Search Results (11,173)

Inconsistent presentation of STAT3 variants in clinical settings makes them challenging to use in diagnostics and the prevention of unfavorable outcomes. Patients harboring the STAT3^R152W variant display a range of autoimmune disorders, including type 1 diabetes, hemolytic anemia, and thrombocytopenia. Because of a complex interplay of genetic and environmental cofactors, it is difficult to discern the direct role STAT3 plays in the development of those conditions. Here, we report a mouse model of the STAT3^R152W variant and describe its hematopoietic populations throughout adulthood. We observed profound changes in both innate and adaptive immunity, including increased splenic Th17 component consistent with a gain-of-function mutation, as described in the literature. At the same time, the mice did not develop obvious symptoms of autoimmunity. R152W mutants show lowered hemoglobin and hematocrit, indicating susceptibility to anemia, but also an increased number of thrombocytes, contradictory to reports of autoimmune thrombocytopenia. We showcase how those changes develop and wane in time, and the differences between male and female animals. Our findings paint the STAT3^R152W variant as a cause of severe immune dysregulation, but only as a cofactor in the development of autoimmunity. Full article

PCIF1 is primarily recognized as an RNA methyltransferase that mediates N⁶-methylation of cap-proximal adenosine (m⁶Am) and plays diverse roles in gene expression. In this study, we uncover a novel role for PCIF1 as a crucial negative regulator of type I interferon (IFN) induction, a pathway critical for antiviral immunity whose dysregulation leads to inflammatory and autoimmune diseases. We demonstrate that PCIF1 deficiency robustly enhances the poly(I:C)-induced type I IFN response, accompanied by augmented STAT1 activation and interferon-stimulated gene (ISG) expression. Mechanistically, PCIF1 suppresses IFNB1 transcription by attenuating IRF3 phosphorylation and nuclear translocation, as shown by increased nascent IFNB1 mRNA synthesis and promoter activity in PCIF1-deficient cells, without affecting the mRNA stability. Crucially, this suppressive function was independent of PCIF1’s canonical RNA methyltransferase activity, as both wild-type PCIF1 and a methyltransferase-inactive mutant effectively attenuated type I IFN induction. Collectively, our findings establish PCIF1 as a novel methyltransferase-independent suppressor of type I IFN responses, revealing its previously unrecognized non-catalytic function. This discovery offers critical insights into the multifaceted regulation of innate immunity and highlights PCIF1’s non-catalytic function as a promising therapeutic target for modulating antiviral responses and inflammatory diseases. Full article

Research has shown that diet significantly influences the chance of developing chronic inflammatory diseases including inflammatory bowel disease, cardiovascular disease, obesity, type 2 diabetes and several types of cancer. Dietary components modulate the immune system by either promoting or mitigating inflammatory pathways. One such pathway is the activation of the NLRP3 inflammasome—a multiprotein complex that is involved in the innate immune response. The NLRP3 inflammasome is triggered by various stimuli including ionic flux, mitochondrial dysfunction, lysosomal damage and ROS. Upon activation through a two-signal process, an immune response is initiated that protects the body against pathogens and cellular stress. In a healthy body, this pathway is closely regulated to maintain homeostasis and prevent excessive inflammation that can result in tissue damage or chronic inflammatory diseases. Several components present in a human diet can activate or inhibit the NLRP3 inflammasome. To support a balanced diet, organizations like the WHO have developed dietary recommendations. These promote the consumption of fruits, vegetables, whole grains, lean proteins and healthy fats. These foods contain a variety of nutrients and bioactive compounds, including saturated fatty acids, cholesterol, omega-6 fatty acids and natural sugars, which are pro-inflammatory. At the same time, they also supply anti-inflammatory compounds such as monounsaturated fatty acids, antioxidants and probiotics. While current literature highlights the NLRP3 inflammasome as a critical regulator of inflammation, it lacks detailed insights into how the specific dietary components of a healthy diet influence its modulation. Therefore, this literature review elucidates the various mechanisms through which these dietary compounds modulate the NLRP3 inflammasome. The significance of maintaining a balance between pro- and anti-inflammatory components in the diet is highlighted by its role as a regulator of inflammatory diseases, for example, through mechanisms such as epigenetic pathways. Full article

Inflammatory and immune-mediated skin diseases are increasingly recognized as disorders in which genetic susceptibility is shaped and sustained by environmentally responsive regulatory programs. Psoriasis, atopic dermatitis (AD), vitiligo, systemic sclerosis (SSc), lupus erythematosus (LE), and lichen planus (LP) are clinically distinct, yet they share chronic or relapsing inflammation, tissue remodeling, and limited durability of many current therapies. Because genetic variation alone cannot fully explain disease onset, flare dynamics, heterogeneity in severity, or lesion recurrence, epigenetic mechanisms have emerged as a plausible link between environmental exposures and stable disease phenotypes in skin. Epigenetic regulation, including DNA methylation, histone modifications, and non-coding RNA networks, controls cell-type-specific transcription without altering the DNA sequence and may contribute to persistent inflammatory states and disease memory despite clinical improvement. The current review synthesizes primary preclinical and translational evidence on epigenetic-targeted therapeutic strategies across these conditions, focusing on interventions that modulate DNA methylation, histone acetylation and deacetylation, histone methylation, chromatin-associated regulatory proteins, and RNA-based approaches. We compare the maturity of therapeutic development across diseases, noting that research and intervention studies are concentrated in psoriasis and AD, whereas evidence for vitiligo, SSc, LE, and LP remains more limited and often derived from systemic or non-cutaneous models. Finally, we outline key gaps that currently restrict clinical translation and discuss why bridging them is essential for determining whether epigenetic modulation can move beyond proof-of-concept toward durable and clinically actionable interventions in inflammatory skin disease. Full article

Objective: This study aimed to identify clinically relevant regulators of pancreatic ductal adenocarcinoma (PDAC), a disease characterized by stromal remodeling and immune suppression, and to define their links to malignant progression and microenvironmental reprogramming. Methods: We integrated multi-cohort bulk, single-cell, and spatial transcriptomic datasets and subsequently validated bulk differential expression and network analyses with machine learning-based prioritization in an independent combined cohort (TCGA-PAAD plus GSE62452). Single-cell mapping was used to assess cell-type specificity, positioning candidates along inferCNV- and pseudotime-defined malignant continua. In Visium sections, a DKK1-associated program score quantified intratumoral spatial heterogeneity and informed our analyses of ligand–receptor communication. Bulk immune deconvolution linked gene levels to immune infiltration patterns, and functional assays were used to test the impact of DKK1 knockdown on migration, proliferation, clonogenic growth, and apoptosis in PDAC cells. Results: Four reproducible tumor-associated genes—DKK1, COL10A1, SULF1, and SLC24A3—were prioritized and validated externally. DKK1 was predominantly expressed by epithelial tumor cells and tracked along a malignant progression continuum. Spatially, the DKK1 program localized to epithelial-dominant regions, revealed pronounced intratumoral heterogeneity, and highlighted epithelial–endothelial and endothelial–immune signaling in high-score areas. Immune deconvolution associated higher DKK1 expression with increased myeloid infiltration and reduced cytotoxic lymphocyte signatures. Functionally, DKK1 knockdown impaired migration, proliferation, and clonogenicity while increasing apoptosis. Conclusions: We demonstrate that DKK1 is an epithelial-derived regulator linked to malignant progression and tumor–stroma–immune remodeling, supporting its potential as a biomarker and therapeutic target in PDAC treatment, including rational combinations with stroma-modulating strategies and immunotherapy. Full article

Background: Diabetes increases the risk of cataract formation fivefold. Immune-mediated inflammation has been reported to play a role in this process; however, whether alterations in the immune landscape are involved remains unknown. Therefore, we conducted a multi-omics analysis to evaluate the impact of immune inflammation on the lens. Methods: Bulk RNA sequencing was performed on peripheral blood mononuclear cells (PBMCs) from diabetic patients and lens tissues from diabetic rats. Single-cell RNA sequencing was utilized to characterize intercellular interactions. Key gene and protein expressions were validated via laboratory assays. Results: An integrated RNA-seq analysis revealed a disruption of the blood–aqueous barrier integrity in the diabetic group, enhanced monocyte migration and adhesion, increased differentiation from classical to non-classical monocytes, and the upregulation of TNF and IFN-γ signaling pathways. The transcriptomic profiling of rat lenses revealed an increased proportion of monocytes and the activation of apoptotic pathways in lens epithelial cells. Immunohistochemistry and immunofluorescence staining demonstrated elevated caspase-3 and IL-6 levels in lens epithelial cells and increased immune cell infiltration in the diabetic group. The qRT-PCR and ELISA confirmed elevated levels of the pro-inflammatory cytokines IL-6 and IFN-γ, alongside reduced anti-inflammatory cytokine IL-10 in the peripheral blood and aqueous humor of diabetic patients. Conclusions: Diabetes alters the peripheral immune microenvironment and disrupts the blood–aqueous barrier, promoting intraocular inflammation and lens epithelial cell apoptosis, thereby accelerating cataract development. Full article

Background/Objectives: To mine single-cell sequencing data for colorectal cancer (CRC), identify CRC epithelial cell subtypes, and explore the heterogeneity of epithelial cells and their impact on the tumor microenvironment (TME). Methods: The GSE201348 dataset, including normal, colorectal adenoma, high-grade colorectal intraepithelial neoplasia, and CRC tumor tissue samples, was downloaded from the Gene Expression Omnibus. The Seurat package of R software was used for data quality control, data integration, normalization, and clustering. The Feature Plot and the Recode function were executed to annotate and group the epithelial cells. Finally, genetic differences, copy number variant heterogeneity, pseudotime, cell–cell communication, and Gene Set Variation Analysis (GSVA) were further conducted. Results: In total, 26,335 gene matrices from 263,872 cells were obtained for subsequent analyses. Four cell clusters, including immune cells, fibroblasts, endothelial cells, and epithelial cells, were identified. Epithelial cells were further divided into 11 subgroups characterized by MKI67, SLC27A6, PLCE1, NKD1, KCNMA1, GDA, CLCA4, BEST4, LRMP, ACTG2, and ASPM. GSVA enrichment analysis suggested a role of the “P53 pathway,” “Wnt–β-catenin signaling,” and “MYC targets V1” pathways in epithelial cells during the malignant progression of tumors. Survival analysis indicated that downregulation of KCNMA1 and upregulation of MKI67 were associated with poor prognosis. Cell–cell communication analysis suggested a bidirectional regulatory role between epithelial and fibroblast subsets. Conclusions: This study analyzed the gene expression characteristics of 11 types of epithelial cells during the malignant progression of CRC. KCNMA1⁺ and MKI67⁺ epithelial subpopulations are important indicators for the malignant progression of CRC. Full article

Understanding the intimate interactions between plants and their microbiota at the cellular level is essential for unlocking the full potential of plant holobionts in agricultural systems. Traditional bulk and microbial community-level sequencing approaches reveal broad community patterns but fail to resolve how distinct plant cell types interact with or regulate microbial colonization, as well as the diverse antagonistic and synergistic interactions and responses existing between various microbial populations. Recent advances in single-cell and spatial multi-omics have transformed our understanding of plant cell identities as well as gene regulatory programs and their dynamic regulation in response to environmental stresses and plant development. In this review, we highlight the single-cell discoveries that uncover the plant cell-type-specific microbial perception, immune activation, and symbiotic differentiation, particularly in roots, nodules, and leaves. We further discuss how integrating transcriptomic, epigenomic, and spatial data can reconstruct multilayered interaction networks that connect plant cell-type-specific regulatory states with microbial spatial niches and inter-kingdom signaling (e.g., ligand–receptor and metabolite exchange), providing a foundation for developing new strategies to engineer crop–microbiome interactions to support sustainable agriculture. We conclude by outlining key methodological challenges and future research priorities that point toward building a fully integrated cellular interactome of the plant holobiont. Full article

The genus Xanthomonas comprises devastating plant pathogens responsible for significant yield losses in globally critical crops such as rice (Oryza sativa L.), citrus (Citrus L. spp.), cassava (Manihot esculenta Crantz), and tomato (Solanum lycopersicum L.). This review synthesizes current knowledge on the molecular mechanisms driving Xanthomonas pathogenicity, including the type III secretion system (T3SS) that translocates effector proteins, transcription activator-like effectors (TALEs) that reprogram host transcription, and extracellular polysaccharides (EPS) that promote biofilm formation and immune evasion, which collectively enable host colonization, immune suppression, and disease progression. Rapid adaptation through genomic plasticity and horizontal gene transfer (HGT) exacerbates challenges in disease management by facilitating evasion of host defenses and environmental stressors. Economically, Xanthomonas spp. inflict billions in annual losses through crop damage, trade restrictions, and eradication efforts, disproportionately affecting resource-limited regions. Emerging antibiotic resistance and climate-driven shifts in pathogen distribution further threaten food security. Sustainable strategies, such as CRISPR-based genome editing to disrupt susceptibility genes, biocontrol agents (e.g., Bacillus and Pseudomonas spp.), and nanotechnology-driven antimicrobials offer promising alternatives to conventional copper-based and chemical controls. This review underscores the urgent need for integrated, climate-resilient management approaches to mitigate the ecological and socioeconomic impacts of Xanthomonas diseases, bridging genomic insights with innovative control measures, to address escalating threats posed by these pathogens in a changing global climate. Full article

Metabolic inflammation, a state of chronic low-grade inflammation linked to insulin resistance, plays a central role in the development of obesity-related conditions such as type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), and cardiovascular disorders. In recent years, two molecules have gained significant prominence in this field, owing to their mechanistic involvement in metabolic inflammation and insulin resistance: fetuin-A (FetA), aliver-derived hepatokine, and chymase, a serine protease released from mast cells. Although they arise from distinct biological sources, they converge on overlapping inflammatory and metabolic pathways. FetA acts as an endogenous ligand for Toll-like receptor 4 (TLR4), activating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, driving proinflammatory cytokine release, and impairing insulin signaling. Chymase, on the other hand, generates angiotensin II and activates transforming growth factor-β (TGF-β), thereby promoting oxidative stress, fibrosis, and secondary metabolic dysfunction. This review proposes a conceptual dual-target framework in which FetA and chymase are considered complementary, rather than independent, mediators of metabolic inflammation. Importantly, this framework is not intended to supersede other established pathways implicated in metabolic inflammation, but rather to provide an integrative perspective that complements existing hepatokine and immune-centered models. Their convergence on NF-κB and TGF-β signaling pathways highlights shared mechanistic nodes within metabolic inflammation. Accordingly, the emphasis of this review is on mechanistic integration within metabolic inflammation, rather than on immediate therapeutic innovation or clinical translation. Full article

Background: Routine admission inflammatory and metabolic biomarkers have been proposed as adjunctive tools in mild traumatic brain injury (mTBI). However, their association with specific traumatic intracranial lesion types remains unclear. Methods: We conducted a prospective observational study including adult patients with isolated mTBI who underwent head computed tomography (CT) on admission. Admission laboratory parameters included the platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and glucose-to-potassium ratio (GPR). Two predefined endpoints were assessed. The first compared biomarker values between CT-positive and CT-negative patients. The second evaluated associations between biomarkers and individual intracranial lesion subtypes, including analyses restricted to isolated lesions. Results: A total of 125 patients were included, of whom 95 (76%) were CT-positive. No significant differences were observed between CT-positive and CT-negative patients for PLR (p = 0.793), GPR (p = 0.531), or SII (p = 0.291). In lesion-specific analyses including all intracranial injuries, subdural hematoma (SDH) was associated with higher GPR compared with patients without SDH (p = 0.016). In analyses restricted to patients with isolated lesions, SDH was associated with higher PLR (p = 0.018) and higher GPR (p = 0.015). No significant associations were observed between any biomarker and intraparenchymal hemorrhage, subarachnoid hemorrhage, or epidural hematoma (all p > 0.05). Patients with multiple intracranial injuries exhibited higher PLR (p = 0.012) and higher SII (p = 0.021) compared with those with isolated lesions. After correction for multiple comparisons, none of the observed associations remained statistically significant. Conclusions: These findings suggest that routine systemic biomarkers have limited global discriminatory value in mTBI. Exploratory lesion-specific associations with SDH did not remain significant after correction for multiple comparisons, underscoring the preliminary nature of these findings. Full article

Melanoma is one of the most aggressive forms of cancer and the leading cause of death related to skin disease. Recent years have seen a significant increase in the number of cases of this type of cancer, underscoring the need to develop effective therapeutic strategies to control it. One of the most promising research directions in this field is anticancer immunotherapy, particularly the use of vaccines aimed at enhancing the body’s cellular immunity. Among the modern methods of this type, mRNA-based vaccines are prominent, gaining increasing importance as a potential tool in cancer therapy. Their main advantages include a relatively rapid and flexible production process, low production costs, and the ability to induce both humoral and cellular immune responses. Despite their numerous advantages, therapeutic mRNA vaccines also pose a number of scientific and technological challenges. These primarily concern the stability of mRNA molecules and their effective delivery to target cells. In this context, delivery systems such as lipid nanoparticles (LNPs) play a key role, protecting mRNA from degradation and facilitating its transport into the cell cytoplasm. Alternatively, systems based on biodegradable polymers are also being developed, which can provide controlled mRNA release and additional biocompatibility. However, before therapeutic mRNA vaccines become a routine component of cancer therapy, extensive clinical trials and a thorough understanding of their mechanisms of action are necessary. This paper provides an overview of the current knowledge regarding the structure and delivery methods of therapeutic mRNA vaccines, with a particular emphasis on their use in melanoma therapy. The results of clinical trials to date are also presented and the challenges associated with implementing this form of therapy in medical practice are discussed. Full article

Background/Objectives: Tissue niches, such as those in the spleen, bone marrow, and lymph nodes, are crucial for the survival and growth of leukemic cells in chronic lymphocytic leukemia (CLL). Methods: A growing amount of research over the last 20 years has shown how important the tumor microenvironment (TME) is to the pathophysiology, development, and resistance to treatment of CLL. This protective environment, which is made up of various cell types (including stromal and immune cells), extracellular matrix components, and soluble factors, supports CLL cells and encourages their survival, growth, and drug resistance. Even in the absence of mutations, Notch2 is functionally activated in the CLL system, in addition to the well-known Notch1. This occurs because leukemic cells aberrantly express the ligand Jagged1/2, which activates the Notch2 receptor on both stromal and CLL cells themselves. Notch2 activation on stromal cells leads to the triggering of the Wnt/β-catenin program in CLL cells, whereas the activation of Notch2 in CLL cells promotes the expression of Mcl-1, which confers drug tolerance (especially in cases with trisomy 12). Results: In addition to these mechanisms, Notch2 acts as a transcription factor that directly controls the expression of key targets, such as CD23 and Hes1, that are fundamental for B cell proliferation, differentiation, and survival in CLL. Conclusions: All of these circuits represent important therapeutic targets and help explain the cells’ dependence on their niche, the formation of proliferation centers, and resistance to modern targeted agents. Full article

Respiratory infections cause substantial morbidity and mortality in older adults and other at-risk adult populations. Despite the availability of effective vaccines, adult vaccination coverage remains suboptimal. This narrative review examines strategies designed to improve vaccine uptake among non-pregnant adults aged ≥18 years and inform future adult vaccination strategies. We conducted a targeted literature search using keywords for vaccination, respiratory diseases, strategy/program/implementation, and adults in PubMed database and CDC, WHO, and ECDC websites, between 2014 and 2024. A snowball search of literature reviews and key references was also performed to identify additional relevant studies. Eligible publications focused on vaccination strategies against influenza, COVID-19, and pneumococcal disease targeting non-pregnant adults (≥18 years). We categorized the strategies by intervention type to describe their influence on vaccination campaigns and vaccine uptake/coverage. We included 45 publications, encompassing strategies focused on individual decision-making, healthcare system functions, and national policy. Educational and awareness interventions (such as healthcare worker/provider recommendations during consultation, phone calls, letters, text messages, and social media outreach) reportedly raised vaccination rates. Access-related factors, including convenient vaccination sites and free or subsidized vaccines, were reported to be important factors in improving coverage in underserved communities. Within healthcare settings, strategies such as continuous vaccine provider training and workflow/process optimization were shown to enhance vaccination delivery. At the local or national policy levels, legislation governing program targets shaped immunization efforts and facilitated collaborations and partnerships to expand campaign reach. The findings may inform policymakers and public health/immunization practitioners in designing context-specific immunization initiatives that effectively reach adult populations. Full article

We present the single-cell transcriptomic analysis of peripheral blood mononuclear cells (PBMC) from individuals during acute HIV-1 infection caused by viral strains circulating in Russia and the Former Soviet Union (FSU) countries. Using 10x Genomics single-cell RNA sequencing (scRNA-seq) on the Illumina NextSeq 550 platform, we have analyzed scRNA-seq data from three treatment-naive patients (viral load > 1 × 10⁶ copies/mL, estimated infection duration ≤ 4 weeks) and three healthy donors. Data integration (Seurat, Harmony), automated cell-type annotation (CellTypist), and GeneOntology (GO) enrichment analysis for highly expressed and low-expressed genes revealed a profound reorganization of transcriptional programs across key immune populations, including memory CD4⁺ and CD8⁺ T cells, non-classical monocytes and natural killer cells (NK-cells). We observed signatures of hyperactivation of pro-inflammatory pathways (NF-kB, TNF, and type I/II interferon signaling), upregulation of genes associated with cellular migration (CXCR4, CCR7) and metabolic adaptation (oxidative phosphorylation components), alongside a mixed pro- and anti-apoptotic expression profile. Notably, our data pointed to a pronounced dysregulation of the TGF-β and mTOR signaling cascades, disrupted intercellular communication networks—particularly between cytotoxic cells and their regulators—altered expression of genes implicated in disease progression (OLR1, SERPINB2, COPS9) and viral persistence control (NEAT1, NAF1). This work provides an initial single-cell transcriptional atlas characterizing early immune responses to HIV-1 sub-subtypes A6 and CRF63_02A6, the predominant drivers of the HIV epidemic across the FSU region. Full article