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The thymus is the primary immune organ responsible for generating self‐tolerant and immunocompetent T cells. However, the thymus gradually involutes during early life resulting in declined naïve T‐cell production, a process known as age‐related thymic involution. Thymic involution has many negative impacts on immune function including reduced pathogen resistance, high autoimmunity incidence, and attenuated tumor immunosurveillance. Age‐related thymic involution leads to a gradual reduction in thymic cellularity and thymic stromal microenvironment disruption, including loss of definite cortical‐medullary junctions, reduction of cortical thymic epithelial cells and medullary thymic epithelial cells, fibroblast expansion, and an increase in perivascular space. The compromised thymic microenvironment in aged individuals substantially disturbs thymocyte development and differentiation. Age‐related thymic involution is regulated by many transcription factors, micro RNAs, growth factors, cytokines, and other factors. In this review, we summarize the current understanding of age‐related thymic involution mechanisms and effects. Age‐related thymic involution has many negative impacts on immune function including reduced pathogen resistance, high autoimmunity incidence, and attenuated tumor immunosurveillance. This review summarizes the current understanding of how age impacts thymic development and function, as well as the mechanisms underlying age‐related thymic involution, particularly TEC transcriptional profile changes during thymic aging.

PurposeTo assess the predictive power of pre-therapy 18F-FDG PET/CT-based radiomic features for epidermal growth factor receptor (EGFR) mutation status in non-small cell lung cancer.MethodsTwo hundred and forty-eight lung cancer patients underwent pre-therapy diagnostic 18F-FDG PET/CT scans and were tested for genetic mutations. The LIFEx package was used to extract 47 PET and 45 CT radiomic features reflecting tumor heterogeneity and phenotype. The least absolute shrinkage and selection operator (LASSO) algorithm was used to select radiomic features and develop a radiomics signature. We compared the predictive performance of models established by radiomics signature, clinical variables, and their combinations using receiver operating curves (ROCs). In addition, a nomogram based on the radiomics signature score (rad-score) and clinical variables was developed.ResultsThe patients were divided into a training set (n = 175) and a validation set (n = 73). Ten radiomic features were selected to build the radiomics signature model. The model showed a significant ability to discriminate between EGFR mutation and EGFR wild type, with area under the ROC curve (AUC) equal to 0.79 in the training set, and 0.85 in the validation set, compared with 0.75 and 0.69 for the clinical model. When clinical variables and radiomics signature were combined, the AUC increased to 0.86 (95% CI [0.80–0.91]) in the training set and 0.87 (95% CI [0.79–0.95]) in the validation set, thus showing better performance in the prediction of EGFR mutations.ConclusionThe PET/CT-based radiomic features showed good performance in predicting EGFR mutation in non-small cell lung cancer, providing a useful method for the choice of targeted therapy in a clinical setting.

In this paper, we study a coefficients inversion problem of a coupled system controlled by three reaction-diffusion equations describing a simple dynamic model of a drug epidemic in an idealized community from the final measurement data. Firstly, the optimization theory is used to transform the given problem into an optimal control problem, and the existence of minimizer is established. Then the stability estimates of the Lipschitz type for the three spatially varying coefficients are proved, where the upper bounds are given by some Lebesgue norms of the final measure.

Mesenchymal stem cells (MSCs) are widely distributed pluripotent stem cells with powerful immunomodulatory capacity. MSCs transplantation therapy (MSCT) is widely used in the fields of tissue regeneration and repair, and treatment of inflammatory diseases. Apoptosis is an important way for tissues to maintain cell renewal, but it also plays an important role in various diseases. And many studies have shown that MSCs improves the diseases by regulating cell apoptosis. The regulation of MSCs on apoptosis is double-sided. On the one hand, MSCs significantly inhibit the apoptosis of diseased cells. On the other hand, MSCs also promote the apoptosis of tumor cells and excessive immune cells. Furthermore, MSCs regulate apoptosis through multiple molecules and pathways, including three classical apoptotic signaling pathways and other pathways. In this review, we summarize the current evidence on the regulation of apoptosis by MSCs.

Background Hydrocephalus is a severe complication of intracerebral hemorrhage with ventricular extension (ICH-IVH) and causes cerebrospinal fluid (CSF) accumulation. The choroid plexus epithelium plays an important role in CSF secretion and constitutes the blood–CSF barrier within the brain–immune system interface. Although the NLRP3 inflammasome, as a key component of the innate immune system, promotes neuroinflammation, its role in the pathogenesis of hydrocephalus after hemorrhage has not been investigated. Therefore, this study aimed to investigate the potential mechanism of NLRP3 in hydrocephalus to discover a potential marker for targeted therapy. Methods A rat model of hydrocephalus after ICH-IVH was developed through autologous blood infusion in wild-type and Nlrp3 −/− rats. By studying the features and processes of the model, we investigated the relationship between the NLRP3 inflammasome and CSF hypersecretion in the choroid plexus. Results The ICH-IVH model rats showed ventricular dilation accompanied by CSF hypersecretion for 3 days. Based on the choroid plexus RNA-seq and proteomics results, we found that an inflammatory response was activated. The NLRP3 inflammasome was investigated, and the expression levels of NLRP3 inflammasome components reached a peak at 3 days after ICH-IVH. Inhibition of NLRP3 by an MCC950 inflammasome inhibitor or Nlrp3 knockout decreased CSF secretion and ventricular dilation and attenuated neurological deficits after ICH-IVH. The mechanism underlying the neuroprotective effects of NLRP3 inhibition involved decreased phosphorylation of NKCC1, which is a major protein that regulates CSF secretion by altering Na + - and K + -coupled water transport, via MCC950 or Nlrp3 knockout. In combination with the in vitro experiments, this experiment confirmed the involvement of the NLRP3/p-NKCC1 pathway and Na + and K + flux. Conclusions This study demonstrates that NKCC1 phosphorylation in the choroid plexus epithelium promotes NLRP3 inflammasome-mediated CSF hypersecretion and that NLRP3 plays an important role in the pathogenesis of hydrocephalus after hemorrhage. These findings provide a new therapeutic strategy for treating hydrocephalus.

Ischemic stroke (IS) is a major threat to human health, and it is the second leading cause of long-term disability and death in the world. Impaired cerebral perfusion leads to acute hypoxia and glucose deficiency, which in turn induces a stroke cascade response that ultimately leads to cell death. Screening and identifying hypoxia-related genes (HRGs) and therapeutic targets is important for neuroprotection before and during brain recanalization to protect against injury and extend the time window to further improve functional outcomes before pharmacological and mechanical thrombolysis. First, we downloaded the GSE16561 and GSE58294 datasets from the NCBI GEO database. Bioinformatics analysis of the GSE16561 dataset using the limma package identified differentially expressed genes (DEGs) in ischemic stroke using adj. p. values < 0.05 and a fold change of 0.5 as thresholds. The Molecular Signature database and Genecards database were pooled to obtain hypoxia-related genes. 19 HRGs associated with ischemic stroke were obtained after taking the intersection. LASSO regression and multivariate logistic regression were applied to identify critical biomarkers with independent diagnostic values. ROC curves were constructed to validate their diagnostic efficacy. We used CIBERSORT to analyze the differences in the immune microenvironment between IS patients and controls. Finally, we investigated the correlation between HRGs and infiltrating immune cells to understand molecular immune mechanisms better. Our study analyzed the role of HRGs in ischemic stroke. Nineteen hypoxia-related genes were obtained. Enrichment analysis showed that 19 HRGs were involved in response to hypoxia, HIF-1 signaling pathway, autophagy, autophagy of mitochondrion, and AMPK signaling pathway. Because of the good diagnostic properties of SLC2A3, we further investigated the function of SLC2A3 and found that it is closely related to immunity. We have also explored the relevance of other critical genes to immune cells. Our findings suggest that hypoxia-related genes play a crucial role in the diversity and complexity of the IS immune microenvironment. Exploring the association between hypoxia-related critical genes and immune cells provides innovative insights into the therapeutic targets for ischemic stroke.

Welding copper (Cu) and aluminum (Al) is highly demanded for lightweight and cost-effective manufacturing. However, it faces significant challenges. First, substantial differences in physical properties may lead to high residual stresses and distortion. Second, brittle intermetallic compounds (IMCs) readily form at the interface, severely compromising the joint’s mechanical properties and electrical conductivity. Third, the native oxide film on Al impedes effective wetting and bonding. Therefore, effective control over the interfacial microstructure of the welded joint is essential. This review provides a critical analysis and comparison of several typical welding techniques, including laser welding (LW), friction stir welding (FSW), ultrasonic welding (UW), brazing and soldering, and welding–brazing. These analyses focus on their process characteristics, joint microstructures, and corresponding formation mechanisms. Furthermore, this review synthesizes key strategies for enhancing joint quality, including process parameter optimization, introduction of functional interlayers, and external assistance, aimed at optimizing joint microstructure and minimizing defects. Based on the analysis, this work provides comparative insights into process selection and microstructure control, and highlights future directions: advancing novel methods such as magnetic pulse welding and transient liquid phase bonding; developing intelligent real-time process control to suppress brittle IMCs and associated defects; promoting sustainable practices and establishing standardized performance evaluation; and systematically investigating long-term reliability to support the industrial application of robust Cu/Al joints.

BackgroundIn recent years, immune checkpoint inhibitor (ICI) therapy has greatly changed the treatment prospects of patients with non-small cell lung cancer (NSCLC). Among the available ICI therapy strategies, programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors are the most widely used worldwide. At present, immunohistochemistry (IHC) is the main method to detect PD-L1 expression levels in clinical practice. However, given that IHC is invasive and cannot reflect the expression of PD-L1 dynamically and in real time, it is of great clinical significance to develop a new noninvasive, accurate radiomics method to evaluate PD-L1 expression levels and predict and filter patients who will benefit from immunotherapy. Therefore, the aim of our study was to assess the predictive power of pretherapy [18F]-fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT)-based radiomics features for PD-L1 expression status in patients with NSCLC.MethodsA total of 334 patients with NSCLC who underwent [18F]FDG PET/CT imaging prior to treatment were analyzed retrospectively from September 2016 to July 2021. The LIFEx7.0.0 package was applied to extract 63 PET and 61 CT radiomics features. In the training group, the least absolute shrinkage and selection operator (LASSO) regression model was employed to select the most predictive radiomics features. We constructed and validated a radiomics model, clinical model and combined model. Receiver operating characteristic (ROC) curves and the area under the ROC curve (AUC) were used to evaluate the predictive performance of the three models in the training group and validation group. In addition, a radiomics nomogram to predict PD-L1 expression status was established based on the optimal predictive model.ResultsPatients were randomly assigned to a training group (n = 233) and a validation group (n = 101). Two radiomics features were selected to construct the radiomics signature model. Multivariate analysis showed that the clinical stage (odds ratio [OR] 1.579, 95% confidence interval [CI] 0.220–0.703, P < 0.001) was a significant predictor of different PD-L1 expression statuses. The AUC of the radiomics model was higher than that of the clinical model in the training group (0.706 vs. 0.638) and the validation group (0.761 vs. 0.640). The AUCs in the training group and validation group of the combined model were 0.718 and 0.769, respectively.ConclusionPET/CT-based radiomics features demonstrated strong potential in predicting PD-L1 expression status and thus could be used to preselect patients who may benefit from PD-1/PD-L1-based immunotherapy.

Background Deregulation of ubiquitin ligases is related to the malignant progression of human cancers. F-box only protein 22 (FBXO22), an F-box E3 ligase, is a member of the F-box protein family. However, the biological function of FBXO22 in HCC and the underlying molecular mechanisms are still unclear. In this study, we explored the role of FBXO22 in HCC and its mechanism of promoting tumor development. Methods We examined the expression of FBXO22 in normal liver cell lines, HCC cell lines, HCC tissue microarrays and fresh specimens. The correlation between FBXO22 and clinical features was analyzed in a retrospective study of 110 pairs of HCC tissue microarrays. Univariate and multivariate survival analyses were used to explore the prognostic value of FBXO22 in HCC. At the same time, the correlation between the FBXO22 and p21 was also studied in HCC samples. Knock-down and overexpression experiments, CHX and Mg132 intervention experiments, ubiquitination experiments, rescue experiments and nude mouse xenograft models were used to determine the potential mechanism by which FBXO22 promotes tumorigenesis in vitro and in vivo. Results The expression of FBXO22 in HCC tissues was significantly higher than in normal liver tissues. The overall survival rate and disease-free survival time of patients with high expression of FBXO22 were significantly shorter than those of patients with low expression of FBXO22. The high expression of FBXO22 in HCC tissues were significantly correlated with serum AFP ( p  = 0. 003, Pearson’s chi-squared test), tumor size ( p  = 0. 019, Pearson’s chi-squared test) and vascular invasion ( p  = 0. 031, Pearson’s chi-squared test). Especially, Multivariate analysis showed that tumor size and the expression of FBXO22 were independent prognostic indicator of OS (95% CI: 1.077–5.157, P <0.05). Correlation analysis also showed that FBXO22 was negatively correlated with p21 in tissue microarrays (r = − 0.3788, P <0.001, Pearson correlation) and fresh specimens (r = − 0.4037, P <0.01, Pearson correlation). Moreover, both in vitro and in vivo experiments showed that knocking down FBXO22 expression could inhibit cell proliferation, while overexpression of FBXO22 promoted tumor formation. Furthermore, we identified that FBXO22 interacts with p21 by regulating protein stability and by influencing the ubiquitination process. A knockdown of FBXO22 decreased the ubiquitylation of p21, while overexpression enhanced it. Conclusions This study uncovered a new mechanism by which FBXO22 functions as an oncogene in HCC pathogenesis and progression by mediating the ubiquitination and degradation of p21. It was also found that tumor size and the expression of FBXO22 were independent prognostic indicator of OS and the expression of FBXO22 and p21 was negatively correlated in clinical samples. Our findings present a new perspective for understanding the development of HCC, which may provide a new target for the treatment and management of this challenging cancer.

Allele-specific expression (ASE) is a phenomenon in which the expression level of an allele from both parents is inconsistent, which is considered to play a key role in the differences between hybrids. As a typical climacteric fruit, banana undergoes a ripening process that affects the quality of the fruit. BaXi (Musa, AAA group) and Fen Jiao (Musa, ABB group) banana fruits show different traits during postharvest ripening, and their high-quality reference genomic sequences have been published. In this work, we analyzed differentially expressed genes (DEGs) in these two banana cultivars based on the transcriptomes during the postharvest stages. Additionally, the imbalance expression of alleles of DEGs in Fen Jiao banana fruit was analyzed, revealing that 27.2% (3 d) and 22.2% (6 d) of the 15,415 DEGs showed ASE. Then, the ASE profiles related to the post-ripening of banana fruit were built, focusing on ripening-related pathways, such as ethylene biosynthesis (62.5–83.3%), starch degradation (0–75%) and cell wall material degradation (34.6–90.9%). The ASE genes involved in ripening were more frequent than those associated with general gene expression. In addition, the candidate key genes of ASE alleles involved in ethylene synthesis and starch degradation were identified, including the alleles of MaACS7/MbACS7, MaACO2/MbACO6, MaACO3/MbACO7, MaACO8/MbACO13 and MaACO6/MbACO17 involved in ethylene biosynthesis, and those of MaAMY1/MbAMY3, MaBMY1/MbBMY2, MaBMY7/MbBMY8 and MaDPE2/MbDPE2 involved in starch degradation. The expression of the B genes of these key enzyme genes (ACS/ACO/AMY) is more active than that of the A genes in Fen Jiao bananas.