撰文丨王聪 编辑丨王多鱼 排版丨水成文 哺乳动物的大脑是一个错综复杂的神经元回路网络，由数十亿个神经元通过数以万亿计的突触相互连接而 成。在这个复杂的结构中，单个神经元在形态、转录身份和功能作用方面表现出显著的异质性。揭开大脑 的组织原则和功能连接性需要具备单细胞分辨率的方法学，以捕捉这种多样性。 基因标记、高分辨率成像和计算分析方面的最新进展，极大地促进了在哺乳动物系统中对整个大脑神经元 形态的重建工作。这些进展为了解介观尺度 （即细胞水平） 的连接性和支撑大脑功能的结构模式提供了关 键见解。然而，要想生成具有单神经元分辨率的全面大规模脑图谱，仍需在 标记准确度和成像效率方面取 得进一步创新。 近日，北京生命科学研究所/清华大学生物医学交叉研究院 林睿 实验室与北京脑科学与类脑研究所 罗敏敏 实验室合作，在 Cell 子刊 Neuron 上发表了题为： Ultrabright Chemical Labeling Enables Rapid Neural Connectivity Profiling in Large Tissue Samples 的研究论文，该论文还被选为当期 封面论文 。 该研究提出了一种 ...

Core Insights - The article discusses a recent study revealing the neuroimmune mechanisms behind social withdrawal during illness, suggesting that this behavior is an active choice driven by specific neurons in the brain rather than a passive response to physical discomfort [2][20]. Group 1: Research Background - Traditional views suggest that social withdrawal during illness is a passive reaction due to discomfort, but evolutionary biologists propose it may serve adaptive purposes, such as preventing disease spread and conserving energy [6]. - The research team from MIT and Harvard Medical School conducted experiments to explore the neural mechanisms underlying this behavior, focusing on cytokines as messengers between the immune and nervous systems [6]. Group 2: Key Molecule - IL-1β - In a large-scale behavioral screening, the study found that among 21 cytokines tested, only IL-1β uniquely induced social withdrawal in mice [8]. - The experimental design allowed mice to explore a runway, showing that those treated with IL-1β exhibited significant social withdrawal compared to normal mice [8]. Group 3: Identifying the "Loneliness Switch" - The study identified that IL-1β's main receptor, IL-1R1, is highly expressed in the dorsal raphe nucleus (DRN), a key source of serotonin neurons that regulate social behavior [12]. - Over 90% of IL-1R1-expressing neurons in the DRN are serotonin neurons, challenging the traditional view that serotonin primarily promotes social behavior [12]. Group 4: Causal Relationship Verification - The research confirmed that activating IL-1R1 neurons led to social withdrawal even without immune challenges, while inhibiting these neurons prevented social withdrawal induced by IL-1β [14][15]. - Gene knockout experiments showed that specifically knocking out IL-1R1 in DRN neurons completely blocked IL-1β-induced social withdrawal without affecting motor suppression [16]. Group 5: Real-World Implications - The study's findings were validated in a natural social environment, where IL-1β-treated mice actively isolated themselves from companions, demonstrating that social withdrawal is a conscious choice during illness [18]. - Both peripheral and central IL-1β contribute to this process, creating a self-reinforcing cycle that prolongs social withdrawal, with microglia playing a crucial role [18]. Group 6: Broader Implications - This research provides insights into the neuroimmune interactions that may help understand social withdrawal in certain mental disorders, such as depression, which often accompanies inflammatory states [20]. - The findings highlight the complexity of the dialogue between the brain and immune system, suggesting that the desire for solitude during illness is a biologically sophisticated self-protection strategy shaped by natural selection [20].

这一技术的核心创新在于将组织中的蛋白质先锚定、再膨胀、再扫描：第一步，锚定蛋白质，即用锚定 试剂将蛋白质锚定在水凝胶网络中，避免蛋白质扩散并去除干扰物质；第二步，使组织线性膨胀3至7倍 且保持结构完整；第三步，给蛋白"拍高清照"，即原位酶解与质谱成像；第四步，通过自主开发的计算 流程解析数据，自动识别组织结构与特异性蛋白。 为验证iPEX的性能与应用价值，研究团队在多种组织、类器官及疾病模型中开展实验。邹贻龙介绍， 在小鼠视网膜研究中，iPEX仅凭蛋白质表达谱就重构出清晰的组织分层，识别出不同细胞层的特异性 蛋白质，这是传统技术无法实现的。此外，研究团队还在小鼠小脑、小鼠肠道、人源脑类器官、小鼠肝 脏组织等样本中展开测试，验证了iPEX的通用性。 "未来，iPEX技术有望在基础研究中助力科学家直接观察蛋白质在精细组织中的分布规律，在临床转化 层面有望为阿尔茨海默病等疾病的早期诊断与治疗提供新路径，为生命科学研究开辟更广阔的视 野。"邹贻龙表示。（记者刘园园，西湖大学供图） 记者11月13日获悉，西湖大学生命科学学院特聘研究员邹贻龙团队与基里尔·皮亚特克维奇（Kiryl D. Piatkevich）团队合作研发 ...

Core Insights - Researchers at Ben-Gurion University of the Negev have discovered a type of immune cell that may help delay aging and provide new approaches for diagnosing and treating age-related diseases [1][2] Group 1: Research Findings - Aging cells in the human body are defined as cells that irreversibly stop dividing due to chromosomal damage under stress, accumulating with age and leading to various age-related diseases [1] - A previously underappreciated subset of CD4 helper T cells accumulates with age, which was initially overlooked by researchers [1] - A study in Japan on centenarians revealed that their immune systems are rich in this subset of helper T cells [1] Group 2: Mechanism and Implications - CD4 helper T cells have the ability to "clean up" aging cells, as confirmed by experiments on mice [1] - Reducing the number of these helper T cells in mice leads to accelerated aging and shorter lifespan, while increasing their numbers helps delay aging [1] - The research suggests that rather than needing an "overactive immune system," a properly functioning immune system aligned with life stages is essential for combating aging [1]

Core Insights - The Changping Laboratory in Beijing, celebrating its 5th anniversary, has gathered top scientists from China, the US, Japan, and Europe to discuss the latest advancements and future trends in "immunology and oncology" for the benefit of global biomedical development and human health [1][2] Group 1: Laboratory's Role and Achievements - The Changping Laboratory is a key national life sciences research institution focused on strategic, forward-looking, and fundamental scientific research, aiming to build a world-class innovation hub in life sciences [2] - Over the past five years, the laboratory has achieved several internationally influential research results [2] - The laboratory provides a broad research platform for young scientists, with ongoing projects utilizing artificial intelligence, big data, and algorithms for antibody drug design [2] Group 2: International Collaboration and Recognition - International experts recognize China's significant emphasis on basic research, which benefits both the nation and global scientific exploration [2] - Clinical research and translational outcomes from China have impressed international scholars, highlighting the potential for direct benefits to patients and improvements in human health [2] - There is a strong desire among international scientists to collaborate with Chinese researchers to explore scientific frontiers together [2][4]

Core Viewpoint - The 5th anniversary of Changping Laboratory highlights its contributions to the field of immunology and oncology, emphasizing the importance of tumor immunotherapy in addressing global health challenges such as aging populations and rising cancer rates [1][2]. Group 1: Scientific Contributions - The laboratory has made significant advancements in cancer treatment, particularly in tumor immunotherapy, positioning China as a key player in the transition to precision immunotherapy [1]. - Notable research achievements include the identification of broad-spectrum neutralizing antibodies, the discovery of tumor memory cells responsive to PD-1 therapy, and the application of stem cell reprogramming in liver disease treatment [3]. Group 2: Collaborative Efforts - The forum featured participation from top scientists from China, the US, Japan, and Europe, fostering international collaboration in life sciences and cancer research [1][2]. - Emphasis was placed on the need for interdisciplinary and cross-national cooperation to enhance basic and applied research in life sciences, leveraging emerging technologies like artificial intelligence and big data [2]. Group 3: Future Directions - Changping Laboratory aims to continue its focus on strategic and foundational scientific research, aspiring to become a world-class center for life science innovation [2]. - The laboratory is encouraged to lead in exploring new ideas and methods for cancer prevention and treatment, contributing significantly to global health initiatives [2][3].

Core Insights - The article discusses the significant relationship between maternal gut microbiome during early pregnancy and the risk of preterm birth, highlighting the need for further understanding of this connection [2][3][4]. Group 1: Research Findings - A study involving a cohort of 5,313 pregnant women identified a direct association between early pregnancy gut microbiome characteristics and preterm birth risk [3][6]. - The gut bacterium Clostridium innocuum was identified as a novel biomarker for predicting preterm birth, with its presence correlating positively with preterm birth risk [3][7]. - The research established a preterm microbiome risk score (MRS) that effectively differentiates between women with shorter gestation periods and higher preterm birth risk [6][7]. Group 2: Mechanisms and Implications - Clostridium innocuum was found to degrade 17β-estradiol, a hormone linked to pregnancy outcomes, suggesting a mechanism by which it influences preterm birth risk [6][8]. - The study indicates that maternal polygenic risk for preterm birth is amplified by the presence of Clostridium innocuum, emphasizing the interaction between genetic susceptibility and microbiome composition [6][7].

Core Viewpoint - Aging is a major risk factor for various neurodegenerative diseases, including Alzheimer's disease, and is associated with the accumulation of senescent cells that propagate the aging process through paracrine signaling [2] Group 1: Research Findings - The research published in Nature Aging demonstrates that border-associated macrophages (BAM) regulate cognitive aging by inducing paracrine senescence in microglia through migrasome-mediated mechanisms [4][8] - In the early stages of brain aging, BAM acquire senescence-related characteristics, potentially due to prolonged exposure to beta-amyloid (Aβ) [7] - Senescent-like BAM exhibit increased production of migrasomes, which transmit aging-related signals to neighboring cells, particularly microglia, inhibiting their apoptosis and promoting senescence induction [8] Group 2: Intervention Strategies - The research team developed intervention strategies targeting migrasome production by delivering siRNA to block Tspan4, which can improve cognitive deficits in aged mice [8] - These findings suggest that migrasomes are powerful carriers of aging regulatory signals and represent a promising target for Senomorphic therapies, which aim to inhibit the senescence-associated secretory phenotype without affecting cell death [8]

Core Viewpoint - The research presents a new model of human gastric organoids, termed "gastroids," which successfully replicates the asymmetric tissue patterning along the anterior-posterior axis during early stomach development, addressing the WNT "signal gradient paradox" in gastric development [4][5][6]. Group 1 - The study was conducted by a collaborative team from Tsinghua University, Kunming University of Science and Technology, and other institutions, and published in the journal Nature [3]. - The gastroids developed from human pluripotent stem cells (hPSCs) exhibit a dual gastric fundus-antrum pattern and closely resemble in vivo gastric development at molecular, cellular, structural, and anatomical levels [5][6]. - The research identifies NR2F2 as a key factor mediating the formation of the gastric fundus-antrum pattern during the development of gastric organoids [5]. Group 2 - The study provides a unified new theory to resolve the existing paradox regarding the WNT signaling gradient in gastric organ development, which has challenged traditional developmental biology paradigms [5][6]. - The gastroids serve as a more realistic experimental platform for advancing research on gastric organogenesis and the development of gastric organoids [4][6].

Core Viewpoint - The study highlights the significant role of the oral virome in human health, particularly its connection to obesity and type 2 diabetes, and introduces the Human Oral Virome Database (HOVD) as a valuable resource for understanding these relationships [3][5][7]. Group 1: Research Findings - The research team constructed the Human Oral Virome Database (HOVD), which includes 24,440 viral operational taxonomic units (vOTUs) and 83 eukaryotic viruses, providing a comprehensive resource for studying oral viromes [3][5][7]. - The study found that the oral virome diversity is reduced in obese patients with type 2 diabetes, indicating a weak correlation with clinical features and enhanced oral-gut virus transmission [6][7]. - The research identified phages that infect Porphyromonas gingivalis, a key pathogen in periodontal disease, and screened for six potential endolysins that can inhibit its growth, suggesting a new therapeutic avenue for managing periodontal disease associated with type 2 diabetes [6][7]. Group 2: Implications for Disease Understanding - The findings suggest that oral viruses may influence the progression of diseases such as oral cancer, periodontal disease, and rheumatoid arthritis, indicating potential prognostic and diagnostic applications based on microbiome composition [5][6]. - The study enhances understanding of host-virus interactions within the oral microbiome and provides new insights for the diagnosis and treatment of human diseases [9].