The chronic recurrence of psoriasis is driven by a self-amplifying inflammatory cascade in which oxidative stress and mitochondrial metabolic dysfunction reinforce each other, and single-target conventional therapies often fail to break this cycle. Here, we present a micro-nano hybrid system, Mito-Ce, constructed by covalently immobilizing ceria nanozymes (CeNPs) onto the surface of isolated functional mitochondria through thiol-maleimide chemistry. This design endows the hybrid with dual functionalities, including mitochondrial bioactivity and durable ROS-scavenging capabilities of CeNPs. In H2O2-stimulated macrophages, upon internalization. Mito-Ce markedly reduced intracellular ROS and consequently suppressed the secretion of pro-inflammatory cytokines (IL-6, TNF-α, and IL-1β). Topical application of Mito-Ce to an imiquimod-induced mouse model of psoriasis visibly resolved psoriatic plaques, reduced the PASI score, and reversed epidermal hyperplasia. Beyond local repair, Mito-Ce rebalanced systemic immunity, evidenced by a decline in splenic pathogenic Th17 cells and polarization toward anti-inflammatory M2 macrophages. Transcriptomic profiling further revealed that Mito-Ce broadly reversed the pathological gene expression program, downregulating stress-responsive and phagocytosis-related genes while upregulating genes associated with metabolism, epidermal proliferation, and tissue homeostatic remodeling. These coordinated networks ultimately re-established immune-barrier homeostasis at the molecular level. Collectively, by integrating nanozyme-mediated ROS scavenging with mitochondrial bioactivity, the Mito-Ce hybrid could treat psoriasis through coordinated disruption of the inflammatory cascade, potentially offering a highly effective platform for various chronic inflammatory disorders.

This study investigates the association between a novel inflammatory marker, the uric acid-to-albumin ratio (UAR), and diabetic kidney disease (DKD). We used multivariable logistic regression models to evaluate the independent associations of UAR with DKD, albuminuria, and reduced estimated glomerular filtration rate (eGFR). We further examined the associations of these renal outcomes with other inflammatory markers, including the Systemic Inflammatory Response Index and Systemic Immune-Inflammation Index (SII), and evaluated the diagnostic performance of these markers using receiver operating characteristic curve analysis. A total of 3984 participants from the National Health and Nutrition Examination Survey (NHANES) 2011-2020 were included, of whom 37.20% had DKD, 31.60% had albuminuria, and 19.80% had reduced eGFR. Spearman correlation analysis showed that UAR was positively correlated with both albumin-to-creatinine ratio and DKD (P < .01) but negatively correlated with eGFR (P < .05). In multivariable logistic regression analyses, each standard deviation increase in UAR was independently associated with higher odds of DKD (odds ratio [OR], 2.257; 95% CI: 1.654-3.080; P < .001), albuminuria (OR, 2.097; 95% CI: 1.541-2.852; P < .001), and reduced eGFR (OR, 6.210; 95% CI: 4.024-9.584; P < .001). Receiver operating characteristic curve analysis further showed that UAR had greater discriminative performance for DKD, albuminuria, and reduced eGFR than uric acid, albumin, Systemic Inflammatory Response Index, and SII. For DKD, UAR yielded an optimal cutoff of 1.609, with a sensitivity of 40.7%, specificity of 79.4%, and area under the curve (AUC) of 0.623. For albuminuria, the optimal UAR cutoff was 1.6282, with a sensitivity of 35.3%, specificity of 78.2%, and AUC of 0.571. For reduced eGFR, the optimal UAR cutoff was 1.5375, with a sensitivity of 62.0%, specificity of 73.7%, and AUC of 0.733. UAR was significantly associated with DKD, albuminuria, and reduced eGFR in T2DM, with the strongest association observed for reduced eGFR. These findings indicate that UAR may serve as a potential marker of renal abnormalities. However, given the cross-sectional design and potential bidirectional relationship between UAR components and renal function, these associations should not be interpreted as evidence of causality or future risk prediction. Prospective studies are needed to establish the temporal relationship between UAR and DKD and clarify causal mechanisms.

Neural regulation of cancer extends beyond anatomical innervation: tumours receive systemic neural and neuroendocrine inputs and locally produce and decode neurotransmitters and neuropeptides. We propose the Tumour Neurotone (TN) as a tumour-level state of neurochemical regulation generated by the combined actions of these signals across malignant, immune, stromal and vascular compartments, shaping proliferative signalling, metabolic adaptation, immune escape, tissue remodelling, dissemination and treatment response. Biologically, a TN state reflects the context-dependent, spatially organised and relatively persistent configuration of neuroactive ligand availability; cell-type-specific signalling competence, including receptors, transporters and metabolic enzymes; proximal pathway engagement; and downstream cellular responses. TN is therefore not synonymous with tumour innervation, nerve density, an instantaneous neurochemical profile, neuroimmune crosstalk or the broader field of cancer neuroscience; it is a narrower state model intended to capture functional organisation beyond any single neurotransmitter pathway. We synthesise evidence across proliferative signalling, metabolic plasticity, immune regulation, sensory-neuropeptide circuits, neural remodelling, bioelectrical communication, vasculo-stromal organisation and circadian timing. Although many constituent mechanisms are causally supported, the existence and predictive value of integrated TN states have not yet been validated clinically. We therefore specify three criteria for assigning a TN state: temporal reproducibility, predictive value beyond individual components and established tumour covariates, and coherent change after targeted perturbation. We also provide a longitudinal experimental workflow, framework-specific predictions and falsification criteria, and an evidence-graded appraisal of neuromodulatory interventions.

Peyer's patches (PPs) in the intestinal mucosa coordinate antibody responses to luminal microbes and dietary antigens. The follicle-associated epithelium (FAE) is traditionally recognized by the presence of microfold cells (M cells) that mediate antigen sampling in PPs. By analyzing Gfi1b-eGFP reporter mice and human PP biopsies, we identified tuft cells as an additional, evolutionarily conserved FAE population that regulates mucosal immunity. Using mouse models and intestinal organoids, we demonstrate that M cells and tuft cells are distinct lineages arising from Pou2f3+ progenitors, whose differentiation is reciprocally regulated by RANKL and interleukin-13 (IL-13), respectively. Tuft cell-derived IL-25 activates type 2 innate lymphoid cells (ILC2s) in PPs. Furthermore, IL-13 production by ILC2 enhances immunoglobulin A class switching and antigen-specific immunity. These findings reveal a dual surveillance system in the FAE, where developmentally related epithelial lineages use distinct mechanisms to coordinate mucosal immunity.

Stimulator of interferon genes (STING) is a highly conserved signaling molecule that coordinates an antiviral innate immune response through activation of the nuclear factor κB (NF-κB) and interferon regulatory factor 3 (IRF3) signaling pathways. In addition to an antiviral response, STING-mediated NF-κB signaling also leads to an inflammatory response, which can cause substantial pathology. However, the molecular mechanism whereby STING drives inflammation is poorly understood, and this has hindered the development of anti-inflammatory strategies targeting this pathway. Here, we define an evolutionarily conserved mechanism whereby STING activates NF-κB signaling via recruitment of inhibitor of NF-κB kinase subunit γ (IKKγ) in an M1-linked ubiquitin-dependent manner. We also show that the more recently evolved carboxyl-terminal tail of STING cooperates with the IKKγ-IKK complex for NF-κB-dependent expression of pro-inflammatory genes in mammalian cells through the kinases TBK1 (TANK-binding kinase 1)/IKKε. Thus, the expression of the key inflammatory genes CCL3 and CCL4 requires the formation of M1-linked ubiquitin and the activation of NF-κB, but we do not detect a role for IRF3 in STING-driven NF-κB signaling.

Innate-like B cells produce natural antibodies and include marginal zone (MZ) B cells and B1 cells. B1 cells are well characterized in mice, where they prenatally seed serous cavities and produce regulatory cytokines. Putative B1 cells have been identified in human prenatal organs, but whether they persist into adulthood remains unclear. Here, we identified B1-like cells in the IgM+ and IgA+ memory compartment across adult human organs. These cells transcriptionally resembled murine and human prenatal B1 cells but not MZ B cells. They expressed canonical murine B1 cell markers, including AHNAK, and spontaneously secreted IgM. B cell receptor sequencing of paired kidney-spleen samples revealed lower diversity and mutation rates in kidney IgM/IgA clones, suggesting spleen-independent seeding. Adult B1-like cells expressed the regulatory cytokine TGFB and had abundant inferred interactions with tissue myeloid cells, which reciprocally expressed B cell prosurvival cytokines. These findings support the presence of B1-like cells across adult human organs in homeostasis.

Cytotoxic T cells [cytotoxic lymphocytes (CTLs)] are crucial for adaptive immunity leading to prolonged survival and potential cures for cancer. Recent clinical data have shown that pharmacological inhibition modifies the tumor microenvironment (TME) and activates CTLs, although the mechanism is not well described. In this study, we found that T cell-specific knockout (KO) of the most prevalent SUMO paralog, Sumo2/SUMO2, in both mouse and human CD8+ T cells significantly enhanced CD8+ T cell activation without enhanced IFN-I (type I interferon)-responsive genes in vitro but increased chromatin accessibility at enhancer regions for AP-1 (activating protein 1) family members, including BATF and JunB, which are known to promote T cell activation and proliferation. Using antigen-specific OT1 and CAR (chimeric antigen receptor) T cell models, we found that Sumo2 KO CD8+ T cells had significantly higher tumor infiltration, as revealed by flow cytometry, immunofluorescence staining, and single-nucleus RNA sequencing (snRNA-seq), and conferred greater tumor growth inhibition than wild-type control T cells. snRNA-seq also revealed that Sumo2 KO in CD8+ T cells increased the expression of TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) in vivo and activated the antitumor immune microenvironment, likely through cell-cell interaction involving more activated CTLs. These findings elucidate a novel mechanism by which SUMOylation controls CTL activation and tumor infiltration that activate antitumor immunity in the TME. SUMO2 KO can also be a potential strategy to enhance adoptive T cell therapies for solid tumors by enhancing their activation, tumor infiltration and ability to modulate the TME.

Rapid development of host immunity is critical during the emergence of viral outbreaks when vaccines are not yet available. Here, we demonstrate that CpG oligodeoxynucleotide-schizophyllan complex (K3-SPG) induces antigen-independent, long-term protection against lethal respiratory virus infection. A single intranasal administration successfully enhanced host resistance to infection for as long as 100 days posttreatment. Mechanistically, we observed a lung-restricted biphasic innate activation of macrophages and innate lymphoid cells. Early protection was mediated by CD11b+CD11c+ macrophages (DP MΦ) and monocyte-derived interstitial macrophages (IMΦ). Late protection was mediated by innate lymphoid cells that were epigenetically reprogrammed, suggesting that two distinct innate immune subsets contribute to the maintenance of disease tolerance in the lung microenvironment. Deficiency of TLR9 or TNF-α abrogated innate activation and protective immunity. Collectively, these findings demonstrate that adjuvant-induced prophylaxis is a promising approach to enhancing host resistance against respiratory virus infection, involving the biphasic cooperation between innate immune cells in the local tissue.

Influenza A virus (IAV) infection during pregnancy is associated with stillbirth and preterm birth. We hypothesized that maternal IAV infection disrupts placental and fetal immune networks in ways that correlate with disease severity. Pregnant pigtail macaques were inoculated with IAV [A/California/07/2009 (H1N1)] and underwent delivery and fetal necropsy 5 days postinfection (N = 11), with comparison to uninfected controls (N = 16). Stillbirth occurred in 18% of infected pregnancies and in no controls. Although vertical transmission was not observed, low levels of viral RNA were detected in two placentas. Maternal infection was associated with induction of a type I interferon response in the placenta and altered innate and adaptive immune cell populations in the fetus. Maternal disease metrics (e.g., lung viral load and interferon-α) were rarely associated with placental immune perturbations but frequently linked to fetal immune cell populations (CD4+ and CD8+ T cells and monocyte subsets). Collectively, these data indicate that maternal IAV disease severity is associated with dysregulated fetal immunity.

Cystic echinococcosis (CE), a neglected zoonotic disease caused by Echinococcus granulosus sensu lato, remains a significant public health and veterinary concern worldwide. Despite efforts to develop recombinant protein-based vaccines against EG95, a key protective antigen, existing platforms suffer from limited immunogenicity, short-lived immunity, and complex production processes. Here, we designed and evaluated three novel mRNA-LNP vaccines, including EG95 mRNA-LNP vaccine, IL-4-EG95 mRNA-LNP vaccine encoding EG95 fused with IL-4 via a flexible linker to enhance immune stimulation, and EG95-EC95 mRNA-LNP vaccine that multivalent formulation incorporating EC95 antigens from Echinococcus canadensis. The vaccine candidates were efficiently encapsulated in lipid nanoparticles and demonstrated robust target expression in vitro and in vivo. Immunization induced significantly stronger, more durable humoral and cellular immune responses compared to a commercial EG95 subunit vaccine both in mice and lambs. Notably, high levels of specific antibodies persisted for over 12 months post-vaccination. Parasites infection challenge experiments confirmed that these three mRNA-LNP vaccines, especially the IL-4-EG95 vaccine conferred superior protection, inhibited protoscolex survival and cyst growth. These results highlight the advantages of mRNA-based vaccines in safety, scalability, and flexibility over conventional approaches, offering a promising strategy for controlling E. granulosus sensu lato transmission and reducing the zoonotic burden of CE.

Osmoregulatory stress is a critical factor in the welfare and performance of salmonids under captive rearing for aquaculture and conservation, and characterizing cellular responses to that stress may foster better husbandry. One approach for early detection of osmotic stress is gene transcriptional profiling, where a suite of qPCR assays designed for related-function genes is used to determine patterns of transcriptional responses to stress. This study describes the development, assessment and application of 28 Taqman qPCR assays for use on the OpenArray® platform as an osmoregulatory stress transcriptional profiling (OSTP) chip. The assays include key genes involved in osmoregulation (twelve), stress response (four), immune function (five), growth/metabolism (four) and endogenous controls (three). Here, using gill and liver tissues from eight salmonid species across four genera, the OSTP chip's performance was evaluated. While results showed both tissue- and species-specific transcriptional differences, the OSTP chip has considerable utility for characterizing molecular stress responses. As a test application of the OSTP chip, we performed a 24-hour saltwater challenge with Chinook salmon and applied the chip to control and challenged fish. This test confirmed the OSTP chip's capacity to detect acute osmotic stress-induced molecular genetic signatures. This OSTP chip will be useful for aquaculture practices by fostering better husbandry as well as providing a valuable tool for future studies of the osmoregulatory response of salmonid fishes to environmental stress.

The Oropouche virus (OROV) is an emerging zoonotic orthobunyavirus responsible for recurring outbreaks of febrile illness and neurological disorders in South and Central America. Despite its growing public health issues, no FDA-approved vaccines or antiviral therapies currently exist. To address this gap, a multiepitope subunit vaccine was designed to target OROV glycoproteins G1 (Gn), G2 (Gc), and the nucleocapsid (N) protein using a reverse-vaccinology (RV) approach. For vaccine construction, suitable epitopes (MHC-I, MHC-II, and linear B-cell) were selected based on percentile rank, antigenicity, allergenicity, and toxicity. However, the biophysical attributes demonstrated advantageous characteristics, including stability and solubility (GRAVY score: -0.432). The structural modelling exhibited a Ramachandran and Z scores of 91.86% (most favoured regions) and -1.81, respectively. However, the molecular docking with TLR-2 and TLR-4 receptors showed probable interactions (-1126.8 kJ/mol) and (-1239.4 kJ/mol), respectively. Moreover, dynamics simulation of the vaccine and Vaccine-TLR-4 complexes confirmed probable dynamic stability and compactness. The codon optimisation for Escherichia coli K12 expression yielded a CAI value of 1.0 and a GC content of (30-70) %, indicating optimal expression. The immune simulation predicted strong antibody-mediated and T cell-mediated immunity, including elevated IFN-γ, IgG, and memory cell populations. These findings suggest the potential of multiepitope subunit vaccines as a promising preventive candidate against OROV. However, additional experimental verification is required to confirm its immunogenicity and safety in experimental settings.

This study assessed the role that natural killer (NK) cells play in a murine model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike mRNA vaccination. Flow cytometric analyses revealed that mRNA vaccination results in recruitment and maturation of NK cells in the spleen. Primed (CD27+ CD11b+) NK cells increased from 0.35% of all CD45+ cells pre-vaccination to 2.44% at 4 d post-vaccination, while terminally mature (CD27- CD11b+) NK cells increased from 0.85% of all CD45+ cells pre-vaccination to 3.91% at 7 d post-vaccination. We next evaluated Spike mRNA and protein expression, circulating cytokines, and Spike-specific antibody and T cell responses in mice depleted of NK cells before primary or booster vaccination. Depleting NK cells prior to mRNA vaccination resulted in decreased serum levels of IL-1β and IL-6 at 6 and 24 h, respectively, after vaccination. NK depletion also caused a significant reduction in Spike mRNA expression in draining lymph nodes, with greater than 5-fold reductions in Spike mRNA copies/μL, as measured by digital droplet PCR. Three weeks post-vaccination with 1 μg mRNA LNP, Spike-specific CD25+ CD4 T cells were also significantly decreased. Despite these decreases in early pro-inflammatory cytokines, Spike mRNA expression, and Spike-specific CD4 T cells, NK depletion had little impact on Spike-specific antibody levels at 1 and 6 mo following single vaccination, as well as at 3 wk after booster vaccination. Together, these data suggest that NK cells contribute to early inflammatory responses induced by mRNA vaccination, yet their depletion does not impair the magnitude of long-term adaptive immune responses induced by this platform.

Mirror bacteria are hypothetical synthetic organisms built from molecules of opposite chirality to those used throughout nature. This primer discusses their potential dangers: because of their chiral mismatch to the natural environment, mirror bacteria could plausibly evade predation, immunity and other ecological control mechanisms to a degree never seen before. This property could simultaneously make them unprecedented invasive species and dangerous pathogens.