Quantitative proteomics analysis based on data-independent acquisition reveals the effect of Shenling Baizhu powder (SLP) on protein expression in MAFLD rat liver tissue.

BACKGROUND: Metabolic associated fatty liver disease (MAFLD) has become the most common chronic liver disease worldwide, and it is also a high-risk factor for the development of other metabolic diseases. Shenling Baizhu powder (SLP) is a traditional Chinese herbal formula with good clinical efficacy against MAFLD. However, its molecular mechanism for the treatment of MAFLD is still not fully understood. This study used quantitative proteomics analysis to reveal the SLP action mechanism in the treatment of MAFLD by discovering the effect of SLP on protein expression in the liver tissue of MAFLD rats. MATERIALS AND METHODS: Q-Orbitrap LC-MS/MS was used to identify the incoming blood compounds of SLP. The 18 SD male rats were randomly divided into 3 groups (n = 6): control group, HFD group and SLP group. The HFD group and SLP group were established as MAFLD rat models by feeding them a high-fat diet for 4 weeks. Afterwards, the SLP group was treated with SLP (10.89 g/kg/d) for 3 weeks. Biochemical parameters and liver pathological status were measured. Rat liver tissue was analyzed using DIA-based quantitative proteomics and the DEPs were validated by western blotting analysis. RESULTS: A total of 18 active compounds of SLP were identified and isolated to enter the bloodstream. Comparison of DEPs between control group vs. HFD group and HFD group vs. SLP group revealed that SLP restored the expression of 113 DEPs. SLP catalyzes oxidoreductase activity and binding activity on mitochondria and endoplasmic reticulum to promote lipid oxidative catabolism, maintain oxoacid metabolic homeostasis in vivo and mitigate oxidative stress-induced hepatocyte injury. And 52 signaling pathways including PPAR signaling, arachidonic acid metabolism and glycine, serine and threonine metabolism were enriched by KEGG. PPI topology analysis showed that Cyp4a2, Agxt2, Fabp1, Pck1, Acsm3, Aldh1a1, Got1 and Hmgcs2 were the core DEPs. The western blotting analysis verified that SLP was able to reverse the increase in Fabp1 and Hmgcs2 and the decrease in Pck1 induced by HFD, and the results were consistent proteomic data. CONCLUSION: SLP ameliorates hepatic steatosis to exert therapeutic effects on MAFLD by inhibiting the expression of lipid synthesis genes and inhibiting lipid peroxidation in mitochondria. This study provides a new idea and basis for the study of SLP in the treatment of MAFLD and provides an experimental basis for the clinical application of SLP.

An attention-based multi-task model for named entity recognition and intent analysis of Chinese online medical questions.

In this paper, we propose an attention-based multi-task neural network model for text classification and sequence tagging and then apply it to the named entity recognition and the intent analysis of Chinese online medical questions. We found that the use of both attention and multi-task learning improved the performance of these tasks. Our method achieved superior performance in named entity recognition and intent analysis compared with other baseline methods; the method is a light-weight solution that is suitable for deployment on small servers. Furthermore, we took advantage of the model's capabilities for these two tasks and built a simple question-answering system for cardiovascular issues. Users and service providers can monitor the logic of the answers generated by this system.

Neuronal Wiskott-Aldrich syndrome protein regulates TGF-ß1-mediated lung vascular permeability.

TGF-ß1 induces an increase in paracellular permeability and actin stress fiber formation in lung microvascular endothelial and alveolar epithelial cells via small Rho GTPase. The molecular mechanism involved is not fully understood. Neuronal Wiskott-Aldrich syndrome protein (N-WASP) has an essential role in actin structure dynamics. We hypothesized that N-WASP plays a critical role in these TGF-ß1-induced responses. In these cell monolayers, we demonstrated that N-WASP down-regulation by short hairpin RNA prevented TGF-ß1-mediated disruption of the cortical actin structure, actin stress filament formation, and increased permeability. Furthermore, N-WASP down-regulation blocked TGF-ß1 activation mediated by IL-1ß in alveolar epithelial cells, which requires actin stress fiber formation. Control short hairpin RNA had no effect on these TGF-ß1-induced responses. TGF-ß1-induced phosphorylation of Y256 of N-WASP via activation of small Rho GTPase and focal adhesion kinase mediates TGF-ß1-induced paracellular permeability and actin cytoskeleton dynamics. In vivo, compared with controls, N-WASP down-regulation increases survival and prevents lung edema in mice induced by bleomycin exposure-a lung injury model in which TGF-ß1 plays a critical role. Our data indicate that N-WASP plays a crucial role in the development of TGF-ß1-mediated acute lung injury by promoting pulmonary edema via regulation of actin cytoskeleton dynamics.-Wagener, B. M., Hu, M., Zheng, A., Zhao, X., Che, P., Brandon, A., Anjum, N., Snapper, S., Creighton, J., Guan, J.-L., Han, Q., Cai, G.-Q., Han, X., Pittet, J.-F., Ding, Q. Neuronal Wiskott-Aldrich syndrome protein regulates TGF-ß1-mediated lung vascular permeability.

FAK-related nonkinase is a multifunctional negative regulator of pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease whose underlying molecular mechanisms are largely unknown. Herein, we show that focal adhesion kinase-related nonkinase (FRNK) plays a key role in limiting the development of lung fibrosis. Loss of FRNK function in vivo leads to increased lung fibrosis in an experimental mouse model. The increase in lung fibrosis is confirmed at the histological, biochemical, and physiological levels. Concordantly, loss of FRNK function results in increased fibroblast migration and myofibroblast differentiation and activation of signaling proteins that drive these phenotypes. FRNK-deficient murine lung fibroblasts also have an increased capacity to produce and contract matrix proteins. Restoration of FRNK expression in vivo and in vitro reverses these profibrotic phenotypes. These data demonstrate the multiple antifibrotic actions of FRNK. More important, FRNK expression is down-regulated in human IPF, and down-regulation of FRNK in normal human lung fibroblasts recapitulates the profibrotic phenotype seen in FRNK-deficient cells. The effect of loss and gain of FRNK in the experimental model, when taken together with its down-regulation in human IPF, suggests that FRNK acts as an endogenous negative regulator of lung fibrosis by repressing multiple profibrotic responses.

Online biomedical named entities recognition by data and knowledge-driven model.

Named entity recognition (NER) is an important task for the natural language processing of biomedical text. Currently, most NER studies standardized biomedical text, but NER for unstandardized biomedical text draws less attention from researchers. Named entities in online biomedical text exist with errors and polymorphisms, which negatively impact NER models' performance and impede support from knowledge representation methods. In this paper, we propose a neural network method that can effectively recognize entities in unstandardized online medical/health text. We introduce a new pre-training scheme that uses large-scale online question-answering pairs to enhance transformers' model capacity on online biomedical text. Moreover, we supply models with knowledge representations from a knowledge base called multi-channel knowledge labels, and this method overcomes the restriction from languages, like Chinese, that require word segmentation tools to represent knowledge. Our model outperforms other baseline methods significantly in experiments on a dataset for Chinese online medical entity recognition and achieves state-of-the-art results.

Advanced Ag nanoparticles for the catalyzation of glyoxylic acid oxidation in through-holes electroless copper metallization.

Advanced Ag nanoparticles (Ag NPs) were prepared by wet chemical oxidation-reduction method, using mainly the tannic acid as reducing agent and carboxymethylcellulose sodium as stabilizer. The prepared Ag NPs uniformly disperse and are stable for more than one month without agglomeration. The studies of transmission electron microscopy (TEM) and ultraviolet-visible (UV-vis) absorption spectroscopy indicate that the Ag NPs are in homogeneous sphere with only 4.4 nm average size and narrow particle size distribution. Electrochemical measurements reveal that the Ag NPs behave excellent catalytic activity for electroless copper plating using glyoxylic acid as reducing agent. In situ fourier transform infrared (in situ FTIR) spectroscopic analysis combined with density functional theory (DFT) calculation illustrate that the molecular oxidation of glyoxylic acid catalyzed by Ag NPs is as the following routes: glyoxylic acid molecule first is adsorbed on Ag atoms with carboxyl oxygen terminal, then hydrolyzed to diol anionic intermediate, and last oxidized to oxalic acid. Time-resolved in situ FTIR spectroscopy further reveals the real-time reactions of electroless copper plating as follows: glyoxylic acid is continuously oxidized to oxalic acid and releases electrons at the active catalyzing spots of Ag NPs, and Cu(II) coordination ions are in situ reduced by the electrons. Based on the excellent catalytic activity, the advanced Ag NPs can replace the expensive Pd colloids catalyst and successfully apply in through-holes metallization of printed circuit board (PCB) by electroless copper plating.

Tumor necrosis factor-alpha regulates the Hypocretin system via mRNA degradation and ubiquitination.

Recent studies recognize that Hypocretin system (also known as Orexin) plays a critical role in sleep/wake disorders and feeding behaviors. However, little is known about the regulation of the Hypocretin system. It is also known that tumor necrosis factor alpha (TNF-α) is involved in the regulation of sleep/wake cycle. Here, we test our hypothesis that the Hypocretin system is regulated by TNF-α. Prepro-Hypocretin and Hypocretin receptor 2 (HcrtR2) can be detected at a very low level in rat B35 neuroblastoma cells. In response to TNF-α, Prepro-Hypocretin mRNA and protein levels are down-regulated, and also HcrtR2 protein level is down-regulated in B35 cells. To investigate the mechanism, exogenous rat Prepro-Hypocretin and rat HcrtR2 were overexpressed in B35 cells. In response to TNF-α, protein and mRNA of Prepro-Hypocretin are significantly decreased (by 93% and 94%, respectively), and the half-life of Prepro-Hypocretin mRNA is decreased in a time- and dose-dependent manner. The level of HcrtR2 mRNA level is not affected by TNF-α treatment; however, HcrtR2 protein level is significantly decreased (by 86%) through ubiquitination in B35 cells treated with TNF-α. Downregulation of cellular inhibitor of apoptosis protein-1 and -2 (cIAP-1 and -2) abrogates the HcrtR2 ubiquitination induced by TNF-α. The control green fluorescent protein (GFP) expression is not affected by TNF-α treatment. These studies demonstrate that TNF-α can impair the function of the Hypocretin system by reducing the levels of both Prepro-Hypocretin and HcrtR2.

Neuronal Wiskott-Aldrich syndrome protein (N-WASP) is critical for formation of α-smooth muscle actin filaments during myofibroblast differentiation.

Myofibroblasts are implicated in pathological stromal responses associated with lung fibrosis. One prominent phenotypic marker of fully differentiated myofibroblasts is the polymerized, thick cytoplasmic filaments containing newly synthesized α-smooth muscle actin (α-SMA). These α-SMA-containing cytoplasmic filaments are important for myofibroblast contractility during tissue remodeling. However, the molecular mechanisms regulating the formation and maturation of α-SMA-containing filaments have not been defined. This study demonstrates a critical role for neuronal Wiskott-Aldrich syndrome protein (N-WASP) in regulating the formation of α-SMA-containing cytoplasmic filaments during myofibroblast differentiation and in myofibroblast contractility. Focal adhesion kinase (FAK) is activated by transforming growth factor-ß1 (TGF-ß1) and is required for phosphorylation of tyrosine residue 256 (Y256) of N-WASP. Phosphorylation of Y256 of N-WASP is essential for TGF-ß1-induced formation of α-SMA-containing cytoplasmic filaments in primary human lung fibroblasts. In addition, we demonstrate that actin-related protein (Arp) 2/3 complex is downstream of N-WASP and mediates the maturation of α-SMA-containing cytoplasmic filaments. Together, this study supports a critical role of N-WASP in integrating FAK and Arp2/3 signaling to mediate formation of α-SMA-containing cytoplasmic filaments during myofibroblast differentiation and maturation.

Downregulation of FAK-related non-kinase mediates the migratory phenotype of human fibrotic lung fibroblasts.

Fibroblast migration plays an important role in the normal wound healing process; however, dysregulated cell migration may contribute to the progressive formation of fibrotic lesions in the diseased condition. To examine the role of focal-adhesion-kinase (FAK)-related non-kinase (FRNK) in regulation of fibrotic lung fibroblast migration, we examined cell migration, FRNK expression, and activation of focal adhesion kinase (FAK) and Rho GTPase (Rho and Rac) in primary lung fibroblasts derived from both idiopathic pulmonary fibrosis (IPF) patients and normal human controls. Fibrotic (IPF) lung fibroblasts have increased cell migration when compared to control human lung fibroblasts. FRNK expression is significantly reduced in IPF lung fibroblasts, while activation of FAK, Rho and Rac is increased in IPF lung fibroblasts. Endogenous FRNK expression is inversely correlated with FAK activation and cell migration rate in IPF lung fibroblasts. Forced exogenous FRNK expression abrogates the increased cell migration, and blocked the activation of FAK and Rho GTPase (Rho and Rac), in IPF lung fibroblasts. These data for the first time provide evidence that downregulation of endogenous FRNK plays a role in promoting cell migration through FAK and Rho GTPase in fibrotic IPF lung fibroblasts.

Psychological State Among the General Chinese Population Before and During the COVID-19 Epidemic: A Network Analysis.

Background: The infectious disease Coronavirus Disease 2019 (COVID-19) outbroke in 2019 spread to multiple countries. The quick spread of the virus and isolation strategies may trigger psychological problems. Our aim was to explore the dynamic network structure of the psychological state before and during the epidemic. Methods: A web-based survey was conducted in two stages: the T1 stage (1 January 2019 to 31 December 2019) and the T2 stage (1 February 2020 to 8 March 2020). In both stages, the Patient Health Questionnaire-9, General Anxiety Disorder-7, and Pittsburgh Sleep Quality Index were used to assess depression, anxiety, and sleep, respectively. Results: We matched the data based on IP addresses. We included 1,978, 1,547, and 2,061 individuals who completed the depression, anxiety, and sleep assessments, respectively, at both stages. During epidemics, psychomotor agitation/retardation, inability to relax, restless behavior, and the frequency of using medicine had high centrality. Meanwhile, the network structure of psychological symptoms becomes stronger than before the epidemic. Conclusion: Symptoms of psychomotor agitation/retardation, inability to relax, and restless behavior should be treated preferentially. It is necessary to provide mental health services, including timely and effective early psychological intervention. In addition, we should also pay attention to the way patients use medicines to promote sleep quality.

How to deal with the negative psychological impact of COVID-19 for people who pay attention to anxiety and depression.

Background: The fear of insecurity and uncertainty caused by the 2019 coronavirus disease (COVID-19), the separation and loss of certain important relationships, and great changes in lifestyle have awakened strong emotional responses, which may cause psychological problems in the general population. However, there is little research on how people who pay attention to anxiety and depression cope with the negative psychological impact during an epidemic or major disaster. This study aimed to identify what behaviors can effectively reduce negative emotions during an epidemic. Methods: From 1 February to 8 March 2020, we conducted a web-based survey and collected information on general demographic data. Probable depression, anxiety symptoms, and coping behaviors were assessed with the Patient Health Questionnaire-9, Generalized Anxiety Disorder-7, and self-made coping behaviors questionnaires. Result: Among 17 249 responders, 7923 and 9326 completed assessments of depression and anxiety respectively, and all responders completed the coping behaviors questionnaires. Our survey population showed a high prevalence rate of possible depression disorders (2746 of 7923, 34.66%) and anxiety disorders (5309 of 9326, 56.93%). Compared with other groups, the elderly, women, people of lower education, and people with lower income were more likely to suffer depression and/or anxiety. In terms of marital status, the cohabiting group showed the highest rate of depression and/or anxiety. Among the careers, students and housewives were high-risk groups suffering from depression and/or anxiety. After adjusting for social-demographic factors (e.g. age, sex), depression and anxiety were positively associated with self-injury, doing housework, and having sex or masturbating, and negatively associated with singing, drawing, or writing, dating friends online, singing, attending lectures, and doing yoga. Conclusion: Our findings identified some spontaneous coping behaviors that can probably relieve the psychological impact of vulnerable groups during the COVID-19 epidemic.