Core Findings - High altitude exposure leads to gut microbiome imbalance, resulting in decreased sperm quality [5] - Increased levels of C. symbiosum produce succinic acid, which damages sperm quality [5] - Succinic acid activates the GPR91/TRPV4/Ca2+ signaling pathway in testicular macrophages, promoting the polarization of these cells [5][4] - The polarization of macrophages induced by succinic acid increases apoptosis of spermatogenic cells [5] Mechanism Insights - The study reveals that high altitude induces changes in the gut microbiome, specifically an increase in C. symbiosum, which negatively impacts sperm quality [4] - Succinic acid acts on G protein-coupled receptor GPR91, leading to the activation of TRPV4/Ca2+ signaling in testicular macrophages, resulting in inflammatory polarization [4][5] - The impact of C. symbiosum or succinic acid on sperm quality is dependent on TRPV4 signaling [4] Implications for Treatment - The research suggests potential therapeutic pathways based on gut microbiome modulation to address altitude-induced sperm damage [7]

编辑丨王多鱼 排版丨水成文 国科大杭州高等研究院 （HIAS） 成立于 2019 年，经中国科学院和浙江省人民政府批准成立，由中国科 学院大学和杭州市人民政府共同建设。HIAS 是中国科学院大学的直属学院，也是杭州市政府直属的公立科 研机构，同时也是浙江省首批省级新型科研开发机构之一。 教学与研究职位 1）资格条件 须为中国国籍。 申请人须具有良好的政治素质、道德品行、遵纪守法、身体健康。 应聘者应具备应聘岗位所需的学历、理论知识和科研能力。 注：优秀候选人可就薪资进行协商；科研启动资金也可协商。 要求具有博士学位或副高级职称，博士学位获得者或副高级职称人员年龄不超过 45 岁，正高级职称 人员年龄不超过 50 岁。 专业领域可包括数学、物理学、地球物理学、光学工程、电子科学与技术、化学、材料科学、生物 学、生物工程、药学、基础医学、环境科学与工程、计算机科学与技术、智能科学与技术等。 2）人才制度与福利 研究员，聘用期限（5年），年薪（50-60万元人民币，税前）； 副研究员，聘用期限（3年），年薪（35-45万元人民币，税前）； 助理研究员， 聘用期限（3年），年薪（22-26万元人民币，税前）； 提供设 ...

Core Viewpoint - T cell exhaustion is a prevalent phenomenon in chronic infections and tumor microenvironments, significantly impairing the effectiveness of anti-tumor and anti-viral immunity [2][4][6]. Group 1: Mechanisms of T Cell Exhaustion - Key external factors leading to T cell exhaustion include persistent antigen exposure, immune checkpoint signaling, and cytokine environments [2][4]. - Internal changes such as metabolic alterations, epigenetic modifications, and transcriptional reprogramming also contribute to T cell dysfunction [2][4][6]. - T cell exhaustion can be seen as a complex and multifaceted process that involves both external immune microenvironment factors and internal cellular changes [4][5]. Group 2: Emerging Therapies - New therapies targeting T cell exhaustion aim to restore immune function and enhance anti-tumor and anti-viral immunity, including immune checkpoint inhibitors, cytokine therapies, metabolic reprogramming, and cell therapies [2][6]. - Despite advancements, challenges remain in reversing T cell exhaustion, such as patient variability, resistance, and potential side effects [2][6]. Group 3: Future Research Directions - Future research should focus on elucidating the remaining mysteries of T cell exhaustion, particularly in the context of complex disease microenvironments, and developing more precise and personalized therapies [6][20]. - The review emphasizes the biological basis of T cell exhaustion and therapeutic interventions that can revitalize exhausted T cells and restore their effector functions [6][17].

松果体 （ pineal gland ） 是大脑中的一个小型内分泌腺体，因其形状类似于松果而得名。尽管它体积很 小 （大约只有米粒大小） ，但它扮演着非常重要的角色。其最核心的功能是通过分泌 褪黑素 （ melatonin ） 来调控调控人体的睡眠-觉醒周期。在白天或光线充足时，松果体活动被抑制，褪黑素分泌减 少，使人保持清醒和活跃；到了夜晚或黑暗环境中，松果体变得活跃，开始大量分泌褪黑素，促使人体产 生困意，准备入睡。 然而，由于松果体难以获取，这严重限制了对其进行研究。 近日，耶鲁大学 In-Hyun Park 团队在 Cell 子刊 Cell Stem Cell 上发表了题为： Generation of human pineal gland organoids with melatonin production for disease modeling 的研究论文。 该研究首次构建了能够产生 褪黑素 的 人类松果体类器官 （ hPGO ） ，成功 模拟了松果体的发育与功 能，并揭示了其可用于疾病建模和细胞治疗的潜力。 在这项最新研究中，为了突破松果体来源的限制，研究团队利用 多能干细胞 （PSC） 开 ...

Group 1 - The core finding of the research indicates that female house mice choose mates based on their own innovation abilities, preferring males with opposite traits, which contributes to maintaining variation in innovation within the population [3][6][10] - The study observed that approximately 23% of the mice were classified as "innovators," and the mating ratio between innovators and non-innovators was 45% higher than expected based on random mating [6][10] - The research highlights the significance of disassortative mating, where individuals prefer partners with contrasting characteristics, challenging the notion of "like attracts like" in mate selection [6][10] Group 2 - The experimental design involved placing 139 wild house mice in semi-natural enclosures and observing their mating behaviors over six months, with problem-solving tasks to access food [6][9] - Results showed that non-innovative female mice preferred to associate with innovative males, while innovative females showed the opposite preference, indicating a clear differentiation in mate choice based on innovation ability [10][12] - The study also revealed a trade-off for male mice between innovation ability and body size, with innovative males being smaller, which is a recognized competitive advantage in rodent species [12][15] Group 3 - The research provides insights into how sexual selection through balancing selection maintains behavioral diversity, preventing the fixation of innovation traits in the population [15][16] - It emphasizes the importance of considering both male and female traits in understanding mate selection, as overlooking female innovation ability could lead to incorrect conclusions about male preferences [16][17] - The findings suggest potential implications for understanding how animals adapt to rapidly changing environments, and raise questions about similar "complementary" mate selection patterns in human societies [17]

Core Viewpoint - The research highlights the need for high-throughput, high-resolution functional genomics platforms based on human normal cells to systematically reveal the pathogenic mechanisms of complex diseases like Type 2 Diabetes (T2D) and provide new paradigms for therapeutic target discovery [3]. Group 1: Research Findings - A study published in Nature Metabolism utilized single-cell perturbation sequencing to decode the functions of genes related to T2D and insulin production in human pancreatic β cells, identifying the previously unknown gene ZZEF1 [4]. - The research team identified 21 significant functional genes affecting β cells, including known genes like ABCC8 and PCSK1, as well as the novel ZZEF1 gene [6]. - ZZEF1's perturbation was found to impact pathways related to β cell homeostasis, MAPK/JNK stress response, protein secretion, and endoplasmic reticulum stress response, indicating its potential as a key regulatory factor [7]. Group 2: Mechanistic Insights - The study constructed cell-specific knockout mouse models to validate ZZEF1's function, revealing that ZZEF1 knockout mice exhibited impaired glucose tolerance and reduced insulin secretion under high-fat diet conditions [8]. - ZZEF1 deficiency led to decreased insulin protein levels without significant transcriptional reduction, suggesting issues in insulin translation or post-translational modifications [8]. - The research categorized β cells into four functional subgroups based on their activity and stress levels, demonstrating that ZZEF1 deficiency shifts these subgroups towards a high-stress state [8]. Group 3: Therapeutic Implications - The research tested various intervention strategies, including the use of adeno-associated virus (AAV) to restore EDF1 expression, which significantly improved insulin secretion in ZZEF1 knockout mice [10]. - The small molecule drug Azoramide was shown to enhance the degradation of misfolded proteins, improving glucose tolerance and partially restoring insulin secretion function in ZZEF1 knockout mice [10]. - These findings suggest that targeting ribosomal stress, protein homeostasis, and the elimination of misfolded protein accumulation could be new strategies for protecting β cells and treating T2D [10]. Group 4: Conclusion - The study demonstrates the advantages of single-cell functional genomics in the genetic analysis of complex diseases, establishing a new paradigm for systematically elucidating the molecular mechanisms and targets of T2D [12].

Core Viewpoint - The article discusses a novel mechanism of activation for a new class of phage-derived Cas12 nucleases, known as Cas12p, which utilizes bacterial thioredoxin (TrxA) for its activation and DNA cleavage [4][12]. Group 1: Research Findings - A new type of ultra-small Cas12 nuclease, Cas12p, has been identified, which consists of 500-700 amino acids and activates its DNA cutting activity by "hijacking" the bacterial thioredoxin [4]. - The research team established an efficient process for discovering new variants of the V-type CRISPR-Cas systems from metagenomic data, indicating that many unknown variants likely exist in nature [8][11]. - Structural analysis using cryo-electron microscopy revealed that Cas12p interacts closely with an endogenous bacterial protein, confirming TrxA as its specific binding partner [12]. Group 2: Mechanism of Action - The study elucidates the molecular basis of TrxA's activation of Cas12p, where TrxA binding induces conformational changes in Cas12p, allowing it to recognize sgRNA-DNA hybrids and activate its nuclease activity [12]. - Genetic experiments demonstrated that knocking out the trxA gene results in the loss of Cas12p's genomic interference capability, while reintroducing trxA fully restores its activity, confirming TrxA as an essential "activation switch" for Cas12p [12]. Group 3: Implications for Gene Editing - Cas12p's compact size lowers the delivery barrier for gene therapy, and the revealed "host factor-assisted activation" mechanism offers new directions for optimizing the efficiency and activity of gene editing tools [12]. - By introducing specific auxiliary factors and modifying related domains, there is potential to enhance the activity of other ultra-small Cas proteins and create "molecular switches" for precise control of gene editing, leading to the development of highly active and safe gene editing systems [12].

Core Viewpoint - The article discusses a novel combinatorial antifungal therapy strategy that utilizes a host defense peptide mimic to enhance the efficacy of antifungal treatments against drug-resistant fungal infections [3][6]. Group 1: Current Clinical Treatment Strategies for Fungal Infections - Current antifungal treatments often rely on single drug therapies, which have shown limited effectiveness and high failure rates against resistant fungal strains [3]. - The mortality rate for systemic fungal infections remains high due to the limited variety of antifungal drugs and their differing distribution in the body [3]. Group 2: New Strategy Proposed by the Research - The research team from East China University of Science and Technology developed a polymer that mimics host defense peptides, capable of forming micelles for the co-delivery of antifungal agents [5]. - This polymer demonstrated a synergistic effect with the classic antifungal drug Amphotericin B (AmB), allowing for the encapsulation of AmB in micelles, which significantly reduces its toxicity and expands its therapeutic window [5]. - In mouse models of systemic candidiasis and cryptococcal meningitis, AmB micelles improved survival rates by 67%-100% compared to existing treatments, indicating potential effectiveness against drug-resistant fungal infections [5].

Core Viewpoint - The article discusses the significant therapeutic effects of PD-1/PD-L1 immune checkpoint blockade therapies across various cancer types, while highlighting the challenge of resistance mechanisms that limit their clinical efficacy [2]. Group 1: Research Findings - A study published in Cell Research reveals that tumor PD-L1 induces β2m ubiquitylation and degradation, facilitating immune evasion by cancer cells [3]. - This research uncovers a novel function of PD-L1 in immune evasion, expanding the understanding of intrinsic resistance mechanisms to immune checkpoint blockade therapies [8]. Group 2: Mechanism of Resistance - β2-microglobulin (β2m) is essential for the stability and surface expression of MHC-I molecules in tumor cells. Defects in the B2M gene can reduce MHC-I levels, weakening CD8+ T cell recognition and leading to resistance against PD-1/PD-L1 therapies [6]. - The study found that PD-L1 possesses E3 ubiquitin ligase activity, which induces β2m ubiquitylation and subsequent degradation, significantly lowering MHC-I levels on tumor and antigen-presenting cells [6]. - This mechanism allows tumor cells to evade recognition by CD8+ T cells, resulting in resistance to PD-1/PD-L1 therapies, particularly in tumors with low baseline β2m expression [6].

编辑丨王多鱼 排版丨水成文 中国科学院深圳先进技术研究院 （SIAT） 诚邀全球杰出的研究人员、科学家和工程师加入，共谋职业发 展。SIAT 正在积极寻找在以下关键战略领域表现卓越的人才，包括但不限于：先进集成技术、生物医学与 健康工程、先进计算与数字工程、生物医学与生物技术、脑认知与脑疾病、合成生物学、先进材料科学与 工程、碳中和技术以及科学仪器。 SIAT 正在打造一个充满活力的研究社区，诚邀各层次学者加入科学探索之旅，也热烈欢迎您推荐杰出的同 行。 招聘职位与任职条件 杰出 PI 发展潜力：我们为您提供一个集研究、教育和产业资源于一体的一站式职业平台，在这里您将与高素质团 队合作，促进创新和职业发展。 薪酬福利：我们提供具有国际竞争力、以学术为导向的协商薪资和福利，让您能够专注于研究工作。 研究支持：我们提供大量的研究资金和专用的实验室空间，全力支持您的研究工作。 公认的学术成就和贡献； PI 青年学者 博士后 其他职位 ：教授级高级工程师、研究助理、助理工程师等。 薪酬与福利 我们为您提供有竞争力的工作支持，并为您打造一个专注的研究环境： 具有国际声誉和影响力； 能够引领学科发展或赶超国际先进水平。 ...