Core Viewpoint - The integration of flexible electronics technology with artificial intelligence (AI) is expected to revolutionize various fields, including robotics, wearable medical devices, and human-computer interaction interfaces. However, significant challenges remain in developing flexible computing hardware capable of efficiently executing neural network inference tasks [3]. Group 1 - A new flexible digital AI chip named FLEXI has been developed for edge intelligence, characterized by its lightweight, thin, and robust design, paving the way for ultra-low-cost AI systems in wearable medical devices [5]. - The FLEXI chip features a maximum operating clock frequency of 12.5 MHz, a power consumption as low as 2.52 mW, and a unit cost of less than 1 USD, with a circuit yield rate stable between 70% and 92% [5]. - The chip can perform 10^10 fixed-point and random multiplication operations with zero error, withstand over 40,000 bending cycles, and maintain stable performance over more than six months of continuous operation [5]. Group 2 - The chip achieves a detection accuracy of 99.2% for arrhythmia tasks on a single 1kb chip and over 97.4% accuracy for monitoring daily human activities based on multimodal physiological signals [5]. - An accompanying article in Nature highlights the collaborative optimization design and technology that enables the efficient operation of neural network tasks on affordable and flexible microchips, validated in wearable medical devices [5].

Core Viewpoint - The article emphasizes the importance of accurate diagnosis in laboratory mouse health observations, highlighting that superficial symptoms may have multiple underlying causes that require systematic evaluation rather than relying solely on intuition [4][6]. Group 1: Observational Challenges - Common observations such as abdominal distension in mice may be misinterpreted as pregnancy or overeating, while the actual causes could include tumors, ascites, or organ swelling [4]. - Clear demarcation of alopecia on the animal's body may be mistakenly attributed to grooming or nutritional issues, but could actually indicate parasitic infections, fungal diseases, or environmental stress [4]. - Immunocompromised mice showing skin abnormalities or weight loss may be dismissed as normal for their strain, yet these signs could be early indicators of serious infections, necessitating more proactive pathogen screening [4]. Group 2: Clinical Symptoms Guide - A comprehensive guide titled "Common Clinical Symptoms of Mice" is introduced, designed to assist in systematic evaluation and management of various health issues in laboratory mice [6][8]. - The guide features clear visual comparisons of symptoms, aiding both beginners and experienced researchers in reducing diagnostic discrepancies [8]. - It is structured into ten modules for quick reference, covering aspects such as overall assessment, activity, fur and skin, limbs, and digestive and immune systems [8][9]. Group 3: Practical Application - Each symptom entry in the guide follows a logical structure of description, common causes, and recommended actions, enhancing practical usability [9]. - The guide provides a tiered approach to management, from observation and intervention to euthanasia assessment, ensuring comprehensive care strategies [9]. - The content is backed by authoritative institutions, ensuring standardized terminology suitable for research documentation and training materials [9].

Core Insights - The article discusses the launch of AlphaGenome, a new AI tool by DeepMind that predicts the effects of single nucleotide mutations in human DNA sequences, enhancing the understanding of genetic diseases and guiding DNA design [2][3]. Group 1: AlphaGenome Overview - AlphaGenome is a DNA sequence model capable of processing up to 1 million base pairs, accurately predicting a wide range of genomic features and mutation effects [10]. - The model represents a significant advancement in genomic AI, moving from specialized models to a unified approach that can handle multiple tasks simultaneously [11][12]. Group 2: Technical Innovations - AlphaGenome achieves a breakthrough by maintaining single-base resolution while analyzing long sequences, combining the strengths of convolutional neural networks and transformer architectures [11][15]. - It can evaluate the impact of genetic mutations on various molecular characteristics in just one second, facilitating rapid identification of potentially disease-causing genetic variations [13]. Group 3: Performance Metrics - In 24 DNA sequence function prediction tasks, AlphaGenome achieved state-of-the-art performance in 22 tasks, and in 26 genetic variant impact prediction tasks, it excelled in 24 tasks, outperforming many specialized models [19]. Group 4: Practical Applications - AlphaGenome has been utilized to explore the mechanisms of mutations related to cancer, linking non-coding region mutations to the activation of oncogenes [22]. - It also aids in understanding rare genetic diseases caused by RNA splicing errors and can guide the design of synthetic DNA sequences for targeted gene therapy [24]. Group 5: Future Implications - The introduction of AlphaGenome signifies a shift in genomic AI from single-task specialists to comprehensive models, paving the way for predictive science in biology [26]. - It enhances the ability to predict molecular functions and mutation effects from DNA sequences, opening new avenues for biological discoveries and applications in biotechnology [26].

Core Viewpoint - The interaction between gut microbiota and adipose tissue plays a crucial role in shaping the immune response to cancer therapy, particularly immunotherapy [2][6]. Group 1: Research Findings - The study identifies an obesity-related microbial feature that enhances the efficacy of immune checkpoint blockade (ICB) therapy, characterized by a microbiome rich in riboflavin-producing bacteria and elevated levels of the microbial metabolite flavin adenine dinucleotide (FAD) [3][4]. - In diet-induced obese (DIO) mice, interventions such as fecal microbiota transplantation (FMT), administration of Lachnospiraceae strains, or FAD supplementation significantly improved the response to anti-PD-1 therapy [3][4]. - The accumulation of FAD in adipose tissue promotes the synthesis of polyunsaturated fatty acids (PUFAs) through the action of fatty acid desaturase-2 (FADS2), which enhances the cytotoxicity of CD8+ T cells and anti-tumor immunity [4][6]. Group 2: Clinical Implications - Increased systemic levels of polyunsaturated fatty acids, particularly docosahexaenoic acid (DHA), correlate positively with enhanced CD8+ T cell infiltration in tumors and better outcomes in immunotherapy [3][4]. - The study suggests that dietary supplementation with DHA can improve the response to ICB therapy in lean mice, indicating potential dietary strategies for enhancing immunotherapy efficacy [3][4]. Group 3: Potential Strategies - The findings highlight the potential for personalized metabolic and microbiome-based immunotherapy strategies, emphasizing the importance of the gut microbiota-adipose tissue axis in anti-tumor immunity [6].

Core Viewpoint - Mental disorders, particularly depression and anxiety, are increasingly recognized as a significant public health burden globally, especially among the workforce, impacting productivity and innovation [3] Group 1: Current Treatment Landscape - Current frontline treatments for depression primarily include SSRIs and SNRIs, but they face three major limitations: a response rate of only about 30%, a slow onset of action (up to 12 weeks), and a high burden of long-term side effects (approximately 38%) [3] - There is an urgent clinical demand for new antidepressants, yet since 2017, the FDA has only approved six new depression medications, highlighting a need for innovative intervention strategies in this field [3] Group 2: Emerging Research on Psychedelics - Psychedelics, particularly psilocybin, have gained significant attention in academia, with the FDA designating them as breakthrough therapies for severe depression since 2017, leading to over 200 clinical trials globally [4] - Despite their promising rapid and lasting therapeutic potential, the subjective effects of psychedelics pose challenges for clinical evaluation and safety [4] Group 3: Mechanistic Insights - The 5-HT 2A receptor is identified as a core target for psychedelics, with traditional views linking its signaling pathways primarily to Gq and β-arrestin pathways [4] - Recent studies suggest that there may be underexplored signaling pathways associated with the 5-HT 2A receptor, as some non-psychedelic compounds can also activate Gq signaling [4] Group 4: Recent Research Findings - A study published in Nature by a collaborative team from various institutions demonstrated that psychedelics elicit effects through 5-HT 2A receptor-mediated Gi signaling, leading to the development of new rapid, long-lasting, and safe antidepressant compounds [5][9] - The research utilized various methodologies to compare the pharmacological mechanisms of different psychedelics and their non-psychedelic counterparts, revealing significant activation of the non-classical Gi signaling pathway by psychedelics [7] - The newly designed compound DOI-NBOMe showed good blood-brain barrier permeability and exhibited rapid and sustained antidepressant and anxiolytic effects without inducing psychedelic behaviors [7][9]

Core Viewpoint - The article discusses the critical role of bile acids in digestion, energy metabolism, and hormone signaling, highlighting the importance of the Ostα/β transport protein in the enterohepatic circulation of bile acids and its unique transport mechanism [2][3][11]. Group 1: Research Findings - A research team from the Shanghai Institute of Materia Medica and affiliated hospitals published a study in Nature revealing the unique structure and transport mechanism of the Ostα/β protein [3]. - The study utilized cryo-electron microscopy, molecular dynamics simulations, and electrophysiological analysis to elucidate the three-dimensional structure and substrate recognition patterns of Ostα/β [3][4]. - The Ostα/β complex was successfully expressed and purified, showing a symmetric tetrameric assembly with a novel seven-transmembrane helix folding pattern [4]. Group 2: Mechanism of Action - The structural analysis identified a substrate-binding groove near the cytoplasmic side of the membrane, which is modified by palmitoylation, creating a microenvironment suitable for binding amphipathic steroid molecules [5]. - The research demonstrated that Ostα/β interacts with physiological substrates, such as taurocholic acid and dehydroepiandrosterone sulfate, through specific electrostatic interactions [5]. - A hydrophilic channel extending from the binding groove to the extracellular side was identified, suggesting a pathway for substrate translocation across the membrane [5]. Group 3: Physiological Implications - The study introduced a novel method to monitor bile acid transport in real-time using whole-cell patch-clamp techniques, demonstrating that the transport direction of Ostα/β is influenced by the electrochemical gradient across the membrane [8][9]. - The findings indicate that membrane potential is a key regulatory factor that biases the transport direction, enhancing the understanding of bile acid excretion under different physiological conditions [9]. Group 4: Clinical Relevance - The research fills a critical gap in understanding bile acid excretion in the enterohepatic circulation, providing insights for potential therapeutic interventions in liver and biliary diseases [11]. - Dysregulation of bile acid metabolism is linked to various liver diseases, and targeting Ostα/β could offer a direct approach to modulate bile acid distribution and alleviate related pathologies [11]. - The structural comparison suggests that Ostα/β may belong to a new class of transport proteins, opening new avenues for research on the TMEM184 protein family and its potential disease associations [11].

Core Viewpoint - Bile acids (BAs) play a crucial role in nutrient absorption, lipid metabolism, and immune regulation, with their transport and distribution in the body being tightly regulated by specific membrane proteins [2][3]. Group 1: Bile Acid Transport Mechanism - The enterohepatic circulation of bile acids relies on the coordinated action of four key transport proteins: ASBT, OSTα/β, NTCP, and BSEP, which are essential for bile acid uptake and recycling [3]. - OSTα/β, a unique member of the solute carrier (SLC) family, requires assembly of α and β subunits to function and can transport bile acids bidirectionally, unlike other transporters that operate as monomers [3][8]. Group 2: Research Findings - A recent study published in Nature by a team from the Chinese Academy of Sciences and Peking University revealed the high-resolution cryo-EM structure of the OSTα/β complex, providing insights into its assembly and transport mechanism [4][5]. - The study identified a unique "2+2" heterotetramer assembly of OSTα/β, with tight interactions between α-β and α-α interfaces enhancing the stability of the complex [8]. - The research also discovered a bile acid binding pocket that facilitates the transport process without significant conformational changes, proposing a novel transport mechanism that relies on a half-embedded membrane channel [8].

Group 1 - The article highlights the publication of seven papers in the prestigious journal Cell, with six authored by Chinese scholars, indicating a significant contribution to the field of scientific research [3]. - AAVLINK, a new strategy for gene therapy, was developed to overcome delivery size limitations, achieving efficient gene recombination and expression of autism-related gene Shank3 and epilepsy-related gene SCN1A in mouse models [5][7]. - The POCKET device, a flexible bioelectronic patch, was created for precise intracellular delivery, demonstrating high delivery efficiency and spatial control in various organs, which could enhance drug delivery and gene transfection [10][12]. Group 2 - A study revealed a novel GPCR-G protein-β-arrestin megacomplex regulated by a versatile allosteric modulator, which could lead to new therapeutic approaches targeting GPCRs, crucial for many clinical drugs [19][21]. - The research on systemic stomatal immunity in plants identified a mobile peptide that transmits danger signals from infected to uninfected leaves, enhancing plant defense mechanisms against pathogens [25][27]. - An innovative urine liquid biopsy method for bladder cancer was developed, improving specificity by removing field effect mutations, which could guide personalized treatment strategies for non-muscle invasive bladder cancer patients [30][32].

Core Viewpoint - The article discusses a novel urine liquid biopsy method developed to enhance the prediction of bladder cancer patients' responses to surgery and Bacillus Calmette-Guérin (BCG) treatment, addressing the limitations of current diagnostic methods due to the "field effect" [3][6][17]. Group 1: Background and Challenges - Non-muscle invasive bladder cancer (NMIBC) is a common type where patients typically undergo tumor resection followed by BCG immunotherapy, but BCG is not effective for all patients, and predictive biomarkers are lacking [6]. - Urine tumor DNA (utDNA) analysis is a non-invasive monitoring method, but the presence of somatic mutations in normal urothelial cells near tumors leads to false positives due to the "field effect," which acts as background noise [6][5]. Group 2: Innovative Methodology - The research team developed a statistical method named RePhyNERX to filter out mutations likely caused by the "field effect" by comparing tumor samples with normal tissues or post-treatment urine, significantly improving the specificity of utDNA detection [8][7]. - In a training cohort, the use of post-treatment urine for filtering yielded the best results, effectively distinguishing patient prognoses with a hazard ratio (HR) of 12.6, indicating a reduction in false positives [8]. Group 3: Clinical Validation - The study prospectively collected urine samples from 61 NMIBC patients undergoing BCG treatment, analyzing samples before surgery, before BCG treatment, and after treatment [10]. - Patients were categorized into three molecular response types: 1. Complete surgical responders: 39.3% had negative utDNA post-surgery, potentially curable by surgery alone 2. BCG responders: 27.9% had positive utDNA pre-treatment but significant decline post-treatment 3. Non-responders: 32.8% had persistent or rising utDNA post-treatment [10][11]. Group 4: Molecular Mechanisms - The research identified biomarkers distinguishing surgical responders from BCG responders, noting that BCG responders had a higher tumor mutation burden (TMB) and enriched immune-related gene expression, indicating a pre-existing immune activation environment is necessary for BCG efficacy [13][12]. - A high T cell/stroma enrichment score (TSE) correlated positively with BCG response, similar to predictive markers for immune checkpoint inhibitors [14]. Group 5: Future Prospects - This research not only improves the accuracy of urine liquid biopsy but also paves the way for personalized treatment strategies, allowing utDNA negative patients to potentially avoid unnecessary BCG treatment and reducing side effects, while positive patients can receive early intensified treatment [17]. - The method has potential applications in other cancers, such as lung and head and neck cancers, addressing the "field effect" issue [18].

撰文丨王聪 编辑丨王多鱼 排版丨水成文 社交隔离 （ social isolation ） 是导致 焦虑症 （ anxiety disorder ） 的一个主要环境因素，但其背后的 神经生物学基础，目前仍不十分清楚。 2026 年 1 月 27 日， 浙江大学 王福俤 教授、 闵军霞 教授、华南理工大学 王卓 副教授、 南方医科大学 邱平 明 教授、 南方医科大学第三附属医院 吕田明 副教授等，在 Cell 子刊 Cell Metabiolism 上发表了题 为： Ferroplasticity drives social isolation-induced anxiety via a ventral hippocampal iron-α- synuclein axis 的研究论文。 该研究揭示了 社交隔离 会引发大脑中一种名为 " 铁可塑性 " （ Ferroplasticity ） 的变化，从而导致 焦 虑 症状。这项研究不仅解释了孤独感如何转化为焦虑，还提出了创新的预防和治疗方法。 孤独感的生物学基础 现代社会，越来越多的人面临 社交隔离 （ social isolation ） 的问题。世界卫生组织 ...