Core Insights - The article discusses the development of a novel protein language model (PLM) called Saprot, which integrates one-dimensional amino acid sequences with three-dimensional structural information to enhance protein structure and function prediction [2][9][19] - The launch of the open-source platform SaprotHub aims to democratize access to advanced PLMs for researchers in the life sciences, bridging the gap between AI developers and biologists [3][8][19] Group 1: Challenges in Protein Research - Protein research faces significant challenges due to the technical expertise required for training and deploying advanced AI models, which creates a barrier for biologists engaged in experimental research [5][19] - The complexity of programming environments, data preprocessing, and model training limits the widespread adoption of AI technologies in fields like medicine and biotechnology [5] Group 2: SaprotHub and Its Components - SaprotHub is a comprehensive ecosystem that combines cutting-edge AI model technology, open-source tools, and a global community to facilitate collaboration in protein research [8][19] - The core engine, Saprot, has been trained using millions of protein structures predicted by AlphaFold2, utilizing 64 NVIDIA A100 GPUs, and has demonstrated superior performance in various protein function prediction tasks [9][19] Group 3: Open-Source Tools and Global Collaboration - The ColabSaprot platform simplifies the training of protein language models, allowing researchers without programming backgrounds to easily engage with advanced AI tools [10][19] - The Open Protein Modeling Consortium (OPMC) is a collaborative initiative that includes top research institutions worldwide, aiming to foster the development of the protein field through shared resources and knowledge [11][19] Group 4: Validation and Real-World Applications - The effectiveness of SaprotHub has been validated through user studies and various biological experiments, showing that non-AI researchers can achieve results comparable to AI experts [12][19] - Successful applications include enhancing the activity of an industrial enzyme by 2.55 times, optimizing gene editing tools for doubled efficiency, and designing a new fluorescent protein with over eight times the brightness of the original [18][19]

撰文丨王聪 编辑丨王多鱼 排版丨水成文 2020 年， 张义 团队 研究团队从感染性心内膜炎患者体内分离出一株 Bergeyella cardium 突变株 （BCV） 。与原始菌株相比，BCV 表现出更强的血清抗性和 致病能力。 在这项最新研究中，研究团队发现， BCV 可诱导 巨噬细胞 产生独特的胞质空泡化细胞死亡和轻微的凋亡样细胞死亡，研究团队将这种细胞死亡方式命名为—— Floatptosis ，这一细胞死亡过程以溶酶体融合相关终止 （ F used L ysosome- a ssociated t ermination ） 为特征，且可被钠通道抑制剂 阿米洛利 特异性抑 制。 实验证实，BCV 分泌的外膜囊泡 （OMV） 或其携带的桶状膜蛋白成分 （包括脂质运载蛋白、β-桶状结构及PorV蛋白） ，通过转染方式足以显著诱导胞质空泡 化表型。分子机制研究显示， SLC9A9 通过促进空泡融合，在 BCV 感染、OMV 及桶状蛋白触发的空泡化死亡通路中发挥关键调控作用。 细菌病原体已进化出多种机制来调控宿主细胞死亡、逃逸宿主免疫并建立持续性感染。 2025 年 10 月 21 日， 山东大学 高等医学研 ...

Core Viewpoint - The article discusses the emerging focus on metabolic cell death as a new frontier in cancer therapy, highlighting the significance of ferroptosis, cuproptosis, and disulfidptosis as potential therapeutic targets against cancer cells that evade traditional cell death pathways [3][4][5]. Group 1: Metabolic Cell Death Mechanisms - Metabolic cell death is characterized by the collapse of metabolic homeostasis, leading to irreversible cell death due to nutrient deprivation or the accumulation of harmful metabolites [3]. - Ferroptosis, discovered in 2012, is an iron-dependent cell death mechanism that results from uncontrolled lipid peroxidation, leading to membrane damage [8]. - Cuproptosis, identified in 2022, is a copper-dependent cell death mechanism where excess copper ions induce protein toxicity by binding to fatty acylated proteins in mitochondria [14]. - Disulfidptosis, proposed in 2023, occurs when cystine accumulation leads to the collapse of the actin cytoskeleton under conditions of glucose deprivation or NADPH depletion [19]. Group 2: Cancer Treatment Implications - Targeting metabolic cell death pathways presents a unique opportunity to exploit cancer cells' vulnerabilities, particularly through the mechanisms of ferroptosis, cuproptosis, and disulfidptosis [5][26]. - The interplay between these pathways suggests that combined interventions could enhance therapeutic efficacy and overcome drug resistance in cancer treatment [24][26]. - Establishing verifiable biomarker systems is crucial for advancing clinical applications and achieving precise patient stratification and treatment [26].

Core Insights - The article discusses the development of engineered thoracic spinal cord organoids (enTsOrg) for potential therapeutic applications in spinal cord injury (SCI) repair, showcasing their ability to restore motor function in paralyzed mice [2][3][11] Group 1: Research Findings - The research team successfully constructed enTsOrg that mimics the heterogeneity and mature neural circuit structure of the thoracic spinal cord, leading to the reorganization of neural circuits and recovery of hind limb motor function in mice with complete spinal cord injury [3][10] - The study highlights the complexity of the central nervous system's development and opens potential pathways for designing organoids tailored for specific anatomical regions in neural injury treatment [4][11] Group 2: Methodology - The engineered organoids were created using induced pluripotent stem cells (iPSCs) derived from fibroblasts and layered double hydroxide (LDH) matrices within a basement membrane hydrogel, successfully reproducing the diverse neuronal distribution and electrophysiological characteristics similar to natural spinal cord tissue [7][9] - The transplantation of enTsOrg into a mouse model of thoracic complete spinal cord injury resulted in significant improvements in motor function, neuronal subtype diversity, and electrophysiological conduction of motor neurons compared to non-segment-specific spinal cord organoids [9][10] Group 3: Mechanisms of Action - LDH promotes the formation of region-specific thoracic spinal cord organoids by activating PTCH1 protein and regulating retinoic acid signaling pathways, enhancing neuronal survival and promoting the differentiation and maturation of motor neurons and interneurons [9][10] - The study indicates that the transplanted enTsOrg formed more refined functional neurons with dorsal and ventral characteristics, crucial for muscle contraction and extension in paralyzed animals [9][10]

Core Viewpoint - The research identifies HMGN1 gene on chromosome 21 as a key factor mediating myocardial reprogramming, leading to congenital heart defects in patients with Down syndrome [3][5]. Group 1: Research Findings - Down syndrome occurs in approximately 1 in every 700 live births, with an increased incidence related to maternal age [2]. - About 50% of Down syndrome patients exhibit congenital heart defects, with atrioventricular canal (AVC) defects being the most common, occurring at a rate approximately 1000 times higher than in the general population [2]. - The study published in Nature reveals that increased copy number of the HMGN1 gene is responsible for heart defects in Down syndrome patients [3][5]. Group 2: Methodology - The research utilized human pluripotent stem cells (hPSCs) and a Down syndrome mouse model to identify HMGN1 as a critical factor for these defects [5]. - Single-cell transcriptomics indicated that Down syndrome causes a transition of human epicardial cells to a ventricular myocardium state [5]. - CRISPR activation combined with single-cell RNA sequencing (CROP-seq) demonstrated that upregulation of HMGN1 mimics this transition, while deletion of one HMGN1 allele in trisomy 21 cells restores normal expression [5]. Group 3: Implications - Reducing Hmgn1 dosage in the Down syndrome mouse model can restore transcriptional changes in AVC myocardial cells, thereby repairing heart valve septal defects [7]. - HMGN1 is highlighted as a dosage-sensitive regulatory factor in the development of AVC and cardiac septum formation in Down syndrome patients [8]. - The study serves as a model for using homologous gene systems to dissect the pathogenesis of aneuploidy-related diseases and locate pathogenic genes within complex genetic syndromes [8].

Core Viewpoint - The research reveals a novel mechanism by which cancer cells evade immune surveillance by hijacking pain-sensing neurons, leading to systemic immune suppression in tumor-draining lymph nodes (TDLN) and providing insights for enhancing immunotherapy and pain relief strategies [3][4][18]. Group 1: Research Findings - Under immune pressure, cancer cells activate pain-sensing neurons through the ATF4-SLIT2 signaling axis, which leads to the remodeling of TDLN into an immunosuppressive environment [6][14]. - The study found that higher densities of pain-sensing neurons in tumors correlate with worse immune system status in patients, characterized by increased M2 macrophages and decreased CD8+ T cells [9][20]. - The activation of pain-sensing neurons in TDLN releases calcitonin gene-related peptide (CGRP), which suppresses anti-tumor immune responses, resulting in a decrease in CD8+ T cells and impaired dendritic cell function [14][15]. Group 2: Treatment Strategies - The research proposes several methods to disrupt the neuroimmune circuit, including gene knockout of SLIT2 or ATF4, chemical denervation of pain-sensing neurons, and the use of CGRP receptor antagonists like remifentanil, which enhance the efficacy of immune checkpoint inhibitors [18][19]. - These strategies not only inhibit tumor growth but also provide dual benefits of pain relief and enhanced anti-tumor immunity [18][19]. Group 3: Clinical Implications - The study suggests that cancer pain may serve as an important indicator of immune evasion, prompting clinicians to monitor pain levels as a potential measure of immunotherapy effectiveness [20]. - Existing drugs like remifentanil could be repurposed for cancer treatment, offering cost-effective options for patients [21]. - The findings indicate the potential for personalized treatment approaches based on individual neuroimmune characteristics, and the mechanism may apply to various cancer types beyond head and neck squamous cell carcinoma [22][23].

Core Viewpoint - The article discusses the unique characteristics and high market value of civet coffee, highlighting recent research that uncovers the reasons behind its distinct flavor profile [1][2]. Group 1: Unique Characteristics of Civet Coffee - Civet coffee, known for its luxurious price, can cost over 100 times that of regular coffee, with prices exceeding $1,300 per kilogram and $75 per cup [6]. - The flavor profile of civet coffee includes notes of nuts, chocolate, earth, and even fish, attributed to specific fatty acids found in the beans [2][10]. Group 2: Recent Research Findings - A recent study published in the journal Scientific Reports reveals that civet coffee beans contain higher concentrations of caprylic and capric acids, which are known for their unique flavor contributions [4][10]. - The research involved comparing 68 samples of civet feces to directly harvested coffee beans, aiming to understand the digestive effects of civets on coffee beans [9][10]. - The study indicates that the fermentation process in the civet's digestive system, influenced by specific bacteria, plays a crucial role in developing the coffee's flavor [10]. Group 3: Market and Production Insights - The popularity of civet coffee has led to the growth of a tourism industry centered around its production, with some farms resorting to caged civets for coffee bean collection [9]. - The article notes that while the study focused on Robusta coffee beans, commercial civet coffee typically uses Arabica beans, suggesting the need for further research on the latter [10].

Core Viewpoint - The article discusses a groundbreaking research study from Shanghai Jiao Tong University that introduces a new paradigm in regenerative medicine, allowing for direct differentiation of human adult adipose tissue into functional organoids without the need for complex cellular manipulation, thus overcoming significant clinical challenges in the field [3][4]. Group 1: Research Breakthroughs - The study presents a novel "tissue → new tissue" reprogramming paradigm that activates the endogenous differentiation potential of adult adipose tissue, enabling the generation of various functional organoids [4]. - Three major advantages of this research are highlighted: 1. Tissue-level reprogramming that preserves the ecological niche and homeostasis of multiple cell types within adipose tissue, avoiding genomic instability risks associated with cellular manipulation [7]. 2. The breakthrough of germ layer restrictions, successfully directing adipose tissue to differentiate into functional endodermal and ectodermal organoids [7]. 3. Clinical safety assurance through a process that avoids pluripotent states and cell passage, with long-term trials showing no tumorigenicity [7]. Group 2: Methodology and Findings - The research team developed an innovative technique that maintains the natural microenvironment of adipose tissue, leading to the formation of three-dimensional active microtissues with a high proportion of mesenchymal stem cells [8]. - The reaggregated microfat (RMF) particles demonstrated significant differentiation potential, successfully constructing functional human-derived bone marrow organoids that exhibited progressive ossification and superior hematopoietic support capabilities [9]. - The study also achieved the construction of pancreatic organoids with a notable percentage of functional β-like cells, significantly enhancing insulin secretion in response to glucose stimulation [10]. Group 3: Clinical Implications - The findings suggest that adipose tissue can serve as a "natural stem cell reservoir," providing a safe, economical, and scalable treatment strategy for conditions such as diabetes, blood disorders, and nerve injuries [13]. - The research team has initiated clinical translation studies for diabetes treatment, potentially leading to a new chapter in regenerative medicine where liposuction can be utilized for significant health benefits [13].

Core Insights - The article discusses the discovery of SARM1 as a new DNA sensor that promotes NAD+ degradation and cell death, revealing a novel immune recognition mechanism and potential therapeutic target for diseases like cancer [3][11][13]. Group 1: SARM1 Discovery and Mechanism - SARM1 has been identified as a new DNA receptor that, when activated by DNA, promotes NAD+ degradation and cell death [3][11]. - The study shows that SARM1 can sense double-stranded DNA (dsDNA) in a sequence-independent and length-dependent manner, leading to the activation of NAD+ degradation [9][10]. - SARM1's activation is tightly regulated, with high concentrations of NAD+ inhibiting its activation, indicating a self-regulatory mechanism [6][7]. Group 2: Implications for Cancer Treatment - The research indicates that knocking out the SARM1 gene can prevent chemotherapy-induced neuropathy (CIN) in mice, suggesting a potential therapeutic intervention for cancer treatment [3][11][10]. - The findings highlight SARM1 as a promising target for therapeutic strategies aimed at diseases characterized by cell death and immune responses [13][11]. Group 3: Structural Insights - SARM1 consists of three domains: ARM, SAM, and TIR, with the TIR domain being crucial for its activation through oligomerization [7][9]. - The study reveals that the TIR domain binds to dsDNA, with basic residues facilitating this interaction, which is essential for SARM1's function [9][10].

编辑丨王多鱼 排版丨水成文 年龄相关的胸腺退化，会增加老年人对癌症和感染的易感性，但其驱动机制及其对外周 T 细胞的影响仍不 明确。 2025 年 10 月 24 日 ，四川大学华西医院 胡洪波 、 张惠媛 、 胡佳 团队及陆军军医大学 吴玉章 院士团 队合作，在 Nature 子刊 Nature Aging 上发表了题为： Single-cell analysis of human thymus and peripheral blood unveils the dynamics of T cell development and aging 的研究论文。 该研究对来自婴 幼儿到百岁老人的 胸腺和外周血 样本进行了大规模 单细胞多组学 测序，构建了详尽的 人类免疫衰老图谱 。 该研究不仅揭示了衰老胸腺中早期祖细胞向 T 细胞发育的谱系潜能降低、炎性成熟 T 细胞积累 ； 还发现 胸腺微环境信号失调， 促进 早期胸腺祖细胞谱系潜能偏移，自身抗原呈递功能受损。该还成功开发了新型 免疫衰老时钟—— n-TIME 。这项研究为理解及干预免疫衰老提供了宝贵的数据资源和理论框架。 在这项最新研究中，研究团队使用单细胞测序 ...