撰文丨王聪 编辑丨王多鱼 排版丨水成文 阿尔茨海默病 （AD） 是全球范围内痴呆症的首要病因，影响着超过 5500 万名患者。近期针对轻度至中度阿尔茨海默病批准的以 β-淀粉样蛋白 （Aβ） 为靶点 的免疫疗法，凸显了可获取的生物标志物的重要性，这些标志物不仅用于检测疾病病理，还用于对病理进行分期，以实现最佳治疗时机的把握和治疗效果的评 估。 能够模拟疾病进展的分期系统，可为检测和监测其漫长病程中的病理变化提供框架，并有助于临床决策。例如，有证据表明，在正电子发射断层扫描 （PET） 中 显示较低的 tau 蛋白示踪剂摄取的阿尔茨海默病患者，对以 Aβ 为靶点的单克隆抗体疗法反应更好，这表明该组患者接受这种治疗的风险效益比可能最为有利。 此外，靶向 tau 蛋白的疗法，也可能对阿尔茨海默病患者更有益处。 基于 血液生物标志物 的 阿尔茨海默病 （AD） 分期系统，能够改善阿尔茨海默病的诊断、预后，还有助于识别最有可能从特定疗法中获益的个体。 在这项新研究中，研究团队利用靶向质谱法，对来自两个独立队列 （BioFINDER-2 和 TRIAD，n=689） 的血浆中的 6 种磷酸化和 6 种非磷酸化 tau 多 ...

Core Viewpoint - The article discusses the development of a novel peptide, SK56, which selectively blocks the GSDMD-NT pore, thereby delaying pyroptosis and mitigating inflammatory responses, offering new therapeutic options for uncontrolled inflammation-related diseases [3][8][10]. Group 1: Research Findings - The research team utilized artificial intelligence (AI) to generate a specific blocker for the GSDMD-NT pore, which can delay pyroptosis and reduce inflammation, potentially benefiting conditions like sepsis and autoimmune diseases [3][10]. - SK56 effectively targets and blocks the GSDMD-NT pore, preventing cell death induced by inflammatory stimuli and reducing cytokine release from macrophages [8][10]. - The study challenges the traditional belief that pyroptosis is irreversible once triggered, demonstrating that SK56 remains effective even after the pyroptotic response has begun [10][11]. Group 2: Implications and Innovations - The findings highlight the potential of AI-guided peptide design in targeting previously deemed "undruggable" biological structures, paving the way for new biopharmaceutical developments [10]. - The research suggests a paradigm shift in managing inflammation, proposing that humans might coexist with inflammation rather than merely suppressing it [11]. - The AI model and training database used in the study have been made publicly available, promoting further research and development in this area [11].

Core Insights - Tuberculosis (TB) remains the leading cause of death and disability from infectious diseases globally, with 1.2 million deaths annually, particularly affecting low- and middle-income countries [2][5] - The only approved TB vaccine, BCG, shows high efficacy in children but significantly reduced effectiveness in adolescents and adults, highlighting the urgent need for more effective vaccines [2][5] - A new study from Harvard Medical School presents a trivalent mRNA-LNP vaccine that enhances and surpasses the protective effects of BCG in mouse models, indicating a promising direction for next-generation TB vaccines [3][6][8] Vaccine Development - The study utilized a comprehensive dataset of CD4 T cell responses from latent TB patients to systematically screen potential vaccine antigens [5][6] - The identified antigens, PPE20 (Rv1387), EsxG (Rv0287), and PE18 (Rv1788), demonstrated enhanced protective effects in various mouse models compared to BCG [6][8] - 84% of individuals exposed to Mycobacterium tuberculosis showed cellular immune responses to these antigens, suggesting potential effectiveness in humans [6][8] Clinical Trials - The research team plans to initiate Phase 1 clinical trials to assess the safety and efficacy of the mRNA vaccine in humans, aiming to provide a new approach to combat TB [7]

Core Viewpoint - Canavan disease is a rare, hereditary neurodegenerative disorder characterized by severe physical and intellectual disabilities, typically manifesting symptoms between 3 to 6 months of age. The disease is caused by mutations in the ASPA gene, leading to toxic accumulation of N-acetylaspartate (NAA) in the brain, which adversely affects myelin development and function [2][5]. Group 1: Clinical Trial Overview - A phase 1/2 clinical trial was conducted to evaluate the safety and early efficacy of a novel recombinant adeno-associated virus vector, rAAV-Olig001, targeting oligodendrocytes for the treatment of Canavan disease [3][5]. - The trial involved 8 participants (5 male and 3 female), who received an intracranial administration of 3.7×10^13 vg of rAAV-Olig001-ASPA (MYR-101) [5]. Group 2: Safety and Efficacy Results - Among the 8 participants, 7 (87.5%) experienced at least one serious adverse event, none of which were deemed related to MYR-101, and all adverse events were resolved [6]. - The treatment resulted in a significant reduction in NAA concentration in cerebrospinal fluid, increased myelination, and improved developmental outcomes as measured by the Mullen Scales of Early Learning (MSEL) [6][7]. Group 3: Implications for Future Research - The reduction in NAA levels and increased myelination suggest successful targeting of oligodendrocytes by the AAV gene therapy, which may pave the way for similar gene therapy strategies for other demyelinating and metabolic brain diseases [7].

Core Viewpoint - The research published in the journal Cell reveals the molecular mechanisms behind the reprogramming of single somatic cells into totipotent states during plant regeneration, addressing a century-old scientific challenge in understanding plant cell totipotency [3][5][11]. Group 1: Research Findings - The study demonstrates that LEAFY COTYLEDON2 (LEC2) can reprogram somatic epidermal cells into totipotent somatic embryonic cells [9]. - LEC2 and SPEECHLESS (SPCH) jointly activate local auxin biosynthesis through targeting TAA1 and YUC4, which is crucial for the specification of somatic embryonic cells [8][9]. - The GMC-auxin intermediate state marks the transition of guard cells from differentiation to totipotency, highlighting the role of transcriptional reprogramming and auxin signaling in this process [9][11]. Group 2: Methodology - The research utilized time-resolved live imaging, single-nucleus RNA sequencing (snRNA-seq), and laser capture microdissection combined with RNA sequencing (LCM-RNA-seq) to uncover the fate decision point in the developmental pathway [7]. - The study confirmed that the MMC (multicellular meristematic cell) is the origin of somatic embryos, and auxin biosynthesis mediated by TAA1/YUC is essential for totipotency and embryogenesis [8]. Group 3: Implications - This research not only solves the mystery of plant cell totipotency but also provides a new theoretical foundation for crop genetic improvement and efficient regeneration [5][11]. - The findings enhance the understanding of the fundamental principles of plant cell development and offer new strategies and tools for precise regulation of plant regeneration and targeted improvement of crop traits [11].

Core Viewpoint - Targeted protein degradation represents a significant advancement in treating diseases previously deemed untreatable, particularly for traditionally "undruggable" targets such as transcription factors and scaffold proteins [2][6]. Group 1: Development of New Screening Methods - A novel high-throughput screening platform named DEFUSE (DE ath FUS ion E scaper) has been developed to identify small molecule protein degraders, enabling efficient degradation of oncoprotein SKP2 [3][10]. - The DEFUSE platform utilizes a fusion of target proteins with a rapidly activated death protein, allowing for a visual representation of cell survival or death based on the presence of degradation compounds [6][8]. Group 2: Discovery of New Degraders - The research team identified a small molecule, SKPer1, which specifically promotes the degradation of the oncogenic protein SKP2 and selectively kills SKP2-expressing cancer cells [8][10]. - SKPer1 functions as a novel molecular glue degrader, recruiting SKP2 to the ubiquitin ligase STUB 1, facilitating its ubiquitination and subsequent degradation [8][10]. Group 3: Implications for Cancer Treatment - SKPer1 demonstrated significant tumor-suppressive effects in vivo and exhibited good safety profiles, indicating its potential as a therapeutic agent [10]. - The study suggests that a 10-amino acid sequence derived from SKP2 can serve as a universal degradation tag, allowing other target proteins fused with this tag to be recruited for degradation by SKPer1 [10].

Core Insights - The article discusses the significant relationship between maternal gut microbiome during early pregnancy and the risk of preterm birth, highlighting the need for further understanding of this connection [2][3][4]. Group 1: Research Findings - A study involving a cohort of 5,313 pregnant women identified a direct association between early pregnancy gut microbiome characteristics and preterm birth risk [3][6]. - The gut bacterium Clostridium innocuum was identified as a novel biomarker for predicting preterm birth, with its presence correlating positively with preterm birth risk [3][7]. - The research established a preterm microbiome risk score (MRS) that effectively differentiates between women with shorter gestation periods and higher preterm birth risk [6][7]. Group 2: Mechanisms and Implications - Clostridium innocuum was found to degrade 17β-estradiol, a hormone linked to pregnancy outcomes, suggesting a mechanism by which it influences preterm birth risk [6][8]. - The study indicates that maternal polygenic risk for preterm birth is amplified by the presence of Clostridium innocuum, emphasizing the interaction between genetic susceptibility and microbiome composition [6][7].

Core Insights - The article emphasizes the critical role of tau protein in neurodegenerative diseases and its potential as a therapeutic target, highlighting its dual role as a protector of neurons and a key player in disease progression [3][4]. Group 1: Background and Importance - Tau protein is a key microtubule-associated protein in the central nervous system, essential for maintaining neuronal structure and axonal transport [3]. - Abnormal post-translational modifications of tau, such as hyperphosphorylation, lead to its detachment from microtubules and aggregation into neurofibrillary tangles, a hallmark of Alzheimer's disease and other neurodegenerative disorders [3]. - Understanding tau's pathogenic mechanisms and exploring tau-related biomarkers and therapeutic strategies are crucial for advancing both basic research and clinical trials [3]. Group 2: Lecture Details - The upcoming online lecture titled "Tau Structure, Modification, and Pathogenesis: Breakthroughs in Diagnosis and Treatment of Neurodegenerative Diseases" will focus on tau protein, discussing its structural features, biological functions, and its role in Alzheimer's disease [4][9]. - Di Zhu, a Senior Product Manager at Sino Biological US Inc., will present insights into tau protein's post-translational modifications and their regulation, as well as the latest advancements in tau-targeted diagnostics and therapies [4][9]. Group 3: Key Topics of Discussion - The lecture will cover the structural characteristics of tau protein, its six isoforms, and biological functions [9][14]. - It will delve into the post-translational modifications of tau and their regulatory mechanisms [9][14]. - The discussion will also include the pathogenic mechanisms of tau-related neurodegenerative diseases, particularly Alzheimer's disease, and the progress and prospects of tau-targeted diagnostic and therapeutic strategies [9][14].

Core Insights - The article discusses the relationship between tau protein and cognitive decline in Alzheimer's disease (AD), highlighting that soluble tau protein, rather than tangles, is closely associated with the clinical progression of AD [2][3][5] - Recent research published in the journal Cell reveals that high-molecular-weight tau protein derived from Alzheimer's patients impairs the bursting activity of hippocampal neurons, indicating a cellular mechanism behind tau-dependent cognitive decline [3][5] Group 1: Research Findings - The study confirms that tau protein selectively weakens the complex bursting activity of CA1 neurons in the hippocampus, which is essential for learning and memory [5] - Impairment of bursting activity is linked to changes in hippocampal network activity, associated with theta rhythms and high-frequency ripple waves, along with a reduction in CaV2.3 calcium channel expression [5] - The research identifies soluble high-molecular-weight tau protein as a key subtype that inhibits bursting activity, suggesting it as a potential therapeutic target for Alzheimer's disease [5] Group 2: Upcoming Events - An online lecture titled "Tau's Structure, Modification, and Pathogenicity: Breakthroughs in Diagnosis and Treatment of Neurodegenerative Diseases" will be held on September 18, focusing on tau protein's dual role in neurons and neurodegenerative diseases [8]

Core Viewpoint - Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by memory decline and cognitive impairment, with significant challenges in drug development despite substantial investments from major pharmaceutical companies [3][4]. Group 1: Alzheimer's Disease Overview - Alzheimer's disease is linked to the abnormal accumulation of tau protein and beta-amyloid (Aβ) in the brain, with tau protein aggregation being more closely associated with cognitive symptoms and severity [3]. - Major pharmaceutical companies, including Pfizer, Johnson & Johnson, and Roche, have invested over $10 billion in research for Alzheimer's treatments, but success has been limited [3]. Group 2: Recent Research Findings - A recent study published in Nature by Dr. Ke Hou from UCLA presents a potential strategy to reduce tau protein neurofibrillary tangles (NFTs) in Alzheimer's patients, which may halt disease progression [4]. - The study reveals that D-type peptides can disassemble tau fibrils by assembling into amyloid-like fibers that induce stress release, leading to fiber breakage without the need for enzymatic activity or external energy sources [4][10]. Group 3: Mechanism of Action - The research team explored the mechanism of D-type peptides in disassembling tau protein fibers, identifying D-TLKIVWI as the most effective variant in vitro [6][7]. - D-type peptides assemble into amyloid-like fibers that create torsional stress on tau fibers, resulting in the disruption of local hydrogen bonds and subsequent fiber breakage [8][10]. Group 4: Implications for Treatment - The study highlights the stability, protease resistance, and good biocompatibility of D-type peptides, which can cross the blood-brain barrier without eliciting harmful immune responses [10]. - This research provides a promising new avenue for treating Alzheimer's and other amyloid-related diseases, such as Parkinson's and Huntington's disease, potentially transforming the treatment landscape for neurodegenerative disorders [4][10].