Core Viewpoint - The article discusses the impact of systemic inflammation on the aging of muscle stem cells (MuSC) and highlights a mechanism linking chronic inflammation to stem cell aging and ferroptosis, suggesting potential therapeutic strategies to combat age-related muscle degeneration [4][11][13]. Group 1: Mechanism of Aging and Inflammation - Systemic inflammation induces epigenetic erosion, promoting ferroptosis in muscle stem cells, while long-term suppression of systemic inflammation can effectively prevent ferroptosis and maintain muscle stem cell numbers [4][11]. - The study reveals that age-related inflammation decreases H4K20 monomethylation levels in MuSCs, disrupting their quiescent state and leading to ferroptosis [11]. - Inflammation signals downregulate the enzyme Kmt5a, which is responsible for H4K20me1 accumulation, resulting in the epigenetic silencing of genes that counteract ferroptosis [11]. Group 2: Impact on Muscle Regeneration - Aging is characterized by a decline in muscle mass, strength, and regenerative capacity, leading to decreased quality of life in the elderly [7]. - Muscle stem cells play a crucial role in muscle repair and maintenance, but their function significantly declines with age due to both intrinsic changes and external factors like inflammation [7][8]. - Chronic systemic inflammation is one of the most important external factors leading to stem cell aging, as it inhibits muscle regeneration [8][9]. Group 3: Research Findings and Implications - The research emphasizes that aging cells are a major contributor to age-related inflammation in the muscle stem cell microenvironment, impairing their regenerative capacity [9]. - Long-term suppression of inflammation starting at middle age (12 months in mice) can restore muscle vitality and promote functional recovery [11][13]. - These findings reveal an epigenetic switch linking chronic inflammation to muscle stem cell aging and ferroptosis, providing potential therapeutic strategies against age-related muscle degeneration [13].

Core Viewpoint - The article discusses the role of the p53 R172H mutation in pancreatic ductal adenocarcinoma (PDAC), highlighting its contribution to creating an immunosuppressive tumor microenvironment and reducing the efficacy of immune checkpoint inhibitors (ICIs) [4][13][15]. Group 1: Background on PDAC - PDAC is a highly aggressive cancer characterized by KRAS gene activation mutations and TP53 gene alterations, with TP53 mutations leading to the loss of tumor suppressor function [2][6]. - Approximately 90% of PDAC cases have KRAS activation mutations, while around 70% exhibit changes in the TP53 tumor suppressor gene, indicating the critical role of p53 in genomic protection [7]. Group 2: Research Findings - A study published by MIT researchers reveals that the common p53 mutation, p53 R172H, occupies enhancers of immunosuppressive chemokines (e.g., Cxcl1), stimulating their expression and establishing an immunosuppressive tumor microenvironment in PDAC [3][4][11]. - The study indicates that knocking out the p53 R172H mutation enhances the efficacy of immune checkpoint inhibitors [13][15]. - Mechanistically, p53 R172H enhances Cxcl1 expression by occupying its distal enhancer, with NF-κB being a crucial cofactor for this process [12][15]. Group 3: Implications for Treatment - The findings suggest that p53 R172H promotes tumor growth by regulating cancer cell-specific gene expression programs that shape the tumor microenvironment, thereby inhibiting anti-tumor immune responses [15][16]. - In mouse models of PDAC, tumors lacking p53 R172H showed fewer T cells and higher levels of myeloid-derived suppressor cells (MDSCs), indicating a more favorable immune environment for tumor growth [15].

Core Insights - Vascular dementia (VaD) accounts for approximately 25% of all dementia cases, making it the second most common type after Alzheimer's disease (AD) [2] - There is a significant overlap between VaD and AD, with 84% of elderly individuals exhibiting features of both conditions, suggesting a potential synergistic effect [2] - Current treatments for VaD are limited and primarily symptomatic, highlighting the urgent need for comprehensive research to identify therapeutic targets [2] Research Findings - A study published in Cell identified the CD39-A3AR signaling pathway as crucial for brain repair in VaD, demonstrating that the A3AR-specific agonist Piclidenoson can promote brain tissue repair and restore memory and gait functions in mouse models [3][11] - The study developed a mouse model that replicates the focal ischemic characteristics of human VaD, addressing the limitations of existing models [8] - The research team constructed a comprehensive VaD interaction network by integrating mouse and human data, identifying conserved signaling pathways altered in VaD [9][10] Mechanisms and Challenges - The understanding of the neurovascular unit (NVU) and its cell-type-specific responses in VaD remains incomplete, which complicates the development of effective therapies [6] - The study emphasizes the need for high-resolution transcriptomic analysis of NVU cells to uncover disease mechanisms and the development of next-generation animal models to bridge the gap between rodent and human pathophysiology [7] Therapeutic Implications - The findings suggest that enhancing CD39-A3AR signaling may aid in the recovery of tissue and behavioral functions in VaD patients, providing a potential new therapeutic target [12][15] - The research indicates that even delayed treatment interventions can be effective, which is critical given that VaD is often diagnosed late [14]

Core Viewpoint - The article discusses the significance of synonymous mutations in genetic research, particularly their role in cucumber domestication through epitranscriptomic regulation, challenging traditional views on these mutations [2][3]. Group 1: Research Findings - The study published in the journal Cell demonstrates that synonymous mutations can regulate important traits in cucumber by altering m6A modifications and mRNA structural conformations [2][3]. - The research identifies two closely linked genes, YTH1 and ACS2, that interact epistatically to influence cucumber fruit length [5][9]. - A specific synonymous mutation, 1287C>T in the ACS2 gene, is identified as a pathogenic mutation that disrupts m6A methylation and alters RNA structure, leading to changes in fruit length [6][9]. Group 2: Genetic Mechanisms - The YTH1 gene encodes an m6A reader protein, while the ACS2 gene encodes a rate-limiting enzyme for ethylene synthesis in plants, both of which are crucial for cucumber domestication [5][9]. - The study reveals that the wild-type cucumber's ACS2 1287C leads to m6A modification and a loose RNA structure, while the cultivated cucumber's ACS2 1287T results in a compact RNA structure, affecting protein levels and fruit length [6][9].

Core Viewpoint - The article discusses an innovative method for chemically recycling mixed plastic waste into valuable chemical products, addressing the environmental challenges posed by plastic waste [2][3]. Group 1: Research Overview - The research, published in Nature, presents a strategy to convert eight common types of plastic waste into their original chemical components or other valuable compounds [3][10]. - The method focuses on identifying functional groups in mixed plastic waste to facilitate the separation and conversion of these materials into useful products [5][8]. Group 2: Methodology - The research team developed a solid-state NMR method to accurately identify the types of plastics present in the mixed waste, which is crucial for the subsequent processing steps [5][6]. - By using selective solvents, the team was able to dissolve and separate specific plastics from the mixed waste, followed by catalytic processes to convert these plastics into valuable products [6][7]. Group 3: Results and Innovations - The study successfully demonstrated the feasibility of the proposed strategy using a real-life plastic mixture, yielding various chemical substances such as benzoic acid, plasticizers, and hydrocarbons [7][8]. - The key innovation lies in the universal strategy designed to tackle the challenge of chemical recycling of mixed plastics, allowing for adjustments in chemical steps based on the initial identification of major components [8][10].

Core Viewpoint - Google’s subsidiary Calico Life Sciences has entered into a nearly $600 million biopharmaceutical deal with Mabwell to acquire rights to a research therapy targeting Interleukin-11 (IL-11), including a clinical-stage monoclonal antibody 9MW3811 for age-related diseases [2][3]. Group 1: Deal Details - Mabwell has explored the therapeutic potential of 9MW3811 in age-related diseases during preclinical research, completing Phase 1 clinical studies in China and Australia, showing promise for treating idiopathic pulmonary fibrosis, and has received approval to conduct Phase 1 clinical studies in the United States [3]. - Under the licensing agreement, Mabwell grants Calico exclusive rights to develop, manufacture, and commercialize 9MW3811 outside Greater China. Calico will pay an upfront non-refundable fee of $25 million, with potential additional payments of up to $571 million based on milestones, as well as tiered royalties based on net sales of the licensed product [3]. Group 2: Company Background - Calico was co-founded by Alphabet, Google's parent company, and industry leader Dr. Arthur Levinson, with the aim of understanding the biological principles of aging to help develop interventions that extend and improve lifespan. Calico has established partnerships with several organizations, including AbbVie and the Broad Institute of MIT and Harvard [3]. - Mabwell is an innovative biopharmaceutical company with a full industry chain layout, focusing on tumors and age-related diseases, covering treatment areas such as oncology, autoimmune diseases, bone diseases, ophthalmology, hematology, and infections [4].

Core Viewpoint - AbbVie is making a significant move into the in vivo CAR-T market by acquiring Capstan Therapeutics for $2.1 billion in cash, aiming to integrate a candidate therapy for autoimmune diseases, CPTX2309, which is currently in Phase 1 clinical trials [2][9]. Group 1: Capstan Therapeutics Overview - Capstan Therapeutics, founded in early 2022, focuses on in vivo reprogramming of T cells to address manufacturing and scalability challenges in CAR-T therapies, allowing patients to avoid lymphocyte-depleting chemotherapy prior to treatment [3][9]. - The company has raised $340 million from various pharmaceutical giants and venture capital firms, with a founding team that includes pioneers in CAR-T cell therapy and mRNA technology [9]. Group 2: In Vivo CAR-T Technology - The in vivo CAR-T technology was developed based on a research paper published by researchers at the University of Pennsylvania in January 2022, which introduced a method to generate CAR-T cells in situ using lipid nanoparticles to deliver mRNA [6][12]. - This innovative approach, similar to mRNA vaccines, aims to simplify the CAR-T cell production process, addressing issues such as complexity, time, and high costs associated with traditional methods [7][14]. Group 3: Clinical Development and Applications - Capstan's lead product, CPTX2309, is currently in Phase 1 clinical trials for treating B cell-mediated autoimmune diseases, with promising preclinical results demonstrated in animal models [11][19]. - The therapy utilizes targeted lipid nanoparticles to deliver mRNA encoding CD19 CAR to CD8+ T cells, effectively generating CAR-T cells that can eliminate autoreactive B cells while allowing for the regeneration of healthy B cells [19][20]. Group 4: Market Context and Potential - Since 2017, the FDA has approved six CAR-T therapies for various B cell malignancies, with hundreds more in clinical trials globally, highlighting the growing interest and potential in the CAR-T market despite existing challenges [14][15]. - Recent advancements in CAR-T therapies for autoimmune diseases have shown significant clinical benefits, indicating a promising avenue for future treatments [15].

该研究 首次通过人类 诱导多能干细胞 （iPSC） 成功构建了 高度血管化的肺类器官和肠道类器官 。这些类器官模型不仅模拟了人类胚胎早期多胚层协同发育的 复杂过程，更突破了传统类器官缺乏功能性血管和器官特异性间充质的瓶颈，为研究人类器官发育和疾病中的复杂细胞间通讯以及再生医学提供了一个先进的平 台。 论文第一作者兼共同通讯作者 苗一非 博士，现为中国科学院动物研究所 人类器官生理病理模拟装置 （ H OPE） 研究员 ；共同第一作者 谈诚 博士现为北京大 学人民医院妇产科主治医师。 撰文丨王聪 编辑丨王多鱼 排版丨水成文 2009 年，荷兰 Hubrecht 研究所的 Hans Clevers 等人使用来自小鼠肠道的成体干细胞培育出首个 肠道类器官 ， 开创了类器官研究时代 。 此后， 类器官领域 研究成果不断，许多新型类器官和更复杂的类器官不断涌现，这些研究新药开发、精准治疗、再生医学等领域带来了更强大的工具 。 然而，目前的类器官中普遍缺乏器官特异性和功能性的血管网络，尤其是肺和肠道等内胚层器官，缺乏有效的血管化方法，导致 肺和肠道类器官 结构和功能的不 成熟，极大地限制了它们在疾病建模和治疗应用方面的应 ...

Core Viewpoint - The article discusses a novel therapeutic approach targeting pathogenic T cells in autoimmune diseases, focusing on the mechanism of LAG-3 and T Cell Receptor (TCR) interaction, which offers a new strategy for treatment [4][10]. Group 1: Mechanism of Action - Autoimmune diseases are caused by overactive immune responses leading to tissue damage, with T cells playing a crucial role in diseases like type 1 diabetes and rheumatoid arthritis [2][3]. - LAG-3, an inhibitory immune checkpoint receptor, is regulated by its classical ligand MHC-II, and its activation is dependent on the spatial proximity to TCR, which is essential for effective suppression of CD4+ T cells [4][5][7]. - The study reveals that LAG-3's optimal function requires not just interaction with MHC-II but also the formation of a spatial proximity with TCR, which is a key molecular mechanism for T cell inhibition [7][8]. Group 2: Therapeutic Development - The research team developed a bispecific T cell silencer (BiTS) that targets the interaction between LAG-3 and TCR, allowing for selective modulation of pathogenic T cells while preserving beneficial T cell functions [5][10]. - This innovative approach has shown significant therapeutic effects in various animal models of autoimmune diseases, indicating its potential for treating conditions like refractory multiple sclerosis and rheumatoid arthritis [5][10]. - The study provides a unique opportunity for precise intervention in T cell-driven autoimmune diseases, addressing the current lack of safe and effective therapies [10].

脑卒中 （俗称"中风"，包括脑梗塞及脑出血） 作为全球造成残疾和社会负担排名首位的神经系统疾病，平均 约 50% 的幸存者在经过现有治疗和复健后，自我代偿和复健等治疗能带来的功能改善会达到极限，并在 6 个月以后进入稳定期，甚至终身伴随偏瘫、语言功能障碍等后遗症。 最新报告显示， 我国 包括缺血性脑卒中 （脑梗塞） 和脑出血在内的脑卒中患者高达 2800 万 人，每年 新 增 病例约 394 万 。 全球 现有偏瘫患者高达 1 亿 人，每年 新增 约 1500 万 人，其中约 67% 为 70 岁以 下人群，22% 甚至发生在 15-49 岁的青壮年群体，并且这一数字仍然在快速增长和继续年轻化。 目前 全球仅有一款 迷走神经刺激器 （VNS） 结合复健 的治疗手段，平均可改善患者的上肢运动功能评分 （FMA-UE） 约 5.8 分 ，并已作为 突破性 器械疗法在 2021 年被 FDA 批准针对 6 个月以上的稳定偏瘫患 者。由于脑卒中后遗症患者的大量功能神经元死亡和神经环路损伤，而成人脑内神经干细胞的数量和再生能力 有限，通过迷走神经刺激等带来的神经可塑性、传统药物与康复治疗对进入稳定期患者的 功能恢复促进 ...