Science China Life Sciences最新文献

Phenotypic diversity of malignant cells within a tumor underlies intratumor heterogeneity (ITH), a key determinant of cancer metastasis and treatment failure. However, the molecular mechanisms driving this heterogeneity are poorly understood. Here, we curated and analyzed a cohort of 3' tag-based single-cell RNA-seq covering 12 common cancer types. We identified thousands of poly(A) site (PAS) peaks representing the 3' ends of previously unannotated transcripts, whose expression is widely associated with diverse malignant cellular states. By integrating multi-omics data, we characterized the expression patterns and epigenetic landscape of these unannotated PAS peak-associated transcripts (UPTs). The expression heterogeneity of UPTs was supported by multi-region sampling bulk RNA-seq data and recapitulated within cancer cell lines. As proof of principle validation, functional experiments confirmed that two noncoding UPTs promoted the proliferation and migration of lung cancer cells. Our results suggest that epigenetic activation of unannotated noncoding transcripts might represent a previously unrecognized mechanism contributing to transcriptomic ITH.

Protected areas play a crucial role in global biodiversity conservation, yet they are increasingly threatened by climate change and human activities. Traditional assessments that focus exclusively on vegetation productivity (vigor) fail to capture essential dimensions of ecosystem health, such as biodiversity structure (organization) and adaptive capacity (resilience). Here, we propose a comprehensive vigor-organization-resilience framework that integrates remote sensing, machine learning, and field data to evaluate ecosystem health across 431 Chinese National Nature Reserves from 1990 to 2020. Our findings reveal that while 60.3% of reserves maintained healthy ecosystems, particularly forests, which outperformed grasslands, we identified a concerning "greening but weakening" paradox. Specifically, vegetation vigor increased by 29.4%, yet ecosystem resilience declined significantly by 26.8%, and organizational integrity decreased moderately by 6.1%. Notably, grasslands exhibited an increase in organizational structure (+7.4%), whereas forests experienced a decline (-9.9%), indicating biome-specific stress responses. Furthermore, the gap in ecosystem health between protected and adjacent non-protected areas narrowed from 3.7% to 1.8%, with measurable spillover effects contributing to an overall improvement in external ecosystem health (+2.8%). Topography, soil properties, and management practices accounted for 60% of the spatial variability in ecosystem health, while climate variability and disturbances were responsible for 51% of the temporal changes observed. By quantifying these decoupled dimensions of ecosystem health, our approach facilitates targeted conservation interventions that are essential for achieving functional, rather than merely area-based, outcomes in line with the Global Biodiversity Framework's 30×30 initiative.

The Epstein-Barr virus (EBV) is associated with multiple lymphoid malignancies and autoimmune diseases. The glycoprotein gp350, the most abundant envelope protein on the EBV virion surface, has been the primary target for the vaccine design. However, all the attempts have failed to prevent asymptomatic infection in clinical trials. This setback highlights an incomplete understanding of the immune response to gp350 and emphasizes the need for more comprehensive antibody studies. Here, we identified three human-derived anti-gp350 monoclonal antibodies from a nonimmune human scFv library. Of these, the S54 antibody exhibited a potent neutralizing activity against virus infection of Raji B cells. Using cryo-EM, we resolved the structure of the S54-gp350 complex, revealing that the S54 epitope substantially overlaps with the CR2 recognition site. Our findings elucidate the molecular mechanism by which anti-gp350 antibodies block EBV infection of B cells in vitro, providing valuable insights for antibody-based therapy and vaccine development.

The pluripotency state of embryonic stem cells (ESCs) is determined by both their epigenome and transcriptome. Sgf29, a subunit of the transcriptional co-activator complex SAGA, plays a critical role in a wide range of biological processes. However, whether and how Sgf29 mediates epigenetic modifications and pluripotency gene transcription is not fully understood. Herein, we found that Sgf29 knockout (KO) induced the differentiation of mouse ESCs (mESCs) by reducing H3K9ac and chromatin accessibility at the promoters and enhancers of key pluripotency genes. Interestingly, Sgf29 interacted with Oct4 and Nanog, but not Sox2, to co-regulate pluripotency genes. Sgf29 KO reduced the binding of Oct4 to the promoter and enhancer loci of Nanog and Klf4, leading to reduced expression of themselves and their downstream pluripotency-related genes. Furthermore, Sgf29 knockdown (KD) significantly reduced blastocyst rate and decreased H3K9ac at the blastocyst stage, leading to aberrant Oct4 and Nanog in the pre-implantation embryo. Together, these findings suggest that Sgf29 maintains chromatin accessibility and regulates the transcription of pluripotency-related genes by forming a functional complex with Oct4 and Nanog, playing a critical role in the regulation of pluripotent cell fate.

Emerging evidence establishes hepatic dysfunction as a critical modulator of breast cancer (BC) progression through metabolic, endocrine, and inflammatory crosstalk, yet the molecular mediators remain incompletely characterized. This review systematically examines the liver-BC axis to identify mechanistic drivers and therapeutic opportunities for patients with comorbid conditions. We conducted an integrated analysis combining a comprehensive literature review with computational biology approaches, including protein-protein interaction network analysis, functional pathway enrichment (KEGG/GO), and multi-omics data mining from GEO, TCGA, and CPTAC databases, supplemented by experimental validations from preclinical models. Our analysis revealed hepatic dysfunction promotes BC progression through five interconnected pathways: insulin resistance-driven IGF1-PI3K/AKT activation, estrogen metabolism imbalance via CYP19A1/ESR1, IL6-STAT3/NLRP3-mediated inflammation, HMOX1/APOE-dependent metabolic rewiring, and FAK-Src/MMP9-regulated ECM remodeling. Key molecular mediators include nuclear receptors (ESR1), cytokines (IL-1β), growth factors (HGF), and receptor tyrosine kinases, with SPP1 and PTPN2 emerging as potential circulating biomarkers linking hepatic dysfunction to aggressive BC phenotypes. The crosstalk between hepatic dysfunction and BC is mediated by a network of proteins and pathways, offering potential targets for therapeutic intervention. Future research should focus on translational validation and personalized strategies for BC patients with comorbid liver conditions. This mechanistic insight may advance early diagnosis and precision treatment paradigms.

Our previous work revealed that the anti-diarrhea effects of alkaline mineral complex (AMC) water improve metabolism and protect the gut during weaning stress. However, whether AMC water can inhibit viral replication and treat viral diarrhea is unknown. The aim of this study was to explore the ability of AMC water to improve nutrient metabolism and protect against infection. In this study, porcine epidemic diarrhea virus (PEDV) or porcine deltacoronavirus (PDCoV) were used as RNA model viruses, and pseudorabies virus (PRV) or porcine circovirus (PCV) were used as DNA model viruses. Compared with those in the infected group, the virus content in the piglets fed AMC water was reduced, and the intestinal mucosal barrier was repaired. Transcriptome and metabolome results revealed that AMC water regulated lipid metabolism through GPAT2, DGKA, OAT3, FXR, LIPC and SULT2A1. Further studies showed that glycerol, cholesterol, and bilirubin levels increased after viral infection, and that AMC water inhibited cholesterol content and promoted bile acid synthesis. In a cellular model, AMC water reduced lipid droplet density by activating the glycerolipid and bile secretion pathways of the GPAT2/SULT2A1 axis. In addition, knockdown of DGKA and overexpression of SULT2A1 significantly affected the expression of the GPAT2/SULT2A1 axis, and the expression of viral proteins colocalized with lipid droplets was significantly decreased. Our findings suggest that AMC water promotes cholesterol metabolism by activating the GPAT2/SULT2A1 axis, inhibiting viral infection in piglets. This study provides theoretical support for the use of nutritional regulation to inhibit viral infection and provides a new method for antiviral therapy.