ，培养条件是 EGF + CHIR99021 （Wnt激动剂） + LDN- 214 ...

Core Viewpoint - Immune checkpoint inhibitors (ICIs) have transformed the treatment of various solid tumors, but resistance remains a significant challenge, particularly in advanced and recurrent ovarian cancer, where response rates to single-agent PD-1/PD-L1 inhibitors are only 5%-15% [2][3] Group 1: Research Findings - A study published in Nature by a team from MD Anderson Cancer Center found that patients with PPP2R1A gene mutations had significantly improved survival after receiving combined anti-PD-1/PD-L1 and anti-CTLA-4 immunotherapy compared to those with wild-type PPP2R1A [3][6] - The presence of PPP2R1A mutations enhances tumor response to immunotherapy, and this finding was validated across various cancer types in clinical cohorts [3][9] - In recurrent ovarian cancer, dual targeting of PD-1/PD-L1 and CTLA-4 showed a response rate of 31.4% compared to 12.2% for single-agent PD-1 therapy, indicating a potential benefit for patients with ovarian clear cell carcinoma (OCCC) [5][6] Group 2: Clinical Implications - The study suggests that targeting PPP2R1A could represent an effective strategy to improve outcomes for cancer patients undergoing immunotherapy [9] - Enhanced immune cell infiltration and signaling pathways were observed in tumors with PPP2R1A mutations, indicating a more favorable immune environment for treatment [8] - The research team is conducting prospective trials to explore the efficacy of dual immune checkpoint blockade in OCCC patients, particularly those with platinum-resistant disease [5][6]

Core Viewpoint - The increasing prevalence of metabolic dysfunction-related fatty liver disease (MASH) necessitates the development of new therapeutic strategies, as current treatment options are limited and the patient population is growing rapidly [2][5]. Group 1: MASH Overview - Approximately 100 million people globally are currently affected by MASH, with projections indicating this number could rise to 357 million by 2030 [2]. - MASH is a critical factor in the progression of liver cirrhosis and hepatocellular carcinoma, and it is a leading cause of liver transplants [2]. Group 2: Research Findings - A new strategy for large-scale acquisition of artificial cell-derived vesicles (ACDV) has been proposed, which allows for the safe and stable oral delivery of RNA drugs targeting the liver [3]. - The study demonstrated that LIMA1 siRNA (siLIMA1) delivered via the modified ACDV effectively inhibited LIMA1 protein expression in the liver, thereby preventing MASH progression and improving liver function [3][11]. Group 3: Mechanism of Action - The development of drugs targeting metabolism, inflammation, and fibrosis is crucial, as excessive accumulation of fats and other metabolic substrates leads to chronic inflammation and liver cell damage [5]. - LIMA1 gene silencing is identified as a promising therapeutic approach for MASH, given its upregulation in lipotoxic liver cells and its role in liver fibrosis associated with metabolic dysfunction [5][6]. Group 4: Delivery System - The study highlights the potential of red blood cell (RBC)-derived extracellular vesicles (RBC-EV) as a non-immunogenic delivery option for RNA drugs, although challenges remain in large-scale production and half-life limitations [7]. - A feasible strategy involves generating ACDV by squeezing red blood cells, which can then be modified with DSPE-PEG and cholic acid to enhance structural integrity and liver-targeting capabilities [8][9]. Group 5: Conclusion - The research indicates that ACDV can be easily obtained and modified to achieve oral liver-targeting capabilities, with the delivery of LIMA1-siRNA showing significant therapeutic effects against MASH [13].

Core Viewpoint - The study reveals that MLKL activates the cGAS-STING pathway by releasing mitochondrial DNA (mtDNA) during necroptosis, leading to the upregulation of interferon β (Ifnb) expression and inflammation, independent of cell membrane rupture [3][10]. Group 1: Mechanism of Necroptosis - Necroptosis is a pro-inflammatory and lytic form of programmed cell death executed by the MLKL protein, which is phosphorylated by RIPK3, causing membrane rupture and the release of damage-associated molecular patterns (DAMPs) [2]. - Phosphorylated MLKL (pMLKL) also translocates to mitochondria, inducing microtubule-dependent mtDNA release, which activates the cGAS-STING pathway [7][8]. - The integrity of microtubules is essential for the release of mtDNA into the cytoplasm [8]. Group 2: Implications for Inflammatory Bowel Disease (IBD) - In a mouse model of IBD mediated by necroptosis, inhibiting the STING pathway accelerates the resolution of intestinal inflammation [3][10]. - The study enhances understanding of necroptosis and its implications for IBD treatment, suggesting that targeting the cGAS-STING pathway may provide therapeutic benefits [10].

Core Viewpoint - The article discusses the promising efficacy of CAR-T cell therapy in treating relapsed or refractory multiple myeloma, highlighting the transition from traditional autologous CAR-T to in vivo CAR-T approaches, which simplify the manufacturing process and reduce costs [2][3][4]. Group 1: In Vivo CAR-T Therapy - In vivo CAR-T therapy involves directly delivering CAR transgenes to endogenous T cells within the body, eliminating the need for complex manufacturing and storage processes associated with traditional CAR-T therapies [3][4]. - A clinical study published in The Lancet reported the first human trial data for in vivo CAR-T therapy targeting B-cell maturation antigen (BCMA) in multiple myeloma patients, demonstrating effective treatment in four patients [4][18]. Group 2: ESO-T01 Development - ESO-T01 is a novel lentiviral vector designed for in vivo T cell engineering, developed by EsoBiotec and Prigen, featuring a humanized single-domain antibody CAR targeting BCMA [6][9]. - The vector has been engineered to reduce immunogenicity and enhance specificity, including mutations to the VSVG protein and overexpression of CD47 to evade the immune system [6]. Group 3: Clinical Trial Results - The ongoing Phase 1 trial involved four adult patients with relapsed or refractory multiple myeloma, all of whom had previously shown disease progression despite multiple treatments [9][10]. - Initial dosing of ESO-T01 was set at 2.0×10^8 transduction units, with all patients experiencing acute inflammatory responses post-infusion, including fever and low blood pressure [11][13]. - By the end of the two-month follow-up, two patients achieved stringent complete responses, while the other two showed partial responses with tumor shrinkage [12][14]. Group 4: Safety and Efficacy Observations - The trial noted significant hematological toxicities, including neutropenia and thrombocytopenia, but most adverse effects resolved during follow-up [13]. - The presence of CAR-T cells was first detected in peripheral blood between days 4-8 post-infusion, peaking between days 10-17, indicating effective T cell expansion [14][18]. - The study provides valuable data for future research on in vivo CAR-T therapies, emphasizing the potential of ESO-T01 in treating difficult-to-manage multiple myeloma cases [19].