Alterations in the gut microbiota and serum metabolomics of spontaneous cholestasis caused by loss of FXR signal in mice

Background: Farnesoid X receptor (FXR) is a key metabolic target of bile acids (BAs) and is also a target for drugs against several liver diseases. However, the contribution of FXR in the pathogenesis of cholestasis is still not fully understood. The purpose of this study is to provide a comprehensive insight into the metabolic properties of FXR-involved cholestasis in mice.Materials and methods: In this study, an alpha-naphthylisothiocyanate (ANIT)-induced cholestasis mouse model and FXR−/− mice were established to investigate the effect of FXR on cholestasis. The effect of FXR on liver and ileal pathology was evaluated. Simultaneously, Untargeted metabolomics combined with 16s rRNA gene sequencing analysis was applied to reveal the involvement of FXR in the pathogenesis of cholestasis.Results: The results showed that ANIT (75 mg/kg) induced marked cholestasis in WT and FXR −/− mice. It is noteworthy that FXR−/− mice developed spontaneous cholestasis. Compared with WT mice, significant liver and ileal tissue damage were found. In addition, 16s rRNA gene sequencing analysis revealed gut microbiota dysbiosis in FXR−/− mice and ANIT-induced cholestasis mice. Differential biomarkers associated with the pathogenesis of cholestasis caused by FXR knockout were screened using untargeted metabolomics. Notably, Lactobacillus_ johnsonii_FI9785 has a high correlation with the differential biomarkers associated with the pathogenesis and progression of cholestasis caused by FXR knockout.Conclusion: Our results implied that the disorder of the intestinal flora caused by FXR knockout can also interfere with the metabolism. This study provides novel insights into the FXR-related mechanisms of cholestasis

MicroRNA-145-5p Regulates the Epithelial-Mesenchymal Transition in Nasal Polyps by Targeting Smad3

Objectives. The annual prevalence of chronic rhinosinusitis (CRS) is increasing, and the lack of effective treatments imposes a substantial burden on both patients and society. The formation of nasal polyps in patients with CRS is closely related to tissue remodeling, which is largely driven by the epithelial-mesenchymal transition (EMT). MicroRNA (miRNA) plays a pivotal role in the pathogenesis of numerous diseases through the miRNA-mRNA regulatory network; however, the specific mechanism of the miRNAs involved in the formation of nasal polyps remains unclear. Methods. The expression of EMT markers and Smad3 were detected using western blots, quantitative real-time polymerase chain reaction, and immunohistochemical and immunofluorescence staining. Differentially expressed genes in nasal polyps and normal tissues were screened through the Gene Expression Omnibus database. To predict the target genes of miR-145-5p, three different miRNA target prediction databases were used. The migratory ability of cells was evaluated using cell migration assay and wound healing assays. Results. miR-145-5p was associated with the EMT process and was significantly downregulated in nasal polyp tissues. In vitro experiments revealed that the downregulation of miR-145-5p promoted EMT. Conversely, increasing miR-145-5p levels reversed the EMT induced by transforming growth factor-β1. Bioinformatics analysis suggested that miR-145-5p targets Smad3. Subsequent experiments confirmed that miR-145-5p inhibits Smad3 expression. Conclusion. Overall, miR-145-5p is a promising target to inhibit nasal polyp formation, and the findings of this study provide a theoretical basis for nanoparticle-mediated miR-145-5p delivery for the treatment of nasal polyps

The conservation and uniqueness of the caspase family in the basal chordate, amphioxus

<p>Abstract</p> <p>Background</p> <p>The caspase family, which plays a central role in apoptosis in metazoans, has undergone an expansion in amphioxus, increasing to 45 members through domain recombination and shuffling.</p> <p>Results</p> <p>In order to shed light on the conservation and uniqueness of this family in amphioxus, we cloned three representative caspase genes, designated as <it>bbtCaspase-8, bbtCaspase-1/2 </it>and <it>bbtCaspase3</it>-like, from the amphioxus <it>Branchiostoma belcheri tsingtauense</it>. We found that <it>bbtCaspase-8 </it>with conserved protein architecture is involved in the Fas-associated death domain-Caspase-8 mediated pro-apoptotic extrinsic pathway, while <it>bbtCaspase3</it>-like may mediate a nuclear apoptotic pathway in amphioxus. Also, <it>bbtCaspase-1/2 </it>can co-localize with <it>bbtFADD2 </it>in the nucleus, and be recruited to the cytoplasm by amphioxus apoptosis associated speck-like proteins containing a caspase recruitment domain, indicating that <it>bbtCaspase-1/2 </it>may serve as a switch between apoptosis and caspase-dependent innate immune response in invertebrates. Finally, amphioxus extrinsic apoptotic pathway related caspases played important roles in early embryogenesis.</p> <p>Conclusions</p> <p>Our study not only demonstrates the conservation of <it>bbtCaspase-8 </it>in apoptosis, but also reveals the unique features of several amphioxus caspases with novel domain architectures arose some 500 million years ago.</p

Multi-Sensor Fault Diagnosis Based on Time Series in an Intelligent Mechanical System

Intelligent mechanical systems are a focused area nowadays. One of the requirements of intelligent mechanical systems is to achieve intelligent fault diagnosis through the real-time acquisition and analysis of data from various sensors installed on mechanical components. In this paper, a new fault diagnosis method is proposed to solve the problems of difficulty in integrating the fault diagnosis algorithm and locating fault parts due to the complexity of modern mechanical systems. The complexity of modern industrial intelligent systems is due to the fact that the systems are composed of multiple components and there are various connections between them. Common fault diagnosis is to design specialized fault identification algorithms for the physical characteristics of each component, and the integration of different algorithms is a major challenge for system performance. Therefore, this paper investigates a general algorithm for the fault diagnosis of complex systems using the timing characteristics of sensors and transfer entropy. The fault diagnosis algorithm is based on the prediction of multi-dimensional long time series using Autoformer, and fault identification is performed based on the deviation of the predicted value from the actual value. After fault identification, a root cause analysis method of faults based on transfer entropy is proposed. The method can locate the component where the fault occurs more accurately based on the analysis of the cause–effect relationship of each component and help maintenance personnel to troubleshoot the fault

Production Capacity Reserve Strategy of Emergency Medical Supplies: Incentive Model for Nonprofit Organizations

In 2020, COVID-19 swept across the globe. To reduce the social harms caused by this public health event, nonprofit organizations (NPOs) cooperated with medical enterprises to produce reserves of emergency medical supplies. In practice, this cooperation was challenged by the different goals of NPOs and medical enterprises and the asymmetry of information between these parties. Enterprises are prone to irregularities or speculative behaviors that can result in insufficient production capacity during public health events, which increase disaster risks. Based on the principal–agent relationship of NPOs and enterprises, this study analyzed a game model between NPOs and enterprises under information asymmetry; constructed an incentive model for reserve emergency medical supply production capacity; and solved the optimal reward and punishment coefficients of NPOs, optimal effort level of enterprises, and benefits of disaster reduction. The study also verified the validity of the model using numerical examples and a sensitivity analysis. In taking up the findings of the study, this paper discusses the effects of several important exogenous variables on the optimal decision strategies of NPOs and enterprises and offers management-related insights for NPOs

Three-Dimensional Device-Free Localization for Vehicle

Device-free localization (DFL) is a promising technique which could provide localization information for a target without requiring an electronic device. With the development of the smart city and smart transportation, DFL could form part of a basic technique that could be used to track and localize roadside vehicles. In this paper, some algorithms for three-dimensional (3D) DFL for vehicle surveillance are developed, including statistical methods for data, a method for communication link selection, a novel method of communication link weight allocation and some other minor approaches to obtain the location and approximate size of a static vehicle, as a basic technique of moving vehicle detection. Then, an experimental system is designed. Through security monitoring wireless sensor networks (WSN), real-time vehicle characteristics (i.e., location and size) are calculated automatically and intuitively displayed through a heat map. Experiments are performed to validate the effect of the proposal and the accuracy of the localization and size estimation

Spatio-temporal variation and prediction of land use and carbon storage in high groundwater level mining area

Mining activities and urbanisation in high dive mining areas can lead to significant changes in land use types, which in turn affect the carbon sequestration capacity of mining areas. Based on the land use data of Panxie mining area from 2002 to 2021, and used the FLUS (Future Land Use Simulation) model to predict land use changes in 2028 under two scenarios: natural development and ecological conservation, using mining, socio-economic and climatic data as drivers, and then The historical carbon stocks in the Panshet mine area from 2002 to 2021 and the future carbon stocks in 2028 under different scenarios were calculated by combining the InVEST (Integrated Valuation of Ecosystem Services and Trade-offs) model, and the spatial and temporal characteristics of the carbon stocks in the Panxie mine area were analysed. The spatial and temporal variability of carbon stocks in the Panxie mine was also analysed. The results show that: ① from 2002 to 2021, land use changes in the Panxai mining area show a continuous decrease in arable land and a continuous increase in wetland and building land, with a decrease of 147.93 km2 in arable land and an increase of 71.01 km2 and 75.76 km2 in wetland and building land, respectively. during this period, the carbon stock in the Panxai mining area decreases from 1.62×105 t, a decrease of 3.83%, with the fastest decrease in carbon reserves from 2018 to 2021. ② The predicted results show that the land use changes in the study area under both scenarios in 2028 are a continuous increase in wetlands and building land, and a continuous decrease in arable land. However, compared to the natural development scenario, the ecological conservation scenario protects and increases the area of arable land in the mine area, while the growth of wetlands and building land slows down. Compared with 2021, the carbon stock in the natural development scenario decreases by 0.74×105 t and the ecological conservation scenario decreases by 0.53×105 t. The results of the study indicate that the decrease in arable land due to sinking water and the expansion of construction land is the main reason for the decrease in carbon stock due to the influence of coal mining subsidence and urban development, and that the adoption of ecological conservation measures can slow down the decrease in carbon stock to a certain extent. Ecological conservation measures can slow down the decline of carbon stocks to a certain extent

Concentration-Dependent Enrichment Identifies Primary Protein Targets of Multitarget Bioactive Molecules

Multitarget bioactive molecules (MBMs) are of increasing importance in drug discovery as they could produce high efficacy and a low chance of resistance. Several advanced approaches of quantitative proteomics were developed to accurately identify the protein targets of MBMs, but little study has been carried out in a sequential manner to identify primary protein targets (PPTs) of MBMs. This set of proteins will first interact with MBMs in the temporal order and play an important role in the mode of action of MBMs, especially when MBMs are at low concentrations. Herein, we describe a valuable observation that the result of the enrichment process is highly dependent on concentrations of the probe and the proteome. Interestingly, high concentrations of probe and low concentrations of incubated proteome will readily miss the hyper-reactive protein targets and thereby increase the probability of rendering PPTs with false-negative results, while low concentrations of probe and high concentrations of incubated proteome more than likely will capture the PPTs. Based on this enlightening observation, we developed a proof-of-concept approach to identify the PPTs of iodoacetamide, a thiol-reactive MBM. This study will deepen our understanding of the enrichment process and improve the accuracy of pull-down-guided target identification

Concentration-Dependent Enrichment Identifies Primary Protein Targets of Multitarget Bioactive Molecules

Multitarget bioactive molecules (MBMs) are of increasing importance in drug discovery as they could produce high efficacy and a low chance of resistance. Several advanced approaches of quantitative proteomics were developed to accurately identify the protein targets of MBMs, but little study has been carried out in a sequential manner to identify primary protein targets (PPTs) of MBMs. This set of proteins will first interact with MBMs in the temporal order and play an important role in the mode of action of MBMs, especially when MBMs are at low concentrations. Herein, we describe a valuable observation that the result of the enrichment process is highly dependent on concentrations of the probe and the proteome. Interestingly, high concentrations of probe and low concentrations of incubated proteome will readily miss the hyper-reactive protein targets and thereby increase the probability of rendering PPTs with false-negative results, while low concentrations of probe and high concentrations of incubated proteome more than likely will capture the PPTs. Based on this enlightening observation, we developed a proof-of-concept approach to identify the PPTs of iodoacetamide, a thiol-reactive MBM. This study will deepen our understanding of the enrichment process and improve the accuracy of pull-down-guided target identification