Polymorphism in the Hsa-miR-4274 seed region influences the expression of PEX5 and enhances radiotherapy resistance in colorectal cancer.

Identifying biomarkers for predicting radiotherapy efficacy is crucial for optimizing personalized treatments. We previously reported that rs1553867776 in the miR-4274 seed region can predict survival in patients with rectal cancer receiving postoperative chemoradiation therapy. Hence, to investigate the molecular mechanism of the genetic variation and its impact on the radiosensitivity of colorectal cancer (CRC), in this study, bioinformatics analysis is combined with functional experiments to confirm peroxisomal biogenesis factor 5 (PEX5) as a direct target of miR-4274. The miR-4274 rs1553867776 variant influences the binding of miR-4274 and PEX5 mRNA, which subsequently regulates PEX5 protein expression. The interaction between PEX5 and Ku70 was verified by co-immunoprecipitation and immunofluorescence. A xenograft tumor model was established to validate the effects of miR-4274 and PEX5 on CRC progression and radiosensitivity in vivo. The overexpression of PEX5 enhances radiosensitivity by preventing Ku70 from entering the nucleus and reducing the repair of ionizing radiation (IR)-induced DNA damage by the Ku70/Ku80 complex in the nucleus. In addition, the enhanced expression of PEX5 is associated with increased IR-induced ferroptosis. Thus, targeting this mechanism might effectively increase the radiosensitivity of CRC. These findings offer novel insights into the mechanism of cancer radioresistance and have important implications for clinical radiotherapy.

Understanding the molecular pathway of triclosan-induced ADHD-like behaviour: Involvement of the hnRNPA1-PKM2-STAT3 feedback loop.

Triclosan (TCS) is an environmental pollutant. In recent years, there has been increasing level of concern regarding the potential toxicity of TCS in animals and humans, especially its effects on the nervous system. However, whether TCS induces ADHD-like behaviour and the mechanism by which it affects neural function are unclear. The impact of 60 days of continuous exposure to TCS on the behaviour of offspring rats was assessed in this research. According to the results of this study, TCS exposure led to ADHD-like behaviour in offspring rats and activated microglia in the prefrontal cortex (PFC), inducing inflammatory factor release. In vitro studies showed that TCS increased the levels of inflammatory cytokines, including interleukin (IL)-1ß, IL-6 and tumour necrosis factor (TNF)-α, in HMC3 cells. More importantly, we found that TCS regulated the STAT3 pathway by upregulating PKM2 via hnRNPA1. In summary, this study suggested that TCS can induce ADHD-like behaviour in offspring rats and continuously activate HMC3 microglia through the hnRNPA1-PKM2-STAT3 feedback loop, promoting inflammatory cytokine secretion.

Long-life triclosan exposure induces ADHD-like behavior in rats via prefrontal cortex dopaminergic deficiency.

In recent years, exposure to triclosan (TCS) has been linked to an increase in psychiatric disorders. Nonetheless, the precise mechanisms of this occurrence remain elusive. Therefore, this study developed a long-life TCS-exposed rat model, an SH-SY5Y cell model, and an atomoxetine hydrochloride (ATX) treatment model to explore and validate the neurobehavioral mechanisms of TCS from multiple perspectives. In the long-life TCS-exposed model, pregnant rats received either 0 mg/kg (control) or 50 mg/kg TCS by oral gavage throughout pregnancy, lactation, and weaning of their offspring (up to 8 weeks old). In the ATX treatment model, weanling rats received daily injections of either 0 mg/kg (control) or 3 mg/kg ATX via intraperitoneal injection until they reached 8 weeks old. Unlike the TCS model, ATX exposure only occurred after the pups were weaned. The results indicated that long-life TCS exposure led to attention-deficit hyperactivity disorder (ADHD)-like behaviors in male offspring rats accompanied by dopamine-related mRNA and protein expression imbalances in the prefrontal cortex (PFC). Moreover, in vitro experiments also confirmed these findings. Mechanistically, TCS reduced dopamine (DA) synthesis, release, and transmission, and increased reuptake in PFC, thereby reducing synaptic gap DA levels and causing dopaminergic deficits. Additional experiments revealed that increased DA concentration in PFC by ATX effectively alleviated TCS-induced ADHD-like behavior in male offspring rats. These findings suggest that long-life TCS exposure causes ADHD-like behavior in male offspring rats through dopaminergic deficits. Furthermore, ATX treatment not only reduce symptoms in the rats, but also reveals valuable insights into the neurotoxic mechanisms induced by TCS.

Targeted Delivery of Macrophage Membrane Biomimetic Liposomes Through Intranasal Administration for Treatment of Ischemic Stroke.

Purpose: Ginsenoside Rg3 (Rg3) and Panax notoginseng saponins (PNS) can be used for ischemic stroke treatment, however, the lack of targeting to the ischemic region limits the therapeutic effect. To address this, we leveraged the affinity of macrophage membrane proteins for inflamed brain microvascular endothelial cells to develop a macrophage membrane-cloaked liposome loaded with Rg3 and PNS (MM-Lip-Rg3/PNS), which can precisely target brain lesion region through intranasal administration. Methods: MM-Lip-Rg3/PNS was prepared by co-extrusion method and was performed by characterization, stability, surface protein, and morphology. The cellular uptake, immune escape ability, and blood-brain barrier crossing ability of MM-Lip-Rg3/PNS were studied in vitro. The in vivo brain targeting, biodistribution and anti-ischemic efficacy of MM-Lip-Rg3/PNS were evaluated in MACO rats, and we determined the diversity of the nasal brain pathway through the olfactory nerve blockade model in rats. Finally, the pharmacokinetics and brain targeting index of MM-Lip-Rg3/PNS were investigated. Results: Our results indicated that MM-Lip-Rg3/PNS was spherical with a shell-core structure. MM-Lip-Rg3/PNS can avoid mononuclear phagocytosis, actively bind to inflammatory endothelial cells, and have the ability to cross the blood-brain barrier. Moreover, MM-Lip-Rg3/PNS could specifically target ischemic sites, even microglia, increase the cumulative number of drugs in the brain, improve the inflammatory environment of the brain, and reduce the infarct size. By comparing olfactory nerve-blocking rats with normal rats, it was found that there are direct and indirect pathways for nasal entry into the brain. Pharmacokinetics demonstrated that MM-Lip-Rg3/PNS exhibited stronger brain targeting and prolonged drug half-life. Conclusion: MM-Lip-Rg3/PNS might contribute to the accumulation of Rg3 and PNS in the ischemic brain area to improve treatment efficacy. This biomimetic nano-drug delivery system provides a new and promising strategy for the treatment of ischemic stroke.

Design, synthesis, and anti-inflammatory activity of indole-2-formamide benzimidazole[2,1-b]thiazole derivatives.

Molecular hybridization is a widely employed technique in medicinal chemistry for drug modification, aiming to enhance pharmacological activity and minimize side effects. The combination of an indole ring and imidazole[2,1-b]thiazole has shown promising potential as a group that exhibits potent anti-inflammatory effects. In this study, we designed and synthesized a series of derivatives comprising indole-2-formamide benzimidazole[2,1-b]thiazole to evaluate their impact on LPS-induced production of pro-inflammatory cytokines NO, IL-6, and TNF-α release, as well as iron death in RAW264.7 cells. The findings revealed that most compounds effectively inhibited LPS-induced production of pro-inflammatory cytokines NO, IL-6, and TNF-α release in RAW264.7 cells. Compound 13b exhibited the most potent anti-inflammatory activity among the tested compounds. The results of the cytotoxicity assay indicated that compound 13b was nontoxic. Additionally, compound 13b was found to elevate the levels of ROS, MDA, and Fe2+, while reducing GSH content, thereby facilitating the iron death process. Consequently, compound 13b showed promise for future development as an anti-inflammatory drug.

Identification of molecular characteristics of hepatocellular carcinoma with microvascular invasion based on deep targeted sequencing.

BACKGROUND: As an indicator of tumor invasiveness, microvascular invasion (MVI) is a crucial risk factor for postoperative relapse, metastasis, and unfavorable prognosis in hepatocellular carcinoma (HCC). Nevertheless, the genetic mechanisms underlying MVI, particularly for Chinese patients, remain mostly uncharted. METHODS: We applied deep targeted sequencing on 66 Chinese HCC samples. Focusing on the telomerase reverse transcriptase (TERT) promoter (TERTp) and TP53 co-mutation (TERTp+/TP53+) group, gene set enrichment analysis (GSEA) was used to explore the potential molecular mechanisms of the TERTp+/TP53+ group on tumor progression and metastasis. Additionally, we evaluated the tumor immune microenvironment of the TERTp+/TP53+ group in HCC using multiplex immunofluorescence (mIF) staining. RESULTS: Among the 66 HCC samples, the mutated genes that mostly appeared were TERT, TP53, and CTNNB1. Of note, we found 10 cases with TERTp+/TP53+, of which nine were MVI-positive and one was MVI-negative, and there was a co-occurrence of TERTp and TP53 (p < 0.05). Survival analysis demonstrated that patients with the TERTp+/TP53+ group had lower the disease-free survival (DFS) (p = 0.028). GSEA results indicated that telomere organization, telomere maintenance, DNA replication, positive regulation of cell cycle, and negative regulation of immune response were significantly enriched in the TERTp+/TP53+ group (all adjusted p-values (p.adj) < 0.05). mIF revealed that the TERTp+/TP53+ group decreased CD8+ T cells infiltration (p = 0.25) and enhanced PDL1 expression (p = 0.55). CONCLUSIONS: TERTp+/TP53+ was significantly enriched in MVI-positive patients, leading to poor prognosis for HCC patients by promoting proliferation of HCC cell and inhibiting infiltration of immune cell surrounding HCC. TERTp+/TP53+ can be utilized as a potential indicator for predicting MVI-positive patients and poor prognosis, laying a preliminary foundation for further exploration of co-mutation in HCC with MVI and clinical treatment.

Telomerase-related advances in hepatocellular carcinoma: A bibliometric and visual analysis.

BACKGROUND: As a critical early event in hepatocellular carcinogenesis, telomerase activation might be a promising and critical biomarker for hepatocellular carcinoma (HCC) patients, and its function in the genesis and treatment of HCC has gained much attention over the past two decades. AIM: To perform a bibliometric analysis to systematically assess the current state of research on HCC-related telomerase. METHODS: The Web of Science Core Collection and PubMed were systematically searched to retrieve publications pertaining to HCC/telomerase limited to "articles" and "reviews" published in English. A total of 873 relevant publications related to HCC and telomerase were identified. We employed the Bibliometrix package in R to extract and analyze the fundamental information of the publications, such as the trends in the publications, citation counts, most prolific or influential writers, and most popular journals; to screen for keywords occurring at high frequency; and to draw collaboration and cluster analysis charts on the basis of coauthorship and co-occurrences. VOSviewer was utilized to compile and visualize the bibliometric data. RESULTS: A surge of 51 publications on HCC/telomerase research occurred in 2016, the most productive year from 1996 to 2023, accompanied by the peak citation count recorded in 2016. Up to December 2023, 35226 citations were made to all publications, an average of 46.6 citations to each paper. The United States received the most citations (n = 13531), followed by China (n = 7427) and Japan (n = 5754). In terms of national cooperation, China presented the highest centrality, its strongest bonds being to the United States and Japan. Among the 20 academic institutions with the most publications, ten came from China and the rest of Asia, though the University of Paris Cité, Public Assistance-Hospitals of Paris, and the National Institute of Health and Medical Research (INSERM) were the most prolific. As for individual contributions, Hisatomi H, Kaneko S, and Ide T were the three most prolific authors. Kaneko S ranked first by H-index, G-index, and overall publication count, while Zucman-Rossi J ranked first in citation count. The five most popular journals were the World Journal of Gastroenterology, Hepatology, Journal of Hepatology, Oncotarget, and Oncogene, while Nature Genetics, Hepatology, and Nature Reviews Disease Primers had the most citations. We extracted 2293 keywords from the publications, 120 of which appeared more than ten times. The most frequent were HCC, telomerase and human telomerase reverse transcriptase (hTERT). Keywords such as mutational landscape, TERT promoter mutations, landscape, risk, and prognosis were among the most common issues in this field in the last three years and may be topics for research in the coming years. CONCLUSION: Our bibliometric analysis provides a comprehensive overview of HCC/telomerase research and insights into promising upcoming research.

Low cycle number multiplex PCR: A novel strategy for the construction of amplicon libraries for next-generation sequencing.

Multiplex PCR is a critical step when preparing amplicon library for next-generation sequencing. However, there are several challenges related to multiplex PCR including poor uniformity, nonspecific amplification, and primer-dimers. To address these issues, we propose a novel solution strategy that involves using a low cycle number (<10 cycles) in multiplex PCR and then employing carrier DNAs and magnetic beads for the selection of targeted products. This technique improves the amplicon uniformity while also reducing primer-dimers and PCR artifacts. To evaluate our technique, we initially utilized 120 DNA fragments from mouse genome containing single nucleotide polymorphism (SNP) sites. Sequencing results demonstrated that with only 7 cycles of multiplex PCR, 95.8% of the targeted SNP sites were mapped, with a coverage of at least 1×. The average sequencing depth of all amplicons was 1705.79 ± 1205.30×; 87% of them reached a coverage depth that exceeded 0.2-fold of the average sequencing depth. Our method had a greater uniformity (87%) when compared to Hi-Plex PCR (53.3%). Furthermore, we validated our strategy by randomly selecting 90 primer pairs twice from the initial set of 120 primer-pairs. Next, we used the same protocol to prepare amplicon libraries. The two groups had an average sequencing depth of 1013.30 ± 585.57× and 219.10 ± 158.27×, respectively; over 84% of the amplicons had a sequencing depth that exceeded 0.2-fold of average depth. These results suggest that the use of a low cycle number in multiplex PCR is a cost-effective and efficient approach for the preparation of amplicon libraries.

The Optimization Design of Macrophage Membrane Camouflaging Liposomes for Alleviating Ischemic Stroke Injury through Intranasal Delivery.

Ischemic stroke is associated with a high mortality rate, and effective treatment strategies are currently lacking. In this study, we aimed to develop a novel nano delivery system to treat ischemic stroke via intranasal administration. A three-factor Box-Behnken experimental design was used to optimize the formulation of liposomes co-loaded with Panax notoginseng saponins (PNSs) and Ginsenoside Rg3 (Rg3) (Lip-Rg3/PNS). Macrophage membranes were coated onto the surface of the optimized liposomes to target the ischemic site of the brain. The double-loaded liposomes disguised by macrophage membranes (MM-Lip-Rg3/PNS) were spherical, in a "shell-core" structure, with encapsulation rates of 81.41% (PNS) and 93.81% (Rg3), and showed good stability. In vitro, MM-Lip-Rg3/PNS was taken up by brain endothelial cells via the clathrin-dependent endocytosis and micropinocytosis pathways. Network pharmacology experiments predicted that MM-Lip-Rg3/PNS could regulate multiple signaling pathways and treat ischemic stroke by reducing apoptosis and inflammatory responses. After 14 days of treatment with MM-Lip-Rg3/PNS, the survival rate, weight, and neurological score of middle cerebral artery occlusion (MCAO) rats significantly improved. The hematoxylin and eosin (H&E) and TUNEL staining results showed that MM-Lip-Rg3/PNS can reduce neuronal apoptosis and inflammatory cell infiltration and protect the ischemic brain. In vivo biological experiments have shown that free Rg3, PNS, and MM-Lip-Rg3/PNS can alleviate inflammation and apoptosis, especially MM-Lip-Rg3/PNS, indicating that biomimetic liposomes can improve the therapeutic effects of drugs. Overall, MM-Lip-Rg3/PNS is a potential biomimetic nano targeted formulation for ischemic stroke therapy.

Integrated plasma proteomics and N-glycoproteomics reveals alterations in the N-glycosylation in Chinese hepatocellular carcinoma patients.

Hepatocellular carcinoma (HCC) is a life-threatening disease that presents diagnostic challenges due to the absence of reliable biomarkers. Recently, plasma proteomics and glycoproteomics have emerged as powerful tools for identifying potential diagnostic biomarkers for various diseases. In this study, we conducted a comprehensive proteomic and glycoproteomic analysis of plasma samples from 11 HCC patients and 11 healthy control (HC) individuals. We identified 20 differentially expressed (DE) proteins and 32 DE intact glycosylated peptides (IGPs) that can effectively differentiate between HCC patients and HC samples. Our findings demonstrate that IGP profiles had better predictive power than protein profiles for screening HCC. Pathways associated with DE proteins and IGPs were identified. It was reported that the protein expression level of galectin 3 binding protein (LGALS3BP) and its N-linked glycosylation at the N398 and N551 sites might serve as valuable candidates for HCC diagnosis. These results highlight the importance of N-glycoproteomics in advancing our understanding of HCC and suggest possible candidates for the future diagnosis of this disease.

RtNAC055 promotes drought tolerance via a stomatal closure pathway linked to methyl jasmonate/hydrogen peroxide signaling in Reaumuria trigyna.

The stomata regulate CO2 uptake and efficient water usage, thereby promoting drought stress tolerance. NAC proteins (NAM, ATAF1/2, and CUC2) participate in plant reactions following drought stress, but the molecular mechanisms underlying NAC-mediated regulation of stomatal movement are unclear. In this study, a novel NAC gene from Reaumuria trigyna, RtNAC055, was found to enhance drought tolerance via a stomatal closure pathway. It was regulated by RtMYC2 and integrated with jasmonic acid signaling and was predominantly expressed in stomata and root. The suppression of RtNAC055 could improve jasmonic acid and H2O2 production and increase the drought tolerance of transgenic R. trigyna callus. Ectopic expression of RtNAC055 in the Arabidopsis atnac055 mutant rescued its drought-sensitive phenotype by decreasing stomatal aperture. Under drought stress, overexpression of RtNAC055 in poplar promoted ROS (H2O2) accumulation in stomata, which accelerated stomatal closure and maintained a high photosynthetic rate. Drought upregulated the expression of PtRbohD/F, PtP5CS2, and PtDREB1.1, as well as antioxidant enzyme activities in heterologous expression poplars. RtNAC055 promoted H2O2 production in guard cells by directly binding to the promoter of RtRbohE, thus regulating stomatal closure. The stress-related genes RtDREB1.1/P5CS1 were directly regulated by RtNAC055. These results indicate that RtNAC055 regulates stomatal closure by maintaining the balance between the antioxidant system and H2O2 level, reducing the transpiration rate and water loss, and improving photosynthetic efficiency and drought resistance.

Predictors of Gleason Grading Group Upgrading in Low-Risk Prostate Cancer Patients From Transperineal Biopsy After Radical Prostatectomy.

RATIONALE AND OBJECTIVES: To investigate the predictors of Gleason Grading Group (GGG) upgrading in low-risk prostate cancer (Gleason score=3 + 3) from transperineal biopsy after radical prostatectomy (RP). MATERIALS AND METHODS: The clinical data of 160 patients who underwent transperineal biopsy and RP from January 2017 to December 2022 were retrospectively analyzed. First, univariate and multivariate logistic regression analysis were used to obtain independent predictors of postoperative GGG upgrading. Then receiver operating characteristic curve was used to evaluate the diagnostic efficacy of predictors. Finally, Linear-by-Linear Association test was used to analyze the risk trends of patients in different predictor groups in the postoperative GGG. RESULTS: In this study, there were 81 cases (50.6%) in the GGG concordance group and 79 cases (49.4%) in the GGG upgrading group. Univariate analysis showed age, free/total prostate-specific antigen (f/tPSA), proportion of positive biopsies, positive target of magnetic-resonance imaging (MRI) and positive target of contrast-enhanced ultrasound had significant effects on GGG upgrading (all P < .05). In multivariate logistic regression analysis, age (odds ratio [OR]=1.066, 95%CI=1.007-1.127, P = .027), f/tPSA (OR=0.001, 95%CI=0-0.146, P = .001) and positive target of MRI (OR=3.005, 95%CI=1.353-76.674, P = .007) were independent predictors. The prediction model (area under curve=0.751 P < .001) had higher predictive efficacy than all independent predictors. The proportion of patients in exposed group of different GGG increased with the level of GGG, but decreased in nonexposed group, and the linear trend was significantly different (all P < .001). CONCLUSION: Age, f/tPSA, and positive target of MRI were independent predictors of postoperative GGG upgrading. The predictive model constructed had the best diagnostic efficacy.

Clinical patterns and risk factors for multiorgan involvement in IgG4-Related disease patients.

Background: IgG4-related disease with multiorgan involvement predicts higher disease activity, thus, it is necessary to identify whether IgG4-related disease involves multiple organs at the early stage. To further clarify the clinical characteristics and risk factors for IgG4-related disease with multiorgan involvement, we conducted an observational study. Methods: We retrospectively analysed the clinical data of 160 patients who were primarily diagnosed with IgG4-related disease at the First Affiliated Hospital of Zhengzhou University from January 2015 to January 2021. According to the number of involved organs, patients were divided into two groups: multiorgan involvement and nonmultiorgan involvement. Patients were divided into a multiorgan group and a nonmultiorgan group according to multiple organ involvement. Results: There were 82 cases identified with multiorgan involvement and 78 cases diagnosed with no multiorgan involvement in this series. Most cases were elderly and male (p > 0.05). The most frequently affected organs in IgG4-RD were the lymph nodes (50.6 %), pancreas (38.7 %) and salivary glands (35.6 %). Multivariate analysis showed that eosinophilia, IgG4>2*ULN, lymph node involvement, salivary gland involvement and lung involvement were independent risk factors for multiorgan involvement (p < 0.05). Conclusions: The main issues in clinical practice are how to accurately diagnose the disease and screen the more vulnerable organs.

Population genomics provides insights into the genetic diversity and adaptation of the Pieris rapae in China.

The cabbage white butterfly (Pieris rapae), a major agricultural pest, has become one of the most abundant and destructive butterflies in the world. It is widely distributed in a large variety of climates and terrains of China due to its strong adaptability. To gain insight into the population genetic characteristics of P. rapae in China, we resequenced the genome of 51 individuals from 19 areas throughout China. Using population genomics approaches, a dense variant map of P. rapae was observed, indicating a high level of polymorphism that could result in adaptation to a changing environment. The feature of the genetic structure suggested considerable genetic admixture in different geographical groups. Additionally, our analyses suggest that physical barriers may have played a more important role than geographic distance in driving genetic differentiation. Population history showed the effective population size of P. rapae was greatly affected by global temperature changes, with mild periods (i.e., temperatures warmer than those during glaciation but not excessively hot) leading to an increase in population size. Furthermore, by comparing populations from south and north China, we have identified selected genes related to sensing temperature, growth, neuromodulation and immune response, which may reveal the genetic basis of adaptation to different environments. Our study is the first to illustrate the genetic signatures of P. rapae in China at the population genomic level, providing fundamental knowledge of the genetic diversity and adaptation of P. rapae.

High spindle and kinetochore-associated complex subunit-3 expression predicts poor prognosis and correlates with adverse immune infiltration in hepatocellular carcinoma.

BACKGROUND: Spindle and kinetochore-associated complex subunit 3 (SKA3) is a malignancy-associated gene that plays a critical role in the regulation of chromosome separation and cell division. However, the molecular mechanism through which SKA3 regulates tumor cell proliferation in hepatocellular carcinoma (HCC) has not been fully elucidated. AIM: To investigate the molecular mechanisms underlying the role of SKA3 in HCC. METHODS: SKA3 expression, clinicopathological, and survival analyses were performed using multiple public database platforms, and the results were verified by Western blot and immunohistochemistry staining using collected clinical samples. Functional enrichment analyses were performed to evaluate the biological functions and molecular mechanisms of SKA3 in HCC. Furthermore, the Tumor Immune Estimation Resource and single-sample Gene Set Enrichment Analysis (ssGSEA) algorithms were utilized to investigate the abundance of tumor-infiltrating immune cells in HCC. The response to chemotherapeutic drugs was evaluated by the R package "pRRophetic". RESULTS: We found that upregulated SKA3 expression was significantly correlated with poor prognosis in patients with HCC. Multivariable Cox regression analysis indicated that SKA3 was an independent risk factor for survival. GSEA revealed that SKA3 expression may facilitate proliferation and migratory processes by regulating the cell cycle and DNA repair. Moreover, patients with high SKA3 expression had significantly decreased ratios of CD8+ T cells, natural killer cells, and dendritic cells. Drug sensitivity analysis showed that the high SKA3 group was more sensitive to sorafenib, sunitinib, paclitaxel, doxorubicin, gemcitabine, and vx-680. CONCLUSION: High SKA3 expression led to poor prognosis in patients with HCC by enhancing HCC proliferation and repressing immune cell infiltration surrounding HCC. SKA3 may be used as a biomarker for poor prognosis and as a therapeutic target in HCC.

Unleashing Intrapreneurial Behavior: Exploring Configurations of Influencing Factors among Grassroots Employees.

Effectively promoting employees' intrapreneurial behavior has become the focus of enterprises. This study takes the middle and grassroots employees in enterprises as subjects and explores the configuration effect of multiple influencing factors on employees' intrapreneurial behavior. Based on employee expectation theory and individual-environment matching theory, this study collates six influencing factors: entrepreneurial self-efficacy, entrepreneurial competence, task school level, perceived value, management support, and reward mechanism. A total of 163 samples were obtained, and the qualitative comparative analysis method based on fuzzy set was used to analyze the influence mechanism and result path of employees' intrapreneurial behavior from the perspective of the interaction between individual factors and organizational factors. Six influencing paths of employees' high intrapreneurial behavior were found, which can be divided into ability-driven and value-driven factors, revealing that the six factors can produce equivalent results in different configurations. Furthermore, five influencing paths of employees' non-high intrapreneurial behavior were divided into three types: ability obstacle type, perception obstacle type, and value obstacle type. These have an asymmetric causal relationship with employees' high intrapreneurial behavior. This study provides management support for effectively stimulating employees' intrapreneurial behavior.

Machine learning-based on cytotoxic T lymphocyte evasion gene develops a novel signature to predict prognosis and immunotherapy responses for kidney renal clear cell carcinoma patients.

Background: Immunotherapy resistance has become a difficult point in treating kidney renal clear cell carcinoma (KIRC) patients, mainly because of immune evasion. Currently, there is no effective signature to predict immunotherapy. Therefore, we use machine learning algorithms to construct a signature based on cytotoxic T lymphocyte evasion genes (CTLEGs) to predict the immunotherapy responses of patients, so as to screen patients effective for immunotherapy. Methods: In public data sets and our in-house cohort, we used 10 machine learning algorithms to screen the optimal model with 89 combinations under the cross-validation framework, and 101 published signatures were collected. The relationship between the CTLEG signature (CTLEGS) and clinical variables was analyzed. We analyzed the role of CTLES in other types of cancer by pan-cancer analysis. The immune cell infiltration and biological characteristics were evaluated. Moreover, the response to immunotherapy and drug sensitivity of different risk groups were investigated. The key gene closely related to the signature was identified by WGCNA. We also conducted cell functional experiments and clinical tissue validation of key gene. Results: In public data sets and our in-house cohort, the CTLEGS shows good prediction performance. The CTLEGS can be regard as an independent risk factor for KIRC. Compared with 101 published models, our signature shows considerable superiority. The high-risk group has abundant infiltration of immunosuppressive cells and high expression of T cell depletion markers, which are characterized by immunosuppressive phenotype, minimal benefit from immunotherapy, and resistance to sunitinib and sorafenib. The CTLEGS was also strongly correlated with immunity in pan-cancer. Immunohistochemistry verified that T cell depletion marker LAG3 is highly expressed in high-risk groups in the clinical in-house cohort. The key CTLEG STAT2 can promote the proliferation, migration and invasion of KIRC cell. Conclusions: CTLEGS can accurately predict the prognosis of patients and their response to immunotherapy. It can provide guidance for the precise treatment of KIRC and help clinicians identify patients who may benefit from immunotherapy.

Antioxidative and antibacterial gallium (III)-phenolic coating for enhanced osseointegration of titanium implants via pro-osteogenesis and inhibiting osteoclastogenesis.

Improving the ability of implants to integrate with natural bone tissue at the initial stage of implantation remains a huge challenge because bone-to-implant interfaces are often accompanied by abnormal microenvironments with infection, reactive oxygen species (ROS) and unbalanced bone homeostasis. In this study, a multifunctional coating was fabricated on the basis of gallium (III)-phenolic networks. It is easily obtained by immersing the implants into a mixed solution of tannic acids (TAs) and gallium ions. The thickness of the coating can be precisely controlled by adjusting the number and time of immersion experiments. The resulting coating displays excellent near-infrared photothermal property. As the coating degrades, TAs and gallium ions with low concentration are released from the coating, which is more rapid in acidic and oxidative stress microenvironments. Photothermal performance as well as released TAs and gallium ions give the coating outstanding broad-spectrum antibacterial ability. Furthermore, the coating effectively reduces intracellular ROS of osteoblasts. In vitro and in vivo experiments demonstrate the capability of the coating enhancing implants' osseointegration via pro-osteogenesis and inhibiting osteoclastogenesis. The findings imply that gallium (III)-phenolic coating holds great promise to promote implant osseointegration by rescuing abnormal microenvironments of infection, oxidative stress and unbalanced bone homeostasis.