Search Results (1,477)

Population immune pressure from vaccination and prior infection continues to drive the evolution of SARS-CoV-2. Systematic characterization of RBD mutations under complex immune backgrounds is essential for understanding viral adaptation and evolutionary trajectories. Here, we applied a deep mutational scanning (DMS) to comprehensively map the neutralization escape landscape of the Omicron variant JN.1 and its descendant lineage XEC, under immune pressure from individuals who experienced Omicron breakthrough infections following three doses of inactivated vaccines. A neutralization escape map for the single amino acid substitutions in the RBD of JN.1 or XEC was generated, and the escape efficiency of each mutation was determined. The results show that RBD escape mutations are hierarchically organized: low-intensity signals are widespread, whereas high-intensity escape is confined to a few key sites. These escape mutations are not confined solely to the receptor-binding motif (RBM) but are broadly distributed across the entire RBD. Many escape sites could accommodate multiple amino acid substitutions. Integration of DMS data with genomic surveillance of circulating variants from 2024 to 2025 revealed significant overlap between experimentally identified escape sites and mutations observed in natural isolates. This overlap increased substantially in 2025, with site concordance rising from 27.17% and 26.81% to 45.09% and 47.10% for JN.1 and XEC, respectively. The natural prevalence of these escape mutations is further shaped by factors such as receptor-binding affinity, protein stability, and epistatic interactions. Overall, our findings suggest that SARS-CoV-2 antigenic evolution follows the pattern of multiple pathways within a constrained space, providing new insights into the adaptive mechanisms of Omicron-derived variants under hybrid immune pressure. Full article

Cancer cachexia is a multifactorial systemic syndrome characterized by progressive muscle loss, with or without adipose tissue depletion, that cannot be reversed by conventional nutritional support. It affects cancer patients and is associated with reduced treatment tolerance, impaired physical function, poor quality of life, and increased mortality. The understanding of cachexia has evolved recently, from the perception of a simple nutritional disorder to a complex immune–metabolic syndrome, based on tumor–host interactions, systemic inflammation, metabolic dysregulation, and multi-organ dysfunction. This review summarizes the progression of cachexia research, highlighting key findings involving inflammatory cytokines, proteolytic pathways, mitochondrial dysfunction, and immune dysregulation. The development of therapeutic strategies is examined, from early nutritional and appetite-stimulating interventions to contemporary targeted therapies, including ghrelin receptor agonists, cytokine inhibitors, and anabolic agents. Despite advances in mechanistic understanding, numerous trials targeting single pathways have failed to produce meaningful functional or survival benefits, underscoring the limitations of reductionist approaches. Emerging evidence supports a paradigm shift toward multimodal, biomarker-guided, and patient-centered interventions that address the interconnected biological mechanisms underlying cachexia. Particular emphasis is given to novel immunomodulatory strategies, including agents such as R-ketorolac, which may restore immune homeostasis and target the root causes of cachexia. It is hypothesized that future therapeutic success will likely depend on integrated approaches combining immunological, metabolic, nutritional, and rehabilitative interventions. Full article

Interleukin-1 receptor-associated kinase 4 (IRAK4) is one of the IRAK family proteins and plays an important role in the regulation of innate and inflammatory responses. In particular, IRAK4 acts as a key regulator of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways and has attracted attention as a therapeutic target for immune and inflammatory diseases. In this study, an integrated computational approach combining machine learning, molecular docking, and molecular dynamics simulations was applied to identify putative IRAK4 inhibitor candidates. Bioactivity data of IRAK4 were obtained from the ChEMBL and PubChem databases and evaluated for multiple binary classification models. The optimized XGBoost model based on ECFP4 and PubChem fingerprints achieved an ROC-AUC of 0.996 and an average precision (AP) of 0.991 on the independent test set. After that, 20 candidate compounds with high predictive probability score were finally selected through subsequent screening of the DrugBank database. Among them, DB12168 (MK-0557), DB15040 (TP-271), and DB18152 (Zilurgisertib) exhibited favorable binding free energies and stable complex formation with IRAK4 through molecular dynamics simulations and MM-PBSA calculations. Overall, these results demonstrate that approaches incorporating machine learning and structure-based computational analysis can be useful for discovering and prioritizing potential IRAK4 inhibitor candidates. Full article

Alternative pre-mRNA splicing is a central layer of gene regulation that enables a limited number of genes to generate a far larger and more context-dependent transcriptome and proteome. In cancer, splicing is disrupted by mutations in cis-regulatory sequences, recurrent lesions in spliceosome components, altered abundance or activity of RNA-binding proteins, and changes in transcription, chromatin, RNA modification, metabolism and stress signalling. These alterations are not merely by-products of malignant transformation. They can create oncogenic protein isoforms, eliminate tumour-suppressive products, remodel cellular identity, promote metastasis and drug resistance, and generate tumour-restricted peptides that are visible to the immune system. Large pan-cancer datasets, long-read sequencing, single-cell isoform profiling, proteogenomics and functional perturbation screens are now resolving this complexity at unprecedented scale. In parallel, multiple therapeutic strategies are advancing, including modulators of the SF3B complex, molecular glues that degrade RBM39, inhibitors of protein arginine methyltransferases and splicing kinases, splice-switching oligonucleotides, programmable RNA-targeting systems, and vaccines or T-cell receptors directed against splicing-derived neoantigens. This review integrates the molecular logic of splice-site selection with the cancer-specific mechanisms that perturb it, summarizes representative isoform switches across the hallmarks of cancer, evaluates emerging technologies and clinical biomarkers, and discusses the opportunities and constraints of translating splicing biology into precision oncology. Particular emphasis is placed on tumour specificity, intratumoural heterogeneity, proteomic validation, therapeutic windows and rational combination strategies. Full article

As a major fungal pathogen of Brassica napus, Sclerotinia sclerotiorum causes significant yield reductions worldwide. Receptor-like proteins (RLPs) are essential components of plant immunity, but the functions of many RLPs in B. napus still remain unclear. In this study, three BnaSOBIR1-interacting leucine-rich repeat RLPs (LRR-RLPs), named BnaRLP-G13-2, BnaRLP-G13-3, and BnaRLP-G13-4, were identified by yeast two-hybrid (Y2H) and bimolecular fluorescence complementation (BiFC) assays. Promoter analysis revealed diverse cis-acting elements involved in stress and phytohormone responses. Overexpression of these genes significantly improved resistance to S. sclerotiorum in both Arabidopsis thaliana and B. napus. Consistently, BnaRLP-G13-2/3/4 restored disease resistance and NLP-induced ROS production in the rlp23-1 mutant. Furthermore, BiFC assays suggested an association between BnaRLP-G13-2/3/4 and Ssnlp24_SsNEP2-associated perception, although direct biochemical binding remains to be demonstrated. These findings advance the understanding of BnaSOBIR1-associated BnaRLP-G13-2/3/4-mediated immunity and provide new insights into enhancing disease resistance in oilseed crops. Full article

Metabolic syndrome (MetS) is a clinical condition defined by the coexistence of interconnected cardiometabolic risk factors, including central obesity, dyslipidemia, elevated blood pressure, and impaired glucose regulation, which collectively increase the risk of type 2 diabetes mellitus and cardiovascular disease. Beyond these clinical diagnostic features, MetS is characterized by complex pathophysiological alterations involving systemic dysregulation of metabolic signaling across adipose tissue, skeletal muscle, liver, vascular endothelium, and the immune system. Key molecular alterations include impaired insulin receptor substrate (IRS)–Akt signaling, chronic nuclear factor kappa B (NF-κB) activation, mitochondrial dysfunction, and oxidative stress. Physical exercise is recognized as a pleiotropic biomedical intervention capable of restoring metabolic homeostasis through coordinated modulation of intracellular signaling pathways and inter-organ communication. Exercise activates AMP-activated protein kinase (AMPK), enhances peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α)-mediated mitochondrial biogenesis, and stimulates nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent antioxidant responses. These adaptations improve glucose uptake, enhance fatty acid oxidation, and reduce ectopic lipid accumulation across metabolically active tissues. At the systemic level, skeletal muscle functions as an endocrine organ by releasing myokines such as irisin, interleukin-6 (IL-6), and fibroblast growth factor 21 (FGF21), which contribute to metabolic regulation across the liver, adipose tissue, and vasculature. These exercise-induced signals promote immune modulation, reduce pro-inflammatory cytokine production, and improve endothelial function. Different exercise modalities including aerobic, resistance, and high-intensity interval training (HIIT) activate both common and modality-specific molecular pathways, supporting individualized exercise strategies. Collectively, exercise targets the multi-organ pathophysiology of MetS and provides a mechanistic foundation for precision exercise medicine in cardiometabolic disease management. Full article

Neurologic manifestations of long COVID, also called neurologic post-acute sequelae of SARS-CoV-2 infection (Neuro-PASC: NP) include persistent alteration of cognitive functions. We investigated whether these could be driven by immune perturbations. We combined flow cytometry (FC), sleep profiling, and single-cell RNA sequencing of peripheral blood immune cells from older adult (>55 years) individuals with and without NP to evaluate relationships with objective cognitive performance. NP participants showed reduced numbers of blood monocytes with increased mitochondrial superoxide, indicating an altered monocyte mitochondrial redox state. Higher peripheral capillary oxygen saturation (SpO₂) was associated with better processing speed in NP participants. Monocyte transcriptional analyses identified mitochondrial adenosine triphosphate (ATP) synthase/Complex V (Complex V) pathway associated with cognitive performance in people without NP; this coupling was abrogated in NP patients, in whom cognitive performance instead showed an opposite relationship with Complex V. Shared leading-edge genes defined a 13-gene monocyte anchor representing this cognition-associated NP phenotype. Higher anchor scores were associated with coordinated oxidative phosphorylation and cytotoxic programs across CD3⁺ T-cell subsets in individuals without NP, but not in NP participants. T-cell receptor stratified analyses showed that this altered relationship occurred in both expanded and unexpanded T-cell populations. FC correlations also supported reduced monocyte-to-lymphocyte mitochondrial coordination in NP. These exploratory findings identify a sleep and cognition-linked monocyte mitochondrial phenotype characterized by altered myeloid–lymphoid immune coordination in NP. Full article

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment landscape of hematologic malignancies but has demonstrated limited efficacy in solid tumors, mainly due to the complex and immunosuppressive tumor microenvironment (TME). Among the strategies to overcome this challenge, targeting the tumor stroma rather than the tumor cells themselves has gained increasing interest. In this context, fibroblast activation protein alpha (FAP), a cell surface protease overexpressed by cancer-associated fibroblasts, represents a promising target. With the aim of remodeling the TME, enhancing immune infiltration, and suppressing tumor growth, numerous FAP-directed CAR T-cell therapies have been developed in the last decade, leading to the clinical translation of two candidates. To improve the flexibility and safety profile of CAR T-cell therapies, several groups have designed more controllable and modular approaches, including adapter CAR T-cell systems, which enable on-demand activation of effector cells through the administration of an adapter molecule. In parallel, the development of FAP-targeted radiotracers, particularly FAP inhibitors (FAPIs), has enabled high-contrast imaging of solid tumors and introduced attractive opportunities for radioligand therapy. The convergence of these advances has given rise to immunotheranostic strategies that integrate CAR T-cell immunotherapy and radioligand delivery within a unified framework. This review traces the evolution of FAP-directed CAR T-cell strategies, from conventional designs to adapter-based and theranostic platforms, and examines how modular adapters bring immunotherapy and radioligand delivery together within a single immunotheranostic framework, across preclinical and clinical settings. Full article

Background/Objectives: Batai orthobunyavirus (BATV) is an emerging mosquito-borne zoonotic pathogen for which no licensed vaccine is currently available. The viral envelope glycoprotein plays an important role in viral attachment and host immune recognition, making it a potential target for rational vaccine design. Methods: In this study, an immunoinformatics-based framework was used to design and evaluate a multi-epitope vaccine candidate targeting the BATV envelope glycoprotein. Selected B-cell, cytotoxic T-lymphocyte (CTL), and helper T-lymphocyte (HTL) epitopes were assembled using appropriate linkers and a human β-defensin adjuvant. Population coverage and in silico immune simulations were conducted to evaluate the potential breadth and magnitude of immune response. Results: The final vaccine construct demonstrated favorable physicochemical characteristics, high predicted antigenicity (0.7959), and non-allergenic properties while maintaining favorable predicted structural characteristics and broad predicted population coverage (99.92%). Structural docking revealed a stable interaction between the vaccine construct and human TLR4, with a weighted docking score of −1194.8, suggesting favorable molecular recognition and receptor engagement. Normal Mode Analysis further supported the structural stability and conformational integrity of the vaccine receptor complex. Immune simulation predicted robust primary and secondary immune responses characterized by elevated IgM and IgG antibody production, sustained memory cell formation, and strong IFN-γ and IL-2 responses, indicating the potential to elicit balanced humoral and cellular immunity. Conclusions: This study presents a structurally optimized and validated multiepitope vaccine candidate against the emerging Batai orthobunyavirus. These computational findings identified a promising vaccine candidate for further investigation; however, its immunogenicity, safety, and protective efficacy before further vaccine development can be considered. Full article

Though a number of Eimeria species have been described in geese, the host responses to these parasites at the molecular level have yet to be explored. In the present study, fresh fecal samples were collected for single-oocyst isolation. The recovered oocysts were identified based on molecular analysis using PCR and sequencing. Subsequently, we examined the transcriptional response of the Landes goose cecum following infection with the isolated Eimeria strain. Molecular analysis showed that the isolated Eimeria strain was Eimeria stigmosa, which was named the E. stigmosa SX-01 strain. Transcriptomic profiling identified 3806 differentially expressed genes (DEGs), including 2238 genes with increased expression and 1568 genes with decreased expression. The results obtained from the quantitative reverse transcription PCR (qRT-PCR) analysis confirmed that the RNA sequencing (RNA-seq) data were reliable. According to pathway enrichment analysis for the obtained DEGs, 24 pathways were significantly affected following infection with the E. stigmosa SX-01 strain, such as cytokine–cytokine receptor interaction, intestinal immune network for IgA production, cell adhesion molecules, gap junction, arachidonic acid metabolism, alpha-Linolenic acid metabolism, retinol metabolism, and PPAR signaling pathway. These transcriptional alterations were observed in E. stigmosa-infected geese without obvious clinical signs, indicating that E. stigmosa infection may trigger a strong subclinical host response related to metabolism, immune and inflammatory responses, and intercellular junctional complex-associated processes. Collectively, these findings have implications for better understanding the E. stigmosa–goose interactions at the molecular level and provide a foundation for future functional and comparative studies to dissect the pathogenic mechanisms and molecular markers associated with disease resistance, which are expected to inform the design of effective control strategies. Full article

Chimeric antigen receptor T-cell therapy and bispecific T-cell engagers have transformed treatment of relapsed and refractory hematologic malignancies, achieving unprecedented response rates. However, their clinical adoption has revealed a complex spectrum of cardiovascular toxicities, differing in frequency and pattern between the two technologies. Manifestations range from common hemodynamic perturbations—hypotension and tachycardia—to severe events, including malignant arrhythmias, left ventricular dysfunction, myocardial infarction, and cardiogenic shock. These complications seem to have different pathophysiological pathways that are yet to be completely understood: on the one hand, they are frequently intertwined with cytokine release syndrome, the hallmark immune complication of T-cell-redirecting therapies, as seen with chimeric antigen receptor T-cell therapy; on the other, a substantial proportion of cardiovascular events—particularly with bispecific T-cell engagers—occur independently of cytokine release syndrome. Proposed cardiotoxic mechanisms include on-target, off-tumor antigen recognition and consequent damage; interleukin-6-driven systemic inflammation; and off-target, off-tumor antigen cross-reactivity. Effective management requires proactive baseline risk stratification, serial cardiac biomarker monitoring, and timely immunosuppressive intervention—primarily tocilizumab—to mitigate cytokine release syndrome-driven injury. Despite rapid clinical expansion, critical gaps remain: long-term cardiovascular outcomes are poorly characterized, validated surveillance protocols are lacking, and cardiovascular endpoints are rarely included in pivotal trials. This narrative review appraises the pathophysiology, clinical spectrum, and management of cardiovascular toxicities associated with these therapies, aiming to define this emerging cardio-oncology frontier, inform multidisciplinary care frameworks and propose a clinical management algorithm. Full article

This study evaluated the effects of dietary supplementation with a commercial lactoferrin–osteopontin complexes preparation (LF-OPN; LF:OPN mass ratio 8:1; 240 mg/kg body weight) on growth, immune indices, antioxidant status, intestinal barrier-related markers, fecal microbiota, short-chain fatty acids (SCFAs), peripheral lymphocyte subsets, and the whole-blood transcriptome of growing British Shorthair kittens. Sixteen kittens were randomly assigned to either a basal diet group (CON) or a group supplemented with LF-OPN complexes (LFT) for 28 days. LF-OPN supplementation did not significantly affect body weight or average daily gain. On D28, the LFT group had a higher serum immunoglobulin M concentration and a lower tumor necrosis factor-α concentration (p < 0.05). Serum superoxide dismutase and glutathione peroxidase activities and total antioxidant capacity were higher, whereas malondialdehyde was lower (p < 0.05) in the LFT group (p < 0.01). Fecal 16S rRNA gene sequencing revealed no significant difference in alpha diversity; howerer, LEfSe identified selective taxonomic difference, including higher relative abundances of Holdemanella and Erysipelotrichaceae and lower relative abundances of Enterobacteriaceae and Escherichia-Shigella in the LFT group. Fecal short-chain fatty acid concentrations were unchanged. Flow cytometry revealed a higher proportions of peripheral CD4+ lymphocytes and a higher CD4+/CD8+ ratio in the LFT group (p < 0.01), whereas the CD8+ proportion was unchanged. Whole-blood RNA sequencing identified 283 differentially expressed genes (199 upregulated and 84 downregulated), with enrichment of immune-related pathways including hematopoietic cell lineage, antigen processing and presentation, cytokine–cytokine receptor interaction, NF-κB signaling, and IL-17 signaling, but these findings were not independently validated. The tested LF-OPN preparation was well tolerated and was associated with elevated antioxidant status, altered immune indices, and selective modulation of the fecal microbiota in growing kittens. The study does not establish synergy or identify the individual contributions of either protein. Full article

Ketogenic metabolic therapy (KMT), typically implemented as a ketogenic diet (KD), has re-emerged as a potential adjuvant strategy in oncology. Its rationale is grounded in the metabolic reprogramming of cancer cells, including their reliance on glucose and lipid substrates and the signaling functions of ketone bodies. Despite extensive preclinical evidence of anti-proliferative and immunomodulatory effects, clinical translation in cancer therapy has been slow and inconsistent. This review critically examines the mechanistic basis, experimental and clinical evidence, and translational challenges of KMT across epithelial cancers. We emphasize that “ketogenic interventions” comprise mechanistically distinct modalities, including classical KD, fasting, fasting-mimicking diets, and exogenous ketone supplementation, which are frequently conflated yet differ substantially in their endocrine and metabolic contexts. Across clinical studies, KMT is generally feasible and associated with improvements in quality of life and metabolic parameters; however, robust evidence for the survival benefit of KMT remains limited and heterogeneous. Mechanistically, ketone bodies exert both metabolic and signaling functions, including inhibition of histone deacetylases, lysine β-hydroxybutyrylation, and receptor-mediated effects. Tumor responses are highly context-dependent: ketolytic capacity, governed by enzymes such as OXCT1, can render ketones either a metabolic vulnerability or an alternative fuel for cancer cells. KMT can modify the complex tumor microenvironment, exerting potentially opposing effects on cancer cells, immune cell populations, fibroblasts, and adipocytes. We argue that the central limitation of the field is not a lack of biological activity, but of insufficient integration of tumor-intrinsic metabolism, host physiology, and microenvironmental context. KD/KMT should therefore be regarded not as a universal anticancer therapy, but as a stratified metabolic intervention, whose progress will depend on biomarker-guided patient selection, improved experimental models, and rational combination strategies within a “press-pulse” therapeutic framework. Full article

Nucleated erythroid cells (NECs) are emerging as important immunoregulators at the feto–maternal interface, yet their chemokine profiles and functional dynamics across pregnancy remain poorly understood. Using a murine allogeneic pregnancy model (CBA × C57Bl/6), we isolated placental and splenic TER-119⁺ NECs at mid- (E12.5) and late (E19.5) gestation. Chemokine production (13-plex), chemokine receptor expression (qPCR), immunosuppressive molecules (PD-L1, TGF-β, and ROS), T-cell proliferation (CFSE), and immune cell migration (Transwell) were assessed. CD45⁺ placental NECs were the main producers of PD-L1, TGF-β, and ROS, with maximal expression at E19.5, suggesting their potential contribution to the immunosuppressive functions observed in the total TER-119⁺ population. Chemokine production showed a striking shift in CCL17 and CXCL9 from the spleen to the placenta as pregnancy advanced (E12.5 → E19.5). Splenic NECs displayed dominant expressions of CCR3 and CXCR4. Unexpectedly, CCL2 and CCL4 blockade enhanced immune cell migration toward placental NECs at E19.5. Placental nucleated erythroid cells potently suppressed T-cell proliferation at E12.5, and this suppressive capacity remained stable until full term. Placental NECs undergo dynamic chemokine reprogramming while maintaining stable T-cell suppression. The paradoxical enhancement of migration after CCL2/CCL4 blockade suggests a complex chemokine network warranting further investigation. These findings provide new insights into the immunobiology of pregnancy and may have implications for understanding pregnancy complications. Full article

Ovarian cancer (OC) remains the most lethal gynecological malignancy, mostly due to its frequent diagnosis at advanced stages, early peritoneal dissemination, ascites formation, and limited sensitivity of currently available approaches for early detection. Extracellular vesicles (EVs), particularly exosomes, mediate intercellular communication through the transfer of proteins, lipids, metabolites, and nucleic acids. In OC, EV-associated protein profiles reflect both tumor-cell-intrinsic programs and the complex interactions between malignant cells and the peritoneal microenvironment. This review summarizes current evidence regarding the involvement of exosomal proteins in OC progression, with particular emphasis on epithelial–mesenchymal transition, mesothelial reprogramming, extracellular matrix remodeling, angiogenesis, immune suppression, peritoneal dissemination, and platinum resistance. Mechanistic studies indicate that exosomal proteins, including CD44, the integrin α5β1/asparaginyl endopeptidase complex, annexin A2, low-density lipoprotein receptor-related protein 1, and programmed death-ligand 1, can directly contribute to metastatic niche formation and tumor progression. In parallel, proteomic studies of plasma-, serum-, ascites-, peritoneal-fluid-, and uterine-lavage-derived EVs have identified candidate liquid-biopsy biomarkers, including MUC1, EpCAM, FOLR1, integrins, complement- and coagulation-related proteins, and proteins associated with treatment resistance. To integrate the biological significance of proteins reported in OC-associated exosomes, we additionally performed protein–protein interaction and functional enrichment analyses. These analyses revealed interconnected protein groups associated with cell adhesion, oxidative stress adaptation, secretory remodeling, lipid metabolism, extracellular matrix organization, and inflammatory signaling. Taken together, the available evidence supports exosomal proteome profiling as a promising approach for investigating OC dissemination and developing minimally invasive diagnostic and prognostic tools. However, standardized EV isolation, quantitative proteomics, functional validation, and independent clinical cohorts remain essential for translation into clinical practice. Full article