撰文丨王聪 编辑丨王多鱼 排版丨水成文 核酸适配体 （Aptamer） 是一类短的单链 DNA 或 RNA 寡核苷酸，通过形成三维空间结构，靶向结合特定蛋白或者细胞发挥作用， 其具有广泛优点，包括高度 特异性、易于合成、可定制、热稳定性好、分子小、组织穿透能力强等。成为选择性靶向特定蛋白质或细胞以治疗多种疾病类型的新选择。 细胞表面蛋白 是关键的疾病生物标志物和治疗靶点，然而，针对这些细胞表面蛋白进行原位核酸适配体筛选的高通量方法，仍然有限。 2026 年 1 月 1 日，中国科学院杭州医学研究所 谭蔚泓 院士、 吴芩 研究员等 （ 罗国焰 、 宋佳 为论文共同第一作者） 在国际顶尖学术期刊 Science 上发表 了题为： SPARK-seq: A high-throughput platform for aptamer discovery and kinetic profiling 的研究论文。 该研究开发了单细胞扰动驱动型核酸适配体识别与动力学测序技术—— SPARK-seq ，这是一个将单细胞 mRNA 测序、核酸适配体测序与基于 CRISPR 的细胞 表面蛋白扰动技术相结合的高通量平台。 在单次实验 ...

Core Viewpoint - The research presents a novel computational method for designing small molecule-regulated protein oligomers, expanding the toolkit for manipulating complex biological processes [2][3]. Group 1: Research Background and Significance - The study focuses on small molecule-regulated protein oligomerization technology, which allows for precise control of biological processes through spatial proximity of proteins [5]. - Despite over 30 years of development, the number of small molecule-responsive oligomerization systems remains limited, primarily restricted to dimerization, which constrains their application in biological processes requiring multiple protein components [5][6]. - There is a growing demand for more diverse small molecule-responsive protein oligomers in cell engineering and therapeutic development [5]. Group 2: Methodology and Innovations - The research introduces a new computational approach that starts from monomeric protein building blocks to design ligand-responsive oligomers, overcoming the limitations of dimerization [6]. - The method employs a "docking-while-binding" strategy to optimize both protein-protein and protein-ligand interactions during the docking process, enabling the creation of ligand binding pockets directly at the protein-protein interface [6]. - The team successfully designed homomeric trimers that respond to the FDA-approved drug amantadine, demonstrating enhanced response capabilities with the design of both single and dual ligand-binding homomeric trimers [6][10]. Group 3: Applications and Potential - Utilizing the inducibility and multivalency of these homomeric trimers, the research team developed transcription activation systems and reversible protein condensation systems, showcasing broad functional applications [7]. - The optimized systems achieved precise spatiotemporal control of protein localization and gene expression, highlighting their potential in biomedical applications [7][10]. - The use of amantadine, which has favorable oral bioavailability, allows for non-invasive, dose-dependent gene expression control in mouse models, emphasizing the system's strong potential for practical applications [7][10].

Core Viewpoint - The article discusses the development of a wireless, battery-free, ultrathin intracranial pressure (ICP) sensor system that integrates piezoelectric thin film resonators with wireless inductive coupling, addressing the limitations of current monitoring systems in clinical settings [2][12]. Group 1: Challenges in Current Monitoring Systems - Current clinical monitoring systems rely on rigid sensors or catheters connected via transcranial leads, which pose high infection risks, limit patient mobility, and are uncomfortable for long-term use [1]. - Despite advancements in flexible electronics and wireless sensing technologies, many devices still depend on rigid wireless modules or batteries, making it difficult to achieve true flexible conformal attachment to soft tissues, especially for implantable applications [1]. Group 2: Innovations in Sensor Technology - The research team from Fudan University has developed a wireless, ultrathin ICP sensor system using a 3-micron thick lithium niobate thin film (LNTF) that can seamlessly integrate with human soft tissues without the need for batteries [2]. - The sensor operates based on changes in resonant frequency due to mechanical deformation, allowing for high-sensitivity, real-time monitoring of various physiological signals [2][6]. Group 3: Performance and Capabilities - The resonator's intrinsic frequency is measured at 58.163 MHz with a quality factor (Q) of approximately 300, providing a foundation for high-sensitivity sensing [7]. - The device can detect strain as low as 0.03% with a sensitivity of 56.9 Hz/με, demonstrating excellent repeatability and stability under dynamic and cyclic strain loading [7]. - The pressure sensor can measure pressures as low as 0.15 mmHg with a sensitivity of 0.223 kHz/mmHg, covering a wide range of 0-240 mmHg, which meets clinical ICP monitoring requirements [9]. Group 4: Validation and Clinical Application - Successful implantation in a rat model demonstrated the device's ability to accurately respond to acute ICP changes and track cerebrospinal fluid volume variations, confirming its capability to capture clinically relevant physiological signals [12]. - The device has shown functional stability and biocompatibility in long-term implantation environments, indicating its potential for continuous monitoring of various physiological signals and disease-related internal pressures [12].

Core Viewpoint - The article discusses the limitations of current spatial transcriptomics (ST) technologies, which primarily operate in two dimensions, and introduces a new computational framework called SpatialZ that enables the reconstruction of dense 3D cell atlases from sparse 2D slices, significantly enhancing the understanding of biological functions and tissue organization [2][3][10]. Group 1: Limitations of Current Technologies - Current ST technologies are limited to 2D observations, making it difficult to capture the continuous gradients of gene expression and the intricate cellular interactions within organs [2]. - The compromise in sampling density along the Z-axis due to high experimental costs leads to significant gaps in data, resulting in a fragmented view of biological tissues [2]. Group 2: Introduction of SpatialZ - SpatialZ is a novel computational framework that integrates optimal transport theory to generate virtual slices between sparse real slices, facilitating the transition from discrete 2D data to dense 3D maps [3][5]. - The framework has successfully constructed a digital mouse brain atlas containing over 38 million cell gene expressions and 3D coordinates, marking a significant advancement in the field of life sciences [3][8]. Group 3: Methodology of SpatialZ - SpatialZ employs a four-step algorithm for high-fidelity 3D reconstruction, including spatial alignment, position generation, cell state inference, and expression profile inference [5]. - The methodology ensures that the generated cells not only have accurate spatial positioning but also reflect the biological states and microenvironment characteristics [5]. Group 4: Validation and Performance - The reliability of SpatialZ was validated using mouse visual cortex data, showing that it accurately restored missing intermediate layer information and maintained high consistency with ground truth data [6][7]. - The framework demonstrated improved correlation and statistical significance compared to unprocessed sparse sampling data, effectively addressing structural information gaps caused by sparse sampling [7]. Group 5: Broader Applications - SpatialZ's underlying logic is highly generalizable, allowing its application in spatial proteomics, spatial metabolomics, and other multi-omics data, providing new perspectives for complex disease research [9]. - The framework has been successfully applied to human breast cancer tissue imaging mass cytometry data, correcting expression anomalies caused by tissue loss or technical artifacts, thus aiding in spatial screening for tumor immunotherapy targets [9]. Group 6: Conclusion - SpatialZ represents a breakthrough in computational methods, bridging the gap from single-cell analysis to organ-level digitalization, and offers a standardized digital reference for neuroscience research [10]. - The framework opens new possibilities for constructing comprehensive 3D spatial maps across modalities, organs, and species, potentially leading to new discoveries in developmental biology, neuroscience, and oncology [10].

Core Viewpoint - The article discusses the development of a novel high-throughput screening technology called FOCAS, which enables the functional dissection of individual m6A sites in mRNA, significantly enhancing the understanding of m6A's role in gene expression regulation, particularly in cancer [3][11]. Group 1: m6A Modification and Its Importance - m6A is the most prevalent chemical modification in mRNA, regulating gene expression without altering RNA sequences [2]. - The m6A modification process is controlled by three types of proteins: "Writers" (METTL3/METTL14 complex), "Erasers" (FTO, ALKBH5), and "Readers" (YTHDF family proteins) [2]. Group 2: FOCAS Technology Development - FOCAS is based on the CRISPR-dCas13b system and FTO, allowing for high-throughput, site-specific functional screening of m6A [4][8]. - This technology provides a powerful and unbiased method for functional analysis of m6A, laying a solid foundation for future basic research and therapeutic development [4][11]. Group 3: Key Findings from the Research - A total of 4,475 genes were identified whose expression is regulated by m6A across four cancer cell lines, affecting cell survival and proliferation [9]. - Many identified m6A-regulated genes are newly associated with cancer, exhibiting dynamic expression changes [9]. - The role of m6A within the same gene varies depending on the cellular environment and the "Reader" proteins involved, indicating a complex regulatory mechanism [9]. - The study identified "universal" m6A patterns present in all cell lines, particularly in transcription-related genes, and "specific" m6A patterns unique to certain cell types, especially in non-coding RNAs [9]. - An extensive interaction network between the m6A modification layer and the gene expression layer was revealed in the SMMC-7721 human liver cancer cell line [9].

2025 年 12 月 29 日，特拉维夫大学的研究人员在 Nature Genetics 期刊发表了题为： p53 inactivation drives breast cancer metastasis to the brain through SCD1 upregulation and increased fatty acid metabolism 的研究论文。 乳腺癌 仍是全世界范围内女性中最常见的恶性肿瘤。早期乳腺癌通常可以治愈，但远端转移的出现显著降低了 5 年生存率。尽管系统性治疗手段有所进步，提高 了生存率，但这些疗法在控制远端转移进展方面的效果仍不尽人意。 乳腺癌最常见的转移部位是骨骼、肺、肝脏和大脑。尤其令人担忧的是 脑转移瘤 （BM） ，它是导致死亡的主要原因。大约 15%-24% 的转移性乳腺癌患者会 出现脑转移，由于有效治疗手段匮乏，这严重损害了患者的生活质量及预后。因此，迫切需要阐明 乳腺癌脑转移瘤 （BCBM） 的细胞和分子机制，以开发更有 效的预防措施和治疗策略。 撰文丨王聪 编辑丨王多鱼 排版丨水成文 脑转移瘤 （BM） 预后不良，但其脑趋向性的分子基础仍不清楚。对 乳腺癌脑 ...

Core Viewpoint - The article discusses the discovery of a hyper-translation pathway in monocytes/macrophages that drives cytokine release syndrome (CRS), suggesting that targeting this pathway could be a potential therapeutic strategy for CRS [2][10]. Group 1: Overview of Cytokine Release Syndrome (CRS) - Cytokine release syndrome (CRS), also known as cytokine storm, is a potentially life-threatening inflammatory condition often triggered by infections or immunotherapy [5]. - It is estimated that 50%-90% of patients receiving CAR-T cell therapy experience CRS, with clinical manifestations ranging from mild fever to life-threatening multi-organ failure [5][11]. - The core of CRS pathogenesis lies in the excessive production of pro-inflammatory cytokines, particularly interleukin-6 (IL-6) [5]. Group 2: Mechanisms and Research Findings - The study published in Cell Reports Medicine identifies monocyte/macrophage hyper-translation as a significant feature of CRS pathogenesis [9][11]. - The research team discovered that BCAP is a key regulatory factor for hyper-translation, activating the RSK-EIF4B signaling axis, which leads to excessive translation in macrophages [9][13]. - Genetic deletion of RSK alleviated CRS-related inflammation, and pharmacological inhibition of RSK reduced CRS symptoms in humanized mouse models [9][10]. Group 3: Implications for Treatment - The findings establish hyper-translation as a critical pathogenic feature of CRS and highlight protein translation as a potential druggable target for therapeutic intervention in CRS and other inflammatory diseases [10][13].

Group 1 - The core viewpoint of the article is that Westlake University is actively recruiting faculty for its Center for Infectious Disease Research (CIDR) to advance research on emerging infectious diseases [2][3] - CIDR focuses on transformative scientific progress in understanding various infectious diseases, including influenza, tuberculosis, hepatitis B, and coronaviruses [2] - The university offers competitive salaries and startup funding to attract outstanding scientists in fields such as pathology, immunology, vaccine research, epidemiology, and drug discovery [3] Group 2 - Applicants are required to have a medical doctorate, PhD, or equivalent degree, along with significant postdoctoral research experience and a strong publication record [2] - The application process includes submitting a cover letter, CV, research statement, and three recommendation letters [4][7] - Applications will be reviewed on a rolling basis until the positions are filled, and inquiries can be directed to the provided email address [5]

Core Viewpoint - The article discusses a significant study identifying rare genetic variants associated with Attention Deficit Hyperactivity Disorder (ADHD), revealing that individuals carrying these variants have a substantially higher risk of developing ADHD compared to the general population [4][9]. Group 1: ADHD Overview - ADHD is a neurodevelopmental disorder affecting approximately 5% of children globally, with about half of these cases persisting into adulthood, leading to various severe consequences [3]. - The study highlights the importance of understanding the biological mechanisms driving ADHD for future treatment and intervention strategies [3]. Group 2: Research Findings - A groundbreaking study published in Nature identified three rare genetic variants—MAP1A, ANO8, and ANK2—significantly linked to ADHD risk, with individuals carrying these variants having a 5.55 to 15.31 times higher risk of developing the disorder [4][9]. - The research involved a large sample size of 8,895 ADHD patients and 53,780 healthy controls, focusing on rare coding gene variants that can severely impact protein function [7]. Group 3: Genetic Mechanisms - MAP1A is crucial for microtubule assembly and neuronal structure, while ANO8 and ANK2 are involved in calcium ion transport, indicating that ion channel dysfunction plays a significant role in ADHD [11]. - The study found that these rare variants not only increase the risk of ADHD but also significantly affect cognitive function and socioeconomic status, with carriers being 24% more likely to complete only basic education and 28% more likely to experience low socioeconomic status [14]. Group 4: Combined Genetic Effects - The research explored the combined effects of common and rare genetic variants, revealing that they contribute to ADHD risk additively, with rare variants acting as risk accelerators [17]. Group 5: Implications for Future Research - The findings suggest that the identified genes explain only 5.2% of the heritability associated with rare variants, indicating that more ADHD risk genes remain to be discovered [19]. - Long-term implications include the potential for developing precise diagnostic methods, personalized treatment strategies, and reducing stigma associated with ADHD by clarifying its biological basis [20].

Core Viewpoint - The article discusses the advancements in anti-aging research, highlighting a shift from basic science to clinical applications, with significant breakthroughs expected by 2025 that could lead to interventions in the aging process and extended healthspan [1]. Group 1: Breakthroughs in Anti-Aging Research - The research from Washington University reveals the role of meningeal lymphatics in regulating synaptic physiology, showing that restoring lymphatic function in aged mice can reverse memory deficits [3][4]. - A study published in Nature identifies the loss of the Y chromosome as a potential new target in anti-aging and cancer research, linking it to cancer progression and immune response deterioration in males [6]. - Research from the Chinese Academy of Sciences demonstrates that the metabolite betaine can mimic exercise effects, providing a new strategy for systemic anti-aging interventions [10]. Group 2: Mechanisms of Aging and Longevity - A study from Harvard Medical School indicates that lithium deficiency is linked to cognitive decline and Alzheimer's disease, with lithium supplementation reversing memory loss in mice [13]. - Research from Altos Labs introduces the concept of "mesenchymal drift," where cells lose their identity with age, and suggests that partial reprogramming can reverse this process [16]. - A study from Baylor College of Medicine reveals how lysosomal changes in parents can promote longevity in offspring through epigenetic mechanisms [19]. Group 3: DNA Repair and Aging - Research from Tongji University highlights a mutation in the cGAS protein in naked mole-rats that enhances DNA repair and extends lifespan, suggesting new strategies for human longevity [21]. - A study on bowhead whales identifies a cold-inducible protein that aids in DNA repair, contributing to their long lifespan and low cancer risk [24][26]. Group 4: Dietary and Reproductive Factors in Longevity - Research from Westlake University shows that protein restriction can reprogram the proteomic landscape in aging mice, offering insights into dietary interventions for longevity [28]. - A large-scale study from Otago University finds that sterilization and contraception can significantly extend lifespan across vertebrates, suggesting that energy allocation away from reproduction may enhance longevity [31][32]. Group 5: Immunity and Aging - A study from Zhang Feng's team demonstrates that mRNA technology can temporarily enhance liver function to produce immune factors, reversing immune aging in mice and improving responses to vaccines and cancer treatments [36].