Protein 4.1R regulates M1 macrophages polarization via glycolysis, alleviating sepsis-induced liver injury in mice.

Acute liver injury (ALI) is a common clinical disease caused by sepsis, metabolic syndrome, hepatitis virus. Macrophage plays an important role in the development of ALI, which is characterized by polarization and inflammatory regulation. The polarization process of macrophages is related to membrane binding proteins and adaptors. Protein 4.1R acts as an adaptor, linking membrane proteins to the cytoskeleton, and is involved in cell activation and cytokine secretion. However, whether protein 4.1R is involved in regulating macrophage polarization and inflammation-induced liver injury remains unknown. In this study, protein 4.1R is identified with the special effect on macrophage M1 polarization. And it is further demonstrated that protein 4.1R deficiency significantly enhance glycolytic metabolism. Mechanistically, the regulation of protein 4.1R on pyruvate kinase M2 (PKM2) plays a key role in glycolysis metabolism. In addition, we found that protein 4.1R directly interacts with toll-like receptor 4 (TLR4), inhibits the activation of the AKT/HIF-1α signaling pathway. In conclusion, protein 4.1R targets HIF-1α mediated glycolysis regulates M1 macrophage polarization, indicating that protein 4.1R is a candidate for regulating macrophage mediated inflammatory response. In conclusion, we have revealed a novel function of protein 4.1R in macrophage polarization and ALI, providing important insights into the metabolic reprogramming, which is important for ALI therapy. We have revealed a novel function of protein 4.1R in macrophage polarization and ALI, providing important insights into the metabolic reprogramming, which is important for ALI therapy.

Anti-Spoofing Method for Improving GNSS Security by Jointly Monitoring Pseudo-Range Difference and Pseudo-Range Sum Sequence Linearity.

Spoofing interference is one of the most emerging threats to the Global Navigation Satellite System (GNSS); therefore, the research on anti-spoofing technology is of great significance to improving the security of GNSS. For single spoofing source interference, all the spoofing signals are broadcast from the same antenna. When the receiver is in motion, the pseudo-range of spoofing signals changes nonlinearly, while the difference between any two pseudo-ranges changes linearly. Authentic signals do not have this characteristic. On this basis, an anti-spoofing method is proposed by jointly monitoring the linearity of the pseudo-range difference (PRD) sequence and pseudo-range sum (PRS) sequence, which transforms the spoofing detection problem into the sequence linearity detection problem. In this paper, the model of PRD and PRS is derived, the hypothesis based on the linearity of PRD sequence and PRS sequence is given, and the detection performance of the method is evaluated. This method uses the sum of squares of errors (SSE) of linear fitting of the PRD sequence and PRS sequence to construct detection statistics, and has low computational complexity. Simulation results show that this method can effectively detect spoofing interference and distinguish spoofing signals from authentic signals.

PPARG: A Novel Target for Yellow Tea in Kidney Stone Prevention.

Kidney stones are a common urological disorder with increasing prevalence worldwide. The treatment of kidney stones mainly relies on surgical procedures or extracorporeal shock wave lithotripsy, which can effectively remove the stones but also result in some complications and recurrence. Therefore, finding a drug or natural compound that can prevent and treat kidney stones is an important research topic. In this study, we aimed to investigate the effects of yellow tea on kidney stone formation and its mechanisms of action. We induced kidney stones in rats by feeding them an ethylene glycol diet and found that yellow tea infusion reduced crystal deposits, inflammation, oxidative stress, and fibrosis in a dose-dependent manner. Through network pharmacology and quantitative structure-activity relationship modeling, we analyzed the interaction network between the compounds in yellow tea and kidney stone-related targets and verified it through in vitro and in vivo experiments. Our results showed that flavonoids in yellow tea could bind directly or indirectly to peroxisome proliferator-activated receptor gamma (PPARG) protein and affect kidney stone formation by regulating PPARG transcription factor activity. In conclusion, yellow tea may act as a potential PPARG agonist for the prevention and treatment of renal oxidative damage and fibrosis caused by kidney stones.

Integrative single-cell RNA and ATAC sequencing reveals that the FOXO1-PRDX2-TNF axis regulates tendinopathy.

Introduction: Tendinopathy, the most common form of chronic tendon disorder, leads to persistent tendon pain and loss of function. Profiling the heterogeneous cellular composition in the tendon microenvironment helps to elucidate rational molecular mechanisms of tendinopathy. Methods and results: In this study, through a multi-modal analysis, a single-cell RNA- and ATAC-seq integrated tendinopathy landscape was generated for the first time. We found that a specific cell subpopulation with low PRDX2 expression exhibited a higher level of inflammation, lower proliferation and migration ability, which not only promoted tendon injury but also led to microenvironment deterioration. Mechanistically, a motif enrichment analysis of chromatin accessibility showed that FOXO1 was an upstream regulator of PRDX2 transcription, and we confirmed that functional blockade of FOXO1 activity induced PRDX2 silencing. The TNF signaling pathway was significantly activated in the PRDX2-low group, and TNF inhibition effectively restored diseased cell degradation. Discussion: We revealed an essential role of diseased cells in tendinopathy and proposed the FOXO1-PRDX2-TNF axis is a potential regulatory mechanism for the treatment of tendinopathy.

Highly Reactive Thermite Energetic Materials: Preparation, Characterization, and Applications: A Review.

As a promising kind of functional material, highly reactive thermite energetic materials (tEMs) with outstanding reactive activation can release heat quickly at a high reaction rate after low-energy stimulation, which is widely used in sensors, triggers, mining, propellants, demolition, ordnance or weapons, and space technology. Thus, this review aims to provide a holistic view of the recent progress in the development of multifunctional highly reactive tEMs with controllable micro/nano-structures for various engineering applications via different fabricated techniques, including the mechanical mixing method, vapor deposition method, assembly method, sol-gel method, electrospinning method, and so on. The systematic classification of novel structured tEMs in terms of nano-structural superiority and exothermic performance are clarified, based on which, suggestions regarding possible future research directions are proposed. Their potential applications within these rapidly expanding areas are further highlighted. Notably, the prospects or challenges of current works, as well as possible innovative research ideas, are discussed in detail, providing further valuable guidelines for future study.

Regulatory effects of IRF4 on immune cells in the tumor microenvironment.

The tumor microenvironment (TME) is implicated in tumorigenesis, chemoresistance, immunotherapy failure and tumor recurrence. Multiple immunosuppressive cells and soluble secreted cytokines together drive and accelerate TME disorders, T cell immunodeficiency and tumor growth. Thus, it is essential to comprehensively understand the TME status, immune cells involved and key transcriptional factors, and extend this knowledge to therapies that target dysfunctional T cells in the TME. Interferon regulatory factor 4 (IRF4) is a unique IRF family member that is not regulated by interferons, instead, is mainly induced upon T-cell receptor signaling, Toll-like receptors and tumor necrosis factor receptors. IRF4 is largely restricted to immune cells and plays critical roles in the differentiation and function of effector cells and immunosuppressive cells, particularly during clonal expansion and the effector function of T cells. However, in a specific biological context, it is also involved in the transcriptional process of T cell exhaustion with its binding partners. Given the multiple effects of IRF4 on immune cells, especially T cells, manipulating IRF4 may be an important therapeutic target for reversing T cell exhaustion and TME disorders, thus promoting anti-tumor immunity. This study reviews the regulatory effects of IRF4 on various immune cells in the TME, and reveals its potential mechanisms, providing a novel direction for clinical immune intervention.

Efficacy and safety of lenalidomide in diffuse large B-cell lymphoma: a meta-analysis of randomized controlled trials.

As an immunomodulatory agent with antitumor activity, lenalidomide has been evaluated for its value in diffuse large B-cell lymphoma (DLBCL). We performed a meta-analysis to gain a better understanding of the efficacy and safety of lenalidomide in DLBCL. PubMed, Cochrane Library, and Embase were searched up to March 2022 for potential studies. The pooled hazard ratio (HR) and relative risk (RR) with 95% confidence interval (CI) were estimated by the fixed/random effects model. Overall, 6 randomized controlled trials including 1938 patients were included. The complete response rate (CRR) of the group containing lenalidomide was 47.7% (95%CI 28.5-67.2%), which was higher than the 37.8% (95%CI 16.7-61.5%) of the control group without lenalidomide (RR = 1.11, 95%CI 1.03-1.20, P = 0.008). The overall estimation of survival showed a benefit for progression-free survival (PFS) (HR = 0.77, 95%CI 0.66-0.90, P = 0.001) but not overall survival (OS) or event-free survival (EFS). The lenalidomide group had a significant incidence of grade ≥ 3 hematological adverse events (AEs) involving neutropenia (RR = 1.56, 95%CI 1.15-2.11, P = 0.004) and febrile neutropenia (RR = 1.81, 95%CI 1.31-2.49, P < 0.001), with the incidence of neutropenia (48.3%, 95%CI 37.5-59.1%) being highest. In conclusion, addition of lenalidomide results in a higher CRR and better PFS but a higher incidence of grade ≥ 3 hematological AEs involving neutropenia and febrile neutropenia.

Single-cell analysis reveals that Jinwu Gutong capsule attenuates the inflammatory activity of synovial cells in osteoarthritis by inhibiting AKR1C3.

Jinwu Gutong capsule (JGC) is a traditional Chinese medicine formula for the treatment of osteoarthritis (OA). Synovitis is a typical pathological change in OA and promotes disease progression. Elucidating the therapeutic mechanism of JGC is crucial for the precise treatment of OA synovitis. In this study, we demonstrate that JGC effectively inhibits hyperproliferation, attenuates inflammation, and promotes apoptosis of synovial cells. Through scRNA-seq data analysis of OA synovitis, we dissected two distinct cell fates that influence disease progression (one fate led to recovery while the other fate resulted in deterioration), which illustrates the principles of fate determination. By intersecting JGC targets with synovitis hub genes and then mimicking picomolar affinity interactions between bioactive compounds and binding pockets, we found that the quercetin-AKR1C3 pair exhibited the best affinity, indicating that this pair constitutes the most promising molecular mechanism. In vitro experiments confirmed that the expression of AKR1C3 in synovial cells was reduced after JGC addition. Further overexpression of AKR1C3 significantly attenuated the therapeutic efficacy of JGC. Thus, we revealed that JGC effectively treats OA synovitis by inhibiting AKR1C3 expression.

Decreased TCF1 and BCL11B expression predicts poor prognosis for patients with chronic lymphocytic leukemia.

T cell immune dysfunction is a prominent characteristic of chronic lymphocytic leukemia (CLL) and the main cause of failure for immunotherapy and multi-drug resistance. There remains a lack of specific biomarkers for evaluating T cell immune status with outcome for CLL patients. T cell factor 1 (TCF1, encoded by the TCF7 gene) can be used as a critical determinant of successful anti-tumor immunotherapy and a prognostic indicator in some solid tumors; however, the effects of TCF1 in CLL remain unclear. Here, we first analyzed the biological processes and functions of TCF1 and co-expressing genes using the GEO and STRING databases with the online tools Venny, Circos, and Database for Annotation, Visualization, and Integrated Discovery (DAVID). Then the expression and prognostic values of TCF1 and its partner gene B cell leukemia/lymphoma 11B (BCL11B) were explored for 505 CLL patients from 6 datasets and validated with 50 CLL patients from Henan cancer hospital (HNCH). TCF1 was downregulated in CLL patients, particularly in CD8+ T cells, which was significantly correlated with poor time-to-first treatment (TTFT) and overall survival (OS) as well as short restricted mean survival time (RMST). Function and pathway enrichment analysis revealed that TCF1 was positively correlated with BCL11B, which is involved in regulating the activation and differentiation of T cells in CLL patients. Intriguingly, BCL11B was highly consistent with TCF1 in its decreased expression and prediction of poor prognosis. More importantly, the combination of TCF1 and BCL11B could more accurately assess prognosis than either alone. Additionally, decreased TCF1 and BCL11B expression serves as an independent risk factor for rapid disease progression, coinciding with high-risk indicators, including unmutated IGHV, TP53 alteration, and advanced disease. Altogether, this study demonstrates that decreased TCF1 and BCL11B expression is significantly correlated with poor prognosis, which may be due to decreased TCF1+CD8+ T cells, impairing the effector CD8+ T cell differentiation regulated by TCF1/BCL11B.

Potential role of tea drinking in preventing hyperuricaemia in rats: biochemical and molecular evidence.

BACKGROUND: Lifestyle and diet play a significant role in hyperuricaemia. Accumulating evidence indicates that tea consumption is associated with hyperuricaemia and gout. However, diverse compounds in different types of tea make it quite difficult to determine the relevant molecular mechanism. Here, we compared the effects of six types of tea on hyperuricaemia induced by potassium oxonate (PO) and hypoxanthine in rats and investigated the possible underlying mechanisms. METHODS: Rats were randomly assigned to ten groups: the control, hyperuricaemia model, benzbromarone positive control, traditional Chinese medicine Simiao San positive control, green tea, yellow tea, black tea, white tea, red tea, and cyan tea treatment groups. After 21 days, uric acid (UA), xanthine oxidase (XOD), alanine aminotransferase (ALT),blood urea nitrogen (BUN), and creatinine (CRE) were assessed. Serum levels of interleukin-1ß (IL-1ß) were measured with an enzyme-linked immunosorbent assay. Haematoxylin-eosin staining and immunohistochemistry were used to assess liver and kidney injury. RESULTS: The levels of UA, CRE, and BUN in the treatment group were decreased to varying degrees. There was a significant reduction in UA, CRE, and BUN levels for yellow tea compared to the positive control drugs. Yellow tea suppressed XOD activity and alleviated hepatic and kidney injury. Network pharmacology and untargeted metabolomics indicated that ten yellow tea bioactive ingredients and 35 targets were responsible for preventing hyperuricaemia, which was mediated by 94 signalling pathways, including IL-1ß and TNF. CONCLUSION: These findings indicate that green tea cannot reduce the serum uric acid level of hyperuricaemic rats. Yellow tea can significantly improve hyperuricaemia by regulating the inflammatory response, autophagy, and apoptosis. This study provides a potential candidate for the treatment of hyperuricaemia and a basis for selecting therapeutic tea for patients with hyperuricaemia.

Application of 3 dimension-printed injection-molded polyether ether ketone lunate prosthesis in the treatment of stage III Kienböck's disease: A case report.

BACKGROUND: Polyether ether ketone (PEEK) is a high-performance medical polymer, and there are some clinical cases of PEEK prosthesis implantation. However, application of 3D-printed injection-molded PEEK lunate prosthesis for treatment of stage III Kienböck's disease has not been reported. This study's purpose was to analyze the clinical efficacy of 3D-printed injection-molded PEEK lunate prosthesis in the treatment of stage III Kienböck's disease and thus provide a good therapeutic choice for Kienböck's disease. CASE SUMMARY: We report a patient with stage III Kienböck's disease. With the healthy lunate bone as reference, 3D lunate reconstruction was performed using a mirroring technique. A PEEK lunate prosthesis was prepared by 3D printing and injection molding, and then it was inserted into the original anatomical position after removing the necrotic lunate bone. Wrist pain and function, anatomical suitability of the lunate prosthesis, and complications were evaluated and analyzed postoperatively. At the last visit (one year after surgery), the range of motion, grasp force, visual analog scale score and Cooney score of the affected wrist were significantly improved, and postoperative X-ray examination indicated that the lunate prosthesis had good anatomical suitability for adjacent bony structures. CONCLUSION: The 3D-printed injection-molded PEEK lunate prosthesis demonstrated definite efficacy in treating stage III Kienböck's disease.

Single-Cell Profiling of Tumor Microenvironment Heterogeneity in Osteosarcoma Identifies a Highly Invasive Subcluster for Predicting Prognosis.

Osteosarcoma is the most common malignant bone tumor in adolescents, and metastasis is the key reason for treatment failure and poor prognosis. Once metastasis occurs, the 5-year survival rate is only approximately 20%, and assessing and predicting the risk of osteosarcoma metastasis are still difficult tasks. In this study, cellular communication between tumor cells and nontumor cells was identified through comprehensive analysis of osteosarcoma single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data, illustrating the complex regulatory network in the osteosarcoma microenvironment. In line with the heterogeneity of osteosarcoma, we found subpopulations of osteosarcoma cells that highly expressed COL6A1, COL6A3 and MIF and were closely associated with lung metastasis. Then, BCDEG, a reliable risk regression model that could accurately assess the metastasis risk and prognosis of patients, was established, providing a new strategy for the diagnosis and treatment of osteosarcoma.

Comprehensive Analysis of the Effects of Genetic Ancestry and Genetic Characteristics on the Clinical Evolution of Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC), a kind of malignant cancer, is associated with increasing morbidity and mortality. Patients with different genetic ancestries may respond differently to clinical treatment. The limited understanding of the influence of genetic ancestry and genetic characteristics on OSCC impedes the development of precision medicine. To provide a reference for clinical treatment, this study comprehensively analyzed multigenomic differences in OSCC patients with different genetic ancestries and their impact on prognosis. An analysis of data from OSCC patients with different genetic ancestries in The Cancer Genome Atlas (TCGA) showed that the overall survival (OS) of African (AFR) patients was lower than that of primarily European (EUR) patients, and differences were also observed in the tumor-stroma ratio (TSR) and tumor-infiltrating lymphocytes (TILs), which are associated with prognosis. FAT1 is a key mutant gene in OSCC, and it has inconsistent effects on clinical evolution for patients with diverse genetic characteristics. PIKfyve and CAPN9 showed a significant difference in mutation frequency between EUR and AFR; PIKfyve was related to Ki-67 expression, suggesting that it could promote tumor proliferation, and CAPN9 was related to the expression of Bcl-2, promoting tumor cell apoptosis. A variant methylation locus, cg20469139, was correlated with the levels of PD-L1 and Caspase-7 and modulated tumor cell apoptosis. A novel ceRNA model was constructed based on genetic ancestries, and it could accurately evaluate patient prognosis. More importantly, although T cell dysfunction scores could determine the potential of tumor immune escape, the efficacy was obviously affected by patients' genetic ancestries. To provide patients with more precise, personalized therapy and to further improve their quality of life and 5-year survival rate, the influence of genetic ancestry should be fully considered when selecting treatments.

Electrochemical analysis of specific catalase activity during development of Aspergillus flavus and its correlation with aflatoxin B1 production.

Aflatoxin B1 (AFB1) contamination causes huge economic losses. To explore the correlation between catalase (CAT) and AFB1 production during fungal development, we fabricated an electrochemical CAT-activity sensor by measuring residual H2O2 after enzymatic degradation. The sensor made by palladium nanoparticles/carbonized bacterial cellulose nanocomposites exhibits a linear range over 0.5-3.5 U/mL and a detection limit of 0.434 U/mL. Both dry weight and CAT activity of mycelia continuously increase. But, the latter shows a greater increase than the former after three days. Specific CAT activity in crude enzyme extract of A. flavus was quantified. It maintains at ~25.00 U/mg for 3 days and enhances to 28.91 and 45.30 U/mg, respectively, on days 4 and 5. AFB1 production follows the same trend. On days 4 and 5, AFB1 concentration reaches 201.35 and 767.9 ng/mL, respectively. The positive correlation between specific CAT activity and AFB1 production suggests that CAT is involved in AFB1 biosynthesis.

Synthesis of merit-combined antimony tetroxide nanoflowers/reduced graphene oxide to synergistically boost real-time detection of nitric oxide released from living cells for high sensitivity.

Nitric oxide (NO) is an important bio-regulatory and signaling molecule associated with various physiological and pathophysiological pathways, but its sensitive real-time detection is still very challenging due to the low concentration, large diffusivity and fast decay in biological samples. Here an antimony tetroxide (Sb2O4) nanoflowers/reduced graphene oxide (rGO) nanocomposite is synthesized via a facile and eco-friendly solvothermal method to merit-combine highly electroactive Sb2O4 nanoflowers with large surficial rGO component for a strong synergistic effect on oxidation of NO. Results demonstrate that the Sb2O4/rGO-based sensor has a low detection limit, high sensitivity, excellent selectivity and fast response for NO detection. The real-time detected NO released from living cells showed significant difference between normal and tumor cells. The Sb2O4 nanoflowers/rGO nanocomposite sensor holds a great promise for important applications in biomedical research fields and clinical diagnosis.

Protein 4.1R negatively regulates P815 cells proliferation by inhibiting C-Kit-mediated signal transduction.

The proliferation of mast cells (MCs) plays a crucial role in either physiological or pathological progression of human physical. C-Kit-mediated signaling pathway has been confirmed to play a key role in MCs proliferation, and the regulatory mechanisms of C-Kit-mediated MCs proliferation need to be further explored. Our previous study found that protein 4.1R could negatively regulate T cell receptor (TCR) mediated signal pathways in CD4+ T cells. Little is known about the function of 4.1R in C-Kit-mediated proliferation of MCs. In this study, P815-4.1R-/- cells were constructed by using CRISPR/Cas9 technique. Lack of 4.1R significantly enhanced P815 cells proliferation by accelerating the progression of cell cycle. 4.1R could also significantly alleviate the clinical symptoms of systemic mastocytosis (SM) and improve the overall survival of SM mice. Further study showed that 4.1R could interact directly with C-Kit to inhibit the activation of C-Kit-mediated Ras-Raf-MAPKs and PI3K-AKT signal pathways. Taken together, our findings demonstrate that protein 4.1R, a novel negative regulator, negatively regulates MCs proliferation by inhibiting C-Kit-mediated signal transduction, which maybe provide a potential target to the prevention and treatment of abnormal MCs proliferation-related diseases.

Controllably facile design of electrophoretic-induced film-forming of nano tungsten oxide (VI) and their anti-wetting functionalization.

There is keen interest for designing promising tungsten oxide (VI, WO3) films or coatings due to their wide applications in fields of energy, engineering, etc. Thus, this paper firstly introduce a novel convenient method of electrophoretic assembly technique (EAT) in an optimal stable suspension of isopropyl alcohol, PEG-1000 and polyethyleneimine for designing the promising anti-wetting functional WO3 (VI) films with relative rough structures and uniform distribution in mild conditions. The product possess a high crystallinity and pureness by x-ray powder diffraction analysis. The EAT dynamic behaviours of WO3 (VI) nanoparticles are investigated in detail. Moreover, obtained films shows excellent anti-wetting properties after suface modification, and the hydrophobic studies results demonstrate that product have a high static water CA of approximate 169° and keep nearly stable even after ultralong exposure time (360 d), and show outstanding properties of anti-soaking, impacting-proof, and moisture resistance even in high relative humidity (90%). These breakthroughs will substantially push forward the convenient processing of other anti-wetting functional coatings with wide potential applications.

Systemic Expression Analysis Reveals Prognostic Significance of WIPI3 in Hepatocellular Carcinoma.

INTRODUCTION: WD repeat domain phosphoinositide-interacting protein 3 (WIPI3) is a member of the WIPI protein family, autophagy marker, that is associated with the malignant progression of various human cancers, but its role in hepatocellular carcinoma (HCC) is still unclear. MATERIALS AND METHODS: Firstly, we collected the mRNA expression of WIPI3 in HCC through the platform of Oncomine, as well as the DNA copy number variations (CNVs), and verified it on human HCC cell line and the GEO database. Then, the subgroups and prognosis of HCC were performed by the UALCAN web tool. The mutation of WIPI3 was analyzed by cBioPortal. The coexpression of WIPI3 in HCC was identified from the LinkedOmics database, and function enrichment analysis was done using the LinkFinder module in LinkedOmics. Coexpression gene network was constructed through the STRING database, and the MCODE plug-in of which was used to build the gene modules; both of them were visualized by the Cytoscape software. Finally, the top modular genes in the same patient cohort were constructed through data mining in The Cancer Genome Atlas (TCGA) liver hepatocellular carcinoma (LIHC) by using the UCSC Xena browser. RESULTS: The results indicated that WIPI3 was frequently overexpressed in HCC, which could lead to a poor prognosis through the Kaplan-Meier (KM) analysis. Moreover, there existed mutations of WIPI3 in HCC, and the prognosis of WIPI3-altered group was significantly poor based on KM plotter data. Coexpression analysis showed that the coexpression gene of WIPI3 was associated with cell cycle and spliceosome. Further analysis suggested that WIPI3 and eukaryotic translation initiation factor 4A3 (EIF4A3) coordinately regulated the cancer cell cycle by spliceosome as a result of the strong positive correlation between them. CONCLUSION: In summary, WIPI3 is constantly overexpressed in HCC tissues, resulting in a poor prognosis; therefore, we can identify it as an effective target for the treatment of HCC.

Cytoskeleton protein 4.1R regulates B-cell fate by modulating the canonical NF-κB pathway.

During the immune response, B cells can enter the memory pathway, which is characterized by class switch recombination (CSR), or they may undergo plasma cell differentiation (PCD) to secrete immunoglobulin. Both of these processes occur in activated B cells, which are reported to relate to membrane-association proteins and adaptors. Protein 4.1R acts as an adaptor, linking membrane proteins to the cytoskeleton, and is involved in many cell events such as cell activation and differentiation, and cytokine secretion. However, the effect of 4.1R on regulating B-cell fate is unclear. Here, we show an important association between B-cell fate and 4.1R. In vitro, primary B cells were stimulated with lipopolysaccharide combined with interleukin-4; results showed that 4.1R-deficient (4.1R-/- ) cells compared with wild-type (4.1R+/+ ) B cells augmented expression of activation-induced cytidine deaminase and germline, resulting in increased IgG1+ B cells, whereas the secretion of IgG1 and IgM was reduced, and CD138+ B cells were also decreased. Throughout the process, 4.1R regulated canonical nuclear factor (NF-κB) rather than non-canonical NF-κB to promote the expression of CSR complex components, leading to up-regulation of B-cell CSR. In contrast, 4.1R-deficient B cells showed reduced expression of Blimp-1, which caused B cells to down-regulate PCD. Furthermore, over-activation of canonical NF-κB may induce apoptosis signaling to cause PCD apoptosis to reduce PCD number. In summary, our results suggest that 4.1R acts as a B-cell fate regulator by inhibiting the canonical NF-κB signaling pathway.

Abnormal expression and prognostic significance of EPB41L1 in kidney renal clear cell carcinoma based on data mining.

BACKGROUND: EPB41L1 gene (erythrocyte membrane protein band 4.1 like 1) encodes the protein 4.1N, a member of 4.1 family, playing a vital role in cell adhesion and migration, which is associated with the malignant progression of various human cancers. However, the expression and prognostic significance of EPB41L1 in kidney renal clear cell carcinoma (KIRC) remain to be investigated. METHODS: In this study, we collected the mRNA expression of EPB41L1 in KIRC through the Oncomine platform, and used the HPA database to perform the pathological tissue immunohistochemistry in patients. Then, the sub-groups and prognosis of KIRC were performed by UALCAN and GEPIA web-tool, respectively. Further, the mutation of EPB41L1 in KIRC was analyzed by c-Bioportal. The co-expression genes of EPB41L1 in KIRC were displayed from the LinkedOmics database, and function enrichment analysis was used by LinkFinder module in LinkedOmics. The function of EPB41L1 in cell adhesion and migration was confirmed by wound healing assay using 786-O cells in vitro. Co-expression gene network was constructed through the STRING database, and the MCODE plug-in of which was used to build the gene modules, both of them was visualized by Cytoscape software. Finally, the top modular genes in the same patient cohort were constructed through data mining in TCGA by using the UCSC Xena browser. RESULTS: The results indicated that EPB41L1 was down-expressed in KIRC, leading to a poor prognosis. Moreover, there is a mutation in the FERM domain of EPB41L1, but it has no significant effect on the prognosis of KIRC. The co-expressed genes of EPB41L1 were associated with cell adhesion and confirmed in vitro. Further analysis suggested that EPB41L1 and amyloid beta precursor protein (APP) were coordinated to regulated cancer cell adhesion, thereby increasing the incidence of cancer cell metastasis and tumor invasion. CONCLUSIONS: In summary, EPB41L1 is constantly down-expressed in KIRC tissues, resulting a poor prognosis. Therefore, we suggest that it can be an effective biomarker for the diagnosis of KIRC.