Selenocysteine (Sec), the 21st genetically encoded amino acid, plays a crucial role in cellular redox regulation and selenium metabolism. Abnormal Sec fluctuations are closely associated with inflammatory oxidative stress and the progression of inflammatory bowel disease (IBD). However, efficient tools for real-time visualization of Sec fluctuations in living systems remain highly limited. Herein, two novel mitochondria-targeted iridium(III) complex probes, Irppy-DNP and Irpiq-DNP, were successfully designed and developed based on a thiolysis-triggered phosphorescence activation strategy for Sec-responsive "turn-on" sensing. Upon reaction with Sec to generate the corresponding hydroxylated products (Irppy-OH and Irpiq-OH), the two probes exhibited distinct photophysical responses, characterized by increased photoluminescence quantum yields (2.3 → 34.3% and 1.3 → 26.9%), prolonged excited-state lifetimes (0.23 → 0.42 μs and 0.62 → 0.70 μs), and reduced nonradiative decay rates (knr) (4.25 × 106 → 1.56 × 106 s-1 and 1.59 × 106 → 1.04 × 106 s-1), respectively. In addition, the two probes exhibited excellent analytical performance, including favorable photostability (60 min), fast response time (15/20 min), low detection limit (0.79/0.70 nM), excellent selectivity and anti-interference capability, low cytotoxicity (>70% cell viability), and visualized endogenous and exogenous Sec in living cells. Especially, the probes showed high selectivity toward Sec over Cys, Hcy, and GSH, benefiting from the greater nucleophilicity of Sec-derived selenolate at physiological pH (7.4) and its efficient thiolysis of the dinitrophenyl ether moiety. Given the key role of Sec-mediated redox regulation in IBD-associated mitochondrial ROS elevation, mitochondrial targeting is essential for monitoring pathological processes, with both probes exhibiting efficient organelle localization (PCC = 0.783/0.803). Notably, Irpiq-DNP enabled longitudinal imaging of Sec fluctuations in dextran sulfate sodium (DSS)-induced colitis mice, where the luminescence intensity closely correlated with disease progression as well as therapeutic response to 5-aminosalicylic acid (5-ASA) treatment. This work provides a promising phosphorescent platform for monitoring Sec fluctuations during inflammatory processes and therapeutic intervention in IBD.

Ulcerative colitis (UC) is a chronic, relapsing condition with a rising global prevalence. At present, there is a lack of therapeutic strategies that provide both high efficacy and minimal adverse effects. Kaempferol-3-O-glucorhamnoside (KA), a natural compound derived from Thesium chinense Turcz., has demonstrated significant anti-inflammatory properties. Nevertheless, its therapeutic potential and the precise molecular mechanisms underlying its effects in UC remain unexplored. In this study, KA administration effectively ameliorated a dextran sulfate sodium (DSS)-induced murine model of UC, as indicated by the restoration of body weight, restoration of colon length, a decrease in the disease activity index (DAI), reduced levels of the pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-17, and increased expression of tight junction proteins Claudin-1, Occludin, and ZO-1. Integrated untargeted metabolomic and transcriptomic analyses revealed that the anti-inflammatory efficacy of KA is primarily mediated by the arginine and proline metabolism pathway, wherein KA enhances downstream polyamine production by modulating the Arg1/ODC/polyamine axis. Furthermore, molecular docking, molecular dynamics (MD) simulations, cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) assays demonstrated that KA directly binds to Arg1, thereby stabilizing the target protein and inhibiting its degradation. Additionally, pharmacological blockade of Arg1 using the specific inhibitor CB-1158 dihydrochloride substantially attenuated the KA-mediated activation of this metabolic pathway. Overall, KA demonstrated significant alleviative effects against experimental UC, indicating that this compound may represent a promising therapeutic candidate for UC.

Translating an image into a reference style is a widely studied problem. Sketches, as a family of highly abstract styles, are usually difficult to synthesize under general image stylization frameworks. A major challenge is that the reference style image could be semantically irrelevant to the content image. Based on recent advances in image stylization using diffusion models, we propose a novel stylized sketch synthesis algorithm that directly manipulates the latent code of the variational autoencoder using the priors of a pretrained diffusion model. In particular, we construct a unified attention distillation loss to align the self-attention layer features with content and style images. To maintain the semantic structures in the content image, we introduce a structural guidance for additional regularization. As for the guidance map, we adopt a dynamic vector sketch that is jointly optimized with the latent code. We also explore possible alternatives: using a fixed Canny edge map or using multiple guidance maps. We evaluated our method on a Diverse-Sketch-Stylization (DSS) dataset that includes various reference sketch styles and also conducted experiments on 4SKST, FS2K, and Anime datasets. The qualitative and quantitative results show that our method can transfer abstract sketch styles while faithfully conveying the original content.

The rising incidence of head and neck squamous cell carcinoma (HNSCC) is linked to both the HPV epidemic and the aging population. As a result, there is an emerging need to develop management strategies for older patients with advanced-stage HNSCC. This study aims to apply machine learning (ML) techniques to compare the effectiveness of definitive concurrent chemoradiotherapy (CRT) and radiotherapy (RT) alone in older patients (≥ 65 years) with stage III-IV non-surgically treated HNSCC. We used Kaplan-Meier (KM) survival curves, Cox proportional hazards models, and ML-based permutation feature importance (PFI) to compare the effectiveness of CRT versus single modality radiotherapy (RT) for disease-specific survival (DSS) in this population of patients with HNSCC. Finally, we used propensity-score matched (PSM) analysis to clarify if there is a significant difference between patients that received either CRT or RT alone. A total of 1525 patients with HNSCC were obtained from the Surveillance, Epidemiology, and End Results (SEER) Program to build the ML model. Furthermore, the PFI analysis evaluated the effectiveness of CRT or RT alone regarding DSS of older (≥ 65 year) patients with HNSCC. Then, we performed a 1:1 propensity-score matched (PSM) analysis to reduce treatment selection bias and to analyze the prognostic role of CRT. Our ML model showed performance accuracy of 55.5% in predicting DSS in this group with HNSCC. The aggregate feature importance showed that treatment option (CRT or RT alone) is among the four most important features for enhancing DSS among these patients. Specifically, our KM curves, Cox proportional hazards model, and PFI analyses all showed that CRT seems more feasible and effective than RT alone for older patients with stage III-IV HNSCC who did not receive surgery. In addition, patients with stage III disease had better survival rates than those with stage IV. The PSM confirmed that there are substantial differences in nearly all covariates between patients who received CRT or RT alone. The results from the SEER database provide insight into a potential survival benefit for CRT in older patients with stage III-IV HNSCC who are not candidates for surgery. This further emphasizes that treatment decisions at an advanced stage may be made according to other patient-related factors rather than chronological (calendar) age alone.

Mast cells (MCs) are increasingly recognized as modulators of intestinal homeostasis and inflammation; however, their precise contribution during colitis remains incompletely defined. Here, we investigated the role of MCs in dextran sulfate sodium (DSS)-induced colitis using a Kit-independent MC-deficient model (Cpa3-Cre; Mcl1fl/fl), in which selective deletion of the anti-apoptotic gene Mcl1 ablates MCs. Despite efficient and tissue-wide MC depletion, MC-deficient mice exhibited macroscopic and histological disease severity comparable to control mice. However, MC deficiency significantly altered epithelial and immune responses during acute intestinal injury. Specifically, MC-deficient mice displayed increased colonic MUC2 expression, together with decreased tight-junction integrity. The impaired epithelial barrier was associated with increased bacterial infiltration and selective accumulation of myeloid cells, including neutrophils, dendritic cells, and macrophages, alongside increased TNF-α and reduced VEGF levels. Systemically, in DSS-treated mice, MC deficiency was associated with splenomegaly and increased splenic neutrophils and dendritic cells. Importantly, adoptive transfer of bone marrow-derived MCs restored the epithelial barrier-associated features and reduced neutrophil accumulation. Collectively, these findings identify MCs as key regulators of epithelial-myeloid crosstalk contributing to the maintenance of barrier integrity and limiting excessive myeloid accumulation and bacterial exposure rather than acting as primary drivers of tissue injury.

Background Thromboembolic complications are common in patients with pancreatic cancer, with up to 20% of patients developing venous thromboembolism. While hypercoagulation in pancreatic cancer has been widely studied, fibrinolysis is less well characterized. Plasmin generation (PG) is a novel approach to assess fibrinolytic activity and may provide new insights into thrombotic risk in this population. This study aimed to compare the PG profile of patients with pancreatic cancer with that of healthy individuals. Methods This single-center cohort study included patients with advanced pancreatic cancer initiating chemotherapy at the Maastricht University Medical Center between 2022 and 2023. Plasma samples were obtained before chemotherapy ( t 0 ) and 8 weeks later ( t 8 ). PG and thrombin generation (TG) were measured; TG/PG ratios were calculated to evaluate the balance between coagulation and fibrinolysis. Thromboembolic events were recorded for 6 months. Results In total, 18 patients with pancreatic cancer and 18 healthy subjects were included. At baseline, patients showed higher endogenous plasmin potential levels compared with controls, whereas PG remained elevated at t 8 despite chemotherapy. PG lag time was prolonged in patients at t 8 . Patients showed lower TG/PG ratios for endogenous thrombin/plasmin potential. Five patients (28%) developed thromboembolic events. Although PG parameters were not associated with thromboembolic events, patients who developed thromboembolic events showed lower TG/PG potential ratios. Conclusion Patients with pancreatic cancer exhibited a disbalance in their PG profile, with a delayed but increased capacity to generate plasmin. Future studies are required to assess whether PG associates with thromboembolic disease and survival.

Globally, almost half of all early childhood deaths are linked to severe undernutrition, herein referred to as severe malnutrition. Mortality in severely malnourished children is often attributed to common infectious diseases, including enteric infections. It has been proposed that impaired intestinal barrier function contributes to mortality, but direct evidence is limited and thus there exists a need to develop improved preclinical models to test these and other mechanistic hypotheses. In this study, we aimed to describe differences in response to enteric inflammation and infection in the colon of malnourished mice compared to well-nourished littermates. C57Bl/6 male weanlings were fed isocaloric diets, either a low 1% protein diet (LPD) or a control 18% protein diet (CPD) for 2-weeks either in combination with oral administration of dextran sodium sulfate (DSS), or Citrobacter rodentium (C. rodentium). LPD-fed mice were more susceptible to DSS or C. rodentium as evidenced by increased clinical severity scores, and reaching their humane endpoints. LPD-fed mice also showed more signs of colonic dysfunction with reduced levels of tight junction proteins, higher colonic pathogen load, and increased systemic inflammation and bacterial spread. Taken together, these observations show that malnourished animals have increased susceptibility to intestinal dysfunction caused by either chemical exposure or infection. These novel preclinical models can be used to further elucidate the processes involved in enteric dysfunction in malnutrition and to test therapies to improve intestinal repair and outcomes.

Inflammatory bowel disease (IBD) has an intricate pathophysiology that greatly impacts patients' quality of life. Wumei Wan, a traditional Chinese medicinal formulation, exhibits specific therapeutic effects on IBD. Kaempferol (KF), an active ingredient in Wumei Wan, may significantly contribute to IBD.