以下文章来源于肥胖世界ObesityWorld ，作者欢迎订阅 肥胖世界ObesityWorld . 《肥胖世界》Obesity World - 同步传真肥胖及代谢国际新学术进展，为医学减重临床、教研人员搭建一座与国际接轨的桥梁，「每医健」旗下内容平台。 虽然身体成分常被误解为被动的脆弱指标，实际上它们积极参与整体代谢调节，在应对急性损伤后的生存中起到关键作用。危重症时，肌肉 与脂肪组织会发生显著调整，这不仅影响住院期间，还会深刻改变出院后的代谢状态。肥胖对全身代谢和病人预后的影响仍有争议。各种底 物诱导的表观遗传变化会改变基因表达谱，进而影响那些直接关联患者生存的代谢路径。 本文综述了 危重症中，从体重调节到免疫反应执行阶段，能量如何在体内流动的核心机制。同时也提出，未来研究应着重于受损的免疫代 谢和表观遗传机制，以期更深入理解其本质，并为危重病人带来更好的治疗预后 。 在危重症过程中，全身炎症会引发器官间特有的代谢变化。在免疫及炎症相关区域，合成代谢的重新编程主要用于支持细胞增殖和完成炎症 反应。同时，脂肪组织和骨骼肌的分解代谢为免疫和炎症细胞的合成代谢提供了必要的碳源和能量。在这些代谢调整中，肝脏至关重 ...

以下文章来源于肥胖世界ObesityWorld ，作者欢迎订阅 肥胖世界ObesityWorld . 《肥胖世界》Obesity World - 同步传真肥胖及代谢国际新学术进展，为医学减重临床、教研人员搭建一座与国际接轨的桥梁，「每医健」旗下内容平台。 虽然身体成分常被误解为被动的脆弱指标，实际上它们积极参与整体代谢调节，在应对急性损伤后的生存中起到关键作用。危重症时，肌肉 与脂肪组织会发生显著调整，这不仅影响住院期间，还会深刻改变出院后的代谢状态。肥胖对全身代谢和病人预后的影响仍有争议。各种底 物诱导的表观遗传变化会改变基因表达谱，进而影响那些直接关联患者生存的代谢路径。 本文综述了 危重症中，从体重调节到免疫反应执行阶段，能量如何在体内流动的核心机制。同时也提出，未来研究应着重于受损的免疫代 谢和表观遗传机制，以期更深入理解其本质，并为危重病人带来更好的治疗预后 。 针对危重症所致的代谢重组的研究表明，细胞机制在调控氧气输送与利用方面扮演着重要角色。与禁食状态或慢性疾病的代谢反应相比，急 性疾病下的代谢特征更为特殊，其主要目标是通过支持免疫和炎症过程来抵御感染和损伤。代谢重组的焦点在于如何分配底物氧化生 ...

Core Viewpoint - The article discusses various methods for weight loss, including low-carb diets, intermittent fasting, weight loss surgeries, and medications like semaglutide, highlighting the increasing interest in these approaches for achieving weight loss goals [6]. Research Findings - Recent studies indicate that reducing food intake can positively impact health and aging in both animal models and humans. A new study published in the journal "Science" suggests that the sensation of hunger alone can slow aging, opening new avenues in the field of anti-aging [7][8]. - A study from the University of Michigan published in May 2023 found that inducing a state of hunger in fruit flies, either through dietary restriction or brain stimulation, resulted in increased lifespan. This suggests that hunger triggers epigenetic changes in the brain that regulate gene expression, influencing eating behavior and aging processes [7][8]. - The research distinguishes the effects of dietary restriction from nutritional interventions, indicating that the mere perception of hunger can lead to longevity benefits [8]. Mechanisms of Hunger and Longevity - Further investigations revealed that changes in neuronal activity related to foraging might be key to extending lifespan. For instance, a low branched-chain amino acids (BCAA) diet induced hunger in fruit flies, leading to increased food intake but also significantly extending their lifespan [11]. - The study employed optogenetics to activate neurons controlling hunger, confirming that inducing hunger sensations, regardless of food intake, can enhance lifespan. The findings suggest that epigenetic regulation plays a crucial role in this process, with hunger perception enhancing foraging behavior and potentially lowering the threshold for hunger over time, contributing to aging delay [13].

Core Viewpoint - The study reveals that hypoxia inhibits ferroptosis through a HIF-independent mechanism by suppressing KDM6A, a key player in lipid metabolism and ferroptosis resistance [2][5]. Group 1: Mechanism of Ferroptosis Regulation - Long-term hypoxia can inhibit ferroptosis in a HIF-independent manner [5]. - Hypoxia suppresses KDM6A, reshaping the lipid profile to confer resistance to ferroptosis [3][5]. - KDM6A acts as a non-classical oxygen sensor in the ferroptosis process, indicating a novel regulatory pathway [2][5]. Group 2: Implications for Cancer - The loss of KDM6A, a tumor suppressor, is commonly observed in bladder cancer, leading to resistance to ferroptosis [5]. - Pharmacological inhibition of EZH2, which opposes KDM6A activity, restores sensitivity to ferroptosis in bladder tumors carrying KDM6A mutations [4][5].

Core Insights - The research reveals a convergent mechanism of echolocation in different mammalian species, providing new perspectives on the evolutionary origins of this complex behavior [1][2] - The study highlights the significance of non-coding regulatory regions in the convergent evolution of behaviors, challenging the traditional focus on protein-coding genes [2] Group 1: Research Findings - The study identifies 222 shared open chromatin regions in the hippocampal area of echolocating species, significantly higher than random expectations, indicating a complex gene regulatory network [1] - Traditional auditory-related genes are found to be abnormally active in the hippocampal regulatory networks of echolocating mammals, suggesting their role in spatial localization functions [2] Group 2: Methodology and Implications - The research employs innovative techniques such as chromatin accessibility sequencing, transcriptome sequencing, and transmission electron microscopy to compare the hippocampal gene regulatory features of various species [1] - The establishment of the Daluoshan pig-tailed mouse as a new model organism offers a valuable platform for further exploration of the neural mechanisms underlying echolocation [2]

Core Viewpoint - The latest research published in Nature reveals that maternal iron deficiency during pregnancy can lead to significant impacts on fetal sex development, specifically causing XY mouse embryos to develop ovaries instead of testes [2][14]. Group 1: Research Findings - The study conducted by a team from Osaka University demonstrates that iron, particularly ferrous ions (Fe²⁺), plays a crucial role in activating male sex determination genes [2][11]. - The Sry gene, located on the Y chromosome, is essential for male development and is activated during a specific time window in embryonic development [3][11]. - Iron metabolism is linked to the expression of the Sry gene, where iron deficiency leads to increased suppression of Sry expression due to epigenetic modifications [5][11]. Group 2: Mechanisms of Action - The research indicates that iron accumulates in key cells responsible for sex determination, with iron-related gene expression significantly higher in these cells compared to others [6][11]. - Experiments showed that blocking iron supply resulted in decreased Sry expression and a shift in XY embryos towards female characteristics [7][11]. - Maternal iron deficiency, induced through dietary means or iron chelation, resulted in a notable percentage of XY offspring exhibiting sex reversal [8][9][11]. Group 3: Implications for Human Health - The findings suggest that severe maternal iron deficiency could be an underrecognized environmental risk factor for certain cases of 46-XY disorders of sex development in humans [14]. - The study emphasizes the importance of adequate iron intake during pregnancy to prevent anemia and ensure proper fetal sex development [14]. - This research challenges traditional views on iron's role, highlighting its influence on gene expression and fetal development, thus calling for nutritional interventions during pregnancy [14].

Core Viewpoint - The research conducted by the team led by Academician Cao Xiaofeng from the Chinese Academy of Sciences provides direct molecular evidence supporting the theory of "acquired inheritance" by demonstrating that environmentally induced epigenetic variations can mediate adaptive traits across generations in rice [2][10]. Group 1: Research Findings - The study established a multi-generational cold stress screening system, successfully obtaining rice strains with significantly enhanced cold resistance that exhibit stable inheritance over at least five generations after the removal of cold stress [4][7]. - The research identified a key variation site in the promoter region of the Arabidopsis galactin gene ACT1, where the loss of methylation allows for the expression of ACT1 to no longer be suppressed by low temperatures [5][8]. - The findings revealed a complete regulatory pathway for cold adaptation, where low-temperature stress downregulates the expression of DNA methyltransferase MET1b, leading to the loss of DNA methylation at the ACT1 promoter, which activates ACT1 expression and confers cold resistance to rice [7][10]. Group 2: Implications for Agriculture - The research introduces a new breeding strategy termed "adversity domestication-epigenetic variation identification-precise editing," which offers innovative solutions for agricultural production challenges posed by global climate change [2]. - The study's analysis of DNA methylation in 131 local rice varieties from three major rice-growing regions in China indicates a "south high, north low" gradient in DNA methylation status of ACT1, suggesting that epigenetic variation is a key domestication site for cold adaptation in rice as it migrates northward [8].

Core Viewpoint - The research highlights the critical role of the epigenetic regulator BAZ2B in hepatic senescence and metabolic dysfunction-associated steatohepatitis (MASH) fibrosis, providing a theoretical foundation for developing new therapeutic strategies [2][4][7]. Group 1: Research Findings - The study reveals an epigenetic mechanism linking liver aging to MASH fibrosis, with the upregulation of chromatin remodeler BAZ2B associated with MASH pathology in certain liver cells [4]. - In mouse models, gene knockout or liver cell-specific knockdown of Baz2b alleviates hepatic senescence and MASH fibrosis by maintaining PPARα-mediated lipid metabolism, which is impaired in naturally aged and MASH mice [4][5]. - BAZ2B directly binds to the promoter regions of genes related to the PPARα signaling pathway, reducing chromatin accessibility and downregulating gene expression [5]. Group 2: Implications - The BAZ2B-PPARα-lipid metabolism signaling axis is identified as a crucial link in the progression from liver aging to MASH fibrosis, suggesting that BAZ2B may serve as a potential therapeutic target for liver aging and fibrosis [7].

Company Overview - Microchip Biotech is a pioneer in original innovative drugs in China, focusing on providing clinically needed revolutionary mechanism drugs for patients [7][38] - The company has established a complete industrial chain layout from early exploratory discovery to commercialization, offering original innovative drugs globally [38] Financial Performance - For the fiscal year 2024, the company reported a net profit attributable to shareholders of -114.57 million yuan, with the parent company achieving a net profit of -88.42 million yuan [5] - The board decided not to distribute cash dividends or issue bonus shares for the fiscal year 2024, despite having positive undistributed profits [5] Product Pipeline - The company has developed two innovative drugs, with multiple indications approved for sale globally, including in the fields of malignant tumors, metabolic diseases, autoimmune diseases, central nervous system diseases, and antiviral treatments [7][39] - Key products include: - **Sida Benamide (西达本胺)**: A first-in-class HDAC inhibitor with multiple indications approved in China and Japan, including for peripheral T-cell lymphoma and breast cancer [8][9][39] - **Siglitazone (西格列他钠)**: A first-in-class PPAR agonist approved for type 2 diabetes and recently for combination therapy with metformin [12][13][40] Research and Development - The company employs a team of experienced scientists to drive drug development, focusing on understanding disease mechanisms and optimizing drug design [22] - The R&D pipeline includes several promising candidates targeting various cancers and metabolic diseases, with ongoing clinical trials demonstrating significant efficacy [17][21][40] Industry Context - The biopharmaceutical industry in China is rapidly evolving, with increasing participation in global biotech innovation and a focus on meeting domestic healthcare needs [26][30] - Despite a low-risk appetite in global financing, Chinese companies are becoming significant players in licensing transactions, with a notable increase in outbound licensing activities [29][41] - The market for innovative drugs in China is projected to grow significantly, with a forecasted market size of approximately $197 billion by 2025 [30]

Financial Data and Key Metrics Changes - Sangamo Therapeutics reduced non-GAAP operating expenses by nearly half year-over-year since 2023 [9] - The company raised over $100 million in funding through non-dilutive license fees, milestone payments, and equity financing in 2024 [9] Business Line Data and Key Metrics Changes - The company advanced its neurology therapies, securing its first-ever neurology IND for idiopathic small fiber neuropathy [7] - The Fabry gene therapy study continues to generate best-in-class data, with pivotal data readout expected in mid-2025 [9][22] Market Data and Key Metrics Changes - Interest in the Fabry program has been strong, with ongoing business development negotiations for a commercial partner [11] - The company is actively engaged in advanced contract negotiations for a third STAC-BBB license agreement [12] Company Strategy and Development Direction - Sangamo's number one priority is addressing its financing needs to fulfill its potential [11] - The company aims to secure a partnership for Fabry that provides capital for executing other programs [12] - The regulatory pathway for accelerated approval in Fabry disease could reduce the time to potential approval by approximately three years [8][29] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in the progress made towards becoming a clinical-stage neurology company [28] - The company is focused on raising additional capital to support its operations and development [30] Other Important Information - The company plans to begin patient enrollment and dosing for ST-503 in mid-2025, with preliminary proof of efficacy data expected in the fourth quarter of 2026 [19] - The FDA has provided a clear regulatory pathway to accelerate approval for ST-920, with a potential BLA submission in the second half of 2025 [25][26] Q&A Session Summary Question: Is the company still waiting on any data for the Fabry program? - Management confirmed they are in late-phase discussions with several partners and look forward to seeing the one-year data for the last patient soon [34][36] Question: Have potential partners seen any data beyond the WORLDSymposium data? - Management indicated that partners have not seen efficacy data beyond what was presented at the WORLDSymposium [45] Question: What is the status of the STAC-BBB deal? - Management hopes to finalize the deal by the end of the quarter and indicated that the partner is a logical blue-chip choice [55] Question: How is the company managing operating expenses going forward? - Management has reduced operating expenses by nearly half year-over-year and plans to maintain the same level of expenses as last year while advancing the neurology pipeline [58] Question: What are the patient enrollment criteria for the Nav1.7% study? - Management stated that the criteria will be published on clinical trial registries and emphasized the importance of a clear result for the one-time treatment [73][76]