Search Results (2,069)

Chimeric antigen receptor-T (CAR-T) cell immunotherapy constitutes a cornerstone in the management of patients with relapsed/refractory B-cell lineage lymphoid malignancies. Toxicities such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and hematotoxicity (ICAHT) have been recognized in the post-infusion period. The initial interplay between CAR-T cells and tumor cells, followed by cytokine release and the bystander activation of the innate immunity cells, result in endothelial cell injury. In the current review, the ongoing research regarding endothelial injury in CAR-T cell recipients is summarized. Various markers of endothelial injury have been investigated in CAR-T cell recipients, including markers of complement activation, such as soluble C5b-9, endothelial dysfunction (angiopoietin-2, VCAM1, ICAM-1), inflammation, and thrombosis (von Willebrand antigen, ADAMTS13, thrombomodulin). The expression level of these endothelial injury markers has been identified as impaired in CAR-T cell recipients, not only when compared with healthy controls but also among patients with severe CRS/ICANS and those with mild toxicities or without toxicities. Furthermore, the Endothelial Activation and Stress Index (EASIX) and modified versions of this score, calculated in the pre- and early post-infusion period, seem to predict development of severe toxicities, ICAHT, and, thus, poor overall survival in CAR-T cell patients. More data concerning the role of these endothelial injury markers and clinical outcomes in CAR-T cell settings are essential. Full article

Vertebrate embryonic development relies on tightly regulated signaling pathways that guide morphogenesis, cell fate specification, and tissue organization. Among these, the Wnt signaling pathway plays a central role, orchestrating key developmental events. The non-canonical Wnt pathways, including the Planar Cell Polarity and Wnt/Ca²⁺ branches, are especially critical for regulating cytoskeletal dynamics during gastrulation. Recent studies highlight that these pathways interface with cytoskeletal effectors to control actin remodeling in response to extracellular cues. One such effector is Profilin, a small, evolutionarily conserved actin-binding protein that modulates actin polymerization and cellular architecture. Profilins, particularly Profilin1 and 2, are known to interact with Daam1, a formin protein downstream of PCP signaling, thereby linking Wnt signals to actin cytoskeletal regulation. Emerging evidence suggests that Profilins are active signaling intermediates that contribute to morphogenetic processes. Their context-dependent interactions and differential expression across species also suggest that they play specialized roles in development and disease. This review synthesizes the current understanding of Profilin’s role in non-canonical Wnt signaling, examining its molecular interactions and contributions to cytoskeletal control during development. By integrating data across model systems, we aim to clarify how Profilins function at the intersection of signaling and cytoskeletal dynamics, with implications for both developmental biology and disease pathogenesis. Full article

Myocardial infarction-induced cardiovascular diseases remain a leading cause of mortality worldwide. Excessive post-infarct fibrosis contributes to adverse cardiac remodeling and the progression to heart failure. In vivo reprogramming strategies offer a promising avenue for heart regeneration by directly converting resident fibroblasts into cardiomyocytes through enforced expression of cardiogenic genes. This approach circumvents the need for invasive biopsies, cell expansion, induction of pluripotency, or autologous transplantation. Despite these advantages, key challenges persist, including low reprogramming efficiency and limited cellular targeting specificity. A critical factor for effective anti-fibrotic therapy is the precise and efficient delivery of reprogramming effectors specifically to fibrotic fibroblasts, while minimizing off-target effects on non-fibroblast cardiac cells and fibroblasts in non-cardiac tissues. In this review, we discuss the cellular and molecular mechanisms underlying in vivo cardiac reprogramming, with a focus on fibroblast heterogeneity, key transcriptional drivers, and relevant intercellular interactions. We also examine current advances in fibroblast-specific delivery systems employing both viral and non-viral vectors for the administration of lineage-reprogramming factors such as cDNA overexpressions or microRNAs. Finally, we underscore innovative strategies that hold promise for enhancing the precision and efficacy of cellular reprogramming, ultimately fostering translational development and paving the way for rigorous preclinical assessment. Full article

Background: Host genetic factors significantly influence individual susceptibility to severe COVID-19, potentially explaining the observed disparities in clinical outcomes across populations. One of the key effectors in innate immunity and antiviral defense is the CD209 gene. This study explored the potential correlation of the CD209 gene SNP rs2287886 with diverse COVID-19 patient outcomes. Materials and Methods: A total of 176 patients (87 in the moderate group and 89 in the severe/critical/death group) were included in the study. Genotyping of patients was performed using the qPCR methodology, through the TAQMAN system. The results were analyzed adopting a significance level of p < 0.05. Results: The GG genotype (compared to AG + AA) and the G allele (compared to the A allele) of the rs2287886 SNP were significantly associated with an increased severity of COVID-19 (p = 0.0005 and p < 0.0001, respectively). The G allele was more frequent in individuals with more severe clinical outcomes (49.43% vs. 25.28%). Furthermore, expression quantitative trait loci (eQTL) analysis indicated that the GG genotype of rs2287886 is associated with higher CD209 gene expression. Furthermore, the observed interaction analysis suggests that the interactions between CD209 and its associated proteins may play a role in modulating the immune response. Conclusions: Our findings suggest that Brazilian patients homozygous for the GG genotype of the rs2287886 polymorphism in the CD209 gene may be at increased risk of severe COVID-19 in the Brazilian population and may act as a potential prognostic marker of disease severity. Full article

Background/Objectives: Immune checkpoint inhibitors (ICIs) do not provide promising benefits to patients with advanced epithelial ovarian cancer (EOC). This study analyzed preoperative peripheral blood mononuclear cells (PBMCs) from these patients to evaluate the prognostic and therapeutic checkpoints. Methods: Preoperative PBMCs of 69 advanced EOC cases were collected to analyze the correlation between IC-expressing immune cells and survivals of patients. Co-expression of various ICs on the T lymphocytes from these patients was examined. Activation potential of programmed cell death 1 (PD-1)⁺herpes virus entry mediator (HVEM)⁺ T cells in PBMCs from the healthy donors and tumoricidal abilities of PMBCs treated with various ICIs were evaluated in vitro. Impact of respective ICIs on activation of T cells in PMBCs was investigated. Results: Percentages of PD-1⁺ CD4⁺ and CD8⁺ T cells in the PBMCs of patients could positively correlate with disease-free or overall survival. HVEM was highly co-expressed on these T lymphocytes. Prediction potential for overall survival of patients by the subpopulation of PD-1⁺ CD4⁺ or CD8⁺ T cells was higher than that by other parameters. The PD-1⁺HVEM⁺ CD4+ and CD8⁺ T cells showed characteristics of activated phenotype under activation signals. PBMCs receiving anti-B and T lymphocyte attenuator (BTLA) plus anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) or anti-PD-1 Ab had potent tumor-killing ability. Anti-BTLA Ab can drive T cells in the PBMCs toward an effector status. Conclusions: Percentages of PD-1⁺ T cells in the PBMCs could predict survival of EOC patients. Targeting HVEM-BTLA axis may be considered for ICI treatment of EOCs. Full article

Porcine deltacoronavirus (PDCoV), an emerging enteropathogenic coronavirus, has inflicted substantial economic losses on the global swine industry. While the severity of infectious disease depends on the dynamic interplay between inoculum dose and host response, the molecular mechanism by which PDCoV dose modulates host immunity remains unclear. Hence, we systematically compared the transcriptomic changes in intestinal epithelial cells infected with different doses of PDCoV, and investigated the relationships between inoculum dose, host immune responses, and disease progression. PDCoV replication peaked at 24 h post-infection, and host responses showed a distinct dose-dependent pattern, with high-dose infection inducing more extensive transcriptional remodeling than low-dose infection. Both doses significantly activated the transcription of STAT1 and its downstream interferon-stimulated genes, while high-dose infection additionally triggered a cytokine storm characterized by excessive IL-6 and TNF-α expression. Functional validation demonstrated that STAT1 overexpression markedly inhibited PDCoV infection by enhancing ISRE promoter activity, and overexpression of its downstream ISG15 and MX2 also exerted independent and significant antiviral effects. These findings reveal the biphasic nature of PDCoV dose-dependent regulation of immunopathological mechanisms and identify STAT1 and specific ISGs (ISG15, MX2) as potent antiviral effectors, providing crucial insights into PDCoV pathogenicity and offering promising targets for developing immunomodulatory therapeutics or vaccines to control PDCoV outbreaks in swine. Full article

Mitogen-activated protein kinases 3 and 6 (MPK3/MPK6) are central to pattern-triggered immunity (PTI) and effector-triggered immunity (ETI) in Arabidopsis, yet the involvement of long noncoding RNAs (lncRNAs, >200 nt) in these pathways is poorly understood. Here, transcriptomic analyses were performed to compare lncRNA and protein-coding gene (PCG) expression profiles in wild-type (WT) and MPK3/MPK6-deficient (MPK6SR) Arabidopsis plants. These plants were inoculated with either Pseudomonas syringae pv. tomato (Pst) DC3000, which elicits both PTI and ETI, or its type III secretion-deficient mutant, Pst DC3000 hrcC⁻, which induces only PTI. RNA sequencing (RNA-seq) analysis of 18 samples identified 1388 known and 70 novel lncRNAs, among which differentially expressed lncRNAs (DElncRNAs) involved in disease resistance were further identified. Using integrative analyses, including weighted gene co-expression network analysis (WGCNA), prediction of lncRNA cis-regulatory targets for PCGs, and validation via reverse transcription-quantitative PCR (RT-qPCR), three core lncRNA-mediated regulatory modules were identified: (i) MPK3/MPK6-dependent PTI and ETI, where lncRNAs amplify signals; (ii) MPK3/MPK6-dependent PTI, where lncRNAs fine-tune basal immunity; and (iii) MPK3/MPK6-independent PTI and ETI, where lncRNAs serve as a backup regulatory network. These modules form a multi-layered immune regulatory network via cis- and trans-regulation and further enable the identification of lncRNA-PCG pairs involved in both regulatory modes. This work enhances the understanding of the molecular mechanisms underlying plant innate immunity. Full article

Iron is essential for cellular respiration, oxidative defense, and host immunity, but its dysregulation is increasingly associated with metabolic disorders, such as obesity and type 2 diabetes. In these diseases, regional iron accumulation occurs in adipose tissue, independent of systemic overload. This process disrupts the mitochondrial redox balance, induces ferroptotic stress, and activates the innate immune pathways. Recent studies have highlighted the NLRP3 (nucleotide-binding domain, leucine-rich repeat, pyrin domain-containing protein 3) inflammasome and its effector cytokine interleukin-1β (IL-1β) as important mediators of the interface between iron and inflammation. In both adipocytes and macrophages, labile iron increased reactive oxygen species (ROS) production and promoted inflammasome formation. Simultaneously, metabolic stress factors upregulate hepcidin expression, suppress ferroportin activity and exacerbate intracellular iron retention. These molecular events converge to maintain low-grade inflammation and impair insulin signaling. Despite these compelling associations, direct mechanistic evidence remains limited, particularly with respect to depot-specific responses and cell type resolution. In this review, I examine the current evidence linking iron handling and inflammasome biology in adipose tissue, focusing on ferroptosis, thioredoxin-interacting protein (TXNIP) signaling, and spatial mapping of iron–cytokine networks. I also discuss novel therapeutic strategies targeting iron overload and inflammasome activation, including chelation, hepcidin modulation, and inflammasome inhibition in the context of metabolic diseases. Full article

Efficient protoplast isolation and gene transfection remain significant challenges in gymnosperms, particularly in Pinus species, where stable transformation is highly limited. Conventional pine protoplast preparation methods have resulted in extremely low transfection efficiencies, hindering functional genomic studies. This study presents an optimized method for isolating high-yield, viable protoplasts from Pinus densiflora (Korean red pine), providing a robust system for transient gene expression assays. Splitting one-month-old cotyledons produced the highest mesophyll protoplast yield (5.0 × 10⁶ cells/g FW), which further increased to 1.2 × 10⁷ cells/g FW after optimizing the enzyme mixture (4.5% cellulase, 0.7% pectinase, 3% hemicellulase), maintaining viability above 86%. Developing xylem and whole-stem protoplasts were also successfully isolated by mitigating resin leakage and debris contamination, with a 17% sucrose gradient yielding 7.4 × 10⁴ cells/g FW at 81.9% viability. Overcoming prior inefficiencies, this protocol significantly enhances gene transfection efficiency, achieving 94.1% GFP transformation with 82.9% viability. Furthermore, transient activation assays confirmed strong activation of pine-derived reporters by native effectors, underscoring the assay’s suitability for studying gymnosperm-specific gene regulation. Given the limited stable transformation strategies available for Pinus species, this optimized protoplast transient gene expression system provides a practical and reliable platform for transient gene expression analysis, offering valuable opportunities for studying gene function and regulation in gymnosperms. Full article

Curvularia lunata (Wakkre) Boedijn is an important pathogenic fungus that causes maize leaf spot, a prevalent disease that caused significant yield losses in maize-growing areas in China in the 1990s. Clpks18, a polyketide synthase (CLPKS18) gene, has been identified as a crucial virulence-related gene in C. lunata. However, the impact of Clpks18 and its biosynthesized virulence factor (R)-(-)-mellein on the expression of maize genes related to the defense signal pathway has never been determined. In this study, it was found that Clpks18 and (R)-(-)-mellein significantly interfere with the signaling pathways of JA and IAA in maize leaves but in different ways and in a time-dependent manner. While CLPKS18 inhibited the maize’s JA and IAA signaling pathways through its related secondary metabolite, (R)-(-)-mellein inhibited the JA signaling pathway but stimulated IAA accumulation in maize leaves. In summary, understanding this novel virulence effector’s mechanism of interference with maize resistance enriches the pathology of Curvularia leaf spot in maize on the one hand and provides a foundation for screening the resistance germplasm and chemical fungicides against the disease on the other. Full article

The Wntβ-catenin signaling pathway is a key regulator of gastrointestinal (GI) tumorigenesis, modulating cellular processes such as proliferation, differentiation, and epithelial-to-mesenchymal transition (EMT). In this review, we evaluate the expression and mutation profiles of core Wntpathway components in the most common GI malignancies. Our findings outline notable alterations in ligands, receptors, co-receptors, and intracellular effectors across different GI cancers. In gastric cancer tissue, elevated levels of Wnt proteins, FZD7 receptor, and LRP5/6, along with β-catenin accumulation and reduced APC expression, are associated with poor prognosis. In colorectal cancer samples, common APC mutations and Wnt ligand overexpression contribute to β-catenin nuclear localization and EMT. Esophageal cancer specimens exhibit co-overexpression of Wnt2 and Wnt5A, as well as receptors such as FZD2 and FZD6, which are linked to worse prognosis and reduced survival. Liver cancer tissue commonly harbors CTNNB1 mutations, which encode β-catenin and are associated with poor differentiation. In pancreatic cancer samples, overexpression of Wnt ligands, FZD receptors, and β-catenin is associated with the presence of distant metastasis and poor clinical outcomes. In conclusion, this pathway represents a promising avenue for identifying novel diagnostic, prognostic, and therapeutic biomarkers in GI cancers, warranting further clinical investigation. Full article

The increasing global burden of mosquito-borne diseases and the widespread development of insecticide resistance in mosquitoes have fueled renewed interest in entomopathogenic fungi as effective tools that are compatible with existing mosquito control strategies. These fungi produce different types of infective propagules, including hydrophobic conidia and yeast-like blastospores, which differ in structure, mode of infection, and virulence. In this study, we evaluated the larvicidal activity of conidial and blastospore propagules from Beauveria bassiana MBC076 and Beauveria brongniartii MBC397 against Aedes aegypti. Conidia exhibited more rapid and more potent larvicidal effects compared to blastospores, but the overall survival at seven days post-infection was similar between the two types of propagules. Interestingly, B. brongniartii blastospore infections resulted in a significantly higher proportion of pupal mortality, suggesting a delayed mode of action. Immune profiling of infected larvae indicated significant induction of antimicrobial effectors such as cecropin, defensin, and attacin, primarily in response to conidial infection. In contrast, blastospore infections were associated with reduced expression of several prophenoloxidase genes, particularly during infection with B. brongniartii blastospores. These findings indicate that different fungal species and their propagule types exert varying levels of virulence and immune modulation in mosquito larvae. This study provides insights into the infection dynamics of fungal propagules and identifies immune markers that can be leveraged to enhance the efficacy of fungal-based larvicides. Full article

Background/Objectives: Effective prophylaxis for Mycobacterium tuberculosis (Mtb) requires greater understanding of immune correlates of protection. With renewed interest in BCG as an Mtb vaccine, particularly via the intravenous (IV) route, our objective was to characterize both innate and adaptive immune correlates of vaccine-induced pulmonary immunity as potential biomarkers for protective efficacy in a murine model of Mtb infection. Methods: Mice were given BCG via different routes and some boosted with recombinant virus constructs encoding Mtb Ag85B. Responding innate lymphoid cell (ILC) populations, T cells and B cells were analyzed by fluorescence activated cell sorting (FACS) for surface markers and by intracellular cytokine staining or antibody ELISPOT. Some immunized mice were challenged with aerosolized Mtb and monitored for bacterial growth in the lungs and spleen. Results: BCG given IV, but not intranasally or subcutaneously, resulted in marked increases in IFNγ expression at 72 h by pulmonary CD49⁺ NK cells, CD69⁺ ILC1, and two ILC3 populations, NCR-ILC3 and LTi cells, the latter also producing IL-22. Pulmonary ILC2 populations in these mice had significantly increased IL-13 expression at 24 h compared to the other routes. Interestingly, high levels of NK cells and ILC1 expressing IFNγ and/or TNFα were sustained at 8 wk, with sustained expression of IL-17A by pulmonary NCR-ILC3 and pronounced tissue-resident and effector memory CD4⁺ and CD8⁺ T cell responses. Intranasal boosting with Ad-Ag85B enhanced these T cell responses and generated Mtb-specific pulmonary IgA and IgG B cells, correlating with significantly reduced bacterial loads following Mtb challenge. Conclusions: BCG given IV primed for both early and persistent pulmonary ILC1/ILC3 responses of a predominantly Th1/Th17-type profile along with local Mtb-specific memory T cell and B cell populations, correlating with enhanced protective efficacy. These are worthy of further study as compartmentalized biomarkers for effective vaccine-induced local immunity against Mtb. Full article

Phytopathogenic fungi secrete numerous effector proteins to disrupt plant defenses. At present, their sequence–structure–function relationships remain poorly understood owing to their diversity. Comprehensive understanding of conserved effectors is necessary to elucidate the molecular relationship between fungi and plants. To fill this research gap, we investigated the Colletotrichum higginsianum effector candidate (ChEC)-88 specifically expressed during infection. Notably, similar to the biotrophy-associated secreted protein 3 (BAS3) from Pyricularia oryzae, ChEC88 inhibited plant cell death caused by necrosis- and ethylene-inducing peptide 1-like protein (NLP1). Nuclear magnetic resonance analysis results revealed that ChEC88 adopted a novel pseudo two-fold symmetrical three-dimensional structure. Homology modeling suggested that BAS3 exhibited a ChEC88-like conformation despite sharing less than 50% sequence identity. Through PSI-BLAST searches, we found that ChEC88 homologs were conserved in various hemibiotrophic phytopathogenic fungi, including Colletotrichum, P. oryzae, and Fusarium species. Functional assays demonstrated that all of the representative homologs suppressed NLP1-induced plant cell death. Mutation experiments identified the residues critical for ChEC88 function. Overall, our findings suggest that hemibiotrophic phytopathogenic fungi share a conserved immune-suppression strategy mediated by ChEC88-like proteins and that such effectors possibly originated from a common ancestral lineage of phytopathogenic fungi. Full article

Skeletal muscle, constituting ~40% of body mass, serves as a primary effector for movement and a key metabolic regulator through myokine secretion. Hereditary myopathies, including dystrophinopathies (DMD/BMD), limb–girdle muscular dystrophies (LGMD), and metabolic disorders like Pompe disease, arise from pathogenic mutations in structural, metabolic, or ion channel genes, leading to progressive weakness and multi-organ dysfunction. Gene therapy has emerged as a transformative strategy, leveraging viral and non-viral vectors to deliver therapeutic nucleic acids. Adeno-associated virus (AAV) vectors dominate clinical applications due to their efficient transduction of post-mitotic myofibers and sustained transgene expression. Innovations in AAV engineering, such as capsid modification (chemical conjugation, rational design, directed evolution), self-complementary genomes, and tissue-specific promoters (e.g., MHCK7), enhance muscle tropism while mitigating immunogenicity and off-target effects. Non-viral vectors (liposomes, polymers, exosomes) offer advantages in cargo capacity (delivering full-length dystrophin), biocompatibility, and scalable production but face challenges in transduction efficiency and endosomal escape. Clinically, AAV-based therapies (e.g., Elevidys^® for DMD, Zolgensma^® for SMA) demonstrate functional improvements, though immune responses and hepatotoxicity remain concerns. Future directions focus on AI-driven vector design, hybrid systems (AAV–exosomes), and standardized manufacturing to achieve “single-dose, lifelong cure” paradigms for muscular disorders. Full article