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Abstract Background Relation extraction (RE) plays a crucial role in biomedical research as it is essential for uncovering complex semantic relationships between entities in textual data. Given the significance of RE in biomedical informatics and the increasing volume of literature, there is an urgent need for advanced computational models capable of accurately and efficiently extracting these relationships on a large scale. Results This paper proposes a novel approach, SARE, combining ensemble learning Stacking and attention mechanisms to enhance the performance of biomedical relation extraction. By leveraging multiple pre-trained models, SARE demonstrates improved adaptability and robustness across diverse domains. The attention mechanisms enable the model to capture and utilize key information in the text more accurately. SARE achieved performance improvements of 4.8, 8.7, and 0.8 percentage points on the PPI, DDI, and ChemProt datasets, respectively, compared to the original BERT variant and the domain-specific PubMedBERT model. Conclusions SARE offers a promising solution for improving the accuracy and efficiency of relation extraction tasks in biomedical research, facilitating advancements in biomedical informatics. The results suggest that combining ensemble learning with attention mechanisms is effective for extracting complex relationships from biomedical texts. Our code and data are publicly available at: https://github.com/GS233/Biomedical .

Paneth cells (PCs), a specialized secretory cell type in the small intestine, are increasingly recognized as having an essential role in host responses to microbiome and environmental stresses. Whether and how commensal and pathogenic microbes modify PC composition to modulate inflammation remain unclear. Using newly developed PC-reporter mice under conventional and gnotobiotic conditions, we determined PC transcriptomic heterogeneity in response to commensal and invasive microbes at single cell level. Infection expands the pool of CD74+ PCs, whose number correlates with auto or allogeneic inflammatory disease progressions in mice. Similar correlation was found in human inflammatory disease tissues. Infection-stimulated cytokines increase production of reactive oxygen species (ROS) and expression of a PC-specific mucosal pentraxin (Mptx2) in activated PCs. A PC-specific ablation of MyD88 reduced CD74+ PC population, thus ameliorating pathogen-induced systemic disease. A similar phenotype was also observed in mice lacking Mptx2. Thus, infection stimulates expansion of a PC subset that influences disease progression.

Abstract Background Thyroid hormone is the key endocrine regulator of growth, development, metabolism, and other bodily functions. α-Klotho has been involved in the aging process and acts as an endocrine factor involved in the regulation of various metabolic processes in humans. However, the relationship between α-Klotho and thyroid profile has not been uniformly recognize. Objective To determine the relationship between α-Klotho and thyroid profile in adult individuals. Methods Population data of 4614 adult individuals were obtained from the NHANES database during the period of 2007–2012. Weighted multivariable regression analysis was performed using a general linear model with serum α-Klotho as the independent variable and thyroid profile as the dependent variables, respectively. The generalized additive model was used for smoothing curve fitting and threshold effect analysis. Results α-Klotho was associated with a slightly higher FT3, TT3 and TT4 level in unadjusted and adjusted regression models. However, a higher α-Klotho level was associated with a lower TSH level. After α-Klotho was grouped as quantiles with reference (Q1), α-Klotho still showed a statistically significant positive correlation with FT3 and TT3 levels in Q2, Q3 and Q4. In addition, α-Klotho was positively corrected with TT4, but negatively associated with TSH in Q4. Conclusions Serum soluble α-Klotho was positively associated with FT3, TT3 and TT4, but negatively correlated with TSH. The significant effect of α-Klotho on thyroid profile suggests its potential as a predictive marker of thyroid functions, indicating its possible involvement in the regulation of thyroid hormone secretion.

Abstract Lymph node metastasis (LNM) is a common invasive feature of hepatocellular carcinoma (HCC) associated with poor clinical outcomes. Through microarray profiling and bioinformatic analyses, we identified the circ-0044539-miR-29a-3p-VEGFA axis as a potential key factor in the progression of HCC LNM. In HCC cells and nude mice, circ-0044539 downregulation or miR-29a-3p upregulation was associated with small tumor size, PI3K-AKT-mTOR pathway inactivation, and downregulation of the key LNM factors (HIF-1α and CXCR4). Furthermore, circ-0044539 was also responsible for exosomal miR-29a-3p secretion. Exosomal miR-29a-3p was then observed to migrate to the LNs and downregulate High-mobility group box transcription factor 1 (Hbp1) in Polymorphonuclear Myeloid-derived suppressor cells (PMN-MDSCs), inducing the formation of a microenvironment suitable for tumor colonization. Overall, circ-0044539 promotes HCC cell LNM abilities and induces an immune-suppressive environment in LNs through exosomes, highlighting its potential as a target for HCC LNM and HCC immunotherapy.

Pericarpium Citri Reticulatae ‘Chachi’ (PCR-C), abundant in flavonoids, is traditionally believed to enhance its pharmacological effects with long-term storage. The efficacy of these flavonoids is closely related to their intestinal absorption, which is primarily affected by P-glycoprotein (P-gp). This study explored the interaction between flavonoid absorption and P-gp in PCR-C flavonoid extracts (PCR-CF) over different storage periods using a Caco-2 monolayer model and KB/MDR cells, respectively. The transported concentrations (TC) of key flavonoids-hesperidin, isosinensetin, nobiletin, and tangeretin-significantly varied with the storage duration of PCR-CF. Notably, nobiletin and tangeretin enhanced the TC of these flavonoids by inhibiting P-gp activity, thereby influencing intestinal absorption of PCR-CF with different storage time. These findings provide a scientific basis for the traditional belief that long-stored PCR-C possesses superior medicinal properties.

Abstract Tulips (Tulipa gesneriana) are one of the most widely cultivated bulbous plants with substantial ornamental value. However, the lack of well-documented reference genomes has limited the research progress and molecular breeding of tulips. In the present study, a full-length transcriptome of a commercial tulip cultivar was obtained using single-molecule long-read sequencing (PacBio Iso-Seq). In total, 244,357 full-length transcripts were identified, which had an average length of 2,044 bp and an N50 value of 3,861; 67,350 of these were annotated to databases. An inaugural integrated analysis of the transcriptome and phytohormone profiles during flower opening and petal senescence was performed using Illumina RNA-seq, coupled with Mfuzz (an R pakage, http://mfuzz.sysbiolab.eu ) and weighted gene coexpression network analysis (WGCNA). A total of 16 gene coexpression and six transcription factor (TF) modules were constructed. Additionally, 26 hormone analogs were comprehensively profiled. Finally, a prominently novel gene, Tulipa gesneriana Homeobox12-like (TgHB12-like), which encodes an homeodomain–leucine zipper (HD-zip) TF, was identified as a pivotal regulator of petal senescence. Overall, this work facilitates the identification of hormones and TFs in plants related to flower opening and senescence in tulips. It also provides an important and valuable genetic basis for further research in them.

Abstract Limited information is available on the cardiovascular health (CVH) index and risk of high-normal blood pressure (HNBP) in elderly people. Randomized cluster sampling, multivariate logistic regression, and mediating effects analysis were used in this study analyze the relationship between CVH index and HNBP in the elderly. 1089 non-hypertensive residents aged 65 years or older completed the study. The positive rate of HNBP was 75.85% (male vs. female: 76.13% vs. 75.64%, P = 0.852); The ideal rate of CVH (ideal CVH index ≥ 5 items) was 14.51% (male vs. female: 15.91% vs. 13.46%, P = 0.256). Compared with people with 0–2 ideal CVH index, the risk of HNBP in people with 4 ideal indexes and ≥ 5 ideal indexes decreased by 50% and 63%, respectively, and their OR (95% CI) were 0.50 (0.31, 0.81) and 0.37 (0.21, 0.66), respectively. The results of the trend test showed that the risk of HNBP decreased by 32% for every increase in the ideal CVH index (trend P

The multidirectional forging (MDF) experiments of Mg-Gd-Y-Zn-Zr alloy were performed. The effects of temperature and cumulative strain on microstructure and mechanical properties of multi-directional forged Mg-Gd-Y-Zn-Zr alloy were studied. The results showed that the recrystallization ratio of the alloy gradually increased with the initial forging temperature after 3 passes of MDF. Under the condition of the initial forging temperature of 500 °C, the grain size was gradually refined with increasing MDF passes, and the average grain size was refined to 1.49 μm after 12 MDF passes. With the increase in MDF passes, the maximum texture density of the alloy gradually decreased. The mechanical properties gradually increased with the MDF passes. In the first 6 MDF passes, the mechanical properties greatly increased, but after that, the increase gradually slowed down with additional MDF passes. The optimal mechanical properties were obtained after 12 MDF passes, and the tensile strength, yield strength, and elongation after fracture were 362 MPa, 294 MPa, and 14.5%, respectively.

BackgroundHepatocellular carcinoma (HCC) poses a significant health burden globally, with high mortality rates despite various treatment options. Immunotherapy, particularly immune-checkpoint inhibitors (ICIs), has shown promise, but resistance and metastasis remain major challenges. Understanding the intricacies of the tumor microenvironment (TME) is imperative for optimizing HCC management strategies and enhancing patient prognosis.MethodsThis study employed a comprehensive approach integrating multi-omics approaches, including single-cell RNA sequencing (scRNA-seq), bulk RNA sequencing (Bulk RNA-seq), and validation in clinical samples using spatial transcriptomics (ST) and multiplex immunohistochemistry (mIHC). The analysis aimed to identify key factors influencing the immunosuppressive microenvironment associated with HCC metastasis and immunotherapy resistance.ResultsHMGB2 is significantly upregulated in HCCTrans, a transitional subgroup associated with aggressive metastasis. Furthermore, HMGB2 expression positively correlates with an immunosuppressive microenvironment, particularly evident in exhausted T cells. Notably, HMGB2 expression correlated positively with immunosuppressive markers and poor prognosis in HCC patients across multiple cohorts. ST combined with mIHC validated the spatial expression patterns of HMGB2 within the TME, providing additional evidence of its role in HCC progression and immune evasion.ConclusionHMGB2 emerges as a critical player of HCC progression, metastasis, and immunosuppression. Its elevated expression correlates with aggressive tumor behavior and poor patient outcomes, suggesting its potential as both a therapeutic target and a prognostic indicator in HCC management.

Background The high metastasis rate is one of the main reasons for the poor prognosis of patients with hepatocellular carcinoma (HCC). Coagulation factor Xa (FXa) and its receptor proteinase-activated receptor-2 (PAR-2) proven to promote tumor metastasis in other forms of cancer. Here, we explore the role and mechanism of FXa in the regulation of resistance of anoikis and immune escape of HCC.Methods In vitro and in vivo experiments were conducted to explore the role of FXa in HCC metastasis and its potential mechanism. The effects of FXa inhibitor rivaroxaban on HCC immunotherapy were evaluated using intrahepatic metastasis animal models and clinical trial (No. ChiCTR20000040540). We investigated the potential of FXa inhibition as a treatment for HCC.Results FXa was highly expressed in HCC and promoted metastasis by activating PAR-2. Mechanistically, FXa-activated PAR-2 endows HCC cells with the ability of anoikis resistance to survive in the circulating blood by inhibiting the extrinsic apoptosis pathway. Furthermore, suspension stimulation-induced phosphorylation of STAT2, which promotes programmed death-ligand 1 (PD-L1) transcription and inhibits the antitumor effects of immune cells by inhibiting the infiltration of CD8+T cells in tumors and the levels of secreted cytokines. In vivo inhibition of FXa with rivaroxaban reduced HCC metastasis by decreasing PD-L1 expression and exhausting tumor-infiltrating lymphocytes. Notably, the combination of rivaroxaban and anti-programmed death-1 monoclonal antibody (anti-PD-1) programmed Death-1 monoclonal antibody (anti-PD-1) induced synergistic antitumor effects in animal models. Most importantly, rivaroxaban improved the objective response rate of patients with HCC to immune checkpoint inhibitors and prolonged overall survival time.Conclusions FXa-activated PAR-2 promotes anoikis resistance and immune escape in HCC, suggesting the potential for combining coagulation inhibitors and PD-1/PD-L1 immune checkpoint blockade to enhance the therapeutic efficacy of HCC.