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 - Alternating Hemiplegia of Childhood (AHC) is a rare neurodevelopmental disorder with no current treatment to alter its progression, primarily linked to mutations in the ATP1A3 gene, which accounts for approximately 70% of cases [2][6]. Group 1: Disease Overview - AHC manifests within the first 18 months of life, characterized by recurrent symptoms such as hemiplegia, muscle tone disorders, abnormal eye movements, and seizures, along with developmental delays and intellectual disabilities [1][6]. - The ATP1A3 gene encodes the α3 subunit of the Na+/K+-ATPase, crucial for neuronal function, and its dysfunction leads to neuronal hyperexcitability and metabolic imbalances [2]. Group 2: Genetic Insights - Over 50 pathogenic mutations related to AHC have been reported, with three mutations (D801N, E815K, G947R) accounting for over 65% of cases [2]. - The dominant-negative disease mechanism of ATP1A3 mutations complicates traditional gene therapy approaches, as these mutations not only lose function but also interfere with normal protein function [2]. Group 3: Research Breakthroughs - A study published on July 21, 2025, in the journal Cell demonstrated the use of prime editing technology to treat AHC in mouse models, effectively correcting common ATP1A3 mutations and restoring Na+/K+ ATPase activity [3][4]. - The research team achieved correction rates of 48% at the DNA level and 73% at the mRNA level in the brain cortex of treated mice, leading to significant improvements in seizure activity, motor deficits, and cognitive impairments, as well as extended lifespan [9][12]. Group 4: Future Implications - The findings suggest that prime editing could serve as a one-time therapeutic approach for AHC, potentially opening avenues for treating other long-considered untreatable neurological disorders [4][11]. - The study emphasizes the importance of patient-centered research, as highlighted by the involvement of RARE Hope's founder, who advocates for increased accessibility to treatments for rare neurological conditions [11].

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].

Core Viewpoint - The article discusses the emerging understanding of synonymous mutations in human cells, challenging the traditional view of these mutations as neutral and highlighting their potential impact on cellular adaptability and disease [2][5][6]. Group 1: Research Background - A study by a team from the University of Michigan suggested that synonymous mutations in yeast may not be neutral and could affect cellular adaptability, reigniting interest in their biological effects [1]. - Previous research has linked a small number of synonymous mutations to human diseases, indicating their potential role as cancer drivers, but experimental confirmation remains limited [6]. Group 2: New Research Findings - A new study published by researchers from Peking University developed a high-throughput screening technology named PRESENT to investigate functional synonymous mutations in the human genome [4]. - The research utilized an advanced prime editing system (PEmax) to create a library targeting 3,644 human protein-coding genes, allowing for large-scale screening of synonymous mutations [7]. Group 3: Methodology and Tools - The study integrated single-cell screening methods with the PRESENT technology, termed DIRECTED-seq, to systematically evaluate the impact of identified synonymous mutations on gene expression [8]. - A specialized machine learning model called DS Finder was developed to analyze the effects of functional synonymous mutations on various biological processes, such as mRNA splicing and transcription [9][11]. Group 4: Key Findings - The research indicated that synonymous mutations exhibit different fitness effects compared to non-synonymous mutations, although their phenotypic distribution was similar to negative controls [9]. - The study identified that synonymous mutations could alter RNA folding and affect translation, with PLK1_S2 being a notable example, and combined screening data with predictive models to identify clinically relevant synonymous mutations [9].