生物学最新文献

Heart failure arises from maladaptive remodelling driven by genetic and epigenetic networks. Using a systems genetics framework, we mapped how DNA variants and CpG methylation shape cardiac transcriptomes during beta adrenergic stress in the Hybrid Mouse Diversity Panel, a cohort of over 100 fully inbred mouse strains. Expression QTLs (eQTLs), methylation QTLs (mQTLs) and methylation-driven eQTLs (emQTLs) were generated from over 13k expressed genes and 200k hypervariable CpGs in left ventricles. We discovered hundreds of regulatory 'hotspots' that control large portions of the genome, including several that regulate over 10% of the transcriptome and/or methylome. Approximately 16% of these hotspots overlapped with prior GWAS or EWAS signals. We focus on a hotspot on chromosome 12 and identify the serpine peptidase inhibitor Serpina3n, as the most likely driver gene in this hotspot. Experimental knockdown of Serpina3n in neonatal rat ventricular cardiomyocytes blunted hypertrophy induced by a variety of hypertrophic signals, while altering predicted target expression and modulating the activity of Nppa and Nppb. Together, these findings position Serpina3n as a major regulator of stress-responsive cardiac gene programs, highlighting how integration of genetic and epigenetic signals can pinpoint key drivers of heart failure.

Actinobacillus pleuropneumoniae causes porcine infectious pleuropneumonia in pigs. We aimed to characterize the phenotypic and genomic features of three A. pleuropneumoniae strains from clinical cases in eastern Chinese provinces. The serovar 5 strain ZJNH2023 was more pathogenic than strains AH2020 and ZJXS2022 in a murine model and was resistant to multiple antimicrobials. The core genome SNP (single nucleotide polymorphism) tree indicates that the three isolates are clustered with serovars 5, 8, and 15 strains of archived genomes. They harbor plasmids conferring resistance to florfenicol and are of substantial genome diversity, having more prophages, genomic islands (GIs), and antimicrobial resistance genes (ARGs) than the strains of corresponding serovars from other studies. The capsule-related gene clusters in strains AH2022 and ZJXS2022 are different from ZJNH2023 and contain an ISApl1 family transposase between the cps and cpx loci. The serovar 5 strain ZJNH2023 has a full set of ApxI genes, Apa1/Apa2, intact flp family genes related to Flp pilus assembly, and a full set tadABCD genes related to adherence, while strains ZJXS2022 and AH2022 carry ApxIII gene set, lack ApxIAC genes and Apa1/Apa2, and do not have intact flp family genes. Thus, we conclude that possession of the cytotoxic ApxI gene set and those involved in adhesion contributes to higher pathogenicity of the serovar 5 strain ZJNH2023. Distinct GIs and floR-containing plasmids in these strains might have been involved in multiple resistance and horizontal transfer of ARGs on the pig farms.

Objectives: Rheumatoid arthritis (RA) is characterized by chronic synovitis and progressive joint destruction. Ferroptosis has been implicated in RA pathogenesis through synovial iron accumulation and oxidative stress. Glutathione peroxidase 4 (GPX4) and acyl-CoA synthetase long-chain family member 4 (ACSL4) are key regulators of ferroptosis, but their specific roles in RA remain incompletely defined. The objective of this research was to explore the therapeutic effects and the mechanisms behind emodin (EMO) in RA.

Methods: The therapeutic efficacy and mechanisms of EMO were evaluated in collagen-induced arthritis mice and lipopolysaccharide-stimulated RAW264.7 macrophages. Joint pathology, inflammation, oxidative stress, ferroptosis, and mitochondrial function were analyzed using histology, micro-computed tomography, western blotting, immunohistochemistry, and microscopy. Key targets were identified and validated using molecular dynamics, molecular docking, proteomics, and network pharmacology.

Results: EMO alleviated joint inflammation and bone destruction, reduced pro-inflammatory cytokines and oxidative stress, restored iron and mitochondrial homeostasis, and inhibited ferroptosis. Mechanistically, EMO inhibited ferroptosis through the GPX4/ACSL4 axis, as evidenced by increased GPX4 and decreased ACSL4 expression.

Conclusions: EMO ameliorates experimental arthritis mainly by suppressing ferroptosis via the GPX4/ACSL4 axis, highlighting ferroptosis as a previously underappreciated therapeutic target in RA and supporting EMO as a potential adjunctive treatment for RA.

Hepatitis B transmission is influenced by environmental variability, immune response and vaccination, making its spread inherently stochastic, while the integration of stochastic modeling with machine learning is particularly important for representing disease uncertainty in varied surroundings. We present a hybrid innovative framework that combines a stochastic epidemiological model with a feed-forward neural network to study hepatitis B virus (HBV) dynamics. We show the well-posedness by establishing the existence of solutions with uniqueness, and analyze extinction and persistence of the disease. In addition, a supervised approach of feed-forward neural network (FFNN) having two hidden layers, each consist of 20 neurons will be used to effectively approximate the dynamics of the model. To evaluate robustness of the network while handling the stochastic model, we evaluate the performance by regression and mean squared error (MSE), and to show a strong alliance among the stochastic trajectories and predicted simulations obtained by the neural network.

In this paper, we introduce a mathematical simulation that captures the dynamics of lumpy skin disease (LSD) by considering three key transmission paths: vector-borne, direct cattle-to-cattle contact and environmental contamination. Additionally, this model incorporates three control measures, including vector control, environmental management and isolation/treatment of infected cattle. We perform a comprehensive mathematical analysis to demonstrate the model well-posedness, like proving the existence, uniqueness, positivity and boundedness of the solution. The basic reproduction number ($R_0$) is calculated. The local and global stability analysis is presented for the disease-free and endemic equilibrium points. Sensitivity analysis for the model parameters is shown, which reveals that isolation and treatment control measures are the most effective in eliminating disease transmission. We construct an objective function to formulate an optimal control problem (OCP) and derive the optimality necessary conditions. Numerical simulations confirm the theoretical findings, demonstrating that strategic implementation of combined control measures can efficiently suppress LSD.

Fetal repair of spina bifida aperta (fSBA) is an established intervention that improves neurological and neurodevelopmental outcomes. The present exploratory study examines whether molecular signatures related to stress regulation are detectable in newborns following this procedure. Specifically, we investigated DNA methylation and gene expression of two stress-regulatory genes, NR3C1 and FKBP5. Within a clinical trial (ID: NCT04027374), we analyzed postpartum saliva samples from newborns who had undergone fSBA repair (fSBA group; n = 30) and compared them with two control groups: newborns exposed to antenatal glucocorticoids for lung maturation (LMI group; n = 12) and healthy controls (HC group; n = 27). Pyrosequencing and qRT-PCR were used for epigenetic and transcriptional analyses. Significant group differences were observed in FKBP5 methylation, particularly at intron 7 CpG sites 5-7. The fSBA group showed lower methylation at site 5 but higher methylation at sites 6-7 compared to controls. No significant methylation differences were detected for NR3C1. Conversely, NR3C1 gene expression was elevated in the fSBA group, whereas FKBP5 expression did not differ between groups. These findings suggest gene- and site-specific molecular variation in newborns following fetal surgery. Given the exploratory nature of the study, the results are not suited to draw specific clinical implications but may inform future work aimed at understanding stress-related molecular alterations surrounding fetal interventions. Larger and longitudinal studies are warranted to clarify the robustness, developmental course, and potential clinical relevance of these molecular patterns.

Human T-lymphotropic virus (HTLV) and human immunodeficiency virus (HIV) are two retroviruses that pose a certain threat to human psychology and physiology. In this paper, we propose a diffusive HTLV and HIV coinfection model with macrophages, two delays, cell-to-cell transmission and three latently infected cells in which latent HIV infected CD4${}^{+}$T cells, latent HIV infected macrophages, and latent HTLV infected CD4${}^{+}$T cells are considered. Four reproduction number and four equilibria, namely, infection-free equilibrium, HIV infection equilibrium, HTLV infection equilibrium and HTLV and HIV coinfection equilibrium, are calculated and proved the global asymptotic stability of the coinfection model. Numerical simulations are executed to showcase the corresponding theoretical outcomes and uncover how macrophages and latently infected cells influence the dynamics of HTLV and HIV coinfection.

Pancreatic adenocarcinoma (PAAD) is a highly aggressive malignant tumor of the gastrointestinal tract. Goosecoid (GSC), translated from a homeobox gene, is a protein participating in metastasis of assorted tumors. This study explores the role of GSC implicated in tumor metastasis, in PAAD progression. GSC expression in PAAD tissues and cells were tested by quantitative polymerase chain reaction (PCR) and western blot. GSC mRNA and protein expressions were elevated in PAAD tissues and cells. The impacts of GSC depletion or upregulation on PAAD cell proliferation, migration, invasion, cell cycle, and apoptosis were determined by colony formation assay, transwell assay, and flow cytometry. E-cadherin and N-cadherin expressions were tested through immunofluorescence to evaluate the epithelial-mesenchymal transition (EMT) process. The results showed that GSC depletion notably restrained cell proliferative and migratory capabilities and cell cycle, declined MMP2 and MMP9 activity, suppressed EMT process, and enhanced cell apoptosis. Nevertheless, GSC overexpression showed the opposite functions. Stem cell markers CD44 and CD133 were suppressed by GSC depletion and enhanced by GSC overexpression. Additionally, a sphere formation assay was implemented to test cell stemness. The levels of key proteins on TGF-β signaling were tested by western blot. GSC could activate TGF-β signaling in cells by promoting SMAD2/3 phosphorylation. The pathway inhibitor SIS3 notably counteracted the functions on cell malignant phenotypes induced by GSC overexpression. Moreover, xenograft tumor-bearing mouse models were established using male BALB/c nude mice to explore the effects of GSC knockdown on tumor growth and metastasis in vivo, and we found that GSC knockdown inhibited PAAD tumor growth and metastasis in xenograft models. GSC is expressed at a high level in PAAD and can facilitate PAAD metastasis by enhancing EMT and stemness via regulating TGF-β/SMAD2/3 signaling.

Glioblastoma multiforme (GBM) is the most common form of malignant brain cancer and is generally approached with palliative intent. Preclinical studies suggest that short-term fasting may be an effective tool for enhancing existing cancer therapies by disrupting the glucose-dependent, oncogenic phenotype of many cancers. In this study, we investigated whether a fasting-mimicking environment (FME) enhances the efficacy of an emerging proapoptotic drug, procaspase-activating compound 1 (PAC-1), in 2D and 3D GBM cell models. Ad libitum food consumption (Fed) and FME conditions were simulated in vitro by modifying glucose, ketone and serum concentrations. The FME conditions enhanced PAC-1 in U87-MG, T98G and 9L-GS monolayer experiments by significantly reducing the PAC-1 50% inhibitory concentration (IC₅₀), delaying cell growth and increasing apoptosis. Similarly, in the 3D spheroid models, the minimum concentration of PAC-1 required to reduce U87-MG and 9L-GS spheroid area was lower in the FME conditions than the Fed conditions. Additionally, we discovered that serum restriction was primarily responsible for the FME-induced PAC-1 enhancement. These finding are the first to demonstrate that fasting-mimicking conditions sensitize 2D and 3D glioma cell models to PAC-1, supporting the use of short-term fasting as a low-cost and widely accessible strategy for enhancing cancer therapies.

The tumor suppressor p53 protects genomic integrity in part by regulating transposable elements (TEs). Studies of p53-TE interactions rely on synthetic DNA and reporter assays, estimating expression only at the family or subfamily level and lacking locus-specific resolution. To address this limitation, we developed a computational pipeline for ChIP-seq and RNA-seq analysis that employs advanced algorithms to accurately assign short reads mapping to multiple genomic locations. This approach enables precise quantification of TE transcripts at the locus level. By integrating p53 ChIP peaks with differentially expressed TE transcripts, we performed a global analysis of TE expression upon p53 binding. Applying this framework to lung fibroblast IMR90 and colon cancer HCT116 cells treated with p53 activators, we observed a striking pattern: TEs were predominantly activated in normal IMR90 cells but repressed in HCT116 cancer cells. Further analysis of 24 transcriptomes and 10 cistromes confirmed this trend as a distinguishing hallmark between normal and cancer cells. At the family level, normal cells showed broad TE upregulation, whereas cancer cells exhibited selective repression of Alu and LINE elements. These findings provide the first comprehensive, locus-specific view of TE expression associated with p53 binding, implicating a potential role of chromatin context in TE regulation.