Search Results (5,381)

(1) Background: Despite the success of combination antiretroviral therapy (cART), immune recovery in treated HIV infection remains heterogeneous, and discordant immune–virologic responses persist in a substantial proportion of people living with HIV (PLWH). These patterns may reflect ongoing immune dysregulation despite effective viral suppression. This study aimed to characterize discordant treatment classifications, evaluate immune imbalance using the CD4/CD8 ratio, identify associated clinical predictors, and assess opportunistic infection burden in a Romanian cohort of people living with HIV receiving long-term cART. (2) Methods: A retrospective cross-sectional study was conducted in 462 adults with HIV-1 infection receiving cART at the “Prof. Dr. Matei Balș” National Institute of Infectious Diseases, Bucharest (2018–2021). PLWH were classified as concordant responders (CR), immunological discordant responders (ID), or virological discordant responders (VD) based on plasma HIV-1 RNA and CD4+ T-cell count thresholds. Immune dysregulation was assessed using the CD4/CD8 ratio. Multinomial logistic, logistic, and negative binomial regression models were used to identify predictors of discordant responses, severe CD4/CD8 ratio inversion, and opportunistic infection burden. (3) Results: Discordant responses were observed in 30.7% of PLWH (14.5% ID, 16.2% VD). CD4/CD8 ratio inversion occurred in 71.2% and severe inversion in 40.0%. Significant differences across clinical classification groups were found for CD4+T-cell counts (H = 153.62, p < 0.001, ε² = 0.33) and CD4/CD8 ratio (H = 115.10, p < 0.001, ε² = 0.25), while CD8+ counts were similar (p = 0.571). Male sex was associated with both ID and VD, and severe CD4/CD8 inversion was strongly associated with ID. Opportunistic infection burden was associated with duration of HIV infection and CDC stage. (4) Conclusions: Discordant immune–virologic responses remain frequent during long-term cART and are characterized by persistent immune imbalance reflected by CD4/CD8 ratio inversion. The CD4/CD8 ratio may provide clinically relevant information on immune recovery beyond CD4+ T-cell counts. Full article

Background: High-grade soft tissue sarcomas (STSs) are heterogeneous tumours lacking robust prognostic or predictive biomarkers. Regnase-1, an immune RNase, enhances antitumour immunity by limiting immunosuppressive tumour microenvironment (TME) components (e.g., myeloid-derived suppressor cells (MDSCs)), but remains unexplored in STS. As CD68⁺ tumour-associated macrophages (TAMs) drive TME suppression and poor prognosis in non-translocation-driven STS, we evaluated Regnase-1 and CD68⁺ TAMs to assess Regnase-1 as an indicator of an immunologically activated TME. Methods: Immunohistochemistry scoring of Regnase-1 and CD68⁺ TAMs was performed in 91 patients. Overall survival (OS) was assessed by Kaplan–Meier and Cox regression, and findings were validated in an independent “The Cancer Genome Atlas” Sarcoma (TCGA-SARC) cohort (n = 212). Results: In UPS, Regnase-1-high predicted longer OS (17.0 months vs. not reached; p = 0.0247) and lower mortality (univariate hazard ratio (HR) = 0.3; p = 0.0343; multivariate HR = 0.4; p = 0.0413), but not after radiotherapy. CD68⁺ TAM-high predicted shorter OS (13.0 months vs. not reached; p = 0.0274) and higher mortality (HR = 2.0, 95% CI 1.1–3.7; p = 0.0325). Both Regnase-1 effects were reproduced in TCGA-SARC. Regnase-1-high tumours showed inflammatory/interferon enrichment, reduced TGF-β signalling, and SERPINE1 upregulation. Conclusions: Regnase-1 marked a pro-inflammatory TME and favourable outcome in UPS, but this effect may reverse upon radiotherapy. Full article

Gray mold caused by Botrytis cinerea poses a severe threat to tomato production. In this study, physiological, biochemical, transcriptomic, and proteomic analyses were integrated to characterize the dynamic responses of tomato ‘Ailsa Craig’ to B. cinerea infection. During B. cinerea infection, peroxidase (POD) activity showed a progressive increase, while catalase (CAT) activity was significantly upregulated at 24 hpi and remained stable through 48 hpi. Malondialdehyde (MDA) and hydrogen peroxide (H₂O₂) contents showed a delayed response, increasing significantly only at 48 hpi, whereas SOD activity exhibited a biphasic pattern. Transcriptome and proteome profiling identified 5824 differentially expressed genes and 124 differentially expressed proteins. Functional enrichment analysis highlighted defense-related pathways, including plant–pathogen interaction, flavonoid biosynthesis, and inositol phosphate metabolism. Notably, the chlorophyll a/b-binding protein SlLhcb13 exhibited post-transcriptional upregulation despite transcriptional suppression. Functional validation demonstrated that overexpression of SlLhcb13 enhanced resistance, whereas silencing increased susceptibility. These findings identify SlLhcb13 as a positive regulator linking photosynthesis to immunity and provide new insights into the defense mechanisms of tomato. Full article

Background: Gaucher disease (GD) arises from pathogenic variants in the GBA1 gene and is known for its wide range of clinical presentations—a variability that genotype alone cannot adequately account for. Objective: This study aimed to explore transcriptomic factors that might help explain why two genetically identical twins with type 1 GD developed noticeably different clinical outcomes. Methods: We isolated peripheral blood mononuclear cells from both twins and two age-matched controls, then differentiated them into macrophages in vitro before conducting RNA sequencing. Gene expression differences were analyzed using established bioinformatics pipelines, and a subset of genes were subsequently assessed by quantitative real-time PCR (qRT-PCR) to confirm the sequencing findings. Results: Both twins shared a GD-associated transcriptional signature broadly reflecting immune activation and lysosomal stress. Interestingly, the twin who experienced systemic complications had a relative enrichment of interferon-responsive transcripts, while the less severely affected twin showed more pronounced suppression of small nucleolar RNA clusters. That said, neither difference held up after correcting for multiple comparisons, so these patterns are best viewed as exploratory trends rather than definitive findings. The qRT-PCR results lend partial support to this picture: stress- and immune-related genes (DDIT4, RPH3A, SAMSN1) trended toward higher expression in patients versus controls, and interferon-stimulated genes (ISG15, RSAD2, IFI44L) were more elevated in M2 than in M1. Conclusions: Taken together, these findings suggest that factors beyond genetics—whether epigenetic, environmental, or otherwise—may play a meaningful role in shaping how GD manifests differently even between individuals with identical DNA. Although the data are preliminary, they point to transcriptomic profiling, paired with targeted validation, as a useful starting point for building hypotheses about why this disease looks so different from one patient to the next, even when the underlying mutation is the same. Full article

Psoriatic arthritis (PsA) is a systemic autoimmune inflammatory disease affecting both the joints and the skin, with the potential involvement of multiple organ systems. A hallmark feature of PsA is enthesitis—inflammation at the sites where tendons and ligaments insert into bone—which arises from a combination of mechanical stress and immune-mediated inflammation. Another defining characteristic of the disease is the paradoxical coexistence of bone erosion and new bone formation, distinguishing it from other inflammatory arthritides. The therapeutic landscape of PsA has evolved considerably over time. Non-steroidal anti-inflammatory drugs (NSAIDs) remain a cornerstone of symptom management, while conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), such as methotrexate, are widely used to control disease progression. The introduction of biologic agents has revolutionized PsA management, with TNF inhibitors, IL-17 inhibitors, and IL-23 inhibitors demonstrating efficacy across a broad range of clinical manifestations. More recently, targeted synthetic small molecules—including JAK inhibitors and TYK2 inhibitors—have expanded the armamentarium of available therapies. The overarching goals of treatment in PsA include the suppression of the underlying inflammatory process and the prevention of structural joint damage. The impact of each therapeutic option on cutaneous psoriasis is an additional and important consideration that guides individualized treatment options. Full article

Tumor-associated macrophages (TAMs) are among the most abundant immune cell populations in breast cancer and have emerged as central regulators of tumor progression, metastatic dissemination, immune evasion, and therapeutic resistance. While TAMs were historically described using a simplified M1/M2 polarization framework, accumulating evidence indicates that TAMs in breast cancer comprise a continuum of phenotypic and functional states shaped by ontogeny (tissue-resident vs monocyte-derived), spatial localization (including hypoxic, perivascular, and invasive niches), tumor-intrinsic programs, and therapy-induced selective pressures. In breast cancer, mechanistic studies integrating lineage tracing, intravital imaging, single-cell and spatial profiling, and clinical analyses have established that TAMs actively coordinate rate-limiting steps of the metastatic cascade. These include promotion of angiogenesis and vascular permeability, orchestration of tumor cell invasion and TMEM-mediated intravasation, facilitation of metastatic seeding and niche formation, and suppression of anti-tumor immunity. TAMs also critically influence therapeutic response by modulating chemotherapy efficacy and limiting the activity of immune checkpoint blockade. Therapeutic strategies targeting TAMs in breast cancer have evolved from depletion approaches (CSF1/CSF1R blockade) to inhibition of monocyte recruitment (CCL2/CCR2 axis), functional reprogramming (CD40 agonism, PI3Kγ inhibition), and macrophage-directed checkpoint modulation (CD47–SIRPα axis). Early clinical studies demonstrate clear pharmacodynamic activity but highlight the need for context-specific and combination-based approaches. This review focuses on TAM biology in breast cancer progression and metastasis, synthesizing key mechanistic and translational evidence and proposing a framework in which spatially and functionally defined macrophage states act as rate-limiting regulators of dissemination and therapy response. We further outline principles for rational TAM-targeting strategies that integrate tumor stage, metastatic niche, and treatment context. Full article

In 2023, a highly immunogenic live attenuated vaccine based on the Nigeria 75/1 strain was introduced in Kazakhstan to provide protection against PPR. This study presents the results of a three-year animal trial evaluating the vaccine’s efficacy, safety, and immunogenicity. The novelty of this study lies in the long-term (up to 36 months) evaluation of protective immunity in adult animals, as well as in the comparative analysis of immune responses across different age groups and the assessment of viral suppression following challenge infection. Sheep and goats of different age groups were included, including lambs and kids aged 1.5 and 3 months, as well as adult animals aged 2–3 years. The vaccine was well tolerated following a single immunization, and no clinically significant adverse effects were observed in vaccinated animals, apart from only mild transient local reactions. A strong humoral (IgG) response to PPRV antigens was detected in all groups, with the highest antibody titers observed in young animals. Seroconversion was detected in 100% of vaccinated animals by day 21 post-vaccination. Long-term protective immunity (at least 36 months) was demonstrated in adult animals, whereas in young animals early protection was confirmed at 21 days post-vaccination along with subsequent humoral immune dynamics following a single immunization with a 1.0 mL dose of the vaccine (Nigeria 75/1 strain, titer 10^3.0 TCID₅₀/mL). These findings indicate that the vaccine is well tolerated, highly immunogenic, and provides sustained protection in adult animals while inducing early immune responses in young animals. Full article

Crimean–Congo hemorrhagic fever virus (CCHFV) and severe fever with thrombocytopenia syndrome virus (SFTSV) are tick-borne pathogens that cause severe illness and high mortality. Early diagnosis is critical, particularly in resource-limited settings, to enable timely intervention. Host gene expression profiling offers a promising approach to identify potential biomarkers for early detection, disease staging, and logical treatment decision-making. Using a transient IFN-α/β receptor-suppressed mouse model, we performed targeted transcriptomic analysis on blood samples collected at 2, 3, and 4 days after CCHFV or SFTSV challenge. A significant increase in viral load and changes in gene expression were observed as early as two days post-challenge. CCHFV induced a progressively evolving interferon-driven response, while SFTSV triggered rapid, sustained immune activation. Affected targets included interferon-stimulated genes, chemokines, cytokines, Toll-like receptors, and genes associated with viral evasion and innate immune response. Despite shared expression patterns, unique genes were identified as potential biomarkers to distinguish between CCHFV and SFTSV infections. Differential gene expression revealed distinct immune response dynamics, with suppression of critical immune regulatory genes suggesting transcriptional signatures associated with viral evasion mechanisms contributing to disease severity. These findings provide a comparative analysis of molecular pathways and gene expression changes, offering critical insights for biomarker discovery, effective triage, and evaluation of appropriate medical intervention. Full article

Chikungunya virus (CHIKV) is an alphavirus that infects dermal fibroblasts as a primary target cell during natural mosquito-borne transmission. While primary human dermal fibroblasts (hDFs) have been implicated as a key source of type I interferon (IFN-I) during CHIKV infection, the dynamics of this response and its sufficiency for antiviral protection remain incompletely understood. Here, we systematically characterize in vitro CHIKV infection of primary hDFs, evaluating the effects of single-passage viral stock origin (mammalian- vs. mosquito-propagated), donor variability, and multiplicity of infection (MOI) on infection kinetics and innate immune induction. We demonstrate that hDFs support high-titered CHIKV replication at both MOI 1 and 0.01, resulting in universal cell death by 72 hpi despite robust IFNβ transcript induction—reaching up to ~2800-fold over mock—and secretion of pro-inflammatory cytokines, including IFNα2, TNFα, IL-1β, and IL-8. Notably, IFNβ protein levels remained below 10 pg/mL under all infection conditions, revealing a disconnect between transcriptional and translational responses, suggesting CHIKV-mediated translational suppression. Pharmacological inhibition of TBK1/IKKε via amlexanox did not suppress IFNβ transcript induction at any tested concentration, suggesting that canonical PRR signaling through this node—including both RIG-I/MAVS and TLR3/TRIF pathways—is not the major driver of the observed transcriptional response. In contrast, co-inoculation with exogenous IFNβ as low as 20 pg/mL activated IFNAR signaling, robustly upregulated interferon-stimulated genes (ISGs), and fully rescued hDFs from otherwise lethal infection. Together, these findings demonstrate that CHIKV-infected hDFs mount a transcriptionally robust but translationally insufficient innate immune response and that the transcriptional response appears to operate independently of TBK1/IKKε. These results have direct implications for understanding how the skin microenvironment may modulate early CHIKV pathogenesis and suggest that paracrine IFNβ signaling from neighboring cell types may be critical for fibroblast survival during natural infection. Full article

Dysregulation of the immune system, gut microbiota alteration, and epithelial dynamics in the colon contribute to the pathogenesis of inflammatory bowel disease (IBD). However, the role of epithelial dynamics, particularly epithelial regeneration, remains incompletely understood. CADM1 encodes an immunoglobulin-superfamily cell adhesion molecule involved in epithelial adhesion, immune cell interactions, and tumor suppression in colon and various cancers. Here, we investigated the role of CADM1 in IBD using a murine model of colitis induced by dextran sulfate sodium in both wild-type and conventional Cadm1-deficient (Cadm1^−/−) mice. Cadm1^−/− mice exhibited more severe colitis than wild-type mice with increased mortality (64% vs. 10%) and delayed recovery. Cadm1^−/− mice showed reduced numbers of Ki-67-positive cells in colonic crypts and delayed epithelial regeneration, whereas no significant differences were observed in epithelial apoptosis, intestinal permeability, or immune responses. Immunohistochemistry revealed that CADM1 expression was restricted to regenerative crypt cells in wild-type mice with nuclear accumulation of β-catenin and phospho-Akt. Furthermore, CADM1 overexpression in colon epithelial cells enhanced Tcf-transcriptional activity in a β-catenin-dependent manner. Immunohistochemistry of human IBD materials revealed that CADM1 expression also correlated with nuclear β-catenin accumulation in crypt epithelial cells. Collectively, CADM1 appears to promote colonic epithelial regeneration through the PI3K/Akt/β-catenin axis to protect against severe epithelial injury in IBD. Full article

Diarrhea is a common gastrointestinal disorder in animals, often worsened by antibiotic use. Pulsatilla chinensis (PC) is traditionally used for gastrointestinal issues, but its bioactive constituents and mechanisms remain unclear. This study investigated the preventive effects of PC in a canine model of antibiotic-associated diarrhea using an integrated multi-omics approach. LC–MS identified key constituents of PC, including anemoside B4, berberine, stigmasterol, and quercetin. In silico analyses predicted that stigmasterol and quercetin target EGFR and AKT1, modulating inflammation and epithelial repair via PI3K–Akt and IL-17 signaling pathways. In vivo, treatment with PC significantly reduced serum pro-inflammatory cytokines such as TNF-α and IL-6 and elevated immune markers including IgG and IgA compared to the control group. Furthermore, 16S rRNA analysis revealed that PC restored gut microbial diversity, reflected by increased Sobs and Chao1 indices, enriched beneficial Lactobacillus, and decreased the abundance of inflammation-associated taxa such as Proteobacteria, Desulfobacterota, and Escherichia-Shigella. These findings suggest that PC suppresses inflammation and remodels the gut microbiome, providing a mechanistic basis for its use as an herbal alternative to antibiotics. Future studies should include fecal microbiota transplantation and targeted metabolomics to establish causality and optimize therapeutic strategies. Full article

Plants in agricultural systems rarely face single stressors; instead, they encounter concurrent biotic (pathogen, pests) and abiotic (drought, salinity, heavy metals) stresses that causes severely reduce crop yields and endanger food security. The traditional methods of breeding, genetic engineering, and agrochemicals tend to target individual stresses and still do not suffice in the complex field conditions. Compared to these approaches, nanotechnology offers distinct advantages: nanoparticles (NPs) can be applied as foliar sprays or seed treatments without lengthy breeding cycles or regulatory hurdles associated with genetically modified organisms. However, nanotechnology is not inherently “better” but rather complementary to crop engineering; each approach has specific strengths. Breeding and genetic engineering provide heritable, long-term solutions, while nanotechnology offers immediate, season-specific, and reversible interventions. Cross-tolerance, the phenomenon whereby exposure to one stress enhances tolerance to another, offers a promising alternative. This review critically examines how NPs act as stress-priming agents that induce cross-tolerance by activating overlapping defense networks, including antioxidant systems (SOD, CAT, APX), phytohormonal crosstalk (ABA, SA, JA), osmolyte homeostasis, and stress-responsive gene expression. We synthesize current evidence on NP uptake, translocation, and cellular interactions, and evaluate their dual role in directly suppressing pathogens while simultaneously enhancing plant immune responses and physiological resilience. However, efficacy is highly dose-dependent: low, subtoxic doses prime defense through hermetic ROS signaling, whereas supraoptimal doses cause phytotoxicity. The current challenges in nano-mediated stress alleviation include: (i) a persistent laboratory-to-field translation gap, with field outcomes averaging only 60–70% of greenhouse efficacy; (ii) dose-dependent phytotoxicity; (iii) poor reproducibility across studies; (iv) scalability and formulation stability issues; and (v) insufficient understanding of long-term environmental fate, including soil accumulation, non-target organism effects, and food chain safety. Future research should consider field-validated formulations (e.g., SiNPs, ZnONPs, Fe₃O₄NPs) across major staple crops); integrating nanotechnology with precision agriculture through nanosensors, remote sensing, and artificial intelligence for site-specific, dose-optimized applications;developing smart, biodegradable nanoparticles with stimuli-responsive release; and establishing harmonized regulatory frameworks for nano-agrochemical approval. When deployed responsibly, nanoparticle-induced cross-tolerance represents a sustainable approach to improve crop resistance against multifactorial stress, with significant implications for climate-resilient agriculture and global food security. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains among the deadliest cancers, with a 5-year survival rate of 13% and broad resistance to therapy. It is driven by severe tumor hypoxia from desmoplasia, aberrant vasculature, and high interstitial pressure. Hypoxia stabilizes hypoxia-inducible factors (HIFs), reshaping the tumor microenvironment (TME) into a nutrient-poor, acidic milieu that fosters immune exclusion and suppression. While immune checkpoint inhibitors (ICIs) have revolutionized treatment, PDAC responses have been negligible. As hypoxia centrally drives PDAC’s ICI-refractory TME, targeted alleviation could offer synergy with ICIs; however, no such combination is being applied in the clinic. One impediment could be the one-size-fits-all approach when investigating hypoxia-modifying therapy. Indeed, using hypoxia gene signatures, we and others have shown that PDAC tumors are not equally hypoxic, with patients having more hypoxic tumors experiencing worse survival and immunosuppressed TME. This review dissects hypoxia’s mechanistic role in PDAC immune evasion and gives an update on the therapeutic advances that directly or indirectly target hypoxia, such as the inhibition of HIFs, hypoxia-activated prodrugs, and vascular and oxygen delivery approaches, with emphasis on their potential to enhance responses to ICIs. It further evaluates the need for hypoxia biomarkers and proposes gene signatures as detection tools to enable precision hypoxia modulation, potentially converting immune-cold PDAC into an ICI-responsive disease. Full article

Background/Objectives: Whole-cell vaccines have demonstrated clinical potential in cancer treatment and recurrence prevention, yet their immunogenicity and dendritic cell (DC) activation remain suboptimal. This study aimed to evaluate whether a needle-free injector (NFI) could enhance the immunogenicity and antitumor efficacy of whole-cell tumor vaccines. Methods: Adaptive immune responses induced by NFI and traditional syringe injection (SYI) were compared following whole-cell vaccine administration. The morphology of vaccine fluid ejected by NFI and SYI was examined, and the effects on DC antigen uptake and activation were assessed. Antitumor efficacy was further evaluated in MC38 colon adenocarcinoma challenge models. Results: NFI administration elicited stronger antigen-specific adaptive immune responses than SYI. The high-velocity pressure generated by NFI resulted in fragmentation of whole-cell vaccine material, and this morphological alteration was associated with enhanced DC antigen uptake and activation. These immunological improvements corresponded with superior tumor suppression in MC38 models following NFI-delivered vaccination. Conclusions: NFI delivery enhances the immunogenicity and antitumor efficacy of whole-cell tumor vaccines. These findings suggest that needle-free injectors may serve as a simple and effective strategy to improve the performance of whole-cell cancer vaccines. Full article

The chloroplast, a key organelle for plant immunity, is frequently targeted by viral proteins to suppress host defense. Here, we demonstrate that NSvc4, the movement protein of rice stripe virus (Tenuivirus oryzaclavatae; genus Tenuivirus), functions as a chloroplast-localized virulence effector. We show that NSvc4 enters chloroplasts and directly associates with NbPsbQ, a subunit of the oxygen-evolving complex (OEC) of Photosystem II. This interaction competitively disrupts the binding of NbPsbQ to its native partners NbPsbO and NbPsbP, thereby dampening the accumulation of chloroplast-derived reactive oxygen species (cROS) and attenuating pathogen-triggered immune signaling. Genetic knockout of NbPsbQ enhanced plant susceptibility to RSV, confirming its role as a positive regulator of antiviral defense. Our study uncovers a distinct strategy whereby a viral movement protein inhibits chloroplast-mediated immunity by targeting extrinsic subunits of the OEC. These findings expand the functional scope of viral movement proteins and highlight the OEC as a critical battleground in plant–virus interactions. Full article