Search Results (672)

Visceral white-nodules disease (VWND), caused by Pseudomonas plecoglossicida, poses a severe threat to the large yellow croaker (Larimichthys crocea) aquaculture industry. Although breeding resistant strains is a promising strategy, the molecular basis of disease resistance in this host remains poorly understood. Here, 1500 fish were artificially infected, and extreme phenotypes (30 resistant, RL; 30 susceptible, SL) were selected based on survival time and liver pathogen load. Liver histopathology revealed that RL fish maintained intact architecture with only mild vacuolation, whereas SL fish exhibited widespread necrosis, inflammation, and hemosiderin deposition. Consistently, RL fish showed lower MDA levels and higher GSH-Px activity and TAC. Transcriptomic analysis identified 172 differentially expressed genes (DEGs): RL fish were characterized by upregulation of anti-inflammatory and tissue-protective genes (Epo, CAV3) and downregulation of pro-coagulant factors (PAI1, K1kb1). Proteomic analysis identified 111 differentially expressed proteins, with significantly enriched pathways including the peroxisome, pentose phosphate, and phagosome pathways. Integrated cross-omics analysis revealed eight co-enriched KEGG pathways; among them, arginine/proline metabolism, phagosome, oxidative phosphorylation, and focal adhesion were consistently upregulated in the RL group. These findings suggest that effective resistance to VWND in L. crocea may involve a coordinated, multi-layered defense program encompassing redox balance, regulated immune responses, metabolic reprogramming, and cellular homeostasis. Cross-omics-supported candidate factors (e.g., P4ha1, COX6B, RAB5A, CAV3) represent promising targets for functional validation via DNA-level experiments in independent sample sets, and the prominent enrichment of arginine-proline metabolism indicates a potential target for dietary intervention that merits further investigation. Full article

Background: Post-treatment erythrocytosis (PT-E⁺)—an increase in red blood cell counts after therapy—is an uncommon but reproducible finding in a subset of Hodgkin lymphoma (HL) survivors, and its biological basis remains undefined. Methods: A targeted DNA sequencing panel of 33 genes was used at diagnosis and during follow-up in PT-E⁺ patients and HL controls who did not develop erythrocytosis (E⁻; those without increased red blood cells). Germline (inherited) and somatic (acquired) genetic variants were compared, and changes in variant frequency over time were assessed. Results: PT-E⁺ patients had a unique molecular profile. They showed inherited variants in genes that regulate oxygen sensing and red blood cell production (EPAS1, EGLN3, HIF3A, PKLR, SH2B3, and RAB4B-EGLN2). Rare, acquired mutations affecting hypoxia, HIF, and EPO pathways (EGLN1/2/3, EPAS1, HIF1A/3A, VHL, EPO, and PKLR) were also found. These changes did not appear in E⁻ controls, who instead had common clonal hematopoiesis mutations (DNMT3A, TET2, ASXL1, and JAK3). Most somatic variants in the hypoxia pathway in PT-E⁺ patients decreased or disappeared after treatment, which suggests these changes are temporary and influenced by the surrounding environment. Conclusions: PT-E⁺ is biologically different from polycythemia vera and from idiopathic or JAK2-unmutated erythrocytosis. Both inherited risk and HL-related hypoxic or inflammatory stress are present. This supports a two-hit model, in which genetically primed red blood cell pathways respond strongly to disease-related triggers. These results suggest a new way to understand erythrocytosis after HL treatment. Full article

Rab proteins are key members of the Ras superfamily that regulate vesicular trafficking in eukaryotic cells, ensuring accurate cargo transport and cellular homeostasis. To investigate the functional role of Rab proteins, RNA interference (RNAi) was employed to silence LmRab11A in Locusta migratoria, followed by integrated transcriptomic and metabolomic analyses. Transcriptomic profiling identified 54 downregulated and 71 upregulated genes upon LmRab11A knockdown. Based on Log2 fold change values and statistical significance, 15 downregulated genes were selected for further analysis. RT-qPCR validation confirmed that 9 of these genes were significantly downregulated following LmRab11A silencing. Subsequent RNAi-mediated knockdown of these 9 genes revealed that silencing of only LOCMI11062 (β-tubulin) resulted in 100% mortality and severe morphological defects in locust nymphs, indicating its critical role in development. Metabolomic analysis identified 11 significantly altered metabolites, including 8 exhibiting increased abundance and 3 exhibiting decreased abundance. Spearman correlation analysis between the 9 downregulated genes and the altered metabolites suggested potential associations between 6 metabolites and specific genes. Collectively, these findings demonstrate that suppression of LmRab11A disrupts downstream gene expression and alters the metabolite network, thereby impairing growth and development. Full article

Understanding adaptive evolution has long fascinated evolutionary biologists. Adaptive phenotypic divergence is often driven by modifications to protein-coding sequences. The Rhinolophus macrotis group exhibits relatively lower echolocation frequencies relative to body size compared with other rhinolophids, implying distinct evolutionary trajectories. Transcriptomes bridge genotypes and phenotypes. Here, we sequenced brain, liver and cochlea transcriptomes from one individual per species representing five taxa of the macrotis group. We performed comparative transcriptomic analyses and detected signals of positive selection. Seven hearing-related genes (CRYM, FOXM1, MAP6, PYCARD, SLC35A2, WRB and SPRY2) were under positive selection. Unexpectedly, we also identified five vision-associated positively selected genes (ARRDC3, LZTFL1, RAB8A, IGFBPL1 and TRNT1) in taxa with relatively lower echolocation frequencies within the macrotis group, indicating selection on sensory genes. Furthermore, candidate positively selected genes were significantly enriched in metabolism-related GO terms such as catalytic and oxidoreductase activity. Our study offers valuable transcriptomic resources for unraveling adaptive genetic mechanisms in horseshoe bats. Full article

Background/Objectives: Persicaria senticosa (Meisn.) H.Gross (PS) has anti-photoaging, anti-inflammatory, and antioxidant activities, but the anti-pigmentation potential of the PS flower absolute (PSFAb) remains largely unexplored. This study aimed to examine the chemical composition and anti-melanogenic and melanosome transport-inhibitory effects of PSFAb using B16BL6 murine melanoma cells. Methods: PSFAb was extracted with hexane and analyzed by gas chromatography–mass spectrometry (GC-MS). The biological activities in B16BL6 murine melanoma cells were evaluated using water-soluble tetrazolium salt (WST) assays, 5-bromo-2′-deoxyuridine (BrdU) incorporation, enzyme-linked immunosorbent assays, and immunoblotting methods. Results: GC-MS analysis identified eight constituents in PSFAb. Cell viability was not significantly altered in B16BL6 cells at concentrations ≤ 100 μg/mL, which were used for additional tests. PSFAb inhibited serum-induced cell proliferation and suppressed α-melanocyte-stimulating hormone (α-MSH)-induced melanin synthesis and tyrosinase activity in B16BL6 cells. PSFAb also downregulated the α-MSH-induced expression of key melanogenic regulators, including microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related protein-1 (TRP-1), and TRP-2. PSFAb decreased extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase phosphorylation but enhanced JNK phosphorylation in α-MSH-stimulated B16BL6 cells. Furthermore, PSFAb reduced the α-MSH-induced expression of melanosome transport-related proteins (melanophilin and Rab27a) in B16BL6 cells. Conclusions: Overall, these results suggest that PSFAb has the potential to exert anti-pigmentation effects by suppressing melanogenesis and downregulating melanosome transport-related proteins. Therefore, PSFAb may be a promising candidate for the development of natural agents targeting hyperpigmentation and skin pigmentation regulation. Full article

Although gastrointestinal distress is both common and debilitating in individuals with autism spectrum disorder (ASD), underpinning mechanisms—and therefore effective management strategies—are not fully elucidated. The current study employed well-established valproic acid ASD model in larval zebrafish to more comprehensively characterize mitochondrial dysregulation. Whole body redox status and mitochondrial respiration, as well as protein expression in the mitophagy-lysosomal axis in the mid-intestine was assessed. In addition, high-resolution microscopy of the gut was used to assess mitochondrial morphometrics and distribution. Redox imbalance was evident from increased oxygen radical levels and decreased endogenous antioxidant capacity, as well as depression of whole body mitochondrial respiration. Upregulation of endo-lysosomal pathway markers (Rab5, LAMP1) together with reduced expression in mitophagy and autophagy markers (PINK1, LC3B) suggests a potential impairment of canonical mitophagy in the ASD-like gut. High-resolution imaging further revealed smaller, more circular mitochondria, indicative of a morphological fission bias. Abnormal mitochondrial distribution patterns were also evident. Together, current data points to primary mitochondrial dysfunction as a potential feature of the ASD-like gut. Furthermore, data suggest potential insufficiencies in mitochondrial recycling as potential role player in ASD-associated (gut) mitochondrial pathology. Full article

Background: Malignant peripheral nerve sheath tumors (MPNSTs) are deadly sarcomas that arise from Schwann cells and lack effective therapies. RABL6A is an oncogenic Rab-like GTPase whose expression is associated with worse survival in many human cancers. It is required for human MPNST cell survival, and its expression is dramatically increased in patient MPNSTs compared to benign precursor lesions. Methods: To model elevated expression of RABL6A in vivo, we developed transgenic mice expressing Cre-inducible Rabl6a. These Rabl6a-tg mice express the murine Rabl6a cDNA with a 5′ hemagglutinin [HA] epitope sequence downstream of a CMV enhancer and separated by a lox–stop–lox cassette. Double transgenic DhhCre; Rabl6a-tg mice were generated to achieve Schwann-cell specific Cre expression from the Desert hedgehog (Dhh) promoter. De novo MPNSTs were induced by CRISPR editing of Nf1, Ink4a, and Arf genes in the mouse sciatic nerve. Results: Cre-dependent expression of transgenic Rabl6a was verified at the mRNA and protein levels in Cre-positive mouse embryo fibroblasts and tissues. Increased Rabl6a expression in DhhCre; Rabl6a-tg mice had no effect on de novo MPNST initiation but significantly accelerated tumor progression relative to DhhCre control mice. The Rabl6a phenotype was associated with increased tumor angiogenesis but not proliferation. Interestingly, many MPNSTs in the DhhCre background exhibited varying levels of rhabdomyoblastic (RMB) features. That immature muscle cell phenotype is a hallmark of malignant Triton tumors, a rare histological variant of human MPNSTs associated with worse outcomes. Conclusions: These data provide direct evidence that Rabl6a is a functional driver of MPNSTs while establishing Rabl6a-tg mice as a suitable model for investigating Rabl6a’s role in other lethal RABL6A-high tumors. Full article

Background: Heart transplantation (HT) remains the definitive therapy for end-stage heart failure, yet rejection and cardiac allograft vasculopathy (CAV) continue to limit long-term outcomes. Beyond donor-specific HLA antibodies, non-HLA antibodies, particularly anti-angiotensin II type 1 receptor antibodies (AT1R-Abs), have been implicated in allograft injury, but published findings are heterogeneous. Aim: The aim of this study is to systematically evaluate the evidence linking AT1R gene expression and anti-AT1R antibodies with key post-heart transplant outcomes. Methods: We conducted a systematic review in accordance with PRISMA guidelines. Scopus, PubMed, Web of Science, and the Cochrane Library were searched (December 2025) for cohort and case–control studies evaluating AT1R gene expression and/or AT1R-Ab status in HT recipients and their association with post-transplant outcomes. Two reviewers independently screened studies, extracted data, and assessed risk of bias using the NIH Quality Assessment Tool. Results: Twelve studies encompassing 951 recipients met the inclusion criteria. Five studies evaluated AT1R mRNA expression, reporting variable patterns: several observed reduced AT1R/AT2R transcription after transplantation without clear clinical correlation, whereas others associated higher donor or recipient AT1R expression with transplant coronary artery disease and recurrent rejection. AT1R-Ab prevalence varied widely and appeared to increase after mechanical circulatory support, with substantial seroconversion reported during LVAD support in initially antibody-negative patients. Associations between AT1R-Ab and acute cellular rejection and antibody-mediated rejection were inconsistent across studies, and survival findings were inconclusive; however, some reports linked elevated AT1R-Abs to poorer long-term freedom from adverse events. Evidence regarding CAV was mixed, with signals of increased vasculopathy risk in some cohorts but not others. Conclusions: Current evidence suggests a potential role for AT1R expression and AT1R-Abs in cardiac allograft dysfunction, including rejection phenotypes and vasculopathy. Larger prospective studies with harmonized testing strategies are needed to define clinically meaningful AT1R-Ab cutoffs and clarify their utility in risk stratification and targeted therapeutic trials. Full article

Current research primarily focuses on post-treatment resistance, leaving the immediate impact of cisplatin on the tumor–immune interaction poorly understood. Tumor cells were co-cultured with immune cells to assess immune cell activation. The correlation with RAB27A/B and CD274 expression levels in non-small cell lung cancer (NSCLC) were analyzed using TCGA. The relationship between RAB27A/B and the tumor microenvironment was assessed by TIMER2.0. Cisplatin significantly increased PD-L1 mRNA levels and surface protein expression, detected by qPCR, flow cytometry and confocal microscopy. In the co-culture assay, cisplatin-induced cell surface PD-L1 protein levels inhibited the activation of Jukat T-cells. Cisplatin also upregulated genes associated with exosome secretion and increased total exosome particle counts and secretion per cell. Pretreatment with GW4869, an exosome release inhibitor, significantly enhanced cisplatin sensitivity in HCC827 cells. While GW4869 reduced intracellular RAB27A/B and EV PD-L1 levels, it did not alter cellular PD-L1 expression. Bioinformatic analysis further revealed that high RAB27A/B expression correlates with poor 5-year survival in NSCLC and is negatively associated with CD8+ T-cell activation, while positively correlating with cancer-associated fibroblasts. Both RAB27A and RAB27B gene expression levels positively correlated with CD274. Conclusions: RAB27A and RAB27B may be crucial proteins in modulating cisplatin-induced exosomal PD-L1 levels and the tumor microenvironment. Full article

Eosinophils are highly granulated white blood and tissue cells that play complex roles in the immune system including host protection against helminthic parasites, viruses, fungi, and bacteria. These bone marrow-derived cells cause tissue damage in a range of diseases and disorders, particularly in allergy, asthma, and chronic rhinosinusitis with nasal polyps. Eosinophils are recruited to tissues in response to chemotactic signals, and during inflammation, they release a plethora of mediators, including immunoregulatory cytokines, through multiple pathways involving degranulation, respiratory burst, lipid mediator release, exosome release, and extracellular trap formation. Degranulation from eosinophils has been implicated as a major effector mechanism in airway diseases, particularly late phase asthma responses and in nasal polyps from patients with chronic rhinosinusitis. In degranulation responses, eosinophils release numerous granule proteins by classical exocytosis, compound exocytosis, piecemeal degranulation, and cytolysis, which refers to cell lysis through membrane rupture and cell destruction. Cytolysis can lead to suicidal extracellular trap formation, which is a regulated form of cell death involving the release of extracellular DNA traps and granule proteins. Granule release from eosinophils is dependent on activation of specific and tightly regulated intracellular signaling pathways, including Rac and Rab guanosine triphosphatases, soluble NSF attachment protein (SNAP) receptors (SNAREs), Cdk5 kinase, and actin dynamics. These observations have shown selective and nonredundant roles for signaling in degranulation responses. In this review, we explore findings from the literature on the mechanisms controlling granule-derived mediator release from eosinophils. Full article

Porcine reproductive and respiratory syndrome (PRRS) is an immunosuppressive disease caused by PRRS virus (PRRSV). PRRSV infection not only compromises the host immune defenses, but also predisposes the host to secondary infections by other pathogens, of which PRV is one of the common secondary infection pathogens. Porcine alveolar macrophages (PAMs) are the primary target cells of PRRSV, and their phagocytic function is critical for immune defense, homeostasis maintenance, and disease regulation. However, PRRSV disrupts PAMs phagocytosis, impairing the host’s ability to combat infection. This study used PRV-pAb complexes as phagocytic indicators, investigated the effect of PRRSV infection on PAMs phagocytosis and its underlying molecular mechanisms. We found that PRRSV infection interfered with phagosome maturation—a process regulated by Rab7 and other regulators, thereby blocking phagocytic degradation and significantly suppressing PAMs phagocytic activity. Further analysis revealed that reactive oxygen species (ROS) play a key role in this process. Elevated ROS levels damaged lysosomal membrane integrity, ultimately inhibiting phagosome-lysosome fusion. Notably, phagocytosis of PRRSV-infected PAMs was partially restored with N-acetylcysteine (NAC) by reducing ROS levels. These findings offer novel insights into PRRSV-induced immunosuppression and secondary infections while providing a theoretical foundation for developing more effective PRRSV prevention and control strategies. Full article

Background/Objectives: Robotic-assisted bronchoscopy has emerged as an advanced technique for the evaluation of peripheral pulmonary lesions, offering improved navigation and targeting accuracy. While several studies investigating other diagnostic modalities have identified factors associated with higher diagnostic yield, such determinants remain poorly defined for shape-sensing robotic-assisted bronchoscopy (ssRAB). This study therefore aimed to identify predictors of diagnostic yield in robotic bronchoscopy. Methods: This retrospective single-center study included all consecutive patients who underwent ssRAB (ION^TM system, Intuitive Surgical, Sunnyvale, CA, USA) between August 2024 and March 2026. Lung nodules undergoing marker placement only or procedures performed without cone-beam CT (CBCT) guidance were excluded. Collected variables included demographic characteristics, lesion size, lesion density (solid, part-solid, ground-glass), biopsy modality, and number of biopsy samples obtained. Diagnostic yield was defined as a definitive pathological diagnosis of the target lesion. Predictors of diagnostic success were assessed using univariable logistic regression. Results: In total, 111 pulmonary nodules were included in the analysis. The overall diagnostic yield was 88.3% (98/111). The mean patient age was 64.94 ± 7.9 years, with a predominance of female patients (58.4%). No significant associations were observed between diagnostic yield and lesion size (odds ratio [OR] 1.014 per mm; p = 0.764), lesion density (p = 0.892), or biopsy instrument (p = 0.835). However, an increased number of biopsy samples showed a positive association with diagnostic yield, showing a statistical trend (OR 1.22 per additional sample; p = 0.084). Conclusions: Robotic-assisted bronchoscopy provides a high diagnostic yield for peripheral pulmonary lesions. The number of biopsy samples appears to be the most relevant modifiable factor influencing diagnostic success, underscoring the importance of adequate tissue acquisition. In contrast, lesion characteristics and biopsy modality did not significantly affect outcomes in this cohort. Full article

Background/Objectives: With increasing frequency in sublobar resections, accurate intraoperative localization has become essential to ensure adequate resection margins and spare lung parenchyma. Our study evaluates the efficacy of shape-sensing robotic bronchoscopy (SS-RAB) with integrated mobile cone-beam CT (mCBCT) for intraoperative localization of lung tumors using indocyanine green (ICG). We further aimed to explore the feasibility of a single intubation-single positioning technique for bronchoscopy and surgery. Methods: We retrospectively reviewed patients who underwent SS-RAB with integrated mCBCT for ICG marking, followed by minimally invasive sublobar resection. ICG marking was deemed successful when it allowed the operative team to localize and resect the lesion with adequate pathology margins. Results: A total of 28 patients with 30 pulmonary lesions from a single institution were included. Median tumor size was 10.5 mm (IQR, 8.7–14.6 mm) and distance from pleura 7.8 mm (IQR, 2.45–13.8 mm). Twenty lesions (66.6%) were solid, 5 lesions (16.6%) semi-solid, and 5 lesions (16.6%) ground-glass. ICG localization was successful in 28 lesions (93%). Nineteen patients (68%) were intubated only with a double-lumen endotracheal tube (DL-ETT), used for bronchoscopy and surgery, and in 10 patients (36%) ICG marking and surgery were both performed in lateral decubitus. One patient developed a small pneumothorax during bronchoscopy which did not prevent ICG injection. Conclusions: SS-RAB with integrated mCBCT for ICG marking is successful and safe. Single intubation with DL-ETT and lateral decubitus positioning for both bronchoscopy and surgery are feasible. Further studies are needed to prove a potential increase in efficiency with this technique. Full article