Tα-1 promotes splenic cDC1 maturation during the phagocytosis of ABs.

Table S1. Candidate miRNAs and their sequencing information Table S2. RNA and miRNA quality metrics of input and IP samples Table S3. Baseline characteristics.

Tα-1 inhibits RNase A-mediated miR146a-5p cleavage to promote DC maturation.

Tissue-engineering strategies combining mesenchymal stem cells (MSCs) or extracellular vesicles (EVs) with bone-regenerative scaffolds may improve healing of critical-size bone defects, yet their comparative efficacy remains unclear. We systematically searched PubMed, Embase, Scopus, Web of Science, and ProQuest for animal studies published up to July 1, 2025. Risk of bias was assessed using the SYRCLE tool. New bone formation was synthesized as bone volume/total volume (BV/TV) using conventional meta-analysis and Bayesian network fixed/random-effects models, reported as standardized mean difference (SMD) with 95% confidence interval (CI)/credible interval (CrI). Subgroup analyses were conducted by MSC source, EV use, scaffold type, anatomical site, and follow-up duration, with sensitivity analyses and assessment of publication bias. In total, 207 studies across 7 animal models were included. MSC-loaded scaffolds significantly enhanced bone regeneration compared with no treatment or scaffold alone, showing a strong short-term effect and consistent benefits at medium and long follow-up. Bone marrow MSC (BMSC)-laden scaffolds underperformed adipose-derived MSC (ADSC)-laden scaffolds, and BMSC-derived EVs further improved outcomes compared with cell-free scaffolds. Calvarial defect models demonstrated greater gains than long-bone models. Network meta-analysis suggested multi-component composite scaffolds had the highest potential for new bone formation among cell-free designs. Overall, MSCs/EVs combined with supportive scaffolds markedly increase bone regeneration in preclinical models, but heterogeneity in models, biomaterials, dosing, and outcome reporting limits direct clinical translation, underscoring the need for standardized protocols and core outcome sets. STATEMENT OF SIGNIFICANCE: This comprehensive meta-analysis incorporated network comparisons across diverse mesenchymal stem cells (MSCs) or extracellular vesicles (EVs) sources and biomaterial categories. It reveals that MSC-EVs, particularly when combined with scaffolds or hydrogels, are the most effective in improving BV/TV ratio (bone volume/total volume) and histological outcomes in animal bone defect models. These data indicate that MSC or EV-enhanced biomaterial strategies may be leading candidates for repairing critical-sized defects and provide a standardized roadmap for transitioning preclinical success into clinical practice.

7080 Background: Mucosa-associated lymphoid tissue (MALT) lymphoma is the most common subtype of marginal zone lymphoma and follows an indolent clinical course. For patients with advanced-stage disease with an indication for treatment, rituximab-based immunochemotherapy is recommended as frontline therapy; however, toxicity and tolerability remain concerns. Zanubrutinib, a next-generation Bruton tyrosine kinase inhibitor, has shown promising antitumor activity with a manageable safety profile in marginal zone lymphoma. This study aimed to evaluate zanubrutinib plus rituximab as frontline treatment for MALT lymphoma. Methods: The ZAMA study (NCT06647732), a multicenter, single-arm, phase II trial, enrolled patients aged ≥18 years with histologically confirmed CD20-positive MALT lymphoma. Eligible patients had newly diagnosed advanced-stage disease or relapsed disease after prior local therapy, had not received prior systemic treatment, and had at least one measurable lesion. Patients received rituximab (375 mg/m 2 ) plus zanubrutinib (160 mg twice daily) in 28-day cycles. Treatment was administered for six cycles, after which patients achieving complete response (CR) entered observation, while those with partial response or stable disease received two additional cycles. The primary endpoint was the CR rate as best response. Results: From October 30, 2024 to December 12, 2025, 39 patients were enrolled. At the data cutoff of January 10, 2026, 23 patients had completed protocol-specified treatment, including 14 patients who received six cycles and 9 patients who received eight cycles. The median age was 58 years (range 24–75); 7 patients were males (30.4%). Most patients (n = 21, 91.3%) had an ECOG performance status of 0–1, and 21 patients (91.3%) had Ann Arbor stage III–IV disease; two patients had relapsed disease after prior local therapy. Eighteen patients (78.2%) achieved CR, and the remaining five patients achieved PR. Treatment-emergent adverse events (TEAEs) occurred in 20 patients (87.0%); hematologic toxicity were most common: neutropenia (n = 2, 8.7%), and thrombocytopenia (n = 2, 8.7%). Grade ≥ 3 TEAEs occurred in 4 patients (17.4%), most frequently neutropenia (n = 2, 8.7%), and thrombocytopenia (n = 2, 8.7%). Conclusions: Preliminary results from the ZAMA study show that frontline zanubrutinib plus rituximab provides encouraging efficacy with manageable safety in MALT lymphoma. The study is ongoing, and patient enrollment is continuing. Clinical trial information: NCT06647732 . Baseline characteristics. Characteristics Patients (n=23) Age, years (median [range]) 58 (24-75) Sex MaleFemale 7 (30.4%)16 (69.6%) ECOG PS 0-12 21 (91.3%)2 (8.7%) Ann Arbor stage III-IV 21 (91.3%) Prior local therapy 2 (8.7%) MALT-IPI score 0 1 (4.3%) 1 21 (91.3%) 2 1 (4.3%) Bone marrow involvement 4 (17.4%)

Postnatal depression (PND) increases the risk of neurodevelopmental impairments in offspring, yet the underlying mechanisms remain elusive. Here, we identify an intergenerational signaling pathway through which maternal psychological state is encoded in breastmilk microRNAs (miRNAs) and transmitted to offspring via breastmilk small extracellular vesicles (sEVs). Using cross-fostering models, we demonstrate that maternal depression disrupts the maturation of newborn neurons in the offspring hippocampal dentate gyrus (DG), leading to cognitive deficits and depressive-like behaviors. Strikingly, gastric administration of PND-derived breastmilk sEVs to healthy pups recapitulates these neurodevelopmental phenotypes. Mechanistically, PND-induced miRNAs are packaged into breastmilk sEVs and delivered to infant brain, where they suppress mGluR8 expression in supramammillary nucleus (SuM) neurons projecting to the DG. This presynaptic mGluR8 deficiency dysregulates glutamate release, triggers aberrant synaptic transmission and calcium overload, and ultimately drives a pathological “high-frequency, low amplitude” neuronal activation pattern that compromises the functional integration of newborn neurons into hippocampal circuits. Critically, inhibiting sEV secretion from the mammary gland or sequestering the culprit miRNAs within offspring SuM neurons rescues these neurodevelopmental deficits. Together, these findings establish breastmilk sEV miRNAs as an epigenetic vector that translates maternal psychological state into maladaptive programming of offspring brain circuitry and behavior.

CRISPR‐Cas13d system decreased miR146a-5p expression.

Tα-1 facilitates migration of cutaneous cDC1s during the phagocytosis of ABs.

Time-series single-cell RNA sequencing enables longitudinal tracking of biological processes, yet cellular trajectory reconstruction informed by experimental time remains challenging. Existing trajectory inference methods either perform de novo reconstruction without leveraging experimental time points, or prioritize transitions between time points while paying less attention to intra-time-point dynamics. To reconcile experimental time points with local precision, we present CellDyc, a semi-supervised learning framework that leverages experimental time-point supervision to reconstruct transcriptomic velocities and recover an intrinsic gene-embedded time. CellDyc consistently outperforms existing approaches in reconstructing cellular trajectories across development, disease, and reprogramming contexts. Biologically, CellDyc provides novel insights, such as resolving temporal heterogeneity in erythroid maturation and quantitatively demonstrating that the immunosuppressive environment delays monocyte differentiation in glioblastoma. CellDyc integrates seamlessly with downstream tools like CellRank and remains robust even when only inferred temporal information is available. Collectively, CellDyc offers a rigorous, data-driven solution for deciphering time-resolved cellular dynamics.

Research on host-associated microorganisms has been dominated by barrier-surface communities, especially the gut microbiome. Yet, humans also harbor a less visible layer of long-term microbial association: persistent intracellular extraintestinal microbes (PIEM) that reside in internal tissues or circulating cells outside classical mucosal and barrier niches. These organisms—including latent viruses and other persistent intracellular or cell-associated microbes—are typically studied as pathogens, but their biological impact may extend beyond overt infection. We propose that PIEMs represent an underappreciated regulatory dimension of the human metaorganism. Their importance lies not in biomass, but in persistence, strategic cellular tropism, latency–reactivation dynamics, and the capacity to tune host setpoints—that is, durable baseline thresholds of immune, vascular, metabolic, and tissue responses. Human cytomegalovirus (HCMV) provides a tractable model for this framework because of its high prevalence, lifelong latency, broad cell tropism, and ability to deploy regulatory proteins and noncoding RNAs, including circulating viral miRNAs. Here we argue that HCMV illustrates a continuum from regulated persistence to disease-promoting dysregulation, with implications for inflammatory, vascular, neoplastic, and age-related disorders. At the same time, many disease associations remain correlational, and distinguishing microbial drivers from passengers or biomarkers will require rigorous causal frameworks. Expanding microbiome thinking beyond the gut may therefore open a new frontier in systems medicine, linking persistent internal host-associated microbes to human homeostasis, disease susceptibility, and precision diagnostics.

Postnatal depression (PND) increases the risk of neurodevelopmental impairments in offspring, yet the underlying mechanisms remain elusive. Here, we identify an intergenerational signaling pathway whereby maternal psychological state is encoded in breastmilk microRNAs (miRNAs) and transmitted to offspring via breastmilk small extracellular vesicles (sEVs). Using cross-fostering models, we demonstrate that maternal depression disrupts offspring hippocampal dentate gyrus (DG) newborn neuron maturation, causing cognitive deficits and depressive-like behaviors. Strikingly, gastric administration of PND-derived breastmilk sEVs to healthy pups recapitulates these neurodevelopmental phenotypes. Mechanistically, PND-induced miRNAs are packaged into breastmilk sEVs and delivered to infant brain, where they suppress mGluR8 expression in supramammillary nucleus (SuM) neurons projecting to the DG. This presynaptic mGluR8 deficiency dysregulates glutamate release, triggers aberrant synaptic transmission and calcium overload, and ultimately drives a pathological “high-frequency, low amplitude” neuronal activation pattern that compromises the functional integration of newborn neurons into hippocampal circuits. Critically, inhibiting sEV secretion from the mammary gland or sequestering the culprit miRNAs within offspring SuM neurons rescues these neurodevelopmental deficits. These findings not only uncover a novel mechanism underlying PND-related offspring neurodevelopmental impairments, but also provide a promising therapeutic target for clinical intervention of intergenerational transmission of maternal mental disorders.

Background Human cytomegalovirus (HCMV) infection is related to the acceleration of transplant vascular sclerosis, atherosclerosis, and coronary restenosis. A shared theme of these vascular illnesses is pathologic angiogenesis. Nevertheless, how HCMV infection causes angiogenesis is not fully understood. Human serum contains HCMV-encoded miRNAs, and it is unclear whether these virus-derived miRNAs can regulate angiogenesis. This research looks into HCMV-encoded miRNA's role in angiogenesis of endothelial cells.Methods Endothelial cell proliferation was examined by CCK8 assay, and cell migration capability was established using a Transwell Boyden Chamber. Western blotting alongside luciferase reporter assay verified the direct regulation of FOXO3 by HCMV-encoded miRNAs, including hcmv-miR-UL36-3p. hcmv-miR-UL36-3p's pro-angiogenic action was examined by angiogenesis assays (in vivo) and capillary tube formation (in vitro), which were performed by giving C57BL/6J mice subcutaneous Matrigel injections containing bFGF along with simultaneous injections of either hcmv-miR-UL36-3p or ncRNA once every 4 days. After 8 days, Matrigel plugs were examined.Results hcmv-miR-UL36-3p was upregulated in patients with atherosclerosis. Overexpression of hcmv-miR-UL36-3p enhanced capillary tube development, motility, and proliferation in endothelial cells. hcmv-miR-UL36-3p promoted endothelial cell tube formation through directly binding to and downregulating FOXO3. Experiments in mice further confirmed that hcmv-miR-UL36-3p promoted angiogenesis in vivo.Conclusions The HCMV-encoded miR-UL36-3p can trigger angiogenesis in endothelial cells by targeting FOXO3. Our work provides a conceivable mechanism of how HCMV-encoded miRNAs contribute to vascular illness.

Deletion of TLR7 impairs Tα-1-mediated DC maturation when phagocytosis of ABs.

Endometriosis is a chronic estrogen-dependent disorder affecting up to 10% of women of reproductive age, and the absence of reliable noninvasive diagnostic tools contributes to delayed diagnosis and disease progression. To identify potential biomarkers, we profiled miRNA expression in serum, saliva, and vaginal mucus from 20 women (10 with endometriosis and 10 controls) using next-generation sequencing. Differentially expressed miRNAs were identified, and their predicted targets underwent Gene Ontology and KEGG pathway enrichment analyses. Serum proteomics by data-independent acquisition LC–MS/MS was integrated with miRNA data to construct potential miRNA–protein interaction networks. Distinct miRNA profiles were observed across the three bodily fluids, with serum showing the most abundant miRNAs and saliva the lowest. Thirteen, three, and six differentially expressed miRNAs were detected in serum, saliva, and vaginal mucus, respectively. Enrichment analysis implicated apoptosis, Wnt signaling, autophagy, and cellular senescence. Integrated analysis revealed 59 upregulated serum proteins targeted by dysregulated miRNAs, including WNK2, CD44, USP15, GNAI3, HUWE1, and NRAS. ROC analysis suggested that serum miR-200a-3p and miR-200b-3p, may have potential utility as noninvasive biomarkers for the diagnosis and monitoring of endometriosis, pending further validation.

Maternal obesity is linked to heightened metabolic disease risk in offspring, but the mediators of this intergenerational effect remain unclear. Using a diet-induced obesity (DIO) mouse model, we showed that maternal circulating small extracellular vesicles (sEVs) crossed the placenta and delivered obesity-associated miRNAs to the fetal liver, with lasting consequences for insulin sensitivity in male offspring. Among these miRNAs, miR-29a-3p was pathologically elevated and targeted both DNA methyltransferases and demethylases, thereby reshaping the DNA methylation landscape. This included hypomethylation of the Pgc-1α locus, a key regulator of gluconeogenesis, which resulted in premature activation of hepatic gluconeogenesis that contributed to the persistent metabolic dysfunction in adulthood in male offspring. These findings identify a transplacental sEV-miRNA-epigenetic axis that perturbs fetal metabolic programming and may represent a conserved mechanism underlying the developmental origins of metabolic disease. The study identifies a transplacental sEV–miRNA–epigenetic axis as a mediator of maternal obesity. Maternal plasma sEVs transfer miR-29a-3p to the fetal liver, epigenetically reprogramming glucose metabolism and driving adult insulin resistance.

OBJECTIVE:Circulating non-coding small RNAs (sRNAs) have recently emerged as promising biomarkers for Mycobacterium tuberculosis (Mtb). However, little is known about the expression patterns and combined diagnostic potential of M. tuberculosis-derived sRNA (TB-sRNA) and endogenous miRNA in the circulation of patients with multidrug-resistant tuberculosis (MDR-TB). METHODS:Illumina sequencing by synthesis technology and quantitative real-time polymerase chain reaction were used to identify TB-sRNAs in serum and sputum from patients infected with drug-resistant TB, drug-sensitive TB (DS-TB), and controls. Simultaneously, four endogenous miRNAs - miR-29c, miR-132, miR-320b, and miR-548e - were chosen for further study. The diagnostic performance of significantly altered sRNAs and miRNAs was analysed using receiver operating characteristic (ROC) curves. RESULTS:Illumina sequencing by synthesis combined with individual quantitative real-time polymerase chain reaction verification successfully identified one TB-encoded sRNA, named TB-sRNA015, and endogenous miR-132 were significantly elevated in patients with MDR-TB compared to patients with DS-TB and controls (P < 0.01). ROC analyses showed that the area under the ROC curve (AUC) for serum sRNA015 discriminating patients with MDR-TB from controls and patients with DS-TB were 0.774 (95% confidence interval [CI], 0.653-0.895) and 0.692 (95% CI, 0.560-0.825), respectively. For serum miR-132, the AUCs were 0.841 (95% CI, 0.735-0.946) for MDR-TB vs. controls and 0.655 (95% CI, 0.518-0.793) for MDR-TB vs. DS-TB. Importantly, combining sRNA015 with miR-132 increased the AUC to 0.860 (95% CI, 0.760-0.960) for discriminating MDR-TB from controls. CONCLUSIONS:The combination of serum sRNA015 and miR-132 may serve as an auxiliary diagnostic tool for MDR-TB infection.

Prognostic prediction models can aid clinical decision-making for high-risk non-small cell lung cancer (NSCLC) patients. We conducted a systematic search across multiple databases and evaluated eligible studies using PRISMA and PROBAST checklists. Of 28,833 references screened, 233 studies describing 268 models were included. Among them, 89 underwent external validation; 67 (75.28%) were classified with high risk for bias. Most models were developed in North America (45.06%). The median area under the receiver operating characteristic curve (AUC) for 1-, 3-, and 5-year predictions were 0.759, 0.720, and 0.691, respectively. The most common predictors were age (54.85%) and stage (58.21%). And, 47.01% of models were sex-specific. Recently, easily accessible radiomic features have been increasingly used in statistical modeling compared to molecular omics. Models integrating radiomic and clinical features showed potential for improved performance (1-, 3-, and 5-year AUCs: 0.931, 0.985, 0.942). Model discrimination varied across different studies, and there is a lack of model calibration and clinical utility. This review highlights advances and limitations in NSCLC prognostic models. To enhance model reliability and generalizability, it remains crucial to adhere to the TRIPOD guideline to perform prediction model study, and to emphasize comprehensive model validation and bias-reduction strategies. Following a step-by-step guide to develop and validate clinical prediction models by Efthimiou, et al. (BMJ, 2024), along with a multifaceted, multidisciplinary and multi-regional approach, is the key way to facilitate the development and clinical application of qualified models.

Background:To date, no robust, non-invasive biomarker for breast cancer (BC) diagnosis has been identified. The study aimed to develop a circulating microRNA (miRNA or miR)-based diagnostic model and explore potential mechanisms of miRNA regulating DNA damage sensitivity. Methods:A differential analysis was performed on The Cancer Gene Atlas (TCGA)-Breast Invasive Carcinoma (BRCA) and Gene Expression Omnibus (GEO) datasets. Three machine-learning algorithms were employed to screen key circulating miRNAs. The serum miRNA levels were detected using real-time quantitative polymerase chain reaction (RT-qPCR). The effect of miR-139-3p on sensitivity to DNA damage and the underlying mechanisms were investigated in vivo and in vitro. Results:Our diagnostic model was based on the identification of four miRNAs (i.e., miR-139-3p, miR-134-3p, miR-629-3p, and miR-191-3p). The model achieved high diagnostic performance in two external datasets and a clinical cohort, which had area under the curve (AUC) values of 0.952, 0.847, and 0.869, respectively. The survival analysis showed that high levels of miR-139-3p were only linked with a better prognosis in the subgroups of patients that underwent chemotherapy [hazard ratio (HR) =0.6, P<0.001]. The overexpression of miR-139-3p in BC cells enhanced cisplatin, olaparib, and irradiation (IR) sensitivity. MiR-139-3p was found to target RPA2 directly, and the overexpression of RPA2 counteracted the effect of miR-139-3p on homologous recombination (HR) repair and DNA damage sensitivity. Conclusions:The diagnostic model based on the four circulating miRNAs could serve as a tool for the liquid biopsy of BC. Targeting the miR-139-3p/RPA2 axis may have potential in modulating the DNA damage pathway in BC.

Tumor appearance and weight measurements in mouse transplantation model.