Core Viewpoint - The study published in Nature Aging indicates that inflammaging, or age-related chronic inflammation, is not universal across different human populations, suggesting that it may be a byproduct of industrialized lifestyles rather than a universal aging process [1][8]. Group 1: Research Findings - The research compared industrialized populations (from Italy and Singapore) with non-industrialized populations (Tsimane from Bolivia and Orang Asli from Malaysia) to assess the universality of the inflammaging phenomenon [1][5]. - In industrialized populations, inflammation increases with age and is associated with age-related chronic diseases such as stroke, cardiovascular diseases, and cancer [7]. - In contrast, the non-industrialized populations exhibited high baseline inflammation levels due to common infections, but this inflammation did not increase with age and was not linked to chronic diseases [6][7]. Group 2: Implications - The findings challenge the existing paradigm surrounding inflammaging and highlight the importance of considering cultural, environmental, and lifestyle factors in aging research [8]. - Further exploration of how specific environmental conditions modulate inflammaging and its health outcomes could lead to targeted strategies for preventing age-related diseases in diverse global populations [8].

Core Viewpoint - Ferroptosis has emerged as a promising anti-tumor treatment strategy, distinct from apoptosis and necroptosis, characterized by uncontrolled lipid peroxidation and high levels of ferrous ions (Fe2+) and reactive oxygen species (ROS) [2][3][7]. Group 1: Mechanism and Inducers of Ferroptosis - GPX4 utilizes glutathione (GSH) to reduce lipid peroxides to lipid alcohols, making targeting GPX4 or GSH a potential strategy for cancer therapy [3]. - Lipid peroxidation may serve as a "find me" signal, enhancing tumor immunotherapy effectiveness [3]. - Inducers of ferroptosis, such as RSL3 and erastin, have shown efficacy in inducing ferroptosis in mouse tumor models and human tumor cell lines [3][4]. Group 2: Research Findings on Acevaltrate - A recent study identified acevaltrate (ACE) as a novel ferroptosis inducer that targets both PCBP1/2 and GPX4 in colorectal cancer cells, leading to rapid and strong induction of ferroptosis [4][8]. - ACE increases intracellular Fe2+ levels by targeting and reducing the expression of iron chaperone proteins PCBP1/2, while also inhibiting GPX4 activity, disrupting the antioxidant system in colorectal cancer cells [9][12]. - Animal experiments indicate that ACE demonstrates superior therapeutic effects compared to known ferroptosis inducers and first-line clinical cancer drugs like capecitabine and TAS-102 [10][12]. Group 3: Implications for Clinical Treatment - The dual mechanism of ACE not only enhances the induction of ferroptosis but also addresses the compensatory resistance issues associated with single-target ferroptosis inducers [12]. - ACE's multi-target characteristics suggest a potential for high efficacy and low toxicity in selectively killing tumor cells, providing a new strategy for clinical treatment of colorectal cancer [12].

Core Viewpoint - The research indicates that sleep is essential for preventing the disruption of the brain phosphoproteome, which is crucial for survival [2][3]. Group 1: Importance of Sleep - Sleep is an indispensable behavior preserved across all animal species, and long-term sleep deprivation (Pr-SD) can lead to mortality in various species [1]. - The core molecular basis linking sleep deprivation-induced lethality and sleep homeostasis in mammals remains unclear [8]. Group 2: Mechanisms and Functions of Sleep - Numerous factors affecting sleep duration or quality have been reported, including biological clock genes, neural circuits, specific kinase signaling pathways, and neurotransmitters [6]. - Research has identified several functions related to sleep, such as cognition, metabolic waste clearance, metabolism, and immune function [6]. Group 3: Research Methodology - The Disk-over-water (DOW) method is utilized to study sleep deprivation by placing animals on a disk above water, forcing them to stay awake [10]. - The study observed an "irreversible point" (PONE) state in rats during DOW experiments, characterized by irreversible mortality even after sleep deprivation is terminated [11]. Group 4: Findings on PONE State - Analysis of the PONE state revealed that the balance of the brain phosphoproteome is critical for sleep regulation and the mortality caused by Pr-SD [12]. - Mice in the PONE state were unable to enter natural sleep, and their brain phosphoproteome exhibited significant disruption, closely related to the PONE state rather than the duration of sleep deprivation [13]. Group 5: Implications for Sleep and Health - Dysfunction in brain kinases or phosphatases affects the development of the PONE state and leads to corresponding sleep abnormalities [14]. - Restorative sleep of 80 minutes daily can significantly delay cognitive decline and restore the brain phosphoproteome [14]. - The findings suggest that sleep is vital for maintaining the homeostasis of the brain phosphoproteome, and its disruption may influence lethality caused by long-term sleep deprivation [14].

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].

Core Viewpoint - The article discusses a recent study that highlights the role of fetal-like transcription programs in promoting phenotypic plasticity in colorectal cancer, which is crucial for cancer progression, metastasis, and treatment resistance [2][3]. Group 1: Research Development - A patient-derived organoid model (CiPDO) was developed to capture the fetal-like plasticity state in colorectal cancer [4]. - The CiPDO system was cultivated under specific conditions using EGF, CHIR99021, LDN-214117, and FGF2, allowing for long-term expansion of colorectal cancer cells while retaining fetal-like characteristics [7]. Group 2: Key Findings - The research identified an oncofetal state (OnFS) enriched in advanced tumors, associated with key plasticity features including epithelial-mesenchymal transition, increased metastasis, and enhanced treatment resistance [8]. - Mechanistically, the FGF2-AP-1 signaling pathway was shown to maintain the OnFS program and related phenotypic plasticity in colorectal cancer [9]. Group 3: Implications - The patient-derived organoid model provides a powerful platform for studying the fetal-like characteristics of cancer cells and their roles in tumor progression and treatment resistance in colorectal cancer [11].

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]