Core Viewpoint - The article discusses the groundbreaking advancements in gene therapy for hereditary hearing loss, particularly focusing on the OTOF gene mutation and its clinical trials, marking a significant paradigm shift in treatment approaches [5][8][54]. Group 1: Gene Therapy Developments - Adeno-associated virus (AAV)-based gene therapy strategies have shown effectiveness in animal models for over 20 genetic mutations causing hereditary deafness [5]. - In 2022, Fudan University completed the world's first clinical trial for genetic therapy of hereditary deafness in Shanghai, establishing a clinical framework for treating congenital hearing loss [5][10]. - As of 2023-2025, seven additional clinical trials targeting OTOF gene mutations have been registered across eight countries, with five trials reporting successful hearing restoration through dual AAV delivery strategies [5][8]. Group 2: Clinical Trial Insights - Eight clinical trials for autosomal recessive deafness type 9 (DFNB9) have been registered in 51 centers across eight countries, accelerating the development of auditory gene therapy [8][10]. - The first DFNB9 gene therapy case was reported in December 2022, with subsequent trials confirming hearing improvement in various patient demographics [13][33]. - The trials face challenges such as precise surgical delivery methods and the establishment of standardized patient selection criteria [14][56]. Group 3: Technical Aspects of Gene Delivery - AAVs are preferred for inner ear gene delivery due to their efficient cochlear transduction and low immunogenicity [16]. - Various AAV serotypes have been tested for their ability to transduce inner hair cells effectively, with non-human primate studies showing promising results [16][17]. - The gene therapy strategies include both gene replacement and gene editing approaches, with ongoing research into optimizing delivery methods and ensuring safety [18][20]. Group 4: Clinical Trial Challenges and Future Directions - The clinical trials for DFNB9 gene therapy face significant challenges, including the anatomical complexity of the inner ear and the need for rigorous safety and efficacy assessments [14][30]. - Future strategies must address the optimization of treatment protocols, including patient age and severity of hearing loss, to maximize therapeutic benefits [55][56]. - The article emphasizes the importance of establishing standardized follow-up protocols to monitor long-term outcomes and potential risks associated with gene therapy [52][56].

Core Viewpoint - The article discusses the role of Fibroblast Growth Factor 21 (FGF21) in the context of heart failure with preserved ejection fraction (HFpEF), highlighting its mechanism of action through inter-organ communication and its potential as a therapeutic target in cardiovascular metabolic diseases [4][5]. Group 1: FGF21's Inter-Organ Communication Effects - FGF21 plays a crucial role in regulating mitochondrial energy metabolism through the adipose-heart axis, which is essential for improving HFpEF [4]. - The protective effects of FGF21 on the heart are dependent on the adiponectin (APN) signaling pathway [5]. Group 2: Biological Functions of FGFs and Drug Development - The article emphasizes the diverse biological functions of FGFs, particularly FGF21, in maintaining metabolic homeostasis, including blood glucose and blood pressure regulation, and its implications for drug development targeting cardiovascular metabolic diseases [5][15]. Group 3: Insights into Protein Drug Development - The discussion includes the clinical translation challenges in the development of protein drugs based on FGF signaling pathways, indicating a need for innovative approaches in this area [5][15]. Group 4: Event Announcement - An upcoming lecture featuring researcher Lin Zhuofeng will delve into the inter-organ communication mechanisms of FGF21 and its implications for cardiovascular metabolic diseases, along with insights into drug development prospects [5][12].

Core Viewpoint - The article discusses a revolutionary approach to neuromodulation using reversible photothermal-gated DNA nanochannels, which offers a universal solution for treating various neurological diseases related to ion transport disorders, such as paralysis, epilepsy, and congenital pain insensitivity [3][8]. Group 1: Current Challenges in Neuromodulation - Existing clinical treatments for neurological diseases often rely on stimulating biological ion channels, but small molecule drugs lack subtype specificity and have rapid metabolism, limiting treatment precision and effectiveness [2] - Invasive methods like intracortical stimulation (ICS) and deep brain stimulation (DBS) carry risks of infection and postoperative complications, while non-invasive methods such as transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS) lack channel-level targeting, leading to unclear mechanisms and limited treatment scope [2] Group 2: Innovative Research Findings - The research team developed a reversible photothermal-gated DNA nanochannel (NC-JNP) that achieves nanoscale spatial resolution and second-level temporal precision for neuromodulation [5] - The system combines thermoresponsive DNA nanochannels with gold-iron oxide Janus nanoparticles, which serve as local near-infrared (NIR) photothermal converters, achieving a 98.4% cell membrane insertion efficiency [5][6] - Under 808 nm wavelength laser irradiation, the nanochannels exhibit a cyclic gate effect for ion transport, enhancing the excitability of dorsal root ganglion neurons within seconds [5][6] Group 3: Implications for Treatment - The NC-JNP strategy successfully restored pain perception in NaV 1.7 gene knockout mice after one minute of laser irradiation, demonstrating its potential for precise neuromodulation [5][6] - This innovative approach overcomes the limitations of traditional tools in achieving high spatiotemporal resolution without the need for genetic editing, providing a promising avenue for treating neurological and neuromuscular diseases [8]

Core Viewpoint - Aspirin, originally used as a pain reliever, has shown potential in preventing and treating various diseases, including colorectal cancer, particularly in patients with specific genetic mutations [2][8]. Group 1: Research Findings - A recent study published in the New England Journal of Medicine demonstrated that low-dose aspirin can reduce the cancer recurrence risk by approximately 50% in colorectal cancer patients with PIK3CA mutations [2][8]. - The study involved a double-blind, randomized, placebo-controlled trial with 2980 patients, where 37% were found to have PIK3CA pathway mutations [3][4]. - In the trial, the 3-year cumulative recurrence rates for the aspirin group were 7.7% compared to 14.1% for the placebo group in mutation group A, and 7.7% versus 16.8% in mutation group B [6]. Group 2: Mechanism of Action - The research suggests that aspirin may lower the risk of colorectal cancer recurrence through multiple mechanisms, including reducing inflammation, inhibiting platelet function, and suppressing tumor growth [8]. - Aspirin is highlighted as an easily accessible and low-cost medication, which could significantly impact global colorectal cancer treatment guidelines [8]. Group 3: Related Research - Additional research published in Nature indicates that aspirin may prevent cancer metastasis by enhancing T cell immunity through the inhibition of platelet TXA2 [10]. - This finding opens avenues for future studies to explore the combination of aspirin with other immunotherapies to enhance its anti-metastatic effects [10].

撰文丨王聪 编辑丨王多鱼 排版丨水成文 代谢通路决定细胞的命运和功能；然而，代谢物在宿主抵御流感病毒中的确切作用，目前仍不明确。 202 5 年 9 月 22 日，中山大学生命科学学院 崔隽 团队 （ 金寿恒 、 何星 为共同第一作者） 在 Nature 子刊 Nature Microbiology 上 发表了题为： Oxaloacetate sensing promotes innate immune antiviral defence against influenza virus infection 的研究论文。 该研究揭示了 细胞质 苹果酸脱氢酶-1 （ MDH1 ） 通过感知细胞内的 草酰乙酸 （OAA） 从而促进固有免疫抗病毒防御以抵御流感病毒感染的通路。 在这项最新研究中，研究团队采用药物抑制和代谢组学分析的方法，证明了 草酰乙酸 （OAA） 代谢通路与针对流感病毒的抗病毒应答是相互整合的。 开放转载 细胞质 苹果酸脱氢酶-1 （ MDH1 ） 感知细胞内的 草酰乙酸 （OAA） 从而发生二聚化，并作为支架招募转录因子 ETS2 ，使其在第 313 位丝氨酸位点被激酶 TAOK1 磷酸化。磷酸化 ...

Core Viewpoint - The research introduces a revolutionary toolset of time-resolved fluorescent proteins (tr-FP) that expands the application of fluorescent microscopy in both temporal and spectral domains, providing a new solution for integrating system complexity and quantitative accuracy in biological research [4][6]. Group 1: Research Findings - The study reports a series of time-resolved fluorescent proteins (tr-FP) with rationally tunable lifetimes, developed without affecting the spectral properties of the fluorescent proteins [5]. - These tr-FPs enable temporal-spectral resolved microscopy, achieving simultaneous imaging of nine different proteins in live cells and correlating various cellular activities with the cell cycle [5]. - The tr-FPs facilitate multiplexing super-resolution microscopy, allowing the visualization of four proteins simultaneously and enabling quantitative studies in cellular proteomics [5][7]. Group 2: Technical Advancements - The research demonstrates that mutations can alter the non-radiative decay of tr-FPs, which span the visible spectrum and possess a wide range of fluorescence lifetimes suitable for microscopy [7]. - The tr-FPs support advanced imaging techniques such as STED-FLIM (Stimulated Emission Depletion Fluorescence Lifetime Imaging Microscopy) and protein chemometrics for quantitative analysis [7].

编辑丨王多鱼 排版丨水成文 空穴选择性 自组装单分子层 （ self-assembled monolayer， SAM） 在推动倒置结构钙钛矿太阳能电池的认证 能量转换效率 （PCE） 达 到 26.7% 的过 程中发挥了关键作用。然而，SAM 的不稳定性往往会损害器件的工作性能，将其其持久稳定性，严重阻碍了实际应用。 此外，研究团队还进一步深入解析了 SAM 的降解机制，为采用高粗糙度基底的 SAM 基器件设计更稳固的埋底界面提供了指导，助力实现高效且长效的钙钛 矿太阳能电池。 总的来说，该研究揭示了 SAM 基器件的不稳定性源于热老化过程中 SAM 结构的破坏，并提出了一种新型交联共 SAM 策略与原子尺度的机理解释，有助于 改善 SAM 分子的分散性和构象稳定性，以解决钙钛矿太阳能电池效率难以提升的难题，同时也为其他采用高粗糙度基底的 SAM 基器件提供了解决方案，对 促进其商业化应用具有重要意义。 论文链接 ： https://www.nature.com/articles/s41586-025-09509-7 9 月 17 日，香港城市大学 任广禹 教授 、中国科学院深圳先进技术研究院 张杰 副研究 ...

Core Viewpoint - The study highlights the role of LYZ2 in mediating remote injury responses in the heart, suggesting that targeting LYZ2 in endocardial cells can promote rapid recovery of non-regenerative hearts after myocardial infarction [3][4][6]. Group 1: Research Findings - Local cardiac injury leads to significantly elevated expression of Lyz2 in both the damaged area and remote regions [7]. - Lyz2 acts as a positive regulator of lysosomal degradation triggered by remote injury [7]. - Gene knockout of Lyz2 can result in rapid functional recovery after myocardial infarction [7]. - Pharmacological inhibition of lysosomal degradation has cardioprotective effects [7]. Group 2: Implications for Treatment - The findings suggest that targeting remote injury responses in non-myocyte cell types could facilitate swift recovery of non-regenerative hearts post-myocardial infarction [6][7].

Core Insights - The article discusses the pervasive presence of nanoplastics/microplastics (NMP) in the environment and their potential health impacts on humans, particularly concerning cognitive decline and Alzheimer's disease [2][3][4]. Group 1: Health Impacts of Nanoplastics - Research from the University of Rhode Island indicates that polystyrene nanoplastics (PS-NMP) can accumulate in the brain and lead to cognitive decline, especially in individuals carrying the Alzheimer's risk gene APOE4 [4][5]. - The APOE4 gene significantly increases the risk of Alzheimer's disease, with a threefold increase in risk for one copy and an 8-12 fold increase for two copies [5]. - The study highlights that lifestyle and environmental factors, alongside genetic predisposition, play a crucial role in the development of Alzheimer's disease [5]. Group 2: Experimental Findings - The research involved genetically modified mice, one group carrying the APOE4 gene and another carrying the APOE3 gene, exposed to PS-NMP in drinking water for three weeks [6]. - Results showed that PS-NMP entered various organs, including the brain, and affected cognitive abilities, with APOE4 mice exhibiting altered behavior and impaired memory recognition [6][7]. - The study found gender-dependent behavioral changes in mice, mirroring observed differences in Alzheimer's patients, where male patients show more apathy and female patients exhibit greater memory decline [7]. Group 3: Broader Implications - The findings raise concerns about the cognitive decline associated with exposure to nanoplastics, which are common environmental toxins [8]. - A related study published in Nature Medicine confirmed the presence of microplastics in human brains, particularly in dementia patients, suggesting a link between microplastics and neurodegenerative diseases [12]. - Another study revealed that microplastics in the bloodstream could induce cerebral thrombosis, leading to neurobehavioral abnormalities [13].

Core Viewpoint - The article discusses the advancements in protein design using generative artificial intelligence, particularly focusing on the breakthrough of RFdiffusion3, which allows for atomic-level precision in designing proteins that can interact with specific small molecules, DNA, and other biomolecules [9][24]. Group 1: RFdiffusion3 Overview - RFdiffusion3 represents a significant advancement in protein design, enabling the design of proteins with atomic-level precision, including interactions with non-protein components [9][10]. - The model is built on previous versions, RFdiffusion and RFdiffusion2, and offers improvements in accuracy, efficiency, and versatility [10][28]. - RFdiffusion3 can handle complex atomic constraints, such as hydrogen bonds and solvent accessibility, and is capable of designing various interactions, including protein-protein, protein-small molecule, and protein-nucleic acid interactions [10][28]. Group 2: Performance and Applications - In benchmark tests, RFdiffusion3 demonstrated superior performance with a computational cost only one-tenth of previous methods, making it significantly more efficient [3][10]. - The model has shown excellent results in designing DNA-binding proteins and enzymes, achieving a binding activity of 5.89±2.15 μM for a designed DNA-binding protein and a Kcat/Km value of 3557 for a designed cysteine hydrolase [21][28]. - RFdiffusion3 has outperformed its predecessor in multiple target designs, producing an average of 8.2 unique successful clusters compared to 1.4 from RFdiffusion [15]. Group 3: Technical Innovations - The core innovation of RFdiffusion3 lies in its all-atom diffusion model, which allows for simultaneous simulation of protein backbone and side chains, as well as interactions with non-protein components [9][10]. - The model employs a unified representation of amino acids, standardizing them to 14 atoms, which facilitates the handling of varying side chain atom counts [13][14]. - The architecture is based on a Transformer U-Net, which includes downsampling, sparse transformer modules, and upsampling to predict coordinate updates [14]. Group 4: Future Implications - The introduction of RFdiffusion3 marks a paradigm shift in protein design, enabling unprecedented control over complex functionalities, such as specifying enzyme active sites and controlling hydrogen bond states [24][25]. - As the technology continues to evolve, it is expected to lead to innovative therapies, new types of proteases, and biomaterials, fulfilling the vision of "designing life molecules" [25].