Core Viewpoint - The research published by Professor Ren Wenkai's team from South China Agricultural University indicates that Lactobacillus reuteri and its metabolite L-theanine enhance the catabolism of branched-chain amino acids (BCAA), providing a potential therapeutic pathway for metabolic disorders associated with elevated BCAA levels [2][6]. Group 1 - The study reveals that gut microbiota can regulate circulating BCAA levels through direct conversion, and it uncovers an indirect mechanism by which gut microbiota influences host BCAA metabolism [4]. - The research team compared germ-free mice and pigs with wild-type counterparts, finding that Lactobacillus reuteri and L-theanine are associated with enhanced BCAA catabolism [5]. - Experiments on pig cell lines demonstrated that L-theanine increases the expression of branched-chain amino transferase (BCAT), which is involved in BCAA catabolism, by promoting BCAT2 mRNA expression and stabilizing the BCAT2 protein [5]. Group 2 - Overall, the study provides a potential pathway for developing therapies targeting metabolic disorders related to elevated BCAA levels [6].

Core Viewpoint - The article emphasizes the significant role of the dynamic interaction between tumor cells and the host in the pathogenesis of cancer cachexia, a syndrome affecting approximately 50%-80% of cancer patients, with varying incidence rates across different malignancies [2][4]. Group 1: Overview of Cancer Cachexia - Cancer cachexia is characterized by systemic inflammation, weight loss, and muscle and fat tissue atrophy, primarily due to increased energy expenditure, hypermetabolism, and anorexia [4]. - Clinical criteria for considering cancer cachexia risk include weight loss of ≥5% within six months, BMI <20 kg/m² with weight loss of ≥2%, and weight loss of ≥2% in sarcopenic patients [4]. - The syndrome significantly impacts patients' quality of life, exacerbates treatment-related toxicities, and increases mortality rates by 20%-30% [4]. Group 2: Mechanisms and Interactions - The review discusses the systemic metabolic syndrome involving multiple tissues and organs, including skeletal muscle, fat, and liver, and how tumors influence distant organs through neural, blood, and lymphatic networks [5][19]. - It posits that catabolic metabolism activation and anabolic metabolism suppression are key features in cancer cachexia, leading to inflammatory responses that disrupt energy homeostasis [5][23]. - The interplay between metabolic reprogramming and inflammatory responses creates a vicious cycle, with immune and stromal cells releasing inflammatory mediators that further disturb systemic metabolism [23][26]. Group 3: Recent Advances and Therapeutic Strategies - Recent studies highlight innovative therapeutic strategies aimed at alleviating cancer cachexia, including the approval of Anamorelin, a ghrelin receptor agonist, which has shown promise in increasing muscle mass and weight [25]. - Targeting specific inflammatory factors, such as GDF15 with Ponsegromab, has demonstrated potential in improving weight and activity levels in early clinical trials [25]. - Metabolic interventions, including supplementation with specific amino acid derivatives and ω-3 fatty acids, have been shown to alleviate symptoms of cancer cachexia [26]. Group 4: Future Research Directions - The complexity of cancer cachexia mechanisms necessitates further research to identify new therapeutic targets, integrating immunology and metabolomics approaches [26]. - The need for more comprehensive studies using optimal animal models to simulate cachexia states is emphasized to enhance understanding of the syndrome's progression [26].

Core Viewpoint - The article discusses a significant advancement in the field of biomanufacturing, focusing on the development of a technology called FLASH (flow-led assembly for spiral hierarchical structure) that enables the scalable fabrication of aligned myocardial tissues with a native-like helical architecture for heart repair [2][5]. Group 1: Research Background - The natural helical arrangement of myocardial fibers is crucial for efficient heart pumping, yet replicating this structure on a large scale remains a major challenge in biomanufacturing [2]. - The research published by Tsinghua University highlights the importance of mimicking the anisotropic structure of human heart tissue to enhance the functionality of engineered myocardium and improve cardiac tissue models' pumping performance [4]. Group 2: FLASH Technology - FLASH technology combines biomimetic structural design with scalable manufacturing processes, paving the way for organ-level cardiac models suitable for disease modeling, drug testing, and regenerative therapy [7]. - This microfluidic platform assembles high cell density microfibers, with a core made of collagen/matrix gel containing cardiomyocytes and a sheath layer of alginate containing endothelial cells [5]. - Compared to traditional bioprinting techniques, FLASH achieves over 90% alignment rate of cardiomyocytes, adjustable mechanical anisotropy, and triples the spatial resolution/manufacturing time (RTM) [5]. Group 3: Experimental Results - The spiral ventricular model constructed using FLASH demonstrates coordinated ventricular scale contraction [5]. - In a rat myocardial infarction model, cardiac patches made using FLASH significantly improved heart function and reduced fibrosis [5].

Core Viewpoint - The study highlights the role of the E3 ubiquitin ligase KLHL6 as a dual negative regulator of T cell exhaustion and mitochondrial dysfunction during chronic antigen stimulation, suggesting its potential as a clinical target to enhance cancer immunotherapy effectiveness [5][7][9]. Group 1: T Cell Dysfunction and Mechanisms - T cell dysfunction, including exhaustion and mitochondrial impairment, is a major barrier in cancer immunotherapy [7]. - The research combines computational analysis with in vivo CRISPR screening to identify KLHL6 as a key factor in regulating T cell exhaustion and mitochondrial health [5][7]. - KLHL6 expression promotes the polyubiquitination and subsequent proteasomal degradation of the exhaustion core regulator TOX, inhibiting the transition from precursor exhausted T cells (Tpex) to terminal exhausted T cells (Tex-term) [7][9]. Group 2: Therapeutic Implications - Enhancing KLHL6 expression in T cells significantly improves anti-tumor and anti-viral efficacy, indicating its critical role in T cell fate and function [5][8]. - The study suggests a new therapeutic approach to restore or enhance KLHL6 expression to reverse T cell exhaustion during chronic TCR stimulation [8][9]. - The findings underscore the potential of targeting protein homeostasis and ubiquitination modifications to improve immunotherapy outcomes [9][10].

Core Insights - The development of artificial intelligence (AI) is accelerating scientific discovery, with the 2024 Nobel Prizes in Physics and Chemistry awarded to scientists in the AI field, establishing the role of AI tools in science [2] - A paradox is revealed where the adoption of AI tools expands individual scientists' influence but narrows the focus of research fields [3][6] Group 1: Research Findings - The study analyzed over 41 million papers, with approximately 311,000 utilizing AI tools, showing that scientists using AI publish 3.02 times more papers, receive 4.84 times more citations, and become project leaders 1.37 years earlier than those who do not use AI [6] - The collective scientific focus has contracted by 4.63%, and collaboration among scientists has decreased by 22% due to the concentration of AI-assisted work in data-rich fields [6][7] Group 2: Implications and Recommendations - The research highlights the potential for AI to lead the scientific community towards "involution," focusing on optimization within a shrinking scope rather than exploring new frontiers [7] - There is a need to consciously establish mechanisms that encourage exploration and reward risk-taking in the use of AI for scientific research to balance efficiency and innovation [7]

Core Viewpoint - The article discusses the advancements in in vitro maturation (IVM) technology, particularly the use of human induced pluripotent stem cells (hiPSC) to improve the success rates of egg maturation and pregnancy outcomes in assisted reproductive technologies [4][5][6]. Group 1: Challenges in Infertility Treatment - Over 10% of the reproductive-age population globally faces infertility issues, with conditions like endometriosis and polycystic ovary syndrome contributing to significant physical and economic burdens [9]. - Traditional in vitro fertilization (IVF) requires high doses of hormones, which can lead to complications such as ovarian hyperstimulation syndrome (OHSS), especially in patients with polycystic ovary syndrome [9]. Group 2: Innovation in Stem Cell Technology - The recent study by Gameto utilized hiPSC technology to differentiate into ovarian support cells (OSC), significantly enhancing the success rates of IVM and clinical pregnancy rates [5][11]. - The OSC product, named Fertilo, was developed through the regulation of three key transcription factors, creating a supportive microenvironment for egg maturation [11][12]. Group 3: Clinical Research Results - Clinical trials showed that using Fertilo's OSC-IVM technology increased egg maturation rates from 52% to 70%, and the clinical pregnancy rate reached 41%, compared to 20% in the traditional IVM group [14]. - The Fertilo group successfully delivered 8 healthy babies, while the traditional IVM group only had 2, demonstrating the potential of hiPSC-derived OSC to improve egg maturation quality and pregnancy outcomes [14]. Group 4: Technical Advantages and Safety - Fertilo's OSC can dynamically respond to the developmental needs of eggs, unlike traditional IVM culture environments [17]. - Safety measures ensure that OSC cells are completely removed before embryo transfer, with genetic testing confirming no residual OSC cells or genetic material in the transferred embryos [17]. Group 5: Future Application Prospects - Fertilo is particularly suitable for high-risk groups for OHSS, such as patients with polycystic ovary syndrome, and offers a safer, more efficient option for cancer patients needing fertility preservation [19]. - As larger clinical trials are conducted, Fertilo has the potential to provide new hope for more couples facing infertility, marking a significant advancement in reproductive medicine and the clinical application of stem cell technology [20].

Core Viewpoint - The research highlights the superior potential of small intracellular vesicles (sIV) over small extracellular vesicles (sEV) in drug delivery and retinal neuroprotection, suggesting a promising avenue for clinical applications in biomedical engineering [3][9][12]. Group 1: Research Findings - The study developed a method for isolating sIV from various cell types and demonstrated that sIV outperforms sEV in uptake, drug delivery, and retinal neuroprotection [3][7]. - sIV are smaller in size and yield higher quantities compared to sEV, exhibiting stronger cellular uptake capabilities in both in vitro and in vivo models [9]. - Molecular analysis revealed that sIV are enriched with endoplasmic reticulum and Golgi apparatus-related proteins, possessing unique microRNA characteristics associated with the intracellular membrane system, and contain higher levels of phospholipids such as phosphatidylcholine and phosphatidylethanolamine [9]. Group 2: Therapeutic Applications - sIV derived from mesenchymal stem cells (MSC) showed remarkable therapeutic effects in a retinal degeneration model by alleviating endoplasmic reticulum stress and delivering neuroprotective factors [9][11]. - The enhanced drug loading and delivery capabilities of sIV allow for effective transport of lipophilic compounds, such as rapamycin, to the retina [11]. Group 3: Implications for Clinical Translation - The findings indicate that sIV could serve as a promising alternative to traditional biological nanovesicles in clinical translation, potentially overcoming the limitations faced by sEV in therapeutic applications [12].

Core Viewpoint - Cellular senescence is a phenomenon characterized by growth arrest, impacting various aspects from embryonic development to aging and diseases. Senescent cells accumulate over time, leading to chronic inflammation through the senescence-associated secretory phenotype (SASP), which can promote tumor growth and metastasis despite initially acting as a barrier to tumor development. Combining chemotherapy with senolytic drugs that selectively clear senescent cells may reduce tumor resistance and recurrence [2][6]. Group 1 - Senolytic drugs have been identified with various targets, but issues such as narrow therapeutic range, off-target toxicity, low efficacy, and limited bioavailability remain [2][6]. - The study published in Nature Aging reveals the anti-aging properties of Sticholysin I (StnI), showing its ability to effectively and specifically kill senescent cells and work synergistically with chemotherapy to induce tumor regression in mice [3][8]. Group 2 - StnI, a pore-forming toxin isolated from Caribbean anemones, binds with high affinity to specific lipids on the target cell membrane, leading to the formation of transmembrane pores that disrupt membrane integrity and cause cell death [6][7]. - The mechanism of StnIG involves the influx of sodium and calcium ions and the efflux of potassium ions, triggering a lethal cascade that results in cell death, particularly effective against senescent cells due to their membrane characteristics [7][8].

Core Viewpoint - The article discusses the relationship between Epstein-Barr virus (EBV) infection and the development of Multiple Sclerosis (MS), highlighting new research that connects environmental and genetic risk factors in MS pathogenesis [3][4][9]. Group 1: Research Findings - A study published in the journal Cell reveals that EBV infection and the HLA-DR15 gene jointly drive the development of MS by presenting myelin peptide antigens and activating autoreactive CD4+ T cells [4][11]. - The research indicates that EBV infection alters the transcriptional and immunopeptidomic profiles of B cells, particularly in individuals carrying the high-risk HLA-DR15 genotype, leading to the presentation of specific myelin basic protein (MBP) peptides [8][9]. - The study provides direct evidence supporting the "molecular mimicry" hypothesis, where similarities between EBV proteins and myelin proteins lead to an autoimmune response against the nervous system [9][18]. Group 2: Implications for Treatment - The findings deepen the understanding of MS etiology and suggest potential new therapeutic approaches targeting specific autoreactive T cells or EBV-infected B cells [11][18]. - The research collectively illustrates how EBV infection can influence both B cell function and induce cross-reactive T cell responses, contributing to MS pathogenesis [18].

Core Viewpoint - The research introduces a novel bioprinting strategy called NEAT (Nanoengineered Extrusion-Aligned Tract) that addresses the challenges in spinal cord repair by enabling the construction of aligned structures from nanofibers to centimeter-scale tissues without post-processing, demonstrating significant functional recovery in animal models [3][4][9]. Group 1 - The NEAT strategy utilizes shear stress during the extrusion printing process to induce directional rearrangement and ordered assembly of chemically modified collagen fibers, maintaining the collagen triple helix structure and bioactivity [6][9]. - In vitro functional assessments show that NEAT-printed aligned tissues exhibit significant advantages in cell differentiation and functional maturity, supporting over 8 weeks of culture [7]. - The NEAT approach successfully resolves technical challenges in manufacturing ultra-soft, high-water-content tissues, establishing a methodological foundation for future in vitro functional models and multi-scale biomanufacturing systems [9]. Group 2 - The research team, led by researchers from the Chinese Academy of Sciences, published their findings in the journal Cell Stem Cell, highlighting the potential of NEAT in promoting axonal reconnection and synapse formation in a rat spinal cord injury model [3][4]. - The NEAT technology integrates topological control, cell programming, and functional integration, providing a robust platform for neural tissue engineering and spinal cord regeneration [4]. - The study emphasizes the importance of optimizing key parameters such as nozzle size, printing speed, and extrusion pressure to achieve continuous fiber alignment from hundreds of nanometers to micrometers [6].