•PAK1 was overexpressed in PBMCs and skin lesions from patients with CTCL.•Knockdown of PAK1 inhibited cell proliferation and promoted spontaneous apoptosis.•The PAK1 inhibitor decreased the ...proliferation of CTCL cells.•PAK1 suppression directly upregulated PUMA and p21 expression in human CTCL cells.
Cutaneous T cell lymphoma (CTCL) comprises a heterogeneous group of skin-homing T cell tumors. The small guanosine triphosphate effector p21-activated kinase 1 (PAK1) plays an important role in many fundamental cellular functions, including cell motility, proliferation, and apoptosis. The expression of PAK1 is up-regulated in several types of human cancers. However, little is known about the role of PAK1 in the pathogenesis of CTCL.
The aim of this study was to evaluate the expression pattern and underlying mechanism of PAK1 in CTCL.
Quantitative real-time polymerase chain reaction(qRT-PCR) was used to detect PAK1 mRNA expression in the peripheral blood mononuclear cells (PBMCs) of patients with CTCL. The expression of PAK1 protein in CTCL tumor tissues was determined by immunohistochemistry. CTCL cell lines were treated with a small molecule inhibitor of PAK1, p21-activated kinase inhibitor III (IPA3), at concentrations of 2, 3.5 and 5 μM for 24 h. Hut 78 and HH CTCL cells were transfected with lentiviral-based PAK1 gene knockdown vectors. We determined the effects of PAK1 knockdown on cell proliferation and apoptosis in CTCL cells by MTS assay and flow cytometry. Animal experiments were performed to investigate the effects of PAK1 knockdown on the growth of tumors in vivo. Transcriptomic sequencing was performed to detect the direct downstream targets of PAK1 silencing. Reverse transcription polymerase chain reaction and western blot analysis were applied to verify the results of the transcriptomic analysis.
We detected PAK1 overexpression in PBMCs and skin lesions from patients with CTCL compared with benign inflammatory dermatoses (BID). Knockdown of PAK1 inhibited cell proliferation and promoted spontaneous apoptosis. In addition, the inhibitory effect of IPA3 was validated in the CTCL cell lines. Additionally, mice injected with PAK1-silenced cells presented with a decreased rate of tumor growth compared with the control groups. Moreover, the mRNA and protein expression of PUMA (BBC3) and p21 (CDKN1A) were increased in PAK1-silenced Hut 78 and HH cells.
Our data indicated that PAK1 is upregulated in CTCL. PAK1 silencing induced apoptosis and inhibited cell growth by stimulating the expression of PUMA and p21. Thus, PAK1 may be a potential tumor marker and therapeutic target of CTCL.
While neutralizing antibodies are highly effective against ebolavirus infections, current experimental ebolavirus vaccines primarily elicit species-specific antibody responses. Here, we describe an ...immunization-elicited macaque antibody (CA45) that clamps the internal fusion loop with the N terminus of the ebolavirus glycoproteins (GPs) and potently neutralizes Ebola, Sudan, Bundibugyo, and Reston viruses. CA45, alone or in combination with an antibody that blocks receptor binding, provided full protection against all pathogenic ebolaviruses in mice, guinea pigs, and ferrets. Analysis of memory B cells from the immunized macaque suggests that elicitation of broadly neutralizing antibodies (bNAbs) for ebolaviruses is possible but difficult, potentially due to the rarity of bNAb clones and their precursors. Unexpectedly, germline-reverted CA45, while exhibiting negligible binding to full-length GP, bound a proteolytically remodeled GP with picomolar affinity, suggesting that engineered ebolavirus vaccines could trigger rare bNAb precursors more robustly. These findings have important implications for developing pan-ebolavirus vaccine and immunotherapeutic cocktails.
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•Cocktail of filovirus GPs elicited ebolavirus bNAb•The ebolavirus internal fusion loop is a conserved site of vulnerability•Proteolytically remodeled GP recognizes bNAb germline precursors with high affinity•Combination of two bNAbs confers full protection against all pathogenic ebolaviruses
Characterization of an immunization-induced broadly neutralizing antibody in macaques against ebolaviruses highlights the fusion loop region of the viral glycoprotein as a promising vaccine target.
Hyperuricemia (HUA) is a common chronic metabolic disease caused by abnormal purine metabolism and uric acid excretion. Despite extensive research on HUA, no clear treatment has been found so far. ...Improving purine metabolism and promoting uric acid excretion is crucial for the effective treatment of HUA. In recent years, traditional Chinese medicine and traditional Chinese medicine prescriptions have shown good effects in treating HUA. This article summarizes the latest progress in treating HUA in rats and mice using traditional Chinese medicine and prescriptions, elaborates on the pathogenesis of HUA, explores the application of commonly used traditional Chinese medicine treatment methods and prescriptions, and discusses the previous pharmacological mechanisms. In general, our research indicates that traditional Chinese medicine can effectively relieve the symptoms related to elevated uric acid levels in HUA rats and mice. However, further exploration and research are needed to verify its efficacy, safety, and feasibility.
Neural networks are very vulnerable to adversarial examples, which threaten their application in security systems, such as face recognition, and autopilot. In response to this problem, we propose a ...new defensive strategy. In our strategy, we propose a new deep denoising neural network, which is called UDDN, to remove the noise on adversarial samples. The standard denoiser suffers from the amplification effect, in which the small residual adversarial noise gradually increases and leads to misclassification. The proposed denoiser overcomes this problem by using a special loss function, which is defined as the difference between the model outputs activated by the original image and denoised image. At the same time, we propose a new model training algorithm based on knowledge transfer, which can resist slight image disturbance and make the model generalize better around the training samples. Our proposed defensive strategy is robust against both white-box or black-box attacks. Meanwhile, the strategy is applicable to any deep neural network-based model. In the experiment, we apply the defensive strategy to a face recognition model. The experimental results show that our algorithm can effectively resist adversarial attacks and improve the accuracy of the model.
Integrative analysis of testicular genome-wide DNA methylome and transcriptome identified key genes and pathways related to steroidogenesis and spermatogenesis processes, which may be the DNA ...methylation-regulated mechanism in male reproductive impairment caused by PM2.5. Display omitted
The effects of ambient fine particles on male reproductive health have raised widespread concern. The particular underlying mechanisms of the damage remain largely unclear and demand more research in new directions. Previous research has revealed that DNA methylation plays an important role in male reproductive development and is also vulnerable to environmental influences. However, there hasn't been enough investigation into the involvement of DNA methylation in PM2.5-induced male reproductive toxicity. Here, we establish a real-time PM2.5 exposure model and revealed that PM2.5 exposure could lead to testicular dysfunction including spermatogenesis impairment and steroid hormone dysfunction. In particular, the decrease in the testicular global level of 5-methylcytosine (5mC) indicated a possible association of DNA methylation with testicular injury induced by PM2.5 exposure. Further genome-wide methylation analysis revealed genomic hypomethylation of testicular DNA and identified more than 1000 differentially methylated regions in both CAP and UA versus FA, indicating that PM2.5 exposure, even low-dose, could modulate the testicular methylome. Furthermore, integrated analysis of methylome and transcriptome identified some key methylated genes and networks, which may be involved in spermatogenesis and synthesis of steroid hormone. The testicular methylation levels of key genes especially Cyp11a1 and Pax8 raised, and their consequent reduced expression may impair the testosterone and sperm production process. Our research provides fundamental knowledge as well as novel insights into the possible involvement of DNA methylation in PM2.5-induced male reproductive harm.
•ARMC8 is downregulated in cSCC samples and cell lines.•ARMC8 is a direct functional target of miR-664.•Downregulation of ARMC8 promotes proliferation and tumorigenicity of cSCC in vitro and in vivo.
...Aberrant expression of Armadillo repeat containing 8 (ARMC8) plays crucial roles in tumor growth and metastasis of various cancers. The specific role of ARMC8 in cutaneous squamous cell carcinoma (cSCC) is yet to be elucidated.
The present study aimed to investigate the molecular mechanisms of ARMC8 and epithelial-mesenchymal transition (EMT) in cSCC development and provide translational insights for future therapeutics.
cSCC tumor specimens were used to determine the ARMC8 by immunohistochemistry. Three cSCC cell lines including HSC-1, HSC-5 and A431 as well as BALB/C mouse tumor model was utilized to study the potential mechanisms in tumorigenesis.
Our data identified ARMC8 as a direct downstream target of miR-664. We found that ARMC8 was remarkably low expression in cSCC patient specimens and cSCC cell lines. Knockdown of ARMC8 promotes tumorigenic behaviors such as increased cell proliferation, migration and invasion capacities in vitro and enhanced tumorigenicity in xenograft mouse model. Whereas ARMC8 over-expression inhibits tumorigenesis in cSCC. Together, it revealed ARMC8 functions as a tumor suppressor via restraining Wnt/β-catenin pathway and epithelial–mesenchymal transition in cSCC.
Our data verifies that aberrant expression of ARMC8 plays a vital role in carcinogenesis of cSCC. And overexpression of ARMC8 will facilitate future development of cSCC therapeutic interventions.
Evaluation of chemical drug-likeness is essential for the discovery of high-quality drug candidates while avoiding unwarranted biological and clinical trial costs. A high-quality drug candidate ...should have promising drug-like properties, including pharmacological activity, suitable physicochemical and ADMET properties. Hence, in silico prediction of chemical drug-likeness has been proposed while being a challenging task. Although several prediction models have been developed to assess chemical drug-likeness, they have such drawbacks as sample dependence and poor interpretability. In this study, we developed a novel strategy, named DBPP-Predictor, to predict chemical drug-likeness based on property profile representation by integrating physicochemical and ADMET properties. The results demonstrated that DBPP-Predictor exhibited considerable generalization capability with AUC (area under the curve) values from 0.817 to 0.913 on external validation sets. In terms of application feasibility analysis, the results indicated that DBPP-Predictor not only demonstrated consistent and reasonable scoring performance on different data sets, but also was able to guide structural optimization. Moreover, it offered a new drug-likeness assessment perspective, without significant linear correlation with existing methods. We also developed a free standalone software for users to make drug-likeness prediction and property profile visualization for their compounds of interest. In summary, our DBPP-Predictor provided a valuable tool for the prediction of chemical drug-likeness, helping to identify appropriate drug candidates for further development.
Vehicle-to-grid (V2G) is an important component of smart grids and plays a significant role in improving grid stability, reducing energy consumption and generating cost. However, while electric ...vehicles are being charged, it is possible to expose the location and movement trajectories of the electric vehicles, thereby triggering a series of privacy and security issues. In response to this problem, we propose a new quadtree-based spatial decomposition algorithm to protect the location privacy of electric vehicles. First of all, we use a random sampling algorithm, which is based on differential privacy, to obtain enough spatial data to achieve the balance between large-scale spatial data and the amount of noise. Secondly, in order to overcome the shortcomings of using tree height to control Laplacian noise in the quadtree, we use sparse vector technology to control the noise added to the tree nodes. Finally, according to the vehicle-to-grid network structure in the smart grid, we propose a location privacy protection model based on distributed differential privacy technology for EVs in vehicle-to-grid networks. We demonstrate application of the proposed model in real spatial data and show that it can achieve the best effect on the security of the algorithm and the availability of data.
In an increasingly complex external environment, innovation is an important way for companies to build sustainable competitiveness. This research discusses employee creativity from the perspective of ...Family Supportive Supervisor Behavior (FSSB) based on conservation of resource theory, social exchange theory, psychological capital theory and emotional spillover theory. Through a series of surveys of employees in different companies and jobs, we can understand the impact of family-supporting supervisors' behavior on their creativity. Combined with the survey data, a structural equation model (SEM) is constructed to analyze the mediating effects of psychological capital and positive emotions based on the causal mediation model. The research found that the positive influence of family-supporting supervisors' behavior on employees' creativity has three forms. First, supervisors improve employees' motivation and sense of efficacy by providing various support resources. Second, supervisors can generate positive spillover effects among employees by influencing employees' psychological state. Third, supervisors stimulate the creativity of subordinates by promoting work participation and mobility. According to the research conclusions, in order to improve the employee creativity, we should provide incentives to encourage supervisors to carry out family support behaviors, identify employee characteristics to help supervisors provide personalized support, cultivate family supportive leaders, and attach importance to emotional support and play the role of psychological capital and positive emotions.
Understanding the variations in microscopic pore-fracture structures (MPFS) during coal creep under pore pressure and stress coupling is crucial for coal mining and effective gas treatment. In this ...manuscript, a triaxial creep test on deep coal at various pore pressures using a test system that combines in-situ mechanical loading with real-time nuclear magnetic resonance (NMR) detection was conducted. Full-scale quantitative characterization, online real-time detection, and visualization of MPFS during coal creep influenced by pore pressure and stress coupling were performed using NMR and NMR imaging (NMRI) techniques. The results revealed that seepage pores and microfractures (SPM) undergo the most significant changes during coal creep, with creep failure gradually expanding from dense primary pore fractures. Pore pressure presence promotes MPFS development primarily by inhibiting SPM compression and encouraging adsorption pores (AP) to evolve into SPM. Coal enters the accelerated creep stage earlier at lower stress levels, resulting in more pronounced creep deformation. The connection between the micro and macro values was established, demonstrating that increased porosity at different pore pressures leads to a negative exponential decay of the viscosity coefficient. The Newton dashpot in the ideal viscoplastic body and the Burgers model was improved using NMR experimental results, and a creep model that considers pore pressure and stress coupling using variable-order fractional operators was developed. The model’s reasonableness was confirmed using creep experimental data. The damage-state adjustment factors ω and β were identified through a parameter sensitivity analysis to characterize the effect of pore pressure and stress coupling on the creep damage characteristics (size and degree of difficulty) of coal.
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