Polycystic ovary syndrome (PCOS) is a prevalent reproductive and metabolic disorder frequently accompanied by obesity, creating a dual burden of infertility and metabolic disease for women, yet therapeutic options addressing both pathologies remain limited. Here, using high-fat diet-induced obese and dehydroepiandrosterone-induced PCOS mouse models, we demonstrate that alnustone, a naturally derived compound, exerts coordinated benefits on both metabolic and reproductive dysfunctions in females. Long-term alnustone administration effectively attenuated body weight gain, adipocyte hypertrophy, and insulin resistance. Critically, hyperandrogenism, estrous cycle irregularity, and polycystic ovarian morphology were concurrently reversed. Mechanistically, alnustone enhanced energy expenditure by activating brown adipose tissue (BAT) and promoting white adipose tissue browning through induction of thermogenic programs. Transcriptomic profiling further revealed that alnustone corrected lipid metabolic dysregulation in obese and PCOS mice via activating adipose tissue AMPK signaling. These findings establish alnustone as a dual-action therapeutic agent that restores both metabolic homeostasis and reproductive function through adipose tissue remodeling, highlighting its potential as a natural intervention for integrated management of obesity and PCOS.

The prediction of absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties plays a critical role in early-stage drug discovery. While artificial intelligence (AI) has demonstrated transformative potential in revolutionizing this field, existing computational tools remain constrained by limitations in throughput, interpretability, and immobilized modeling frameworks. To address these challenges, we developed ADMETPred, an innovative platform that integrates machine learning and graph neural networks to deliver rapid, accurate, and comprehensive ADMET profiling. Trained on rigorously curated datasets comprising 120,616 compounds, ADMETPred employs 189 models combining LightGBM, XGBoost, Random Forest, and graph attention network to predict 27 drug pharmacokinetic, metabolism, and toxicity endpoints. Compared with current tools, ADMETPred demonstrates superior predictive accuracy by leveraging multi-algorithm synergy, high-throughput batch processing capabilities with parallelized architecture, and customizable workflows for improved prediction flexibility. Notably, the platform integrates an interpretable, attention-driven substructure highlighting module to bridge predictions with actionable structural optimization insights. Case studies spanning post-market drug surveillance, natural product toxicity screening, and lead compound preclinical safety assessment demonstrated alignment with experimental and clinical evidence. In summary, ADMETPred provides a practical resource to enhance early-stage drug development by combining lowered usage barriers with reliable ADMET profiling, freely accessible at http://admetpred.pumc.ai-tcm.cn/ .

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.

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.

Hypertension is a chronic cardiovascular disease that significantly impacts human quality of life. Gut microbiota and its metabolites have been reported to be involved in lipid metabolism and blood pressure regulation, but the specific alterations and pathogenic mechanisms of gut microbiota in obesity-related hypertension (OrHTN) remain unclear. In this study, we observed a significant proliferation of Desulfobacterota and Proteobacteria, while a decrease in the abundance of several butyrate-producing bacterial genera, accompanied by decreased fecal and plasma butyrate levels in high-fat diet (HFD)-induced OrHTN rats. Histone 3 lysine 9 butyrylation (H3K9bu) modification in the kidney of OrHTN rats was reduced and downregulated the expression of the hypertension-related gene MAS1. Subsequent transplantation of cecal contents from OrHTN rats on HFD into recipient rats on a normal chow diet resulted in hypertension but without obesity. Furthermore, in vitro experiments suggested that sodium butyrate increased H3K9bu modification and the expression of MAS1 in a concentration-dependent manner. In conclusion, our findings suggest that gut microbiota may contribute to the development of OrHTN by altering the expression of hypertension-related genes through butyrate-mediated histone butyrylation. This work may provide new insights into the prevention and treatment of hypertension by targeting the regulation of gut microbiota and metabolites.

Tetrahymena is a well-established ciliate model organism, known for its nuclear dualism and unique mechanism for transposon defense, wherein transposons are kept within the highly heterochromatinized micronucleus (MIC), which is transcriptionally inert except during meiosis. The discovery of preferential transcription in the meiotic MIC at regions enriched with transposons and the identification of MIC transcription regulatory proteins emphasize the necessity to elucidate the underlying mechanisms driving this process. In this study, we demonstrate that G/C-rich tracts are overrepresented in meiotic non-coding RNA (ncRNA) transcription regions and that RNA polymerase II (Pol II) is highly enriched at and around these tracts. Further analysis revealed that Pol II's association with G/C-rich tracts is not abolished in cells lacking Rib1, a Mediator complex-associated protein essential for MIC ncRNA biogenesis. Nevertheless, in the absence of Rib1, Pol II showed abnormal association with the meiotic MIC chromatin, suggesting that Rib1 is critical for maintaining Pol II's binding specificity. Through Rib1 truncation analysis, we found that the intrinsically disordered region, which contains putative phase-separating peptides, is crucial for its function. Disruption of phase-separation, either by deleting these peptides or by treating cells with a phase-separation disruption reagent, leads to aberrant localization of both Rib1 and Pol II on the MIC chromatin, implicating that Rib1 likely facilitates the MIC ncRNA transcription via phase-separation.

The prevalence, epidemiological history and disease risk posed by pathogenic tick-borne viruses (TBVs) remain poorly understood in Northeast Asia. Here, over 12,000 ticks were collected from diverse ecological environments in Northeast China, leading to the identification of 44 TBVs from which 1,221 viral sequences were assembled. This included six human/mammal-infecting TBVs: Alongshan virus, Beiji nairovirus, Mukawa virus, Nuomin virus, tick-borne encephalitis virus (TBEV), and Yezo virus. Aga, Izumo, and Nishinomiya in Japan were identified as tick diversity hotspots, while Shangzhi City, Genhe City, and Raohe County in China were classified as TBV hotspots. We then performed an ecological modelling of seven human-infecting TBVs and their major tick species. Both TBVs and their tick vectors were projected to have a wider distribution potential than previously recognized, including the human-infecting Wetland virus (WELV) identified in 2024. Notably, aside from WELV, the other six human-infecting TBVs were predicted to circulate in all five Northeast Asian countries. Specifically, severe fever with thrombocytopenia syndrome virus was projected to potentially impact 266.74 million people, including nearly 100% of the population of Liaoning of China, the Republic of Korea (ROK) and the Democratic People's Republic of Korea (DPRK), and 91.6% of the Japanese population. TBEV was modelled to have the widest distribution potential area of 8.56 million km2 (95.4%), potentially impacting 226.65 million people (71.1%). Overall, our study highlighted Northeast China and its adjacent countries as high-risk regions for several human-infecting TBVs. It is imperative to prioritize preventive and therapeutic measures for these high-risk TBVs.

Fungi, arthropods, and nematodes are chitin-containing organisms that cause severe damage to crop production. Plants can sense chitin to activate immunity against these invaders. In Arabidopsis thaliana (Arabidopsis), the lysin motif-containing receptor kinases (LysM-RKs) AtLYK5 and AtCERK1 are considered the primary chitin receptor and coreceptor for chitin binding and signaling, respectively. However, several studies indicate that AtCERK1 also possesses chitin-binding ability, raising a critical question: can AtCERK1 respond to chitin independently? To address this question, we generated an octuple mutant allele lacking all LysM receptors and hierarchically complemented the LysM-RKs involved in chitin perception. Our results revealed that while AtCERK1 alone could respond to chitin, it required an additional receptor to fully restore chitin-induced immune responses. Surprisingly, AtLYK4, the closest paralog of AtLYK5, forms a minimal chitin receptor complex with AtCERK1. Furthermore, we demonstrated that both N-glycosylation modifications of the extracellular domain of AtLYK4 and two key residues within its chitin-binding pocket were important for chitin recognition. Our findings not only revise the long-prevailing model of chitin perception but also define the core architecture of the chitin receptor complex in Arabidopsis. Additionally, we identify bipartite molecular determinants that regulate chitin-receptor interactions in plants.