编辑丨王多鱼 排版丨水成文 "脂肪工厂"是如何运作的？ 该研究显示，尼安德特人在猎获大型动物 （马、鹿等） 后，不仅吃肉，他们还还会将富含油脂的骨头 （尤其是四肢骨） 收集起来。他们并非简单地砸骨获取骨髓，而是采用了更"高级"的工艺： 提到 尼安德特人 ，我们的印象往往是原始、粗野、智力落后于 智人 （现代人类） 的"失败者"，然而，一 项最新研究显示，这可能是一个刻板印象。 2025 年 7 月 2 日， Nature 在其官网头条报道了一项最新研究—— 尼安德特人在"脂肪工厂"中熬煮动物 骨头以获取珍贵的脂肪，这比已知的现代人类最早炼制动物脂肪的行为还要早 10 万年。 该研究以： Large-scale processing of within-bone nutrients by Neanderthals, 125,000 years ago 为 题，于 2025 年 7 月 2 日，发表在了 Science 子刊 Science Advances 上。 研究团队在德国莱比锡附近 的 Neumark-Nord 考古遗址进行发掘时，发现了一个大型的"脂肪工厂"，生 活在距今 12.5 万年前的尼安德特人， ...

Core Viewpoint - The article discusses the significance of taurine and its transporter TauT, highlighting recent research that reveals the structural and functional mechanisms of TauT, which may have implications for understanding taurine-related diseases and potential therapeutic strategies [2][9]. Group 1: Taurine and TauT Overview - Taurine is a sulfur-containing β-amino acid essential for various physiological functions, including cell stability, neurotransmission regulation, lipid metabolism, and antioxidant activity [2]. - The ability to synthesize taurine decreases with age, making external intake via TauT crucial [2]. Group 2: Recent Research Findings - A study published in Nature Communications by the Shanghai Institute of Organic Chemistry identified multiple oligomeric states of human TauT in a nanodisc environment using cryo-electron microscopy [3]. - The research revealed a novel dimerization mechanism for TauT, differing from other transporters in the SLC6 family, with cholesterol playing a role in facilitating this oligomerization [6]. Group 3: Mechanism of Substrate Recognition and Transport - The study detailed the structural dynamics of TauT in various states, elucidating its substrate specificity and transport mechanism, where the central site can bind one substrate, two Na⁺, and one Cl⁻, transitioning from an open to a closed state [7]. - Key residues Gly57 and Phe58 are critical for substrate specificity, undergoing conformational changes during substrate release [7][12]. Group 4: Implications for Health and Disease - The findings underscore the importance of lipid microenvironments in regulating TauT oligomerization and provide a structural framework for understanding TauT's function, which may aid in exploring treatment strategies for diseases related to taurine deficiency [9].

Core Viewpoint - The article discusses a recent study that highlights the role of fetal-like transcription programs in promoting phenotypic plasticity in colorectal cancer, which is crucial for cancer progression, metastasis, and treatment resistance [2][3]. Group 1: Research Development - A patient-derived organoid model (CiPDO) was developed to capture the fetal-like plasticity state in colorectal cancer [4]. - The CiPDO system was cultivated under specific conditions using EGF, CHIR99021, LDN-214117, and FGF2, allowing for long-term expansion of colorectal cancer cells while retaining fetal-like characteristics [7]. Group 2: Key Findings - The research identified an oncofetal state (OnFS) enriched in advanced tumors, associated with key plasticity features including epithelial-mesenchymal transition, increased metastasis, and enhanced treatment resistance [8]. - Mechanistically, the FGF2-AP-1 signaling pathway was shown to maintain the OnFS program and related phenotypic plasticity in colorectal cancer [9]. Group 3: Implications - The patient-derived organoid model provides a powerful platform for studying the fetal-like characteristics of cancer cells and their roles in tumor progression and treatment resistance in colorectal cancer [11].

Core Viewpoint - Immune checkpoint inhibitors (ICIs) have transformed the treatment of various solid tumors, but resistance remains a significant challenge, particularly in advanced and recurrent ovarian cancer, where response rates to single-agent PD-1/PD-L1 inhibitors are only 5%-15% [2][3] Group 1: Research Findings - A study published in Nature by a team from MD Anderson Cancer Center found that patients with PPP2R1A gene mutations had significantly improved survival after receiving combined anti-PD-1/PD-L1 and anti-CTLA-4 immunotherapy compared to those with wild-type PPP2R1A [3][6] - The presence of PPP2R1A mutations enhances tumor response to immunotherapy, and this finding was validated across various cancer types in clinical cohorts [3][9] - In recurrent ovarian cancer, dual targeting of PD-1/PD-L1 and CTLA-4 showed a response rate of 31.4% compared to 12.2% for single-agent PD-1 therapy, indicating a potential benefit for patients with ovarian clear cell carcinoma (OCCC) [5][6] Group 2: Clinical Implications - The study suggests that targeting PPP2R1A could represent an effective strategy to improve outcomes for cancer patients undergoing immunotherapy [9] - Enhanced immune cell infiltration and signaling pathways were observed in tumors with PPP2R1A mutations, indicating a more favorable immune environment for treatment [8] - The research team is conducting prospective trials to explore the efficacy of dual immune checkpoint blockade in OCCC patients, particularly those with platinum-resistant disease [5][6]

Core Viewpoint - The increasing prevalence of metabolic dysfunction-related fatty liver disease (MASH) necessitates the development of new therapeutic strategies, as current treatment options are limited and the patient population is growing rapidly [2][5]. Group 1: MASH Overview - Approximately 100 million people globally are currently affected by MASH, with projections indicating this number could rise to 357 million by 2030 [2]. - MASH is a critical factor in the progression of liver cirrhosis and hepatocellular carcinoma, and it is a leading cause of liver transplants [2]. Group 2: Research Findings - A new strategy for large-scale acquisition of artificial cell-derived vesicles (ACDV) has been proposed, which allows for the safe and stable oral delivery of RNA drugs targeting the liver [3]. - The study demonstrated that LIMA1 siRNA (siLIMA1) delivered via the modified ACDV effectively inhibited LIMA1 protein expression in the liver, thereby preventing MASH progression and improving liver function [3][11]. Group 3: Mechanism of Action - The development of drugs targeting metabolism, inflammation, and fibrosis is crucial, as excessive accumulation of fats and other metabolic substrates leads to chronic inflammation and liver cell damage [5]. - LIMA1 gene silencing is identified as a promising therapeutic approach for MASH, given its upregulation in lipotoxic liver cells and its role in liver fibrosis associated with metabolic dysfunction [5][6]. Group 4: Delivery System - The study highlights the potential of red blood cell (RBC)-derived extracellular vesicles (RBC-EV) as a non-immunogenic delivery option for RNA drugs, although challenges remain in large-scale production and half-life limitations [7]. - A feasible strategy involves generating ACDV by squeezing red blood cells, which can then be modified with DSPE-PEG and cholic acid to enhance structural integrity and liver-targeting capabilities [8][9]. Group 5: Conclusion - The research indicates that ACDV can be easily obtained and modified to achieve oral liver-targeting capabilities, with the delivery of LIMA1-siRNA showing significant therapeutic effects against MASH [13].

Core Viewpoint - The study reveals that MLKL activates the cGAS-STING pathway by releasing mitochondrial DNA (mtDNA) during necroptosis, leading to the upregulation of interferon β (Ifnb) expression and inflammation, independent of cell membrane rupture [3][10]. Group 1: Mechanism of Necroptosis - Necroptosis is a pro-inflammatory and lytic form of programmed cell death executed by the MLKL protein, which is phosphorylated by RIPK3, causing membrane rupture and the release of damage-associated molecular patterns (DAMPs) [2]. - Phosphorylated MLKL (pMLKL) also translocates to mitochondria, inducing microtubule-dependent mtDNA release, which activates the cGAS-STING pathway [7][8]. - The integrity of microtubules is essential for the release of mtDNA into the cytoplasm [8]. Group 2: Implications for Inflammatory Bowel Disease (IBD) - In a mouse model of IBD mediated by necroptosis, inhibiting the STING pathway accelerates the resolution of intestinal inflammation [3][10]. - The study enhances understanding of necroptosis and its implications for IBD treatment, suggesting that targeting the cGAS-STING pathway may provide therapeutic benefits [10].

Core Viewpoint - The article discusses the promising efficacy of CAR-T cell therapy in treating relapsed or refractory multiple myeloma, highlighting the transition from traditional autologous CAR-T to in vivo CAR-T approaches, which simplify the manufacturing process and reduce costs [2][3][4]. Group 1: In Vivo CAR-T Therapy - In vivo CAR-T therapy involves directly delivering CAR transgenes to endogenous T cells within the body, eliminating the need for complex manufacturing and storage processes associated with traditional CAR-T therapies [3][4]. - A clinical study published in The Lancet reported the first human trial data for in vivo CAR-T therapy targeting B-cell maturation antigen (BCMA) in multiple myeloma patients, demonstrating effective treatment in four patients [4][18]. Group 2: ESO-T01 Development - ESO-T01 is a novel lentiviral vector designed for in vivo T cell engineering, developed by EsoBiotec and Prigen, featuring a humanized single-domain antibody CAR targeting BCMA [6][9]. - The vector has been engineered to reduce immunogenicity and enhance specificity, including mutations to the VSVG protein and overexpression of CD47 to evade the immune system [6]. Group 3: Clinical Trial Results - The ongoing Phase 1 trial involved four adult patients with relapsed or refractory multiple myeloma, all of whom had previously shown disease progression despite multiple treatments [9][10]. - Initial dosing of ESO-T01 was set at 2.0×10^8 transduction units, with all patients experiencing acute inflammatory responses post-infusion, including fever and low blood pressure [11][13]. - By the end of the two-month follow-up, two patients achieved stringent complete responses, while the other two showed partial responses with tumor shrinkage [12][14]. Group 4: Safety and Efficacy Observations - The trial noted significant hematological toxicities, including neutropenia and thrombocytopenia, but most adverse effects resolved during follow-up [13]. - The presence of CAR-T cells was first detected in peripheral blood between days 4-8 post-infusion, peaking between days 10-17, indicating effective T cell expansion [14][18]. - The study provides valuable data for future research on in vivo CAR-T therapies, emphasizing the potential of ESO-T01 in treating difficult-to-manage multiple myeloma cases [19].

编辑丨王多鱼 排版丨水成文 电压门控钠 （ Na v ） 通道通过介导膜去极化时钠离子 （ Na + ） 的快速内流来控制神经元和肌肉的膜兴奋性。这些功能由核 心的 Na v 结构驱动，该结构由一 个中央孔道结构域 （PD） 和四个环绕的电压感受结构域 （VSD） 组成。 在人类的九种 Na v 亚型 （Na v 1.1 - 1.9） 中，由 SCN8A 基因编码的 Na v 1.6 在中枢神经系统中广泛表达，尤其在轴突远端起始段的密度极高，其功能紊乱 与 癫痫 等神经疾病密切相关。然而，Na v 1.6 虽然功能强大，但靶向药物极少，开发其精准、特异性强的新型分子一直是神经药理领域的一大挑战。 2025 年 7 月 4 日 ， 深圳医学科学院 颜宁 / 黄健 团队在 Cell Research 期刊发表了题为： Phrixotoxin-3 binds to three distinct antagonistic sites on human Na v 1.6 的研究论文。 该研究首次揭示了 蜘蛛毒素 Phrixotoxin-3 （PaurTx3） 通过三位点协同调控人源电压门控钠通道 Na v 1.6 ，为 ...

Core Viewpoint - The article discusses a promising strategy for inhibiting tumor metastasis by targeting tumor extracellular vesicles (TEV) through a newly developed lipidated nanophotosensitizer that can track and disable TEV, effectively suppressing both tumor growth and metastasis [2][4][8]. Group 1 - The research team from Southern Medical University has published a study in Nature Cancer, focusing on the concurrent inhibition of tumor growth and metastasis using a lipidated nanophotosensitizer [3]. - The developed lipidated nanophotosensitizer can efficiently track and destroy TEV, leading to a dual effect of inhibiting tumor growth and metastasis [4][8]. - The study utilized engineered palmitic acid surface-displaying nanoparticles that are effectively taken up by tumor cells and can actively track TEV, combining their distribution within tumor cells and TEV [6]. Group 2 - Upon near-infrared light exposure to the primary tumor site, reactive oxygen species (ROS) are generated both inside tumor cells and within TEV, resulting in photodynamic inhibition of the primary tumor and blocking intercellular communication by inhibiting TEV [6]. - The research demonstrated effective suppression of tumor growth and metastasis in various tumor models in female mice [6].

Core Viewpoint - The article discusses the efficacy of Tirofiban, a platelet glycoprotein IIb-IIIa receptor antagonist, in improving functional outcomes for patients with acute ischemic stroke who receive intravenous thrombolysis within 4.5 hours of symptom onset [3][11]. Group 1 - Intravenous thrombolysis remains the standard treatment for acute ischemic stroke within 4.5 hours, and the use of antiplatelet drugs may prevent reocclusion in the first 24 hours post-thrombolysis [2]. - The ASSET-IT trial, published in NEJM, involved 832 patients with non-cardiogenic stroke who received thrombolysis and assessed the impact of early Tirofiban infusion on functional outcomes [3][10]. - The study was led by Professor Wei Hu from the First Affiliated Hospital of the University of Science and Technology of China, with contributions from multiple co-authors [6]. Group 2 - The trial was a multicenter, double-blind, randomized controlled study conducted across 38 medical centers in China, focusing on patients who were not candidates for thrombectomy [9]. - Patients were randomly assigned to receive either Tirofiban or a placebo within 60 minutes after thrombolysis, with the primary outcome being the proportion of patients achieving a good functional outcome at 90 days [10]. - Results indicated that 65.9% of the Tirofiban group achieved a good functional outcome compared to 54.9% in the placebo group, with a hazard ratio of 1.20 [11]. Group 3 - The incidence of symptomatic intracranial hemorrhage was 1.7% in the Tirofiban group versus 0% in the placebo group, while the mortality rate at 90 days was 4.1% for Tirofiban and 3.8% for placebo [11]. - The study fills an evidence gap regarding the use of antiplatelet drugs in the post-thrombolysis window for stroke patients, providing high-quality evidence to optimize treatment strategies in China [12].