这一关乎 " 同一性 " 与 " 异质性 " 的辩证矛盾，是困扰生物学界数十年的 " 生命同源异质 " 之问。其核心便隐藏在每 个细胞不尽相同的转录活动中，一种被称为 " 基因表达噪声 " 的微观波动，是探索生命复杂性的关键入口。 长期以来，相关研究多聚焦于基因表达的平均水平，而将这种噪声波动视为技术误差。然而，它恰恰蕴藏着细胞命运决 策、机体衰老与疾病发生的关键线索。为什么在高度一致的条件下，细胞仍表现出如此丰富的转录异质性？这些波动又 如何在生理与病理过程中发挥作用？解析 基因表达噪声 的遗传基础，不仅有望填补 " 遗失的遗传力 " ，更将为复杂疾 病的机制研究开辟全新视角，具有重要的科学价值与临床意义。 202 5 年 11 月 23 日，中国医学科学院基础医学研究所 龙尔平 / 倪晓琳 团队与美国国家癌症研究所 张同武 团队合 作，在 Cell Reports 期刊 在线发表了题为： Genetic determinants of gene expression noise and its role in complex trait variation 的研究论文 。 该研究建立了基于百万级单细胞数据 ...

Core Insights - Metabolic dysfunction-associated fatty liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is increasingly recognized as a global health crisis, with potential progression to severe liver conditions [3] - Currently, only one drug, Remetiro, is approved specifically for the treatment of metabolic dysfunction-associated steatohepatitis (MASH), highlighting the urgent need for alternative strategies, with prebiotics emerging as a promising candidate [3] Research Findings - A study published in Cell Metabolism revealed that individual variability in gut microbiome mediates the efficacy of resistant starch (RS) on MASLD, indicating that different baseline gut microbiomes can drive variations in intervention responses [4] - The research team conducted a randomized, placebo-controlled clinical trial showing that RS, a natural prebiotic, has therapeutic effects on MASLD, although 30% of participants exhibited limited benefits, a finding corroborated in a multicenter clinical trial [6] - Multi-omics analysis and fecal microbiota transplantation (FMT) indicated that baseline gut microbiome is a major determinant of treatment response, with Prevotella inhibiting the degradation of RS, leading to low response rates [7] - Bifidobacterium pseudocatenulatum was isolated from the cohort, which can restore RS degradation and improve the response to RS inhibited by Prevotella [7] - A predictive model integrating baseline microbiome and clinical characteristics was developed, achieving an AUC of 0.74 - 0.87 for personalized intervention [8] Key Findings - Approximately one-third of MASLD participants showed poor response to RS intervention [11] - Prevotella mediates low response to RS by inhibiting RS-degrading bacteria [11] - Bifidobacterium pseudocatenulatum enhances the efficacy of RS [11] - A machine learning model based on baseline gut microbiome characteristics can predict responses to RS treatment [11] - The study suggests that gut microbiome determines the heterogeneity of RS treatment for MASLD, offering a potential for microbiome-guided precision therapy [12]

Core Viewpoint - The study published by Professor Wu Baojian's team from Guangzhou University of Chinese Medicine in Cell Metabolism highlights the role of the intestinal clock in regulating the sleep-wake cycle through maintaining glutamine homeostasis, suggesting potential new targets for enhancing sleep rhythms and treating sleep disorders [2][7]. Summary by Sections Research Findings - The integrity of the intestinal epithelial cells (IEC) is essential for maintaining the circadian sleep-wake cycle [4]. - BMAL1 in the intestinal epithelial cells drives the circadian expression of SLC6A19, promoting glutamine absorption during active periods, which enhances the activity of glutamatergic neurons in the hypothalamus, thereby increasing wakefulness and reducing sleep [4][5]. - A lack of REV-ERBα in intestinal epithelial cells leads to elevated glutamine levels during rest phases, which is causally linked to sleep abnormalities characterized by reduced sleep [4][5]. Implications - The intestinal clock regulates glutamine homeostasis temporally, shaping the circadian sleep-wake cycle, and may serve as a potential target for enhancing sleep rhythms and treating sleep disorders [7].

Core Viewpoint - Jiangsu Runhe Software Co., Ltd. has signed a strategic cooperation agreement with the Guangzhou Institute of Biomedicine and Health, focusing on enhancing biological research processes through digital technologies [1] Group 1: Strategic Cooperation - The partnership will concentrate on the human cell lineage big science research facility [1] - Collaboration will involve domestic operating systems, smart IoT, big data analysis, and artificial intelligence [1] Group 2: Technological Enhancement - The aim is to improve the standardization, intelligence, and visualization of biological research processes through digital technology [1]

Core Viewpoint - The article discusses the significance of Total Neoadjuvant Therapy (TNT) in the treatment of locally advanced rectal cancer (LARC) and highlights the need for a deeper understanding of the immune remodeling mechanisms involved in its efficacy [3][6]. Group 1: Treatment Strategies and Mechanisms - LARC accounts for over one-third of both incidence and mortality in colorectal cancer, which is the third most common and the second deadliest cancer globally [3]. - Recommended treatment strategies for LARC include TNT or neoadjuvant chemotherapy (nCT), with additional options like radiotherapy for cases with poor response [3]. - The immune remodeling mechanisms behind the efficacy of TNT remain unclear, necessitating further research into the tumor microenvironment (TME) changes induced by this therapy [6]. Group 2: Research Findings - A study published in Cancer Cell reveals that TNT significantly remodels the immune microenvironment in LARC, with CD8+ T cells and endothelial cells interacting as a potential key factor for clinical efficacy [4][10]. - The research utilized single-cell RNA sequencing and spatial transcriptomics to analyze pre- and post-treatment samples, showing that TNT is associated with a reduction in regulatory T cells (Treg) and an increase in IFNG+ CD8+ effector memory T cells, which may enhance complete response rates [6][7]. - The abundance of tumor-infiltrating CD8+ T cells post-TNT correlates with the enrichment of ACKR1+ endothelial cell subpopulations, which are activated by IFNγ released from CD8+ T cells, enhancing their antigen-presenting capabilities [6][7][10]. Group 3: Implications for Clinical Practice - The study provides new insights into optimizing clinical treatment strategies for rectal cancer by elucidating the complex mechanisms of immune response during neoadjuvant therapy [4][10]. - The findings suggest that the quantity of IFNG+ CD8+ T cells and peripheral blood IFNG signaling could serve as markers for response to TNT [8].

Core Viewpoint - The research published by the Beijing Brain Science and Brain-like Research Institute highlights the significant role of adenosine signaling in the rapid antidepressant effects of ketamine and electroconvulsive therapy (ECT), proposing a new intermittent hypoxia intervention to safely induce adenosine release in the brain for effective depression treatment [1] Group 1: Research Findings - The study identifies adenosine as a key signaling molecule that mediates the rapid antidepressant actions of ketamine and ECT [1] - The research confirms that the adenosine signaling pathway is a common mechanism underlying the rapid antidepressant effects of both treatments [1] - The findings provide a solid theoretical basis and clear targets for developing new generation antidepressant strategies that are based on adenosine signaling modulation, potentially leading to smaller side effects [1] Group 2: Implications for Treatment - The proposed intermittent hypoxia intervention (aIH) aims to safely and controllably induce adenosine release in the brain, achieving significant antidepressant effects [1] - This research deepens the understanding of the mechanisms behind rapid antidepressant effects, which could lead to innovative treatment options [1] - The study opens avenues for the development of small molecule drugs and non-drug interventions targeting adenosine signaling for depression treatment [1]

Core Insights - The study identifies Mesothelin (MSLN) as a biomarker and potential therapeutic target for bone destruction in rheumatoid arthritis (RA) [4][8] - MSLN levels are significantly elevated in RA patients and collagen-induced arthritis (CIA) animal models, indicating its role in disease pathology [6][9] Group 1: Research Findings - MSLN is involved in various biological processes, particularly in regulating immune responses, but its role in osteoclastogenesis is not well understood [6] - Inhibition of MSLN through pharmacological and genetic methods significantly impairs osteoclast differentiation and bone resorption [6] - Downregulation of MSLN in animal models effectively reduces bone destruction [6] Group 2: Mechanism of Action - MSLN interacts directly with PI3K, leading to the activation of the PI3K/AKT signaling pathway, which promotes the expression and translocation of NFATc1, thereby facilitating osteoclast differentiation [6][9] - MSLN is upregulated in the synovial tissue and plasma of RA patients, driving osteoclast differentiation and mediating pathological bone destruction [9] Group 3: Implications for Treatment - Targeting MSLN may represent a novel therapeutic strategy for addressing bone destruction associated with rheumatoid arthritis [8][9]

Core Insights - Researchers from Kobe University and other institutions have revealed the mechanism of a potent "brake" molecule in cancer, which may provide new ideas for developing novel therapeutic drugs [1] Group 1: Research Findings - The study identifies the Ras-ERK signaling pathway as closely related to cancer cell proliferation [1] - DA-Raf, a molecule present in very low quantities within cells, is known to effectively inhibit the Ras-ERK signaling pathway, but its specific mechanism of action was previously unclear [1] - The research demonstrates that DA-Raf occupies a critical position in the signaling pathway by binding to a key molecule called Ras, preventing it from interacting with other molecules that would lead to cancer cell proliferation [1] Group 2: Implications for Treatment - The findings suggest that altering the structure of the DA-Raf molecule could adjust its ability to inhibit the Ras-ERK signaling pathway [1] - This research provides new insights for the treatment of cancer and diseases related to muscle atrophy that are associated with the Ras-ERK signaling pathway [1]

Core Insights - Researchers at Tel Aviv University have discovered a biological mechanism that significantly enhances myelin generation in the brain, potentially opening new avenues for treating neurodegenerative diseases such as Alzheimer's and multiple sclerosis [1][2] - The study highlights the role of a protein called Tfii-i, which has been identified as a "biological brake" that inhibits myelin production [1][2] Group 1: Research Findings - The research team found that knocking out the Tfii-i gene in engineered mouse models led to a significant increase in myelin protein levels, thicker myelin structures, and faster nerve signal transmission compared to normal mice [2] - Behavioral tests indicated that the Tfii-i knockout mice exhibited improved motor coordination and agility [2] Group 2: Implications for Treatment - This research represents one of the few studies that reveal how to promote myelin generation in the brain, suggesting that inhibiting Tfii-i activity could be a novel therapeutic strategy for repairing myelin damage in neurodegenerative diseases [2] - The mechanisms identified in this study may provide new directions for interventions and treatments for conditions such as Alzheimer's disease, multiple sclerosis, Williams syndrome, and autism spectrum disorders [2]

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].