To address the misclassification of visually similar ground objects and inaccurate boundary localization caused by background interference, as well as small-object omission, fragmented regions, and incomplete boundaries resulting from scale variations, this study proposes MASwin-Unet for semantic segmentation of complex mining areas. The model incorporates a Spatially Adaptive Feature Modulation Module (SAFM) to suppress background noise and similar-texture interference while enhancing key regions and boundary details. It also introduces a Multi-Scale Context Fusion Module (MSCF) to integrate contextual information across different receptive fields and improve multi-scale feature modeling. An experimental dataset was constructed from UAV imagery of the Dongshan Xiuqing Mining Area, and experiments were also conducted on AeroScapes and LoveDA. MASwin-Unet achieved an OA of 97.18%, a Kappa coefficient of 95.79%, an mIoU of 85.14%, and an mF1 of 90.73%, outperforming BEDSN, FADC, DeepLabV3 + , PSPNet, HRNet, SegFormer, TransUNet, U-Net, and Swin-Unet. The results demonstrate good generalization on public datasets and show that the model effectively reduces similar-object misclassification, small-object omission, and incomplete boundary segmentation in complex UAV scenes.

Atherosclerosis (AS) and its complications are the leading causes of death worldwide. Endothelial cell (EC) senescence plays a crucial role in the development of AS by aggravating endothelial erosion and plaque instability. Neuronal pentraxin 1 (NPTX1) is a secreted glycoprotein that plays a key role in various neurological functions, such as synaptic function, plasticity at excitatory synapses, and neurite damage. Although NPTX1 is upregulated in senescent ECs, its role in EC senescence and AS remains unknown. Here, we investigated the role of NPTX1 in ischemic stroke and its potential mechanism in regulating EC senescence and AS. Using a middle cerebral artery occlusion (MCAO) mouse model, we observed dynamic NPTX1 expression: levels were minimal at 1 h post-MCAO but surged by 12 h and persisted for 28 days. Moreover, exogenous NPTX1 administration worsened post-stroke brain injury and blood-brain barrier disruption. Notably, MCAO accelerated both AS progression and EC senescence in vivo, while neuron-derived NPTX1-enriched conditioned medium induced EC senescence in vitro. Mechanistically, RNA sequencing and pharmacological inhibition revealed that NPTX1 promotes human umbilical vein EC senescence via an AKT-related pathway, as confirmed by senescence-associated β-galactosidase staining, impaired tube formation, and altered senescence markers. Critically, adeno-associated virus-mediated NPTX1 knockdown attenuated post-stroke AS and EC senescence in mice. Finally, the knockdown of NPTX1 through a short-hairpin RNA adeno-associated virus ameliorates AS and EC senescence in post-stroke mice. These findings establish NPTX1 as a key regulator of stroke-induced EC senescence and AS pathogenesis, highlighting its therapeutic potential for AS treatment in stroke patients.

Heart rate-corrected (QTc) interval prolongation is frequently linked to fatal arrhythmias and sudden cardiac death in chronic kidney disease (CKD) patients. In this cross-sectional study, we assessed the prevalence of prolonged QTc intervals and identified clinical factors associated with them across different stages of kidney failure. 723 patients with CKD stages 2–5 who had electrocardiogram records available were analyzed retrospectively. QTc intervals were calculated by correcting the QT intervals for all patients included in the study. QTc interval prolongation defined as a QTc interval ˃ 440 ms was assessed for its prevalence and its association with various clinical factors. A total of 723 patients with CKD stages 2–5 were finally included in this study, among which 420 (58.1

Endothelial cells (ECs) are a monolayer of flat cells lining the inner surfaces of blood and lymphatic vessels. They play a key role in many physiological and pathological processes. Specifically, they maintain vascular permeability and structural stability and participate in immune responses, inflammation, coagulation, and other vital functions. ECs play a decisive role in various age-related diseases; however, their involvement in pulmonary fibrosis (PF) remains poorly understood. PF refers to a group of chronic interstitial lung diseases characterised by progressive scarring of the pulmonary parenchyma, primarily caused by aberrant tissue repair mechanisms. These changes lead to irreversible loss of lung function. Although the exact pathophysiological mechanism underlying PF has not yet been elucidated, recent studies have indicated that ECs may play a pivotal role in PF. This review outlines the involvement of pulmonary vascular ECs in PF, focusing on the regulation of vascular remodelling and endothelial barrier integrity and on the maintenance of angiogenesis through EC-specific markers, such as vascular endothelial growth factor. This review also explores processes such as endothelial-to-mesenchymal transition, immune cell interactions, anti-EC antibody reactions, metabolic dysregulation, and cellular senescence. By elucidating recent advancements in understanding the role of ECs in PF and examining drugs targeting ECs for the treatment of PF, this study provides novel insights into the pathological mechanisms of PF and the development of endothelium-based therapeutic agents.

Gemcitabine is a widely employed first-line chemotherapeutic drug for pancreatic cancer (PCa). However, the rapid emergence of gemcitabine resistance poses a major clinical hurdle. Here, we identified REG3A as a crucial determinant of poor prognosis in PCa. Notably, REG3A was upregulated in tumor tissues from clinical gemcitabine-resistant PCa patients. Through comprehensive in vitro cellular assays and in vivo studies using Reg3g (the murine homolog of REG3A) knockout mice, we demonstrated that REG3A deficiency sensitized PCa to gemcitabine treatment. Mechanistically, RNA sequencing (RNA-Seq) combined with Protein-Protein Interaction (PPI) analysis revealed that REG3A functioned as an exocytosis protein binds to the novel membrane receptor GPR54. The interaction increased membrane localization of GPR54, which subsequently engaged ARRB2 as a scaffolding molecule, leading to activation of the ERK1/2 pathway and suppression of gemcitabine-induced apoptosis. Moreover, the GPR54 agonist KP10 synergistically enhanced gemcitabine resistance in conjunction with REG3A, while interference with GPR54 or its antagonist KP234 attenuated REG3A-induced gemcitabine resistance. Targeting REG3A or pharmacologically inhibiting its downstream signaling molecules may represent a promising strategy to overcome gemcitabine resistance. Overall, REG3A could serve as a potential biomarker for gemcitabine resistance in PCa, offering a new avenue for therapeutic intervention and patient stratification.

Purpose Myelodysplastic neoplasms (MDS) are heterogeneous neoplasms that originate from bone marrow (BM) hematopoietic stem cells. S100A8 and S100A9 (S100A8/9) are crucial molecules involved in the innate immune pathogenesis of MDS. This study aimed to explore the value of these molecules in the differential diagnosis of MDS, and analyze the correlations between their concentrations and clinical characteristics. Methods We measured the concentrations of S100A8/9 in BM supernatant from patients newly diagnosed with MDS (n = 80) or aplastic anemia (AA) (n = 26) by enzyme-linked immunosorbent assay (ELISA). Correlations between clinical characteristics and S100A8/9 were explored based on patients' clinical information. Results Our study found the concentrations of S100A8/9 in the BM supernatant of MDS patients were significantly higher than those in AA patients (Both P < 0.05). The concentrations of S100A8/9 in the group of very low/low/partial intermediate (IPSS-R score ≤ 3.5) risk MDS patients were also higher than those in AA patients (Both P < 0.05). The serial or parallel diagnostic tests combining these two molecules for differentiating IPSS-R score ≤ 3.5 MDS and AA yielded high positive or negative predictive values, respectively. Moreover, the concentrations of S100A8/9 in MDS patients were positively correlated with the patients' age and the proportion of granulocytic series in BM (All P < 0.05). Meanwhile, the concentrations of the two molecules had significantly negative correlations with the proportion of erythrocytic series in BM (Both P < 0.05). However, intergroup differences in concentrations of S100A8/9 were not significant among different MDS risk groups, whether by IPSS-R or IPSS-M (All P > 0.05). Conclusion The concentrations of S100A8/9 in BM supernatant have potential value in the differential diagnosis of MDS and AA. The correlations between the molecules' concentrations and clinical characteristics could provide new perspectives for future research in MDS.

Near-infrared-II (NIR-II) fluorescence imaging is pivotal in biomedical research. Organic probes exhibit high potential in clinical translation, due to advantages such as precise structure design, low toxicity, and post-modifications convenience. In related preparation, enhancement of NIR-II tail emission from NIR-I dyes is an efficient method. In particular, the promotion of twisted intramolecular charge transfer (TICT) of relevant NIR-I dyes is a convenient protocol. However, present TICT-type probes still show disadvantages in relatively low emission, large particle sizes, or limited choice of NIR-I dyes, etc. Herein, the synthesis of stable small-sized polymer NIR-II fluoroprobes (e.g., 7.2 nm), integrating TICT and Förster resonance energy transfer process to synergistically enhance the NIR-II emission is reported. Strong enhanced emissions can be obtained from various NIR-I dyes and lanthanide elements (e.g., twelvefold at 1250 nm from Nd-DTPA/IR-808 sample). The fluorophore provides high-resolution angiography, with high-contrast imaging on middle cerebral artery occlusion model mice for distinguishing occlusion. The fluorophore can be rapidly excreted from the kidney (urine ≈65% within 4 h) in normal mice and exhibits long-term renal retention on acute kidney injury mice, showing potential applications in the prognosis of kidney diseases. This development provides an effective strategy to design and synthesize effective NIR-II fluoroprobes.

Deubiquitinases are a group of proteins that identify and digest monoubiquitin chains or polyubiquitin chains attached to substrate proteins, preventing the substrate protein from being degraded by the ubiquitin-proteasome system. Deubiquitinases regulate cellular autophagy, metabolism and oxidative stress by acting on different substrate proteins. Recent studies have revealed that deubiquitinases act as a critical regulator in various cardiac diseases, and control the onset and progression of cardiac disease through a board range of mechanism. This review summarizes the function of different deubiquitinases in cardiac disease, including cardiac hypertrophy, myocardial infarction and diabetes mellitus-related cardiac disease. Besides, this review briefly recapitulates the role of deubiquitinases modulators in cardiac disease, providing the potential therapeutic targets in the future.

Reperfusion therapy, employed in the treatment of acute stroke, frequently proves to be inadequate in addressing the primary brain tissue injury and may even give rise to secondary damage. The study introduces a satellite nanoparticle platform named MEps, which combine the neural repair properties of bone marrow mesenchymal stem cell exosomes (Exos) with the inflammatory site-targeting abilities of macrophage membranes (MMs). MMs and Exos in MEps act like satellites, ensuring precise positioning and information transmission. MEps rapidly form a protective barrier on the damaged cerebral vascular endothelial cells through the interaction of adhesion molecules with their receptors, blocking the infiltration of neutrophils. Subsequently, repair factors in Exos repair the damaged cells and initiate neurogenesis. The results indicate that this innovative approach effectively mitigates ischemic-reperfusion injury at multiple levels and demonstrates strong biocompatibility. This strategy holds promise for clinical applications in alleviating ischemic-reperfusion injury. The authors introduce MEps, a nanoplatform integrating the neuroregenerative attributes of mesenchymal stem cell-derived exosomes (Exos) with the inflammation-targeting capacity of macrophage membranes (MM). This platform swiftly establishes a protective shield over impaired brain endothelial cells, facilitating the repair of damaged cells and instigating neurogenesis. image

Background: Dysregulated fatty acid metabolism is closely linked to the development of alcohol-associated liver disease (ALD). KCs, which are resident macrophages in the liver, play a critical role in ALD pathogenesis. However, the effect of alcohol on fatty acid metabolism in KCs remains poorly understood. The current study aims to investigate fatty acid metabolism in KCs and its potential effect on ALD development. Methods: Wild-type C57BL/6 mice were fed a Lieber-DeCarli ethanol liquid diet for 3 days. Then, the liver injury and levels of intrahepatic bacteria were assessed. Next, we investigated the effects and underlying mechanisms of ethanol exposure on fatty acid metabolism and the phagocytosis of KCs, both in vivo and in vitro. Finally, we generated KCs-specific Fasn knockout and overexpression mice to evaluate the impact of FASN on the phagocytosis of KCs and ethanol-induced liver injury. Results: Using Bodipy493/503 to stain intracellular neutral lipids, we found significantly reduced lipid levels in KCs from mice fed an alcohol-containing diet for 3 days and in RAW264.7 macrophages exposed to ethanol. Mechanistically, alcohol exposure suppressed sterol regulatory element-binding protein 1 transcriptional activity, thereby inhibiting fatty acid synthase (FASN)-mediated de novo lipogenesis in macrophages both in vitro and in vivo. We show that genetic ablation and pharmacologic inhibition of FASN significantly impaired KC’s ability to take up and eliminate bacteria. Conversely, KCs-specific Fasn overexpression reverses the impairment of macrophage phagocytosis caused by alcohol exposure. We also revealed that KCs-specific Fasn knockout augmented KCs apoptosis and exacerbated liver injury in mice fed an alcohol-containing diet for 3 days. Conclusions: Our findings indicate the crucial role of de novo lipogenesis in maintaining effective KCs phagocytosis and suggest a therapeutic target for ALD based on fatty acid synthesis in KCs.

Background: Crohn's disease has been associated with the formation of Alzheimer's disease. In this study, we investigated the bidirectional causal relationship between Crohn's disease and Alzheimer's disease using a Mendelian randomization analysis. Methods: A two-sample bidirectional Mendelian randomization analysis between Crohn's disease and Alzheimer's disease was performed using MR Egger, weighted median, simple mode, weighted mode, and inverse variance weighted regression algorithms. We focused on theinverse variance weighted analytical method. Subsequent sensitivity analyses were performed via a heterogeneity test, a pleiotropy test, and the leave-one-out method. Results: The forward Mendelian randomization results revealed that Crohn's disease was causallyrelated to Alzheimer's disease (p = 0.0194), and Crohn's disease was a risk factor for Alzheimer's disease (b = 0.0109). There was no causal relationship between Alzheimer's disease and Crohn's disease based on the inverse variance weighted method applied to a reverse Mendelian randomization analysis, nor with the remaining four methods. The reliability of the results was confirmed the by the sensitivity analysis. Conclusion: Our study supported a causal relationship between Crohn's disease and Alzheimer's disease. Crohn's disease was a risk factor for Alzheimer's disease without the influence of reverse causality. This study provides new ideas for further exploring the relationship between Crohn's disease and Alzheimer's disease. The information is relevant to the prevention of Alzheimer's disease.

Abstract Objective By analyzing the clinical history, laboratory test indexes, and intraoperative ultrasound imaging data of patients receiving ultrasound-guided percutaneous transluminal angioplasty (UG-PTA) for the first time, the application value of UG-PTA in the treatment of peripheral stenosis of autogenous arteriovenous fistula (AVF) and the related factors affecting postoperative patency were investigated. Methods A total of 381 patients with dysfunction of radio-cephalic AVF were treated with UG-PTA from June 2017 to September 2019. According to the inclusion and exclusion criteria, 199 patients were included in this study. Baseline characteristics of patients, including demographic, clinical, and laboratory data, were collected. Kaplan–Meier’s survival curve was used to demonstrate the cumulative primary patency rate of UG-PTA. Univariate and multivariate Cox regression analysis was performed on clinical, anatomic, biochemical, and medication variables to identify the predictors of postintervention primary patency. Results The early technical success rate of UG-PTA was 98.4% (375/381). One hundred and ninety-nine patients, with an average age of 52.9 years, were analyzed, 97 of whom were males (48.7%). The median follow-up duration was 21 months. No major complication was observed. Postintervention primary patency rates were 87.7%, 75.8%, and 60.0% at 6, 12, and 24 months, respectively. A previously failed AVF (HR, 1.935, 95% CI 1.071–3.494; p = .029) and an increased level of parathyroid hormone (HR per 100 pg/mL increase, 1.105; 95% CI 1.014–1.203; p = .004) were identified as independent negative predictors of primary patency of UG-PTA. Conclusions UG-PTA is a safe and effective method for the treatment of peripheral stenosis of AVF. Previously failed AVF and elevated parathyroid hormone levels are associated with lower primary patency rate.

Department of Nephrology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Pancreatic cancer (PC) is featured with low survival rate and poor outcomes. Herein, we found that the expression of caspase-recruitment domain-containing protein 9 (CARD9), predominantly expressed in innate immune cells, was positively related to the prognosis of PC patients. CARD9-deficient PC mice exhibited rapider cancer progression and poorer survival rate. CARD9 knockout decreased dendritic cell (DC) maturation and impaired DC ability to activate T cells in vivo and in vitro. Adoptive DC transfer confirmed that the role of CARD9 deficiency in PC relied on DCs. Creatine was identified as the most significant differential metabolite between WT DCs and CARD9(-/-) DCs wherein it played an essential role in maintaining DC maturation and function. CARD9 deficiency led to decreased creatine levels in DCs by inhibiting the transcription of the creatine-specific transporter, solute carrier family 6 member 8 (SLC6A8). Furtherly, CARD9 deletion blocked p65 activation by abolishing the formation of CARD9-BCL10-MALT1 complex, which prevented the binding between p65 and SLC6A8 promoter. These events decreased the creatine transport into DCs, and led to DC immaturity and impairment in antitumor immunity, consequently promoting PC progression.

Pancreatic sympathetic innervation can directly affect the function of islet. The disorder of sympathetic innervation in islets during the occurrence of type 1 diabetes (T1D) has been reported to be controversial with the inducing factor unclarified. Several studies have uncovered the critical role that sympathetic signals play in controlling the local immune system. The survival and function of endocrine cells can be regulated by immune cell infiltration in islets. In the current review, we focused on the impact of sympathetic signals working on islets cell regulation, and discussed the potential factors that can induce the sympathetic innervation disorder in the islets. We also summarized the effect of interference with the islet sympathetic signals on the T1D occurrence. Overall, a comprehensive understanding of the regulatory effect of sympathetic signals on islet cells and local immune system could facilitate better strategies design to control inflammation and protect β cells in T1D therapy.

M1-like macrophages have been reported to play critical roles in acute kidney injury (AKI). Here, we elucidated the role of ubiquitin-specific protease 25 (USP25) in M1-like macrophages polarization and AKI. High USP25 expression was correlated with a decline in renal function in patients with acute kidney tubular injury and in mice with AKI. In contrast, USP25 knockout reduced M1-like macrophage infiltration, suppressed M1-like polarization, and improved AKI in mice, indicating that USP25 was necessary for M1-like polarization and proinflammatory response. Immunoprecipitation assay and liquid chromatography-tandem mass spectrometry showed that the M2 isoform of pyruvate kinase, muscle (PKM2) was a target substrate of USP25. Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated the USP25 regulated aerobic glycolysis and lactate production during M1-like polarization via PKM2. Further analysis showed that the USP25-PKM2-aerobic glycolysis axis positively regulated M1-like polarization and exacerbated AKI in mice, providing potential therapeutic targets for AKI treatment.