Core Insights - The article discusses the release of the "World's Top 2% Scientists" list for 2025, highlighting the impact and achievements of researchers in various fields, particularly in pathology [3][5]. Group 1: Overview of the Ranking - The ranking is a collaboration between Stanford University and Elsevier, focusing on both lifetime scientific influence and annual achievements of researchers [3]. - The data is sourced from Scopus, analyzing over 21.9 million author profiles to select the top 2% of scientists based on citation metrics and H-index [3]. Group 2: Notable Chinese Scientists in Pathology - Five Chinese experts were recognized in the "Lifetime Scientific Influence" category in pathology: Chen Guozhang, Bian Xiuwu, Li Tiejun, Ding Yanqing, and Lai Maode [5]. - Nine Chinese scholars were included in the "Annual Scientific Influence" list for pathology, with notable names such as Chen Guozhang, Bian Xiuwu, and Li Tiejun [5].

撰文丨王聪 编辑丨王多鱼 排版丨水成文 胆管癌 （ Cholangiocarcinoma，CCA ） ， 是一种起源于胆管上皮的高度恶性消化道肿瘤，全球发病率 逐年上升，患者的五年生存率不足 20% 。目前临床治疗手段有限，亟需开发新的有效策略。 2025 年 9 月 24 日，上海交通大学医学院附属仁济医院，上海市肿瘤研究所肿瘤系统医学全国重点实验室 金浩杰 研究组在《 美国国家科学院院刊 》 （ PNAS） 发表了题为： CRISPR screens identify the ATPase VCP as a druggable t herapeutic vulnerability in cholangiocarcinoma 的研究论文。 该研究通过 全基因组 CRISPR-Cas9 筛选 ，发现 ATP 酶 VCP （ Valosin-Containing Protein ） 是胆管 癌的关键依赖性基因。 VCP 抑制剂 CB-5339 可诱导 胆管 癌细胞衰老；进一步联合使用 衰老细胞清除剂 （ Senolytics ） ，能显著清除由 VCP 抑制剂诱导的衰老肿瘤细胞，从而为胆管癌提供了一种" 诱导 ...

Core Viewpoint - The article discusses the advancements in CAR-T cell therapy, particularly focusing on enhancing its efficacy against low-antigen expressing cancers through the integration of intrinsically disordered regions (IDR) with CAR molecules [2][4][6]. Group 1: CAR-T Cell Therapy Overview - CAR-T cells have shown unprecedented success in treating hematological malignancies and are being explored for various diseases, including cancers, infections, autoimmune diseases, and fibrosis [2]. - A significant limitation of CAR-T therapy is its low sensitivity to antigens, requiring hundreds of antigen molecules for activation, which restricts its application to cancers with high antigen expression [2][3]. Group 2: Research Findings - A study published by a team from Yale University demonstrated that fusing IDR with CAR molecules enhances the cytotoxicity of CAR-T cells against low-antigen cancers by promoting biomolecular condensation [4][6]. - The research involved constructing CAR-IDR fusion proteins targeting CD19, CD22, and HER2, which improved the binding of CAR-T cells to cancer cell targets and increased the release of cytotoxic factors [6][8]. Group 3: Implications of IDR Integration - The integration of IDR into CAR-T cells resulted in better anti-tumor effects in both hematological and solid tumor models without spontaneous activation in the absence of antigens, indicating a novel mechanism of action [8]. - This approach expands the toolkit for CAR engineering, suggesting that IDR can serve as a new modular element to enhance the anti-tumor efficacy of CAR-T cells [8].

Core Insights - The article discusses the development of a multimodal AI robotic platform named CRESt, aimed at accelerating the discovery of advanced materials through real-world experimental validation [2][3][4]. Group 1: CRESt Platform Overview - CRESt integrates large multimodal models (LMM) with knowledge-assisted Bayesian optimization (KABO) and robotic automation to enhance material design and performance optimization [3][8]. - The platform utilizes a combination of chemical composition, text embeddings, and microscopic structural images to create a coherent framework for material exploration [7][8]. Group 2: Experimental Achievements - In a three-month period, CRESt autonomously explored over 900 catalyst chemical compositions and conducted 3,500 electrochemical tests, identifying a state-of-the-art catalyst with a cost-specific performance improvement of 9.3 times compared to traditional catalysts [4][12]. - The identified catalyst composition includes elements such as palladium, platinum, copper, and others, showcasing the platform's ability to navigate complex chemical spaces [12]. Group 3: Technological Innovations - CRESt's core innovation lies in its ability to interpret and synthesize heterogeneous data types, allowing for a multidimensional understanding of material systems [8][9]. - The platform's integration with advanced robotic synthesis and characterization enables a rapid feedback loop, transforming traditional material development into an agile closed-loop system [8][9]. Group 4: Future Implications - The framework of CRESt suggests a future where experimental laboratories operate as intelligent ecosystems, driven by AI to autonomously guide research directions and experimental designs [13][14]. - The success of CRESt in the field of electrochemical catalysis indicates its potential transformative impact across various scientific domains, paving the way for rapid prototyping in renewable energy, electronics, and pharmaceuticals [13][14].

撰文丨王聪 编辑丨王多鱼 排版丨水成文 人体组织由 细胞 和 细胞外基质 （ECM） 组成，二者在衰老过程中都会发生退行性变化。目前有关衰老的研究主要集中在细胞衰老及相关事件上 （例如细胞衰 老、干细胞耗竭、基因组不稳定、端粒缩短和表观遗传改变等） ，而衰老过程中细胞外基质的变化及其影响仍鲜有探索。 在组织损伤或退行性变化的情况下，细胞外基质会出现异常重塑和过度降解，导致尿液和体液 （包括血清和滑液） 中游离的细胞外基质片段增加。衰老相关疾病 （例如动脉粥样硬化、慢性阻塞性肺疾病） ，都与血清中 弹性蛋白 （ELN） 片段水平升高有关。同样，软骨退行性病变会导致各种类型的胶原蛋白 （COL） 片段和纤维连接蛋白 （FN） 片段释放到滑液和/或血清中。而乳腺癌和膀胱癌会分别增加血清和肿瘤微环境中透明质酸 （HA） 片段的水平。 这些发现都提示了我们—— 体液中的游离 细胞外基质 （ECM） 片段，可能与全身系统性衰老相关。 该研究首次揭示了 细胞外基质 （ECM） 的 降解片段作为血液循环中的衰老驱动因素，进而提出了一种靶向特定弹性蛋白片段信号的衰老干预策略。 2025 年 9 月 29 日，浙江大学基础医学院 ...

Core Insights - The article discusses the evolutionary emergence of type V CRISPR-Cas systems from transposons, highlighting the discovery of a key evolutionary intermediate named TranC, which bridges the gap between transposons and CRISPR systems [3][11]. Group 1: Research Findings - The research team identified 146 CRISPR candidate proteins closely related to TnpB through a combination of sequence similarity, shared structural domain features, and conserved catalytic motifs [6]. - Six evolutionary intermediate families were identified and named TranC, representing multiple independent evolutionary paths from TnpB to Cas12 [6][7]. - The study revealed that the core mechanism driving the evolution of TnpB transposase to the Cas12 system is the "functional splitting" of guide RNA, rather than fundamental changes in protein structure [3][11]. Group 2: Functional Mechanisms - The TranC system exhibits a unique "dual RNA guiding mechanism," allowing it to utilize both its own CRISPR RNA and ancestral TnpB-derived RNA for targeted cutting [7]. - Structural biology analysis showed that the TranC protein is highly conserved in three-dimensional structure compared to its ancestor TnpB, with differences primarily at the RNA level [8]. - The research demonstrated that the transition from a single RNA-guided TnpB mechanism to a dual RNA-guided CRISPR mechanism can be achieved by functionally splitting the reRNA module [9]. Group 3: Applications and Innovations - The LaTranC genome editing system was engineered to create a high-efficiency variant, TranC11a, which outperforms existing small nucleases and shows comparable editing efficiency to SpCas9 in certain loci [12]. - TranC series core patents have passed the Freedom to Operate (FTO) review, laying a solid foundation for its application in biomedicine and agricultural breeding [13].

Core Insights - The article discusses the potential of circular RNA (circRNA) as a next-generation RNA therapy platform, highlighting its advantages over traditional mRNA therapies, particularly in stability, immunogenicity, and safety [2][4]. Group 1: CircRNA Advantages - CircRNA exhibits superior stability, immunogenicity, and safety compared to chemically modified mRNA and viral vector-based therapies [2]. - CircRNA can utilize internal ribosome entry site (IRES) sequences, eliminating the need for expensive 5' cap modifications and resulting in lower immunogenicity without chemical modifications [2]. Group 2: Research Findings - A study published in Nature Communications demonstrates that circRNA-based protein replacement therapy can alleviate osteoarthritis in male mice [3][4]. - Osteoarthritis (OA) is characterized by cartilage degradation and bone spur formation, with recent research indicating that the expression of Na v 1.7 in chondrocytes leads to cartilage degeneration and pain [6]. Group 3: Mechanism and Treatment Strategy - The study identifies that the downregulation of the RNA-binding protein Musashi2 (MSI2) in chondrocytes is a key factor in the pathogenesis of osteoarthritis [7]. - A local delivery strategy was developed to achieve high and sustained protein expression in chondrocytes, demonstrating that injecting ivcRNA encoding MSI2 effectively slows the progression of osteoarthritis in a mouse model [7][9].

Core Insights - Aera Therapeutics presented preclinical data for its candidate therapy AERA-109 at the 10th CAR-TCR Summit, targeting various B cell-mediated autoimmune diseases, showing significant B cell depletion in humanized mouse models and non-human primates [3][19][22] - The company plans to advance AERA-109 into clinical development by mid-2026, utilizing a proprietary targeted lipid nanoparticle (tLNP) delivery platform for in vivo CAR-T cell therapy [3][22] Company Overview - Aera Therapeutics was founded by CRISPR pioneer Professor Zhang Feng and other executives from Alnylam Pharmaceuticals, completing a $193 million financing round in 2023 [4][5] - The company's vision is to unlock the potential of gene therapies and transform human health by overcoming existing delivery technology limitations [4] Technology and Platforms - Aera Therapeutics has developed three proprietary delivery platforms: targeted lipid nanoparticles (tLNP), antibody-oligonucleotide conjugates (AOC), and protein nanoparticles (PNP) [12][14][15] - The tLNP platform is designed to target cell types and tissues beyond the liver, enhancing therapeutic applications [14] - AOC combines the targeting ability of antibodies with the programmable functionality of oligonucleotides, aiming to expand applications beyond traditional immunology and oncology [15] - PNP is a disruptive delivery platform that utilizes human endogenous proteins for gene therapy delivery, offering modularity and scalability [10][15] Research and Development - AERA-109 utilizes the tLNP platform to deliver CAR mRNA directly to CD8+ T cells in vivo, eliminating the need for pre-treatment and enabling the generation of CAR-T cells within the body [19][20] - Preclinical results demonstrated dose-dependent CAR-T cell generation and significant B cell depletion in both humanized mouse models and non-human primates [20][21] - The therapy showed good tolerability with no significant adverse clinical manifestations or changes in hematological or serum chemistry parameters [22]

Core Insights - CAR-T cell therapy represents a significant breakthrough in cancer treatment, showing potential beyond blood cancers to solid tumors and autoimmune diseases [3][7] - Despite its promise, CAR-T cell therapy faces major challenges, including T cell adaptability, limited proliferation, and immune suppression in the tumor environment [3][8] - Recent studies published in Nature utilized CRISPR technology to enhance CAR-T cell efficacy by identifying and knocking out specific genes [3][10] Group 1: Research Findings - The research from the Austrian Academy of Sciences introduced the CELLFIE platform for CRISPR screening to enhance CAR-T cells across multiple clinical targets [8] - Key findings included the identification of the RHOG gene knockout as a powerful method to enhance CAR-T cell function, outperforming standard CAR-T cells in various models [9] - The study established a foundation for optimizing cell-based immunotherapies through the characterization of CRISPR-enhanced CAR-T cells [9] Group 2: Additional Research Insights - A separate study from Harvard Medical School focused on identifying modifiers of CAR-T cell function in multiple myeloma using in vivo CRISPR screens [10][11] - The research highlighted specific genes, such as RASA2 and SOCS1, that enhance T cell expansion, while CDKN1B was identified as a critical factor limiting CAR-T cell adaptability [11][12] - The findings emphasize the dynamic nature of gene disruption effects on CAR-T cells over time and in different environments, suggesting CDKN1B as a promising target for developing effective CAR-T therapies for multiple myeloma [12]

撰文丨王聪 编辑丨王多鱼 排版丨水成文 众所周知， 衰老 会大大增加 癌症 患病风险。 长期以来，人们一直认为，随着衰老进行的癌症发病率上 升，是由于 CD8⁺ T 细胞 的功能耗竭及其抗肿瘤免疫功能受损所致。 2025 年 9 月 25 日，美国国家衰老研究所的研究人员在 Nature 子刊 Nature Aging 上发表了题为： A distinct population of CD8⁺ T cells expressing CD39 and CD73 accumulates with age and supports cancer progression 的研究论文。 该研究发现了一个 独特的 CD8⁺ T 细胞亚群 ， 其会随着年龄的增长而累积，并促进癌症的发展 ，从而提 出了衰老相关癌症发病率上升的新机制——功能健全的 CD8⁺ T 也可能会促进癌症发展。 https://www.nature.com/articles/s43587-025-00966-3 在这项最新研究中，研究团队提出了一种新机制—— 在衰老过程中，癌症的发展也得到了功能健全的 CD8⁺ T 细胞的帮助 。 研究团队发现，这些 ...