Search Results (770)

Rational design of capripoxvirus-based vaccine vectors can be achieved by knockout of immunomodulatory genes. In this study, the effect of knockout of the immunomodulatory genes LSDV005, LSDV008 and LSDV066 on the replication of Lumpy skin disease virus in cell cultures and the immune response to an integrated foreign antigen were assessed. The knockout of genes was performed by homologous recombination under conditions of temporary dominant selection. It was found that single knockout of the LSDV005 gene and the LSDV008 gene did not affect the replicative activity of recombinant viruses in vitro (Atyrau-5 and Atyrau-B). Both single knockout of the LSDV066 gene and in combination with knockout of LSDV005 or LSDV008 led to a decrease in the replicative activity of recombinant LSDVs. The recombinant Atyrau-5J(IL18) with LSDV005 gene knockout induced production of antibodies to the integrated antigen in mice. Prime-boost vaccination with all studied recombinants increased the level of interferon-γ. In addition, during immunization with the recombinant Atyrau-5J(IL18) secretion of interleukin-2 was significantly increased. The study of the functions of immunomodulatory genes and their effect on the expression of inserted sequences of foreign antigens is promising for the creation of highly effective polyvalent vector vaccines for animals. Full article

The development of anticancer peptides (ACPs) has emerged as a promising strategy in targeted cancer therapy due to their high specificity and therapeutic potential. Cathelicidin-derived antimicrobial peptides represent a particularly attractive class of ACPs, yet systematic evaluation of their anticancer activity remains limited. In this study, we conducted virtual screening of eight cathelicidin-derived peptides (AL-38, LL-37, RK-31, KS-30, KR-20, FK-16, FK-13, and KR-12) to assess their potential against colon cancer. Among these, LL-37 and FK-16 were identified as the most promising candidates, with LL-37 exhibiting the strongest inhibitory effects on both non-metastatic (HT-29) and metastatic (SW-620) colon cancer cell lines in vitro. To overcome challenges associated with peptide stability and delivery, we employed the probiotic lactic acid bacterium Limosilactobacillus fermentum KUB-D18 as both a biosynthetic platform and delivery vehicle. A genome-scale metabolic model (GEM), iTM505, was reconstructed to predict the strain’s biosynthetic capacity for ACP production. Model simulations identified trehalose, sucrose, maltose, and cellobiose as optimal carbon sources supporting both high peptide yield and biomass accumulation, which was subsequently confirmed experimentally. Notably, L. fermentum expressing LL-37 achieved a growth rate of 2.16 gDW/L, closely matching the model prediction of 1.93 gDW/L (accuracy 89.69%), while the measured LL-37 concentration (26.96 ± 0.08 µM) aligned with predictions at 90.65% accuracy. The strong concordance between in silico predictions and experimental outcomes underscore the utility of GEM-guided metabolic engineering for optimizing peptide biosynthesis. This integrative approach—combining virtual screening, genome-scale modeling, and experimental validation—provides a robust framework for accelerating ACP discovery. Moreover, our findings highlight the potential of probiotic-based systems as effective delivery platforms for anticancer peptides, offering new avenues for the rational design and production of peptide therapeutics. Full article

In this paper, we investigate the generalized coupled Zakharov system (GCZS), a fundamental model in plasma physics that describes the nonlinear interaction between high-frequency Langmuir waves and low-frequency ion-acoustic waves, including the influence of magnetic fields on weak ion-acoustic wave propagation. This research aims to achieve three main objectives. First, we uncover soliton solutions of the coupled system in hyperbolic, trigonometric, and rational forms, both in single and combined expressions. These results are obtained using the extended rational sinh-Gordon expansion method and the $\left({\displaystyle \frac{G^{\prime }}{G}},{\displaystyle \frac{1}{G}}\right)$-expansion method. Second, we analyze the dynamic characteristics of the model by performing bifurcation and sensitivity analyses and identifying the corresponding Hamiltonian function. To understand the mechanisms of intricate physical phenomena and dynamical processes, we plot 2D, 3D, and contour diagrams for appropriate parameter values. We also analyze the bifurcation of phase portraits of the ordinary differential equations corresponding to the investigated partial differential equation. The novelty of this study lies in the fact that the proposed model has not been previously explored using these advanced methods and comprehensive dynamical analyses. Full article

Introduced species of trees and shrubs used in landscaping of cities in the steppe zone are exposed to the combined negative impact of the ever-increasing load of various anthropogenic factors and unfavorable zonal natural and climatic conditions. In this regard, the assessment of the degree of plant resistance to unfavorable factors in the urban ecosystems of the steppe zone is a necessary condition for rationalizing the selection of the assortment and improving the condition of green spaces. This paper presents the results of the analysis of the vital state of 5509 representatives of 78 introduced species of trees and shrubs growing along the road and transport network in the territory with increased anthropogenic pressure. The age structure of plantings, as well as a number of biological and ecological characteristics of the species composition, are analyzed. The variation in the level of vitality in groups united by individual characteristics—taxonomic affiliation, geographical origin, morphobiological characteristics (habitus), growth rate and age of plants—is shown, and groups with the highest level of vitality are identified. As a result, a number of criteria are selected that can serve as indirect markers of plant adaptability to the ecological conditions of steppe zone cities when forming an assortment for landscaping. Using the examples of the features “plant height” and “plant age”, the species-specific reaction of plants is shown, expressed in the limitation of growth and development, as well as the reduction of life expectancy under conditions of increased anthropogenic and climatic loads. The data obtained can be used to adjust the species composition of urban trees and shrubs, optimize their ratio and spatial and functional placement, and thereby optimize the operational characteristics of green spaces and increase the duration of their use. Full article

In the digital context, how to achieve symmetrical integration between subjective evaluation and structural stability becomes the key to improving the design effect of iterative product optimization. In this paper, we propose an iterative design method for CIHFS-DEMATEL products that incorporates structural symmetry analysis. The method is based on online review mining and constructs a credibility-based interval hesitant fuzzy set (CIHFS) to symmetrically express the ambiguity and credibility differences in the decision-maker’s subjective evaluation. In turn, a novel exact score function called credibility interval hesitant fuzzy score function (CHFSF), incorporating information symmetric weights, is proposed to realize the bidirectional symmetric mapping between subjective fuzzy inputs and objective exact outputs. Subsequently, the CIHFS-DEMATEL model is introduced to identify the causal paths and a symmetric interaction structure between potential users’ demands. Finally, the demand module mapping matrix is constructed to realize the symmetric decision-making closure loop from demand to solution. Taking the “Intelligent Classified Trash Can” as a case study, we verify the superiority of the method in terms of recognition accuracy, rationality of weight allocation, and structural stability. This study emphasizes the structural symmetry between “input–evaluation–output”, which provides a theoretical foundation and practical framework for the optimal design of products with complex multi-source information. Full article

Piscine orthoreovirus (PRV) is a globally distributed viral pathogen that causes heart and skeletal muscle inflammation (HSMI) in Atlantic salmon (Salmo salar) and affects other salmonids, yet no commercial vaccines are currently available. Major barriers to vaccine development include the inability to propagate PRV in cell lines and the low, variable immunogenicity of its proteins, particularly the outer capsid protein σ1, which mediates viral attachment. This protein is hypothesized to be immunologically relevant due to its homology with Mammalian orthoreoviruses. Recombinant σ1 expressed in conventional systems exhibits poor antibody recognition, whereas structural modifications such as lipidation or fusion with molecular chaperones improve epitope exposure. Formalin-inactivated vaccines have shown inconsistent protection, often failing to elicit robust innate or adaptive responses, especially under cohabitation challenge. In contrast, DNA vaccines encoding σ1 and the non-structural protein μNS have demonstrated partial efficacy, likely due to enhanced intracellular expression and antigen presentation. Nonetheless, the considerable variability observed in immune responses among individual fish and viral genotypes, together with suggestions that PRV may interfere with antiviral pathways, represent additional barriers to achieving consistent vaccine efficacy. This review summarizes the current status of PRV vaccine development and discusses future directions for rational design based on optimized antigens and intracellular delivery platforms. Full article

Background: Most immunologically “cold” tumors do not respond durably to checkpoint blockade because tumor antigen (TA) release and presentation are insufficient to prime effective T-cell immunity. While prior work demonstrated synergy between cisplatin and a TLR7/8/9 agonist (CR108) in 4T1 tumors, the underlying mechanism—particularly whether chemotherapy functions as a broad antigen-releasing agent enabling TLR-driven immune amplification—remained undefined. Methods: Using murine models of breast (4T1), melanoma (B16-F10), and colorectal cancer (CT26), we tested multiple chemotherapeutic classes combined with CR108. We quantified intratumoral and systemic soluble TAs, antigen presentation and cross-priming by antigen-presenting cells, tumor-infiltrating lymphocytes, and cytokine production by flow cytometry/ICS. T-cell receptor β (TCRβ) repertoire dynamics in tumor-draining lymph nodes were profiled to assess amplitude and breadth. Tumor microenvironment remodeling was analyzed, and public datasets (e.g., TCGA basal-like breast cancer) were interrogated for expression of genes linked to TA generation/processing and peptide loading. Results: Using cisplatin + CR108 in 4T1 as a benchmark, we demonstrate that diverse chemotherapies—especially platinum agents—broadly increase the repertoire of soluble tumor antigens available for immune recognition. Across regimens, chemotherapy combined with CR108 increased T-cell recognition of candidate TAs and enhanced IFN-γ⁺ CD8⁺ responses, with platinum agents producing the largest expansions in soluble TAs. TCRβ sequencing revealed increased clonal amplitude without loss of repertoire breadth, indicating focused yet diverse antitumor T-cell expansion. Notably, therapeutic efficacy was not predicted by canonical damage-associated molecular pattern (DAMP) signatures but instead correlated with antigen availability and processing capacity. In human basal-like breast cancer, higher expression of genes involved in TA generation and antigen processing/presentation correlated with improved survival. Conclusions: Our findings establish an antigen-centric mechanism underlying chemo–TLR agonist synergy: chemotherapy liberates a broadened repertoire of tumor antigens, which CR108 then leverages via innate immune activation to drive potent, T-cell-mediated antitumor immunity. This framework for rational selection of chemotherapy partners for TLR7/8/9 agonism and support clinical evaluation to convert “cold” tumors into immunologically responsive disease. Full article

Introduction/Background: Rift Valley fever virus (RVFV) and peste des petits ruminants virus (PPRV) are significant pathogens affecting small ruminants, causing substantial economic losses in the affected regions. The development of effective vaccines against both viruses is crucial for disease control. Recombinant viruses expressing heterologous antigens have shown promise as multivalent vaccine candidates. Unlike conventional PPRV vaccines, our recombinant RVFV-vectored vaccines offer a novel dual-protection strategy against RVF and PPR, combining safety, immunogenicity, and a DIVA strategy. Methods: Recombinant RVFVs (ZH548 strain) were generated to express either the hemagglutinin (H) or fusion (F) proteins from the PPRV strain Nigeria 75/1. The stability of these recombinant viruses was assessed through consecutive passages in cell culture. Immunogenicity studies were carried out in both mice and sheep to assess the induction of cellular and humoral immune responses capable of providing protection against RVFV and PPRV. These studies included intracellular cytokine staining (ICS), IFN-γ ELISAs, standard ELISAs for antibody detection, and virus neutralization assays. Results: The recombinant RVFVs expressing PPRV H or F proteins demonstrated stability in cell culture, maintaining high viral titers and consistent transgene expression over four passages. Immunization of mice resulted in the production of serum antibodies capable of neutralizing both RVFV and PPRV in vitro as well as cell-mediated immune responses specific to PPRV and RVFV antigens. In mice vaccinated with a high dose (10⁵ pfu), RVFV neutralizing titers reached ≥1:160 and PPRV neutralizing titers ranged from 1:40 to 1:80 by day 30 post-immunization. In sheep, neutralizing antibody titers against RVFV exceeded 1:160 as early as 2 days post-inoculation, while PPRV-specific neutralization titers reached up to 1:80 by day 21 in responsive individuals. In mice, administration of rZH548ΔNSs:F_PPRV elicited a detectable CD8+ IFNγ+ T-cell response against PPRV, with levels ranging from 1.29% to 1.56% for the low and high doses, respectively. In sheep, rZH548ΔNSs:F_PPRV also induced a robust IFNγ production against PPRV at 14 and 21 days post-infection (dpi). Conclusions: The successful generation and characterization of recombinant RVFVs expressing PPRV antigens demonstrate the potential of using rationally attenuated RVFV as a vector for multivalent vaccine development. Notably, the strategy proved more effective for the recombinant virus expressing the F protein, as it consistently induced more robust cellular and humoral immune responses. These results suggest that this approach could be a viable strategy for simultaneous immunization against Rift Valley fever and other prevalent ruminant diseases, such as peste des petits ruminants. Even though challenge studies were not performed in target species, the strong immune response observed supports including them in future studies. Full article

Background: Given the increasing problem of antibiotic resistance in A. baumannii, this study examines in vitro how combinations of colistin, meropenem, and sulbactam influence the expression of genes associated with multiresistance in this pathogen. Methods: Three multidrug-resistant strains, isolated from clinical infections in Panama (2022–2023), were identified using Vitek 2 compact. Susceptibility by broth microdilution, qualitative synergy, time-kill curves, and gene expression analysis by quantitative PCR were performed. Results: Synergistic effects were observed for the colistin–meropenem combination in all three strains, while the sulbactam–colistin combination exhibit synergy only in one of the A. baumannii isolates. Time-kill assays revealed bactericidal effects for the colistin–meropenem and sulbactam–colistin combinations. qPCR analyses indicated that colistin, meropenem, and sulbactam modified the expression of the genes under study. Colistin–meropenem and meropenem–sulbactam combinations decreased the expression of blaADC and blaOXA-51, while sulbactam–colistin did not have a significant effect. carO expression levels were not reduced with any antibiotic combination, while adeB expression was reduced with all the combinations tested. omp33–36 expression varied depending on the antibiotic and strain. Conclusions: Therefore, this study offers a new perspective on how rational combinations of clinically used antibiotics have the potential to modulate gene expression and contribute to the control of MDR strains, indicating that high-dose combination therapy with sulbactam and colistin could offer improved efficacy in treating multidrug resistant Acinetobacter baumannii infections. Full article

Background/Objectives: Neuroblastoma (NB) is an aggressive pediatric malignancy that accounts for nearly 15% of all childhood cancer-related deaths, with high-risk cases showing a poor 20% prognosis and limited response to current therapies. Survivin, encoded by the BIRC5 gene, is an anti-apoptotic protein frequently overexpressed in NB and linked to treatment resistance and unfavorable clinical outcomes. Methods and Results: An analysis of 1235 NB patient datasets revealed a significant association between elevated BIRC5 expression and reduced overall and event-free survival, highlighting survivin as an important therapeutic target in NB. To explore this strategy, we evaluated the efficacy of YM-155, a small-molecule survivin inhibitor, across multiple NB cell lines. YM-155 displayed potent cytotoxic activity in six NB cell lines with IC₅₀ values ranging from 8 to 212 nM and significantly inhibited colony formation and 3D spheroid growth in a dose-dependent manner. Mechanistic analyses revealed that YM-155 downregulated survivin at both mRNA and protein levels, induced apoptosis by about 2–7-fold, and caused G0/G1 phase cell cycle arrest. Moreover, YM-155 treatment enhanced p53 expression, suggesting reactivation of tumor suppressor pathways. Notably, combining YM-155 and the chemotherapeutic agent etoposide resulted in synergistic inhibition of NB growth with ED75 values ranging from 0.17 to 1, compared to either agent alone. In the xenograft mouse model, YM-155 inhibited tumor burden in contrast to controls by about 3-fold, and without any notable toxic effects in vivo. Conclusion: Overall, our findings identify YM-155 as a promising therapeutic agent for high-risk NB by directly targeting survivin and enhancing chemosensitivity. These results support continued preclinical development of survivin inhibitors as part of rational combination strategies in pediatric cancer treatment. Full article

Neural networks have become a fundamental tool for solving complex problems, from image processing and speech recognition to time series prediction and large-scale data classification. However, traditional neural architectures suffer from interpretability problems due to their opaque representations and lack of explicit interaction between linear and nonlinear transformations. To address these limitations, Kolmogorov–Arnold Networks (KAN) have emerged as a mathematically grounded approach capable of efficiently representing complex nonlinear functions. Based on the principles established by Kolmogorov and Arnold, KAN offer an alternative to traditional architectures, mitigating issues such as overfitting and lack of interpretability. Despite their solid theoretical basis, practical implementations of KAN face challenges, such as optimal function selection and computational efficiency. This paper provides a systematic review that goes beyond previous surveys by consolidating the diverse structural variants of KAN (e.g., Wavelet-KAN, Rational-KAN, MonoKAN, Physics-KAN, Linear Spline KAN, and Orthogonal Polynomial KAN) into a unified framework. In addition, we emphasize their mathematical foundations, compare their advantages and limitations, and discuss their applicability across domains. From this review, three main conclusions can be drawn: (i) spline-based KAN remain the most widely used due to their stability and simplicity, (ii) rational and wavelet-based variants provide greater expressivity but introduce numerical challenges, and (iii) emerging approaches such as Physics-KAN and automatic basis selection open promising directions for scalability and interpretability. These insights provide a benchmark for future research and practical implementations of KAN. Full article

The performance of unsupervised stereo matching in complex regions such as weak textures and occlusions is constrained by the inherently local receptive fields of convolutional neural networks (CNNs), the absence of geometric priors, and the limited expressiveness of MLP in conventional ViTs. To address these problems, we propose an Adaptive Geometry-aware Stereo-KANformer Network (AGSK-Net) for unsupervised stereo matching. Firstly, to resolve the conflict between the isotropic nature of traditional ViT and the epipolar geometry priors in stereo matching, we propose Adaptive Geometry-aware Multi-head Self-Attention (AG-MSA), which embeds epipolar priors via an adaptive hybrid structure of geometric modulation and penalty, enabling geometry-aware global context modeling. Secondly, we design Spatial Group-Rational KAN (SGR-KAN), which integrates the nonlinear capability of rational functions with the spatial awareness of deep convolutions, replacing the MLP with flexible, learnable rational functions to enhance the nonlinear expression ability of complex regions. Finally, we propose a Dynamic Candidate Gated Fusion (DCGF) module that employs dynamic dual-candidate states and spatially aware pre-enhancement to adaptively fuse global and local features across scales. Experiments demonstrate that AGSK-Net achieves state-of-the-art accuracy and generalizability on Scene Flow, KITTI 2012/2015, and Middlebury 2021. Full article

Methylation reactions catalyzed by S-adenosylmethionine (SAM)-dependent methyltransferases are essential to numerous biological functions, including gene expression regulation, epigenetic modifications, and biosynthesis of natural products. Dysregulation of these enzymes is associated with diseases, including cancer and neurodevelopmental disorders, making them attractive drug targets. This review explores the contribution of computational methods, particularly quantum chemical calculations and molecular dynamics (MD) simulations, in elucidating the mechanisms of SAM-dependent methyltransferases. These techniques enable detailed characterization of transition states and reaction pathways, often inaccessible by experimental methods. The review discusses molecular modeling approaches such as the quantum chemical cluster approach (QM-cluster) and hybrid QM/MM methods, emphasizing their applications in studying methyl group transfer, substrate specificity, and the roles of water molecules and metal ions in catalysis. Additionally, dynamic aspects of enzyme function are addressed using classical MD and QM/MM MD simulations. Case studies demonstrate how computational predictions align with experimental data and enable rational design of selective inhibitors and engineered enzymes with altered specificity. Overall, computational chemistry offers a powerful, atomistic view of SAM-dependent methyltransferases, not only complementing experimental studies but also providing a foundation for the design of future experiments in this field. Full article

The complex condition of an adjacent tunnel in urban city includes high water content, limited construction space, and the presence of an adjacent tunnel. To address these challenges, the artificial ground freezing method is employed to ensure construction safety and stability. Considering the complex problem of temperature field interaction in the freezing construction process of adjacent tunnels, for the first time, this paper proposes a generalized analytical solution for two-dimensional steady-state temperature fields suitable for the annular double-loop freezing system of adjacent tunnels. Based on the polar coordinate heat conduction control equation and the conformal transformation method, the complex geometric arrangement is mapped into a linear system that can be solved, and the analytical solution expression is constructed by combining the heat source superposition principle. In this paper, a numerical model of the adjacent tunnel annular double-loop freezing pipe is established through COMSOL Multiphysics 6.2 software. At the same time, the formula of the analytical method is programmed and solved using Python 3.12, and finally the temperature fields obtained by the two methods are compared. The results show that the analytical solution has good consistency in isotherm distribution, temperature field trend and characterization of frozen core area, which verifies the theoretical rationality and practicability of the constructed model. Full article

Background/Objectives: Extended-spectrum β-lactamase (ESBL)-producing Escherichia coli poses a significant global health challenge, as it leads to antimicrobial treatment failure and is associated with elevated mortality rates. The use of β-lactam/β-lactamase inhibitor combinations offers an alternative approach for combating ESBL-producing bacteria. Ceftriaxone (CRO) and sulbactam have been coadministered in the clinical settings; however, discrepancies in their pharmacokinetics raise concerns regarding the rationality of this combination. Methods: This study was designed to investigate the postβ-lactamase inhibitor effect (PLIE) under both static and dynamic conditions, with the aim of supporting the clinical application of this combination. Results: The minimum inhibitory concentration (MIC) of CRO/SBT (2:1 ratio) against E. coli NCTC 13353 was determined to be 32/16 μg/mL. The PLIEs were determined to be −1.26, −0.57, and 0.37 h at CRO/SBT concentrations ranging from 1/2 MIC to 2 MIC, respectively. The results of CRO concentration, β-lactamase activity, bla_CTX-M-15 expression, and cell morphology collectively support that SBT exerts PLIEs and protects against the antibacterial activity of CRO. In the dynamic hollow-fiber infection model, CRO monotherapy showed no inhibitory effect on E. coli, whereas CRO/SBT combination therapy rapidly eliminated SBT, achieved comparable bactericidal effects, prolonged CRO exposure, and maintained low β-lactamase activity levels. Conclusions: In conclusion, CRO/SBT exerts an inhibitory effect on enzyme-producing strains by being able to produce PLIE to maintain the inhibition of β-lactamase. Full article