Core Viewpoint - The article discusses advancements in base editing technology, specifically focusing on the development of high-precision cytosine base editors (CBE) to enhance the accuracy of genetic modifications, which is crucial for clinical applications [3][7]. Group 1: Base Editing Technology - Base editors are created by fusing cytosine deaminase or adenine deaminase with a CRISPR protein that has lost nuclease activity, allowing for specific base conversions in the genome [2]. - Current base editors modify all cytosines or adenines within the editing window, which limits their precision [3]. Group 2: Research Development - A research team from the University of Chicago published a study in Nature Biotechnology, focusing on evolving nucleic-acid-recognition hotspots in deaminase to develop high-precision CBEs [3][6]. - The study involved the directed evolution of the tRNA-specific adenine deaminase (TadA) from E. coli to address the issue of non-specific editing in existing base editors [4][5]. Group 3: Results and Applications - The research team developed 16 variants of TadA that cover all possible -1 and +1 contexts for target cytosine editing, providing customizable deaminases for base editing [5]. - These variants were applied to correct disease-related T:A to C:G conversions with an accuracy improvement of 81.5% compared to traditional base editors [6]. - The study also simulated two cancer-driving mutations, KRAS G12D and TP53 R248Q, demonstrating the practical applications of the developed high-precision CBEs [6].

Core Viewpoint - Sudden Cardiac Death (SCD) is a major global health issue, particularly in patients with Hypertrophic Cardiomyopathy (HCM), where current clinical guidelines show low performance and inconsistent accuracy in risk assessment [1][2]. Group 1 - SCD has an annual incidence of 50-100 cases per 100,000 people in North America and Europe, with ventricular arrhythmias being the primary mechanism [1]. - Implantable Cardioverter Defibrillators (ICDs) can effectively terminate arrhythmias and reduce mortality in high-risk patients when implanted preventively [1]. - The current risk stratification paradigm, based on Left Ventricular Ejection Fraction (LVEF) below 30%-35%, is primarily applicable to ischemic and dilated cardiomyopathy patients but fails to provide comprehensive risk assessment [2]. Group 2 - A recent study published by researchers from Johns Hopkins University introduced a multimodal AI model named MAARS (Multimodal Artificial intelligence for Ventricular Arrhythmia Risk Stratification) to predict arrhythmic death in HCM patients [3][4]. - MAARS utilizes a Transformer-based neural network that learns from electronic health records, echocardiograms, radiology reports, and contrast-enhanced cardiac MRI, which is a unique aspect of the model [8]. Group 3 - MAARS demonstrated an Area Under the Curve (AUC) of 0.89 in internal cohorts and 0.81 in external cohorts, significantly outperforming current clinical guidelines which have AUCs ranging from 0.27-0.35 (internal) and 0.22-0.30 (external) [10]. - Unlike clinical guidelines, MAARS shows fairness across different population subgroups, enhancing the transparency of AI predictions and identifying risk factors for further investigation [10]. - Overall, MAARS is a powerful and reliable clinical decision support tool for risk stratification of SCD in HCM patients, with potential to significantly improve clinical decision-making and patient care through integration with automated data extraction systems or as a concept validation for personalized patient care [10].

Core Viewpoint - The recent study published by Jonas Frisen's team provides compelling evidence that neurogenesis continues in the adult human hippocampus, addressing a long-standing debate in neuroscience regarding the adaptability of the human brain [2][9]. Group 1: Research Findings - The study identifies proliferating neural progenitors in the adult human hippocampus, confirming that new neurons are generated even in late adulthood [2][6]. - The research utilized advanced techniques such as RNAscope and Xenium to locate these cells, confirming their presence in the dentate gyrus, a region critical for memory formation and cognitive flexibility [7][10]. - The findings indicate that human adult neural progenitor cells share similarities with those in mice, pigs, and monkeys, although there are differences in gene activity among individuals [8]. Group 2: Methodology - The research analyzed brain samples from individuals aged 0 to 78 years, revealing all stages of neural progenitor cells in early childhood and identifying proliferating progenitor cells in adults using the Ki67 antibody and machine learning algorithms [10]. - The study's methodology highlights the importance of single-cell transcriptomics in understanding the neurogenic environment in the adult human brain [11].

Core Viewpoint - The research highlights a novel RNA modification sequencing method, LIME-seq, which shows potential for early cancer detection through the analysis of microbiome-derived cell-free RNA (cfRNA) in plasma samples [2][3][5][8]. Group 1: Research Development - The study introduces LIME-seq (Low-Input Multiple Methylation Sequencing) as a new method for analyzing cfRNA modification patterns, capable of detecting various tRNA and small noncoding RNA from both human and microbial sources [5][8]. - The research team demonstrated that the RNA modification patterns in microbiome-derived cfRNA can accurately reflect the activity of the host microbiome [8]. Group 2: Clinical Findings - In plasma samples from colorectal cancer patients and non-cancer controls, LIME-seq analysis revealed significantly elevated methylation levels of various microbiome-derived cfRNA, effectively distinguishing cancer patients from non-cancer individuals [8]. - Similar differences in methylation levels of microbiome-derived cfRNA were observed in pancreatic cancer samples, indicating the method's applicability for early detection of both intestinal and non-intestinal cancers [8]. Group 3: Implications for Cancer Screening - The study systematically demonstrates the feasibility and effectiveness of cfRNA modification profiling for cancer early screening in over a hundred clinical samples [8]. - Compared to traditional RNA expression detection, cfRNA modifications are more stable and provide earlier signals, making them particularly suitable for capturing subtle biological changes in early cancer stages [8].

Core Viewpoint - The research highlights the development of a high-throughput and ultra-sensitive single-nucleus ATAC sequencing technology (UUATAC-seq) and a deep learning model (NvwaCE) for predicting regulatory sequences in vertebrates, providing valuable resources for understanding the regulatory language of vertebrate genomes [5][15]. Group 1: Technology Development - The UUATAC-seq technology allows for the efficient construction of chromatin accessibility maps within a single day for a given species [8]. - The NvwaCE model is designed to interpret the "grammar" of cis-regulatory elements (cCRE) and can directly predict cCRE landscapes from genomic sequences with high accuracy [11]. Group 2: Research Findings - The study found that the conservation of regulatory grammar is significantly stronger than that of nucleotide sequences, revealing the sequence basis for cell-type-specific gene expression [6]. - The analysis indicated that differences in genome size among species affect the number of cCREs but not their size [10]. Group 3: Practical Applications - The NvwaCE model accurately predicts the impact of synthetic mutations on lineage-specific cCRE functionality, aligning with quantitative trait loci (QTL) and genome editing results [13]. - A specific gene mutation site (HBG1-68:A>G) was predicted to have curative potential for sickle cell disease, marking the first instance of an AI-designed functional site being validated in human cells [14].

Core Viewpoint - The article discusses the development of an orthogonal transcription mutation system (OTM) that significantly enhances the efficiency and specificity of protein evolution, addressing limitations in traditional methods and expanding applications in both model and non-model organisms [2][6]. Group 1: System Development - The OTM system integrates three broadly compatible phage RNA polymerases with two deaminase variants, creating a modular platform for protein evolution [3]. - The core design allows RNA polymerase to unwind DNA, enabling deaminases to edit exposed single-stranded DNA, achieving base mutations of C:G to T:A and A:T to G:C types [3][4]. - The system can complete directed evolution of proteins in just one day, with mutation efficiency improved by 1.5 million times compared to spontaneous mutations [3][6]. Group 2: Functional Capabilities - The research team successfully constructed dual-function orthogonal transcription mutation elements that can introduce both C:G to T:A and A:T to G:C mutations simultaneously [4]. - The system demonstrates orthogonality, allowing different phage RNA polymerases to specifically recognize their respective promoters, minimizing cross-interference [5]. - The OTM system shows excellent performance in both non-model organisms (e.g., Halomonas bluephagenesis) and model organisms (e.g., E. coli), overcoming previous efficiency challenges in non-model industrial strains [5][6]. Group 3: Practical Applications - The system has been applied to mutate fluorescent proteins and pigment proteins, resulting in engineered strains with various colors [5]. - Targeted mutations in cytoskeletal and division-related proteins led to engineered strains with diverse morphologies, providing new insights for morphological engineering [5]. - In industrial applications, the system successfully evolved σ70 global transcription regulator RpoD and lysine export protein LysE, enhancing L-arginine tolerance and transport capabilities [5][6]. Group 4: Future Prospects - The OTM system has significant potential for further development, including integrating other types of deaminases to diversify mutation libraries [6]. - Future exploration may focus on the system's compatibility and applicability in other non-model organisms [6]. - The mutation system can accelerate the optimization of key enzymes in biomanufacturing, contributing to the advancement of a green bio-economy [6].

近日， 上海人工智能实验室青年研究员 谈攀 联 合 上海交通大学自然科学研究院/物理天文学院/张江高研院/药学院 洪亮 教授团队，在 Nature Communications 期刊发表了题为： Harnessing Protein Language Model for Structure-Based Discovery of Highly Efficient and Robust PET Hydrolases 的研究论文。 该研究发布了用于酶挖掘的蛋白质大模型—— VenusMine ，该 模型融合了蛋白质语言大模型与三维结构分析，通过蛋白质序列、结构和功能之间的隐含映射规则，能在海量的蛋白 数据库中高效挖掘同源性低但功能优异的酶分子。 应用该模型，研究团队成功发现了一系列 PET 水解酶，其中来自 Kibdelosporangium banguiense 的 KbPETase 表现出极高的催化效 率和热稳定性，其最适酶活是模板 IsPETase 的 97 倍。 编辑丨王多鱼 排版丨水成文 塑料废弃物，带来了重大环境挑战，尤其是 聚对苯二甲酸乙二醇酯 （PET） ，是当今使用量最大的饮料包装，用于 碳酸饮料 ...

Core Insights - Gastric cancer is the fifth leading cause of cancer-related deaths globally, primarily caused by chronic infection with Helicobacter pylori, which is preventable through effective treatment [1][4] - The incidence of gastric cancer is rising among younger populations (under 50 years), and due to aging and population growth, the number of cases and deaths is expected to increase in the coming decades, potentially reversing recent efforts to reduce mortality and incidence rates [2] Summary by Sections - **Global Estimates**: A study published by IARC/WHO in Nature Medicine estimated that among the global population born between 2008-2017, approximately 15.8 million individuals are expected to develop gastric cancer in their lifetime, with 76% (11.9 million cases) attributable to Helicobacter pylori infection [3][8] - **Prevention Strategies**: Most gastric cancers, particularly non-cardia gastric cancer, are caused by chronic Helicobacter pylori infection, which can be prevented through a combination therapy of antibiotics and proton pump inhibitors. A systematic review indicates that treatment can prevent gastric cancer in Helicobacter pylori-positive individuals [4] - **Screening Recommendations**: In 2013, IARC/WHO recommended that countries explore population-based screening and treatment programs for Helicobacter pylori based on local disease burden and cost-effectiveness analyses [5] - **Implementation Challenges**: Despite the high-risk areas, there has been little attempt to implement such population-level projects. The development of a Helicobacter pylori vaccine could be a powerful tool for preventing gastric cancer, but there seems to be a lack of motivation to advance its research [6] - **Future Burden Projections**: The study predicts that without intervention, 15.6 million individuals born between 2008-2017 will be diagnosed with gastric cancer, with 11.9 million cases (76%) linked to Helicobacter pylori infection. It is estimated that 10.6 million new cases (68%) will occur in Asia, with India and China expected to account for 6.5 million cases [8] - **Impact of Interventions**: The research highlights the importance of Helicobacter pylori management in gastric cancer prevention, showing that if screening and treatment interventions are 100% effective, gastric cancer cases could be reduced by up to 75%. Effectiveness rates of 90% and 80% would result in reductions of 67.5% and 60%, respectively [10] - **Call to Action**: The research team calls for increased investment in gastric cancer prevention, particularly through population-wide Helicobacter pylori screening and treatment programs to reduce the global burden of gastric cancer [11]

Core Viewpoint - The article discusses the promising potential of adoptive T cell therapy (ACT), particularly CAR-T cell therapy, in cancer treatment, while highlighting its limitations in solid tumors due to various factors such as immune suppression and tumor heterogeneity [2]. Group 1: CAR-T Cell Therapy Developments - CAR-T cell therapy has shown remarkable success in treating hematological malignancies but remains less effective in solid tumors due to challenges in the tumor microenvironment [2]. - A recent study published in Nature introduces a method to enhance CAR-T cell anti-tumor efficacy by using endogenous gene promoters to control cytokine expression, thereby reducing systemic toxicity [3]. Group 2: Armoured T Cells - A promising approach to improve CAR-T cell efficacy in solid tumors involves engineering T cells to express immune-modulatory factors, referred to as "Armoured T Cells" [5]. - Several studies have demonstrated the potential of T cells armed with cytokines like IL-2, IL-12, and IL-15, but the peripheral expression of these cytokines can lead to toxicity, necessitating strategies to restrict expression to tumor sites [5][6]. Group 3: Gene Editing and Specificity - The advent of CRISPR gene editing technology allows for precise insertion of transgenes at specific genomic loci, enabling controlled expression of transgenes through endogenous regulatory mechanisms [8]. - The latest research indicates that using CRISPR to insert IL-12 and IL-2 into specific promoter sites can significantly enhance therapeutic responses in mouse models without evident toxicity [11]. Group 4: Long-term Immunity and Future Implications - Mice treated with the modified CAR-T cells exhibited durable immunity against secondary tumors, suggesting that re-engineered CAR-T cells can not only eliminate existing tumors but also provide long-lasting immune memory [12]. - Overall, the study proposes that utilizing endogenous gene regulation mechanisms for localized expression of pro-inflammatory payloads could address key challenges in treating solid tumors, thereby expanding the therapeutic scope of adoptive cell therapies [15].

Core Viewpoint - CAR-T cell therapy has shown significant effects in hematological malignancies and is expanding into clinical trials for solid tumors, infectious diseases, and autoimmune diseases, with notable advancements in treating autoimmune diseases like systemic lupus erythematosus and myasthenia gravis [2][3][5]. Industry Developments - AbbVie acquired Capstan for $2.1 billion, focusing on in vivo CAR-T therapy for autoimmune diseases, indicating a growing market interest [2]. - AstraZeneca's acquisition of EsoBiotec for $1 billion earlier this year also highlights the increasing investment in CAR-T therapies [2]. - The industry is on the brink of a breakthrough, particularly in in vivo CAR-T therapies, as evidenced by these high-value acquisitions [2]. Research Progress - The application of CAR-T therapy in autoimmune diseases began with Professor Georg Schett's team in Germany, successfully treating a patient with refractory systemic lupus erythematosus in 2021 [3]. - A recent review by Professor Schett in Nature Reviews Rheumatology discusses advancements and challenges in CAR-T therapy for autoimmune diseases, including suitable diseases and safety considerations [4][5]. Mechanism and Targeting - CAR-T therapy involves engineering immune cells to target specific antigens, primarily focusing on the depletion of pathological B cells in autoimmune diseases [6][8]. - The therapy can effectively eliminate B cells, which are central to the pathogenesis of diseases like systemic lupus erythematosus and idiopathic inflammatory myopathy [8]. - Current CAR-T therapies primarily target CD19 and BCMA, with CD38 also being a significant target for its ability to selectively eliminate antibody-producing cells [11][12]. Challenges and Considerations - The effectiveness of CAR-T therapy is influenced by the physiological mechanisms of diseases and the availability of measurable clinical endpoints, which can pose challenges in long-term studies [10]. - Certain autoimmune diseases, such as psoriasis and inflammatory bowel disease, may require alternative therapies due to the involvement of abnormal T cell activation [9]. Future Directions - The transition of CAR-T therapy from oncology to autoimmune diseases is reshaping treatment paradigms, with a focus on developing more targets and dual-target combinations to enhance safety and efficacy [13]. - Companies like Yiqiao Shenzhou are providing comprehensive CAR-T therapy development solutions to support clients through various research stages [14].