Core Viewpoint - GLP-1 receptor agonists and co-agonists, initially developed for type 2 diabetes treatment, have expanded benefits including weight loss and reduced incidence of chronic diseases such as cardiovascular disease, chronic kidney disease, and metabolic dysfunction-related fatty liver disease [2][3][27]. Summary by Sections GLP-1 Class Drugs Overview - GLP-1 drugs like liraglutide, dulaglutide, semaglutide, and tirzepatide enhance insulin secretion, reduce glucagon secretion, and slow gastric emptying, contributing to weight loss and appetite suppression [2]. - These drugs have been approved for treating type 2 diabetes and obesity, with additional benefits in reducing chronic kidney disease, myocardial infarction, stroke, and cardiovascular mortality [2]. Clinical Evidence and Expanding Benefits - Daniel J. Drucker's article highlights the benefits of GLP-1 drugs beyond diabetes and obesity, including cardiovascular disease, chronic kidney disease, metabolic dysfunction-related fatty liver disease, osteoarthritis, obstructive sleep apnea, and peripheral artery disease [3]. Cardiovascular and Kidney Disease - Semaglutide received FDA approval in 2024 as the first weight loss drug proven to reduce major adverse cardiovascular events in adults with obesity or overweight and established cardiovascular disease [7]. - In clinical trials, semaglutide significantly reduced the incidence of non-fatal myocardial infarction and stroke, with a risk ratio of 0.8 compared to placebo [7]. - In patients with heart failure with preserved ejection fraction (HFpEF), semaglutide improved symptoms and reduced cardiovascular death and heart failure-related events by 31% [10]. Metabolic Dysfunction-Related Fatty Liver Disease - In a clinical trial involving 1,200 adults with metabolic dysfunction-associated steatotic liver disease (MASH), semaglutide improved liver histology and increased the rate of fatty liver resolution [13]. - The benefits of semaglutide may be secondary to weight loss or improvements in liver metabolism and inflammation [13]. Osteoarthritis - The STEP 9 trial showed that semaglutide treatment significantly reduced pain scores in patients with knee osteoarthritis and resulted in greater weight loss compared to placebo [17]. Obstructive Sleep Apnea - The SURMOUNT-OSA trial demonstrated that tirzepatide significantly reduced the apnea-hypopnea index in adults with moderate to severe obstructive sleep apnea [19]. Peripheral Artery Disease - The STRIDE trial indicated that semaglutide improved walking distance in patients with peripheral artery disease, correlating with weight loss [21]. Neuroprotective Effects - GLP-1 drugs have been associated with reduced stroke incidence and may lower the risk of all-cause dementia, including Alzheimer's disease [23]. - Ongoing trials are exploring the potential of oral semaglutide in modifying Alzheimer's disease [23]. Mechanisms of Action - The exact mechanisms by which GLP-1 drugs provide benefits independent of weight loss remain unclear, but they may involve improvements in insulin sensitivity and inflammation reduction [25][26]. - GLP-1 drugs consistently lower inflammatory biomarkers, suggesting immune-modulating effects that may contribute to their therapeutic benefits [26]. Conclusion and Future Directions - The broad benefits of GLP-1 drugs extend to various chronic conditions, with ongoing research exploring their applications in substance abuse, mental health, and neurodegenerative diseases [27]. - Understanding the dose-response relationship and optimal treatment duration for conditions beyond diabetes and obesity may open new therapeutic avenues for GLP-1 drugs [27].

Core Viewpoint - The article highlights significant research published in the journal Cell, with a focus on groundbreaking studies from Chinese scholars in various fields, including Alzheimer's disease treatment, cartilage regeneration, and innovative RNA-protein interaction technologies [2]. Group 1: Alzheimer's Disease Research - A study by researchers from Gladstone Institutes and UCSF identified two FDA-approved cancer drugs, letrozole and irinotecan, that can reverse gene expression changes associated with Alzheimer's disease, significantly improving memory and reducing pathological features in a mouse model [4][7]. Group 2: Cartilage Regeneration - Research from Tongji University and Hainan Medical University discovered Procr+ chondroprogenitors that are sensitive to mechanical stimuli, crucial for maintaining cartilage homeostasis and promoting regeneration after joint injury, indicating potential for treating knee diseases like osteoarthritis [9][12]. Group 3: Prime Editing for Neurological Disorders - The Broad Institute's study demonstrated the use of prime editing technology in mice to correct common ATP1A3 gene mutations associated with alternating hemiplegia of childhood, leading to significant improvements in clinical symptoms and lifespan [14][17]. Group 4: RNA-Protein Interaction Technology - A new RNA-binding protein identification technique called SPIDR was developed, allowing for the analysis of multiple RNA-binding proteins' binding sites, which could enhance understanding of RNA biology and mechanisms of translational suppression under cell stress [19][21]. Group 5: Post-Stroke Brain Inflammation - Research from Johns Hopkins University revealed that the mast cell receptor Mrgprb2/MRGPRX2 mediates brain inflammation after a stroke, and inhibiting this receptor can reduce inflammation and improve neurological outcomes in mice [23][25]. Group 6: Aging Proteome Atlas - A comprehensive study by the Chinese Academy of Sciences constructed a proteome aging atlas across a 50-year lifespan, identifying aging trajectories and key proteins like GAS6 that drive vascular and systemic aging [27].

Core Viewpoint - The article discusses the role of mast cell receptor Mrgprb2 in mediating post-stroke brain inflammation, highlighting its potential as a therapeutic target to improve neurological outcomes after stroke [4][10]. Group 1: Research Findings - The study published in Cell reveals that the mast cell-specific receptor Mrgprb2 mediates brain inflammation after stroke through a dural-brain signaling axis [5][10]. - Inhibition of Mrgprb2 reduces post-stroke brain inflammation in mice, leading to improved neurological function and increased survival rates [5][10]. - Mrgprb2 acts as a key "gatekeeper" for the migration of immune cells from the skull bone marrow to the brain [13][14]. Group 2: Mechanisms of Action - Mrgprb2 activation leads to degranulation of mast cells in the meninges, releasing immune mediators that recruit neutrophils to the dura mater and promote their migration into brain tissue [8][14]. - The study indicates that mast cell proteases can cleave semaphorin proteins, facilitating neutrophil infiltration into the brain [14]. Group 3: Related Research - Another study published on the same day in Cell by Jonathan Kipnis's team discusses how mast cells regulate the brain-dura interface and cerebrospinal fluid (CSF) dynamics [15][19]. - The findings suggest that mast cells are crucial regulators of CSF flow and meningeal immunity, with potential implications for enhancing CNS clearance and defense mechanisms against infections [19].

Core Viewpoint - The research identifies Desmocollin 2 (DSC2) as the primary entry receptor for Epstein-Barr virus (EBV) infection in epithelial cells, providing a significant foundation for future studies and potential therapeutic developments against EBV infections [2][3][5]. Group 1 - The study utilized CRISPR-Cas9 screening technology to confirm that DSC2 is the main receptor for EBV entry in epithelial cells [3][5]. - Knocking out the DSC2 gene reduced EBV infection in nasopharyngeal and gastric epithelial cell lines, while restoring DSC2 expression reinstated the infection [6]. - The research found that DSC2 directly binds to EBV glycoproteins H and L through its extracellular domain, particularly the preEC-EC2 region, which can be targeted by polyclonal antibodies to block EBV infection in primary epithelial cells [7]. Group 2 - The findings contribute to the development of animal models for EBV infection, which are currently unavailable, thus facilitating the research and development of therapies targeting EBV infections [9].

Core Viewpoint - The article discusses a groundbreaking research study that introduces a large language model (LLM)-based biological age prediction method, which estimates overall and organ-specific aging through health examination reports, aiming to enhance health management for the general public [3][4][5]. Group 1: Research Background and Importance - Accurately assessing an individual's aging level is crucial for identifying health risks and preventing age-related diseases, yet current aging indicators face methodological limitations and lack broad applicability [2][8]. - Aging is a major risk factor for mortality and chronic diseases, contributing significantly to societal health burdens, and understanding both overall and organ-specific aging is essential for comprehensive health assessments [7]. Group 2: Methodology and Framework - The research team developed a novel framework that converts health examination data (e.g., blood pressure, liver function) into textual reports for input into a large language model (e.g., Llama3), which analyzes numerous indicators to produce two key outputs: overall biological age and organ-specific ages for six major organs [10][11]. - The LLM does not rely on preset formulas but utilizes a pre-trained medical knowledge base to intelligently infer aging metrics based on individual health details [12]. Group 3: Validation and Results - The study validated its predictive framework using data from over 10 million individuals across six major databases, achieving impressive accuracy rates: 75.7% for predicting all-cause mortality risk, 70.9% for coronary heart disease risk, and 81.2% for liver cirrhosis risk, outperforming traditional models [15][20]. - The age difference predicted by the LLM correlates with increased health risks, with each additional year in predicted age raising all-cause mortality risk by 5.5% and coronary heart disease risk by 7.2% [16]. Group 4: Clinical Applications and Innovations - The research introduces a disease radar warning system, revealing that an increase in cardiovascular age difference correlates with a 45% increase in coronary heart disease risk, while liver age difference correlates with a 63% increase in liver cirrhosis risk [19]. - The study identifies 322 key proteins as potential "aging accelerators," with 56.7% being new targets linked to mortality risk, highlighting the predictive power of the LLM in personalized health management [19]. - By analyzing three years of continuous health examination data, the LLM can generate individual aging rate curves, improving disease outbreak predictions by three times compared to single examination assessments [19].

Core Viewpoint - The article discusses recent research that uncovers the biosynthesis pathway of salicylic acid in plants, which is crucial for their defense mechanisms and has implications for developing disease-resistant crop varieties [4][14][20]. Group 1: Research Findings - A team from Sichuan University published a study in Nature revealing a three-step biosynthesis pathway of salicylic acid from benzoyl-CoA in plants [4][5]. - The study identified three key enzymes involved in this pathway: BEBT, BBO, and BSH, which are conserved across various plant species [13][14]. - The research provides a molecular basis for understanding the differences in disease resistance among different plant groups, particularly major food crops [6][14]. Group 2: Comparative Studies - Concurrently, two other studies from Zhejiang University and Zhejiang Normal University also published in Nature focused on the biosynthesis of salicylic acid from phenylalanine, contributing to a more comprehensive understanding of this process [16][18][20]. - These studies collectively address the long-standing gaps in knowledge regarding salicylic acid biosynthesis pathways in plants [20].

撰文丨王聪 编辑丨王多鱼 排版丨水成文 生成具有时间分辨率的多细胞预测仍然是一个开放性的计算挑战。 生物信息学 技术和 机器学习 可以根据 单细胞分析中的瞬时快照预测单个细胞类型的细胞轨迹和动态表型变化，但它们无法解释整个多细胞生态 系统中更复杂的时序变化。 因此，我们需要更先进的计算工具来填补测量时间点之间的空白，并利用生物学知识和机制从头预测多细 胞系统中未观测到的新兴行为。 该论文提出一个概念框架—— 细胞行为假设语法 （ Cell Behavior Hypothesis Grammar ） ， 该框架利 用自然语言描述细胞规则来构建数学模型，能够系统地整合生物学知识和多组学数据以生成计算机模拟的 虚拟细胞 （ Virtual Cell ） 模型，从而开展虚拟的"思维实验" （ Thought Experiments ） ，以检验并拓 展我们对多细胞系统的理解，并生成新的验证的假设。 该研究进一步展示了该语法在从头构建机制模型以及利用多组学数据构建模型方面的应用，例如预测癌症 转移、破解癌症耐药性，展示了其应用潜力，并通过模拟大脑发育展示了其更广泛的应用性。该方法将生 物学、临床医学和系统生物学研究与大 ...

Core Insights - The research presents a comprehensive human proteome profile across a 50-year lifespan, revealing aging trajectories and signatures [2][3][21] - It identifies a significant aging turning point around the age of 50, with blood vessels being the earliest and most affected tissue [4][12][21] - The study highlights the decline in protein homeostasis as a core mechanism of aging, with implications for chronic inflammatory diseases and conditions like Alzheimer's [9][10][22] Group 1: Research Methodology - The study utilized ultra-sensitive mass spectrometry combined with machine learning algorithms to construct a proteomic aging map across seven physiological systems and 13 key tissues [3][21] - A total of 516 samples from 76 individuals aged 14-68 were collected, covering various organs such as the heart, aorta, lungs, and muscles [6][21] - The research identified 12,771 proteins, establishing organ-specific protein expression characteristics [7][21] Group 2: Key Findings on Aging - The research found that the correlation between mRNA and its translated proteins significantly decreases with age, particularly in the spleen, muscles, and lymph nodes [7][21] - Aging leads to a collapse of protein homeostasis, characterized by decreased synthesis capabilities, impaired folding and transport, and accumulation of amyloid proteins and immunoglobulins [9][21] - Blood vessels are identified as a "senohub," driving systemic aging processes through the expression of pro-aging proteins like GAS6 [14][15][21] Group 3: Implications for Anti-Aging Strategies - The study suggests potential anti-aging interventions targeting pro-aging proteins, such as developing CAR-T cell therapies against membrane proteins like GPNMB and neutralizing circulating proteins like GAS6 [18][21] - It emphasizes the importance of early intervention before the age of 50 to protect blood vessels and potentially delay systemic aging [18][21] - The findings provide a new paradigm for understanding systemic aging mechanisms through the lens of protein homeostasis imbalance and vascular aging [22]

Core Viewpoint - The article discusses the unprecedented marine heatwaves experienced globally in 2023, highlighting their record duration, coverage, and intensity, which are linked to climate change and have significant ecological impacts [1][3][7]. Group 1: Marine Heatwaves Overview - In 2023, global marine heatwaves (MHW) surged dramatically, setting new records in duration, coverage, and intensity, with a cumulative marine heatwave activity intensity reaching 53.6 billion ℃ days km², deviating more than three standard deviations from historical norms since 1982 [5]. - Significant events included the North Atlantic heatwave, occurring once every 276 years, and the Southwest Pacific heatwave, occurring once every 141 years [5]. Group 2: Research Findings - A study published in the journal Science by researchers from Ningbo University and Southern University of Science and Technology revealed the distribution characteristics, evolution patterns, and key physical driving mechanisms of the extreme marine heatwaves in 2023 [2][3]. - The research established a diagnostic framework based on high-resolution ocean reanalysis data, quantitatively characterizing the unprecedented features of marine heatwaves in terms of intensity, duration, and spatial coverage [7]. Group 3: Key Driving Mechanisms - The study identified different driving mechanisms for marine heatwaves in four key ocean regions: - The North Atlantic and North Pacific are primarily driven by enhanced shortwave radiation flux and shallower mixed layers - The Southwest Pacific is dominated by reduced cloud cover and enhanced advection - The Tropical East Pacific is influenced by oceanic advection [5][7]. Group 4: Implications - The findings underscore the escalating ecological impacts of global warming, providing a solid scientific foundation for understanding and addressing global climate change and extreme weather events [7].

Core Viewpoint - The article discusses a groundbreaking study that constructs a comprehensive human proteome aging map across a 50-year lifespan, revealing critical insights into the molecular mechanisms of aging and potential intervention targets [3][4][19]. Group 1: Research Findings - The study integrates ultra-sensitive mass spectrometry and machine learning to create a dynamic landscape of protein aging across seven physiological systems and 13 key tissues [4]. - It identifies protein information disruption as a core feature of organ aging, highlighting the role of mRNA-protein decoupling and pathological amyloid deposition in the systemic collapse of proteostasis networks [7]. - The vascular system is established as a "pioneer organ" in the aging process, significantly deviating from homeostatic trajectories early in life [7]. Group 2: Molecular Characterization of Aging - The research confirms that aging is accompanied by systemic proteostasis imbalance, characterized by a breakdown of the central dogma information flow, leading to impaired conversion of genetic information into functional proteins [9]. - Key findings include widespread accumulation of pathological proteins, forming an inflammatory aging network, which serves as a molecular basis for inflammaging [9][10]. Group 3: Aging Milestones and Mechanisms - The study identifies around 30 years of age as a critical inflection point for aging trajectories, with adrenal tissues showing early aging characteristics [12]. - A significant biological transition occurs between 45-55 years, where most organ proteomes experience a "molecular cascade storm," marking a key window for systemic aging acceleration [12][21]. Group 4: Vascular Aging Mechanisms - The research validates the "vascular aging hub" hypothesis, demonstrating that specific senescence-associated secretory factors, such as GAS6, drive endothelial and smooth muscle cell aging [15][16]. - Evidence supports the theory of "aging diffusion," where local aging tissues influence distant organs through specific secretory factors [16]. Group 5: Implications for Aging Research and Interventions - The study proposes a new framework for systemic aging research, moving beyond single-tissue models to a multi-organ interaction network [19]. - It introduces a novel tool for precise aging assessment through the development of organ-specific "proteome aging clocks," enabling non-invasive evaluation of biological age [20]. - Key intervention targets are identified, including factors mediating inter-organ signaling and common biomarkers, with the 45-55 age range highlighted as a critical intervention window [21]. - The findings pave the way for proactive aging disease prevention strategies, shifting from reactive treatment to early intervention based on molecular aging clocks [23]. Group 6: Methodological Innovations - The research successfully combines ultra-sensitive mass spectrometry, AI modeling, and multi-scale omics analysis to create a comprehensive framework for studying aging [24]. - This methodological advancement enhances the understanding of human aging and accelerates the translation of life sciences technologies into clinical applications [24].