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].

Core Viewpoint - Bayer and Tsinghua University have signed the sixth phase of their strategic research cooperation agreement, aiming to enhance the translation of basic research into new drug development across multiple key areas such as oncology, cardiovascular and renal diseases, neurology, rare diseases, and immunology [1][3]. Group 1: Research Collaboration - Bayer will continue to fund joint research projects for the next three years and reward Tsinghua University scientists who make significant contributions in life sciences and drug innovation [2]. - Since 2009, Bayer has collaborated with Tsinghua University on 75 joint research projects, resulting in 15 co-authored papers published in renowned international academic journals [3]. - The establishment of the "Bayer Research Transformation Fund" in 2022 has supported 9 projects in the past three years, further enhancing the translation of early research outcomes [3]. Group 2: Innovation and Development - Bayer's collaboration with Tsinghua University is seen as a model for cooperation between multinational pharmaceutical companies and local academic institutions in China, contributing to significant advancements in scientific research and drug development [4]. - The partnership aims to address global health challenges and accelerate the conversion of basic research into drug applications, marking an important milestone in their long-term strategic cooperation [4]. - Bayer emphasizes its commitment to local research collaboration and supports the transformation of original innovations and new drug development in China [5]. Group 3: Local Ecosystem Engagement - As China becomes a major source of biotechnological innovation, Bayer is actively integrating into the local innovation ecosystem and exploring open innovation with Chinese partners [6]. - Bayer Co.Lab, set to open in September 2024, aims to empower 10 to 15 local startups focusing on cutting-edge innovations in oncology, cardiovascular and renal diseases, and cell and gene therapies [6]. - Bayer has entered a global licensing agreement with a Chinese biotechnology company for a selective oral small molecule PRMT5 inhibitor targeting MTAP-deficient tumors, with the first patient already recruited for Phase I clinical trials [6].

Core Viewpoint - The article discusses the development of a new oral medication, ATR-258, which shows similar blood sugar regulation and weight loss effects as injectable GLP-1 receptor agonists, without the common side effects associated with GLP-1 drugs [2][3][15]. Group 1: Drug Development and Mechanism - ATR-258 is a β2 adrenergic receptor agonist that activates skeletal muscle metabolism positively, improving metabolic health without reducing muscle mass [3][6]. - The research utilized ligand-based virtual screening and chemical evolution techniques to develop a selective agonist that couples with G protein-coupled receptor kinases (GRK) [8][12]. - ATR-258 demonstrates lower cardiac side effects compared to standard β2 receptor agonists and lower muscle side effects compared to GLP-1 receptor agonists like liraglutide [12][15]. Group 2: Clinical Trials and Future Prospects - A Phase 1 clinical trial involving 48 healthy subjects and 25 type 2 diabetes patients showed that ATR-258 has good pharmacokinetic properties and tolerability [13]. - Atrogi AB plans to conduct a larger Phase 2 clinical trial to observe the positive effects seen in preclinical animal models in human patients with type 2 diabetes or obesity [16].

Core Viewpoint - The article discusses a significant breakthrough in the treatment of systemic sclerosis (SSc) through the use of an iPSC-derived CD19/BCMA CAR-NK cell therapy, QN-139b, which has shown promising results in a patient with refractory diffuse cutaneous systemic sclerosis (dcSSc) [2][4][10]. Group 1: Research and Development - Systemic sclerosis is characterized by vascular abnormalities, immune activation, and progressive tissue fibrosis, presenting challenges in clinical treatment due to limited drug efficacy and high disease heterogeneity [2]. - The study published in Cell highlights the first successful clinical translation of iPSC-derived CAR-NK therapy in a patient with dcSSc, marking a global first in this area [3][4]. - QN-139b targets both CD19 and BCMA to eliminate pathogenic B cells and plasma cells, developed using a high-throughput gene editing technology platform [6]. Group 2: Clinical Application - A 36-year-old female patient with a 20-year history of severe dcSSc was treated with QN-139b, receiving a total of four doses [8][9]. - After six months of follow-up, the patient exhibited significant clinical improvement, including a notable decrease in autoantibodies and a reduction in the modified Rodnan skin score (mRSS) [9][10]. - The therapy demonstrated good overall safety, with no significant adverse effects reported during the treatment period [9][10]. Group 3: Expert Opinions - Professor Xu Huji, leading the clinical team, emphasized the strong research capabilities and technological platform of Qihang Biotech, expressing confidence in the partnership [12]. - Academician Pei Gang highlighted the innovative advancements in universal off-the-shelf cell therapies, indicating a new direction for treating autoimmune diseases [12][14]. - Dr. Yang Luhan, CEO of Qihang Biotech, expressed satisfaction with the clinical outcomes and reiterated the company's commitment to providing better solutions for patients with autoimmune diseases [13][14].

研究团队通过祖先重建表明，酸耐受性的增强可能与鸟类重新获得甜味感知能力在进化树上的出现时间相 同 ，也就是 鸟类酸味耐受能力与甜味感知能力存在潜在的协同演化机制 ， 使鸟类不仅能有效耐受果实中 的有机酸 （酸味） ，还能敏锐感知其中的糖分 （甜味） ，这种转变或许使鸣禽能够以更广泛的水果为 食，从而影响了它们进化和多样化。 论文链接 ： https://www.science.org/doi/10.1126/science.adr7946 鸟类的酸味觉感知和耐受适应机制 撰文丨王聪 编辑丨王多鱼 排版丨水成文 味觉在塑造动物感知方面至关重要。 酸味 是主要味觉之一，这种味道通常令哺乳动物反感，然而，许多鸟 类却经常食用酸性水果，这表明它们可能对酸味具有耐受性。 2025 年 6 月 19 日， 中国科学院昆明动物研究所 赖仞 团队 在国际顶尖学术期刊 Science 上 发表题为： Molecular evolution of sour tolerance in birds 的研究论文。 研究团队发现并揭示了鸟类对酸味的强大耐受能力的分子机制，它们的这一特性可能助其开拓更广阔的生 态位，为理解动物感官演化与生 ...

Core Viewpoint - The article discusses the launch of PFMBench, a comprehensive benchmarking tool for evaluating protein foundation models (PFMs) across various tasks, addressing the need for standardized assessments in the rapidly evolving field of protein science driven by AI advancements [2][3][24]. Summary by Sections Introduction to Protein Science and AI - Proteins are essential for life activities, and understanding them is crucial for disease treatment and new drug development. The AI wave is revolutionizing protein science, with models like ESM-2 and ProtT5 emerging to predict protein structures and functions [2]. The Need for Benchmarking - The protein model field faces challenges similar to comparing students taking different exams, leading to difficulties in assessing model performance. Existing benchmarks are either too limited in tasks or overlook multimodal models, resulting in fragmented evaluation results [7][8]. PFMBench Development - PFMBench was developed by West Lake University and BioMap, encompassing 38 tasks and 17 models across eight protein science domains, serving as a "final exam" for protein models [10]. Core Design of PFMBench - PFMBench is designed with modularity and efficiency in mind, integrating tasks, models, and tuning methods into a unified framework. It includes: 1. **Task Library**: 38 tasks categorized into eight types, covering the entire protein lifecycle [12]. 2. **Model Library**: 17 top models categorized into four types, with 12 core models selected based on performance benchmarks [14]. 3. **Tuning Protocols**: Supports parameter-efficient fine-tuning methods, allowing for quick adaptation to new tasks [15]. Key Findings from PFMBench - The analysis revealed four critical conclusions: 1. Task relevance allows for focusing on 11 representative tasks instead of testing all 38 [18]. 2. Multimodal models outperform pure sequence models, with ProTrek achieving a 75% win rate compared to ESM-2's 50% [19]. 3. Zero-shot evaluations may mislead developers, emphasizing the need for supervised tasks [20]. 4. The cost-effectiveness of model scaling is low, with DoRA fine-tuning emerging as a superior method [21]. Significance of PFMBench - PFMBench is a milestone in the industry, providing a standardized evaluation framework that promotes innovation and guides future research directions. It aims to accelerate biopharmaceutical applications by offering reliable assessments that shorten development cycles [24][25].

Core Viewpoint - Semaglutide, developed by Novo Nordisk, is a GLP-1 receptor agonist that suppresses appetite and reduces caloric intake, approved for treating type 2 diabetes and weight loss. Its emergence has disrupted the weight loss drug market, with sales exceeding $7.8 billion in Q1 this year. However, Eli Lilly's Tizepatide has surpassed Semaglutide's weight loss records, achieving an average weight reduction of 20.2% in a head-to-head clinical trial [2][3]. Group 1: Sales and Market Impact - Tizepatide's sales in Q1 have already exceeded $6.1 billion, narrowing the gap with Semaglutide [3]. - The clinical trial results published in NEJM indicate that Tizepatide outperforms Semaglutide in weight loss effectiveness [2][3]. Group 2: Clinical Trials and Results - The REDEFINE 1 trial showed that the combination of Cagrilintide and Semaglutide resulted in an average weight loss of 20.4% over 68 weeks among non-diabetic overweight/obese participants, with 34.7% losing ≥25% of their body weight [11][13]. - In the REDEFINE 2 trial, the same combination led to a 13.7% average weight loss in overweight/obese participants with type 2 diabetes, significantly higher than the placebo group [17][19]. Group 3: Health Benefits and Safety - Cagrilintide and Semaglutide combination therapy showed improvements in various health metrics, including a 9.9 mmHg reduction in systolic blood pressure compared to 3.2 mmHg in the placebo group [13]. - The incidence of gastrointestinal adverse events was higher in the combination therapy group (79.6%) compared to the placebo group (39.9%), but most events were transient and mild to moderate in severity [14][20].

编辑丨王多鱼 排版丨水成文 自然界演化出了一套精妙但却有限的化学反应，支撑着所有生物体的功能。相比之下，合成有机化学领域能够实 现自然界中未观察到的反应性，将这些非生物反应整合到生物系统中，为利用可再生原料可持续合成许多工业化 学品提供了一种优雅的解决方案。 生物相容性反应 ——即能够与细胞代谢相衔接的非酶促化学转化——是拓展活体系统合成能力的一种新兴方 法。利用现代有机化学中确立的合成策略，生物相容性反应可用于控制细胞功能、体内代谢物的多样化以及获取 工业生物技术中难以处理的原料。这种方法补充了细胞中非生物催化作用的现有方法，包括定向进化、利用人工 辅因子或非天然氨基酸创建非天然活性位点，以及利用计算方法从头设计酶。然而，在体内重组全新天然生物催 化剂颇具挑战性，这常常限制了它们仅能用于体外反应。在活细胞中，尤其是细胞代谢的背景下，将非天然化学 物质整合到代谢过程中，仍是化学生物技术领域的一大挑战。 塑料废弃物是一个日益严重的问题，以可持续的方式升级改造塑料仍是当前的首要任务。然而， 能否利用 生物 相容性反应 将塑料升级改造成有用产物，目前仍不明 确。 2025 年 6 月 23 日，爱丁堡大学的研究人员 ...

Core Viewpoint - CAR-T cell therapy has shown remarkable efficacy in treating B-cell malignancies, but its effectiveness in solid tumors remains limited due to poor infiltration capabilities [2][3]. Group 1: Research Findings - The study published by Professor Yang Xuanming's team reveals that co-stimulation via OX40 significantly enhances CAR-T cell anti-tumor activity against solid tumors, including pancreatic, breast, and lung cancers [3][5]. - Heparan sulfate (HS) is identified as a ligand for OX40, promoting CAR-T cell infiltration and persistence in solid tumors [3][7]. - The interaction between OX40 and heparan sulfate activates key signaling pathways (AKT, MAPK, and NF-κB), enhancing cell adhesion and the functional affinity of CAR-T cells to tumor cells [7][10]. Group 2: Implications for CAR-T Therapy - CAR-T cells expressing OX40 demonstrate improved infiltration and persistence in solid tumors, relying on the interaction with heparan sulfate [8][10]. - The findings suggest that the OX40-heparan sulfate interaction can be leveraged to enhance CAR-T cell therapies for a broader range of solid tumors, opening new avenues for treatment strategies [10].

Core Viewpoint - Adolescent obesity is a global public health crisis with rising prevalence, leading to increased risks of cardiovascular and metabolic diseases, as well as cognitive impairments [2] Group 1: Research and Development - A research team from Shanghai Jiao Tong University and other institutions developed the world's first VR-based exercise intervention system, REVERIE, aimed at overweight adolescents [4][8] - The REVERIE system utilizes deep reinforcement learning and a Transformer-based virtual coach to provide safe, effective, and empathetic exercise guidance [4][8] Group 2: Study Design and Methodology - The study included a randomized controlled trial with 227 overweight adolescents, comparing outcomes between VR exercise, real-world exercise, and a control group [11] - Participants were assigned to different groups, including VR and real-world sports, with all groups receiving uniform dietary management over an eight-week intervention [11] Group 3: Results and Findings - After eight weeks, the VR exercise group lost an average of 4.28 kg of body fat, while the real-world exercise group lost 5.06 kg, showing comparable results [13] - Both VR and real-world exercise groups showed improvements in liver enzyme levels, LDL cholesterol, physical fitness, mental health, and exercise willingness [13] - VR exercise demonstrated superior cognitive function enhancement compared to real-world exercise, supported by fMRI findings indicating increased neural efficiency and plasticity [14] Group 4: Safety and Implications - The injury rate in the VR exercise group was 7.69%, lower than the 13.48% in the real-world exercise group, with no severe adverse events reported [15] - The REVERIE system is positioned as a promising solution for addressing adolescent obesity and promoting overall health improvements beyond weight loss [16][17]