Core Viewpoint - The article discusses a groundbreaking experimental treatment for a rare genetic condition caused by HPDL gene mutations, which leads to a deficiency in Coenzyme Q10, crucial for mitochondrial function. The treatment involves a precursor molecule, 4-HB, showing significant improvement in a young patient’s condition. Group 1: Patient Case and Treatment - An 8-year-old boy experienced rapid deterioration of health due to HPDL gene mutation, leading to severe mobility issues within months [1][2] - The boy underwent experimental treatment with 4-HB, a precursor to CoQ10, under FDA's special permission, resulting in remarkable recovery [3][4] - After less than a month of treatment, the boy could walk 1 kilometer and eventually engage in activities like running and cycling [4][11] Group 2: Research Background and Findings - The research team, led by Professor Michael Pacold, published findings in Nature, revealing the role of HPDL in converting 4-HMA to 4-HB, essential for CoQ10 synthesis [5][7] - The study demonstrated that primary CoQ10 deficiency-related neurological symptoms could be stabilized or improved by supplementing with precursor substances rather than CoQ10 itself [13] Group 3: Market Potential - The decline of CoQ10 levels is associated with aging and various diseases such as heart disease, diabetes, and Alzheimer's, indicating a potential multi-billion dollar market for restoring CoQ10 levels [14]

Core Viewpoint - The article discusses the challenges and advancements in assessing Variants of Uncertain Significance (VUS) in the ATM gene, which is crucial for DNA damage response and cancer susceptibility [2][5][6]. Group 1: ATM Gene and Its Importance - The ATM gene plays a key role in DNA damage response and is associated with Ataxia Telangiectasia when mutated [2][5]. - Mutations in the ATM gene can lead to increased risks of various cancers, including breast, colorectal, pancreatic, and prostate cancers [5]. - Comprehensive functional assessment of all possible single nucleotide variants (SNVs) in the ATM gene is essential for predicting cancer risk and patient prognosis [5][10]. Group 2: Recent Research Findings - Researchers from Yonsei University published a study in Cell that functionally assessed all 27,513 possible ATM SNVs using prime editing and deep learning [3][10]. - The study identified critical amino acid residues in the kinase domain that cannot tolerate missense mutations [10]. - A deep learning model named DeepATM was developed to predict the functional effects of the remaining 4,421 SNVs with unprecedented accuracy [9][10]. Group 3: Implications for Precision Medicine - The comprehensive evaluation of ATM gene mutations aids in precision medicine and provides a framework for addressing VUS in other genes [12]. - The research findings contribute to cancer risk assessment and prognosis, enhancing the understanding of ATM's role in cancer [9][10].

编辑丨王多鱼 排版丨水成文 有 结核分枝杆菌 （ Mycobacterium tuberculosis ） 感染史的患者，往往会出现不可逆且进行性的 肺损 伤 ，但其潜在机制尚不完全清楚。 2025 年 7 月 14 日，中国科学院动物研究所 刘光慧 研究员联合天津大学海河医院 陈怀永 教授、首都医 科大学宣武医院 王思 教授及中国科学院动物研究所 曲静 研究员团队，在 Nature Microbiology 期刊 发表了 题为： A single-cell transcriptomic atlas reveals senescence and inflammation in the post-tuberculosis human lung 的研究论文。 该研究构建了首个 结核杆菌 感染后肺组织的高精度细胞分子网络，并运用多维度分析策略系统阐明： 细胞 衰老与炎症是结核感染后肺损伤的关键病理特征，而内皮细胞衰老及血管炎症则是这一过程中的核心事件 。并进一步首次阐明了 FOXO3 表达下调协同凝血酶-炎症信号通路驱动结核杆菌感染导致的慢性肺损伤的 分子机制，为该疾病提供了潜在干预靶点。 在这项最新研究中，研究团 ...

Core Viewpoint - The article discusses the discovery of an alternative receptor for adeno-associated viruses (AAV), named AAVR2, which enhances the efficacy of AAV-mediated gene therapy and provides insights into reducing dose-related toxicity associated with AAV vectors [3][8]. Group 1: AAV and Its Applications - AAV is currently the most commonly used vector for in vivo gene therapy, approved for treating various diseases such as retinitis pigmentosa, spinal muscular atrophy, Duchenne muscular dystrophy, and hemophilia [1]. - The clinical success of human gene therapies relies on the safe and effective transduction of AAV into various tissues [2]. Group 2: Research Findings - AAVR2 (CPD) was identified as an alternative receptor that can restore the transduction of E branch AAVs, including AAV8, in the absence of AAVR, and provides a unique entry pathway for unclassified AAV11 and AAV12 [3][6]. - The research team characterized the direct binding between AAV8 capsid and AAVR2 using cryo-electron microscopy, identifying the amino acid residues involved in the interaction [6][9]. - A minimal functional AAVR2 (miniAAVR2) was overexpressed to enhance in vivo AAV transduction, allowing low doses of AAV to achieve similar therapeutic effects [6][9]. Group 3: Implications for AAV Biology - This research provides new insights into AAV biology and offers clinically applicable solutions to mitigate dose-related toxicity associated with AAV vectors [8].

Core Viewpoint - The research conducted by Professor Liu Jin's team at Sun Yat-sen University presents a novel scheme for cavity-induced spontaneous two-photon emission (STPE), achieving a high fidelity of 99.4% for on-demand triggered quantum entangled light sources, which is expected to revolutionize photon quantum science and technology [2][3]. Group 1 - The study reports a STPE phenomenon with brightness comparable to competitive single-photon radiation, originating from a single semiconductor quantum dot coupled to a high-quality microcavity [3]. - The research team utilized photon statistical measurements to reveal quantum characteristics associated with STPE within a cavity quantum electrodynamics system [3]. - The development of a new type of entangled quantum light source using STPE demonstrates nearly perfect entanglement fidelity (99.4%) and the on-demand photon emission characteristics required for atomic quantum radiation sources [3]. Group 2 - This breakthrough provides critical support for the advancement of next-generation quantum precision measurement technologies and the construction of functional photonic quantum information processing chips [3]. - The findings deepen the understanding of two-photon processes in quantum systems and are expected to empower the development of photon quantum technologies through nonlinear quantum radiation [3].

编译丨王聪 编辑丨王多鱼 排版丨水成文 体细胞干细胞，通常被称为 成体干细胞 ，通过稳态更新维持组织，并通过再生反应修复组织。因此，这些干细胞群体必须进化出维持自身活力的机制，以适应其 维持的组织在不同生物体中的不同寿命。然而，随着不同寿命的生物体的衰老，这些干细胞功能的衰退在组织稳态受损以及对损伤或疾病的再生能力下降方面表 现得十分明显。 近日，加州大学洛杉矶分校、斯坦福大学和贝勒医学院的研究人员在 Cell 子刊 Cell Stem Cell 上发表了题为： Hallmarks of stem cell aging 的综述论文。 该综述系统性描述了可用来表征干细胞衰老的五个关键标志—— 1） 静息深度 （ depth of quiescence ） ，2） 自我更新倾向 （ self- renewal propensity ） ，3） 子代细胞命运 （ fate of progeny ） ，4） 再生修复能力 （ resilience ） ，5） 群体异质性 （ population heterogeneity ） 。 并进一步探讨了这些标志的变化如何导致干细胞功能的衰退。这些特征不仅为衰老过程提供了见解 ...

Core Viewpoint - The article discusses the challenges and advancements in the preclinical evaluation of drugs targeting Th2-type immune response diseases, specifically atopic dermatitis and asthma, highlighting the need for improved animal models and evaluation systems [1][2]. Group 1: Disease Mechanisms and Challenges - Atopic dermatitis and asthma are chronic inflammatory diseases driven by abnormal Th2 immune responses, involving pathways such as IL-4, IL-13, and IL-5, as well as epidermal barrier dysfunction and neuroimmune dysregulation [1]. - Despite the clinical application of targeted biologics improving patient outcomes, issues such as individual response variability, acquired resistance, and long-term safety remain unresolved [1]. Group 2: Preclinical Research Dilemmas - Key questions in preclinical research include how to establish more accurate animal models that simulate skin barrier defects in atopic dermatitis and airway hyperreactivity in asthma [1]. - There is a need to optimize the drug efficacy evaluation system for Th2 immune responses to enhance clinical translation rates [1]. - New technologies are required to overcome existing model limitations in simulating neuroimmune interactions [1]. - Personalized preclinical evaluation plans must be designed for candidate drugs with different mechanisms of action [1]. Group 3: Online Course Information - An online course titled "Preclinical Drug Evaluation Models for Th2 Immune Response Diseases: Aiding New Drug Development for Atopic Dermatitis and Asthma" will delve into these topics [2]. - Participants will learn about the latest research advancements in Th2 immune diseases, methods for constructing clinically relevant animal models, and key challenges in developing innovative mouse models [2]. - The course will also cover technical solutions and case studies related to autoimmune disease efficacy platforms, along with an interactive Q&A session with the lecturer [2]. Group 4: Instructor Background - Dr. Yu Jing, a senior scientist in the pharmacodynamics research department at Saiye Bio, specializes in the development of animal models for immune reconstruction, tumor models, metabolic diseases, and autoimmune diseases, with extensive experience in efficacy validation [7]. Group 5: Efficacy Evaluation Platform - Saiye Bio offers a stable efficacy evaluation platform for autoimmune and inflammatory diseases, providing comprehensive pharmacodynamic evaluation and mechanism research services [12]. - The platform includes various models such as induced models, gene editing, and humanized models, focusing on physiological and biochemical indicators, pathological analysis, and immune cell function assessment [9][12].

撰文丨王聪 编辑丨王多鱼 排版丨水成文 整合应激反应 （ Integrated Stress Response， ISR） 是一种保守的应激反应，可维持真核细胞的内环境稳定。调节整合刺激反应 （ISR） 对包括病毒感染、癌 症和神经退行性疾病在内的多种疾病具有治疗潜力，但目前鲜有已知化合物能够在无毒副作用的情况下实现这一调节。 2025 年 7 月 11 日，Broad 研究所 James Collins 教授 、 Integrated Biosciences 公司 的 Felix Wong 、 Maxwell Wilson 等人在国际顶尖学术期刊 Cell 上 发表了题为： Optogenetics-enabled discovery of integrated stress response modulators 的研究论文 【1】 。 该研究将 光遗传学 技术用于 药物发现 ，开发了一个用于发现能够选择性调节 整合刺激反应 （ISR） 的化合物的光遗传学平台，筛选出了能够选择性消除在各种 应激压力条件下具有高 ISR 的细胞的化合物，这些化合物在体外和小鼠体内均表现出 广谱抗病毒活性 。 Felix W ...

Core Viewpoint - Spinocerebellar ataxia type 3 (SCA3) is a common hereditary disorder with no effective treatment, leading to significant burdens on patients and healthcare systems [1][2]. Recent research indicates that transcranial alternating current stimulation (tACS) may provide a safe and effective intervention for improving symptoms in SCA3 patients [3][11]. Summary by Sections Disease Overview - SCA3 is caused by the expansion of CAG repeats in the ATXN3 gene, leading to progressive cerebellar ataxia, which manifests as unsteady gait, speech difficulties, swallowing problems, and poor motor accuracy [1]. - Most SCA3 patients lose mobility within 10-20 years of onset, with a survival period of 20-25 years from onset to death [2]. Recent Research Findings - A randomized controlled trial published in Cell Reports Medicine demonstrated that tACS is safe, effective, and well-tolerated, improving the severity of ataxia by modulating brain functional connectivity in SCA3 patients [3][11]. - The study involved 82 SCA3 patients, randomly assigned to receive either active tACS or sham stimulation for 2 weeks, with significant improvements observed in the active group [8]. Clinical Trial Details - The trial was a triple-blind, parallel-group, sham-controlled study assessing the effects of tACS on ataxia severity and quality of life, using functional MRI to evaluate changes in brain connectivity [7]. - Results showed that 80% of participants in the active tACS group met the primary outcome measure, compared to only 10% in the sham group, with significant reductions in SARA scores [8]. Implications for Future Treatment - The findings suggest that tACS could be a promising intervention for SCA3 and potentially other cerebellar disorders, highlighting the need for further research into its long-term effects [11].

撰文丨王聪 编辑丨王多鱼 排版丨水成文 自然界中存在着多种生殖方式，除了 有性生殖 ，还有些动植物能够进行 孤雌生殖、 孤雄生殖 。但是对于高等的哺乳动物来说，只能进行 有性生殖 ，每一个 哺 乳动物生命都始于卵子与精子融合形成的受精卵，其中包含两套基因组，一套来自母亲，一套来自父亲。然而，有些基因只有来自父亲的等位基因表达，有些则 只有来自母亲的等位基因表达，也就是所谓的 基因组印记 ，这种基因组印记是通过表观遗传学的甲基化实现的，基因组印记的存在，阻碍了孤雌生殖或 孤雄生 殖 的实现。 近日，上海交通大学医学院附属仁济医院生殖医学中心 魏延昌 等人在《 美国国家科学院院刊 》 （PNAS） 上发表了题为： Fertile androgenetic mice generated by targeted epigenetic editing of imprinting control regions 的研究论文。 在这项新研究中，研究团队报告了由两个精子细胞的遗传物质培育出的成年哺乳动物后代。研究团队将这些小鼠称之为孤雄生殖小鼠，是通过基于 CRISPR 的表 观基因组工程对 7 个印记控制区域 （ICR） ...