Core Viewpoint - The excessive intake of added sugars has become a significant public health issue, particularly among children and adolescents, leading to potential long-term effects on obesity, metabolic disorders, and cognitive functions [2][4]. Group 1: Research Findings - A study published by a team from Beijing Normal University indicates that excessive sucrose consumption during early life alters cortical dynamics and adaptive behavior in adulthood [2][5]. - The research utilized wide-field calcium imaging to monitor the activity of the dorsal cortex in adult mice that had consumed high-sugar beverages since weaning, comparing them to a control group [4]. - Findings revealed that mice consuming high-sugar beverages exhibited changes in cortical dynamics and behavioral flexibility, despite no abnormalities in weight gain or glucose tolerance [4][7]. Group 2: Specific Observations - Mice exposed to sucrose during early life showed reduced cortical responses to sucrose in adulthood [7]. - These mice displayed delayed and prolonged learning-related cortical activity during early learning stages [7]. - There was a noted decrease in functional connectivity between the anterior and posterior cortices in mice that consumed sucrose early in life, along with heightened sensitivity to cue-reward association changes [7].

撰文丨王聪 编辑丨王多鱼 排版丨水成文 一名 8 岁小男孩在短短几个月内病情迅速恶化。2023 年 8 月，他还在跑步、踢足球，而到 9 月，他的双踝就出现了不自主的肌肉收缩，10 月，他已无法跑步 和进行体育运动，而到了 11 月底，他开始频繁摔倒，医生建议他靠轮椅行动。 基因检测确认了这个小男孩的病因：他遗传了来自父母的 HPDL 基因纯合突变，HPDL 蛋白有助于生成一种名为 辅酶 Q10 （CoQ10） 的抗氧化剂，这种抗氧化 剂对于线粒体发挥正常功能至关重要。实际上，他的两个哥哥姐姐因为该疾病在婴儿时期就已离世，而他的严重程度略低，在 8 岁时才突然病情恶化。 该疾病没有可用的治疗药物或方法，幸运的是， 纽约大学的 Michael Pacold 教授 团队此前发现了 一种 辅酶 Q10 前体 分子—— 4-HB ，有望治疗辅酶 Q10 合成缺陷相关线粒体脑病，但这尚未在人体上验证过。在美国 FDA 的特别许可下，研究团队对这名小男孩进行了 实验性治疗。 经过不到一个月的治疗，这个小男孩就可以走上 1 公里的路，现如今，他已经可以徒步 6 公里，还能跑步，甚至还能骑自行车了 ，他的力气正在恢复，精力和 ...

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].