编译丨王聪 编辑丨王多鱼 排版丨水成文 线粒体 是哺乳动物细胞中受双重遗传控制的半自主细胞器。在超过二十亿年的进化过程中，线粒体保留了两个关键特征——作为"能量工厂"生成 ATP 的能力， 以及被双层膜包裹的环状线粒体 DNA （mtDNA） 。 线粒体 DNA 编码了 22 种转运 RNA （tRNA） 、2 种核糖体 RNA （rRNA） 和 13 种蛋白质。tRNA 和 rRNA 参与线粒体基质内的蛋白质翻译，而 13 种蛋白 质则作为线粒体氧化磷酸化 （OXPHOS） 系统的亚基，该系统对于电子和质子的转运至关重要。然而，大多数 OXPHOS 蛋白质 （至少 70 种） 由核基因编 码，随后被导入线粒体。因此，核基因或 mtDNA 的紊乱，都会破坏线粒体呼吸链，损害 ATP 生成，并导致线粒体功能障碍。这些疾病被归类为 原发性线粒体疾 病 （PMD） ，通常表现为复杂的多器官受累，且往往难以治疗。 由于 线粒体 DNA （mtDNA） 的 多拷贝特性，其突变通常表现为基因型与表型之间复杂的关联，且个体差异显著。由于线粒体的双层膜结构，靶向 mtDNA 的 基因修饰受到限制，这阻碍了疾病建模、发病机制的 ...

Core Insights - The article discusses a significant study on Polycystic Ovary Syndrome (PCOS), revealing a detailed genetic map and identifying 94 independent genetic loci, including 73 previously unreported loci [2][5][6] - The research highlights the genetic overlap between Chinese and European populations despite different evolutionary pressures, providing insights into the metabolic and reproductive drivers of PCOS [5][6] Genetic Findings - The study involved a genome-wide association study (GWAS) of 12,419 Chinese PCOS patients and 34,235 controls, followed by a meta-analysis with 13,773 European cases and 411,088 controls [5] - A specific missense mutation (rs10407022) in the AMH gene was found to have a stronger effect in East Asian populations, potentially linked to increased follicle count and elevated androgen levels in PCOS patients [5] Pathological Mechanisms - Gene enrichment analysis indicated that PCOS-related genes are significantly enriched in the PPARG signaling pathway, with single-cell RNA sequencing data showing active expression in ovarian granulosa cells, underscoring their importance in PCOS development [5][6] Drug Discovery and Treatment Strategies - The study utilized a genetics-driven approach to identify multiple drug targets (e.g., GATA4, HOXD3) and opportunities for drug repurposing (e.g., betaine, telmisartan, atazapine), paving the way for personalized treatment strategies [5][6] Future Directions - The findings provide a foundation for further functional experiments, clinical translation, and individualized treatment approaches for PCOS, with the potential for precise prevention and treatment in the future [6]

Core Viewpoint - The research identifies FPR1 signaling as a potential mechanism for the progression of Multiple Sclerosis (MS), suggesting that FPR1 could serve as a new therapeutic target for MS treatment [2][3]. Group 1: Research Findings - The study published in Science highlights the development of the FPR1 small molecule antagonist T0080, which can reduce brain inflammation and neurodegeneration, thereby alleviating the progression of MS [3]. - In active MS, the presence of reactive microglia and macrophages contributes to the development of tissue-restrictive inflammation, leading to progressive tissue damage and exacerbating neurodegeneration [5]. - The research team found significant expression of FPR1 in microglia and infiltrating macrophages in MS patients, with levels of endogenous N-formyl peptides correlating dynamically with disease progression [5][6]. Group 2: Mechanism of Action - Activation of FPR1 initiates a PKC-dependent signaling cascade, leading to the release of reactive oxygen species (ROS) and inflammatory cytokines like TNF-α, which damages neuronal axons and promotes a neuroinflammatory environment [6]. - The study demonstrates that FPR1-expressing microglia secrete CCL5, facilitating the recruitment and clonal expansion of myelin-reactive CD4+ T cells, which further amplifies myelin destruction and neuroinflammation [6][8]. Group 3: Implications for Treatment - The findings suggest that targeting FPR1 with the antagonist T0080 may have therapeutic potential in slowing the progression of MS, as it has shown efficacy in various MS mouse models by mitigating autoimmune responses and inhibiting microglia-mediated axonal degeneration [6][8].

Core Insights - The article discusses the relationship between maternal cholesterol levels during pregnancy and the risk of congenital heart defects (CHD) in offspring, highlighting the importance of cholesterol in fetal development [2][10]. Group 1: Research Findings - A study published in "Signal Transduction and Targeted Therapy" indicates that low maternal cholesterol levels during pregnancy are significantly associated with an increased risk of CHD in offspring, particularly during mid to late pregnancy [3][6]. - The research involved a cohort of 5,041 family trios and found a notable correlation between maternal low cholesterol levels and the incidence of CHD in children [6]. - The study utilized cholesterol-lowering drugs, ezetimibe and atorvastatin, on pregnant mice, which resulted in a significant increase in the incidence of CHD in their offspring [8]. Group 2: Genetic Insights - Whole-genome sequencing of 103 children with CHD identified a pathogenic mutation in the CYP51A1 gene, which affects cholesterol synthesis and disrupts Hedgehog (Hh) signaling, leading to CHD [8]. - The study created a Cyp51 I383V gene knock-in mouse model to further investigate the link between cholesterol synthesis and CHD, confirming that dietary cholesterol supplementation could significantly reduce the risk of CHD in offspring of mutant mothers [8][10]. Group 3: Implications for Maternal Health - The findings suggest that maternal cholesterol supplementation during pregnancy could be an effective strategy to lower the risk of CHD in children, emphasizing the need for further research in this area [10].

Core Viewpoint - Exposomics is a discipline that studies all environmental exposure factors throughout an individual's life and their association with health, aiming to understand how external exposures influence disease occurrence, complementing genomics and metabolomics [2] Group 1: Research Development - The core challenge in exposomics is converting mass spectrometry data into chemical structures, complicating the tracking of millions of chemical substances in humans and the environment [3][6] - A research team from Nanjing University developed a Molecular Structure Generator (MSGo) that can directly generate chemical structures from mass spectrometry data, discovering unknown perfluorinated compounds in the exposome [6][7] Group 2: Methodology and Performance - MSGo utilizes a Transformer neural network trained on virtual spectral data, achieving a 48% correct identification rate of structures in the validation set and outperforming expert levels in detecting novel perfluorinated compounds in wastewater samples [6][7] - The application of probability-guided masking techniques on virtual spectral data is key to enhancing the performance of MSGo [6]

Core Insights - The article discusses the domestication, global dissemination, and improvement trajectories of soybean, highlighting its significance as a major source of protein and oil for human consumption and animal feed [3][4][7]. Group 1: Research Findings - The research utilized genomic information from 8,105 soybean accessions, covering wild types, local varieties, and modern cultivated varieties, to conduct a systematic comparative genomic analysis [4][7]. - Key genes related to soybean adaptability and improvement were identified, providing insights that could guide future breeding efforts and sustainable agricultural development [7][8]. - The study revealed that black soybean serves as a crucial intermediate type in the domestication process, with two independent domestication centers identified in China: the Huang-Huai-Hai region and the Northwest region [7][9]. Group 2: Implications for Breeding - The research highlights the temporal changes in breeding focus for soybean in China, shifting from high-protein varieties in the early years to an emphasis on high yield, high oil content, and stress resistance in recent years [8][9]. - An online database was established, including a high-density soybean genome variation map and quantitative trait nucleotide (QTN) library, to facilitate global research collaboration [8][9]. Group 3: Institutional Background - The Yanzhou Bay National Laboratory, established in September 2022, focuses on major scientific and technological issues related to national food security and seed industry innovation [11].

Core Insights - The ADAR (Adenosine deaminases acting on RNA) family plays a crucial role in RNA editing, immune homeostasis, and neurological functions, with significant advancements in ADAR-mediated RNA editing technology in recent years [2] - Unlike CRISPR-based editing, ADAR-based RNA editing requires only the expression of endogenous deaminase ADAR in cells, avoiding delivery challenges and related immunogenicity issues, thus providing a safer option for precise RNA editing without altering genomic sequences [2] - ADAR-mediated RNA editing shows great potential in treating genetic diseases and cancers, with clinical trials approved for therapies targeting conditions like α-1 antitrypsin deficiency (AATD) and Stargardt disease, as well as inhibiting tumor growth by precisely editing oncogenic mRNA [2] Group 1 - ADAR1 is closely associated with various diseases, including type I interferon diseases, cancer, and viral infections, making it an important drug target [3] - Development strategies for ADAR1 inhibitors are diverse, including targeting its catalytic domain, regulating upstream and downstream signaling pathways, and employing PROTAC degradation technology, showing broad prospects in cancer and autoimmune disease treatment [3] - A live lecture titled "Decoding ADAR: From RNA Editing, Innovative Inhibitor Development Strategies to SignalChem Screening Services" was held on November 20, featuring experts discussing the role of ADAR-mediated RNA editing in cancer treatment and the significance of ADAR1 as a drug target [3][4] Group 2 - The lecture included key topics such as the structural characteristics and biological functions of the ADAR family, applications of ADAR-mediated RNA editing in cancer therapy, the relationship between ADAR1 and diseases, and its importance as a drug target [8][12] - Strategies and methods for developing ADAR1-targeted inhibitors and SignalChem's ADAR inhibitor screening services were also discussed, highlighting their systematic support for research and new drug development in related disease treatments [9][12]

Core Viewpoint - The research published in Science reveals genomic evidence of the co-dispersal of dogs and humans across Eastern Eurasia during the Holocene, highlighting the long-term and indispensable role of dogs in human societies [2][3][8]. Group 1: Research Findings - The study analyzed 73 ancient dog genomes from the late Pleistocene to early Holocene, providing clear evidence of the genetic relationship between dogs and human populations, indicating their simultaneous migration over time and space [3][6]. - The research included 17 newly sequenced ancient dog genomes, with 14 samples from ancient dogs in China, marking the first acquisition of ancient dog genomes from China [6]. - The findings suggest a connection between dog lineages and specific ancient human groups from Eastern Europe to Eastern Siberia, including ancient Siberians, eastern hunter-gatherers, East Asians, and steppe pastoralists [6][8]. Group 2: Historical Context - As the first domesticated animal, dogs likely spread alongside different cultural groups during the late Pleistocene and Holocene [6]. - The study constructed a lineage evolution map of dogs from East Asia to Western Eurasian steppes, revealing multiple changes in dog ancestry that correspond with the migrations of specific hunter-gatherers, farmers, and pastoralists [6]. Group 3: Implications - The research underscores the integral role of dogs in human civilization, suggesting that they have been a part of human societies for at least 10,000 years [3][8].

一篇论文来自 纽约大学 Robert Montgomery 团队和哥伦比亚大学 Megan Sykes 团队；另一篇论文来自纽约大学 Brendan J Keating 团队。 猪器官的人体移植 手术由 Robert Montgomery 领导完成，值得一提的是，他于 2021 年 10 月领导完成了首次猪器官人体移植手术，将基因编辑改造的猪肾脏移植给了一名脑死亡 女性。 Explore content ▽ About the journal ✓ Publish with us ▼ Subscribe nature > articles > article 撰文丨王聪 编辑丨王多鱼 排版丨水成文 在过去三年里，约有十几名在世者接受了基因编辑改造的猪器官移植，包括 猪心脏 、 猪肾脏 、 猪肝脏 和 猪胸腺 。但这些移植到人体内的猪器官大多最终因功 能衰竭或带来的益处无法抵消所需免疫抑制治疗产生的副作用，而被移除。迄今为止，接受猪器官移植的活体患者最长存活时间约为半年。 2025 年 11 月 13 日， Nature 期刊背靠背发表了两篇研究论文， 首次提供了如何逆转器官移植后排异反应的证据 ，研究团队成功阻 ...

Core Viewpoint - The treatment landscape for systemic lupus erythematosus (SLE) has significantly changed in recent years, particularly with the emergence of targeted cell immunotherapy focusing on pathogenic B cells, such as CAR-T and CAR-NK cell therapies [3][4][6]. Group 1: CAR-T Cell Therapy - CAR-T cell therapy has shown promising results in achieving disease remission in refractory severe SLE patients, but it faces challenges such as complex production, high costs, and potential risks like cytokine storms and infections [3][4]. - The study published in The Lancet highlights the efficacy and safety of allogeneic CD19 CAR-NK cell therapy in SLE, indicating it as a viable alternative to autologous CAR-T cell therapy [5][6]. Group 2: CAR-NK Cell Therapy - Allogeneic CD19 CAR-NK cell therapy has demonstrated good safety, tolerability, and therapeutic effects in a clinical study involving patients aged 18-65 with refractory or difficult-to-treat SLE [8][9]. - The study included 18 patients, with a median follow-up of over 12 months, showing that 67% of patients achieved complete DORIS remission and improved quality of life [9][11]. - The therapy was well-tolerated, with only 6% of patients experiencing mild cytokine release syndrome, and no severe adverse events related to CAR-NK therapy were reported [9][12]. Group 3: Research and Development - The research team utilized NK cells from healthy donors, genetically engineered to create off-the-shelf CD19-targeted CAR-NK cells, developed by Enraykano [8][12]. - This study represents the first human clinical trial of allogeneic CAR-NK cell therapy for SLE, potentially addressing the limitations of current autologous CAR-T therapies regarding scalability, accessibility, safety, and cost [6][12]. - The findings contribute to establishing a new paradigm for "off-the-shelf, low-toxicity, broad-target" precision treatment for autoimmune diseases [18].